Neurology Research and Resources

Neurology

Neurology is the official journal of the American Academy of Neurology.
Current Issue:

  • Clinical Reasoning: A 46-year-old man with persistent hiccups, cognitive dysfunction, and imbalance
    A 46-year-old, right-handed, African American man presented to the emergency department after 1 week of persistent hiccups and 3 days of nausea and vomiting. His family member also noted that he had been experiencing right-hand tremor and gait imbalance for the last 3 months. Over the 6 months prior to presentation, the patient's coworkers had noticed that he was completing his work more slowly, that he was forgetting how to perform simple tasks, and that several times he had come to work at the wrong hours. The patient had a history of HIV diagnosed 10 years earlier and reported good adherence to an antiretroviral regimen consisting of tenofovir, emtricitabine, and atazanavir boosted by ritonavir, without any changes for several years. His viral load was undetectable when tested 8 months prior to presentation.
  • Teaching NeuroImages: Artery of Percheron thrombosis causing selective downgaze palsy
    A 47-year-old man with migraines presented with sudden onset of vertical diplopia, dysarthria, right facial weakness, and downgaze palsy (figure 1). Brain MRI revealed ischemic strokes in the midbrain periaqueductal gray, bilateral thalamic–midbrain junction, and thalamus (figure 2, A–C). Gradient echo and T1 MRI showed hypointensity in the interpeduncular fossa (figure 2, D and E). No flow could be visualized in this structure on CT angiogram or catheter angiogram, demonstrating a thrombosed artery of Percheron (figure 2, F–H). Downgaze palsy, which improved 18 months later, may result from bilateral lesions of the mesencephalic–diencephalic junction involving the rostral interstitial nucleus of the medial longitudinal fasciculus.1,2
  • Teaching NeuroImages: Spontaneous involution of symptomatic delayed tumefactive cyst following radiosurgery for AVM
    A 65-year-old woman underwent radiosurgery for a left temporal arteriovenous malformation (AVM) (figure 1A). Follow-up MRI/magnetic resonance angiography 3 years later demonstrated postradiation changes (figure 1B) and AVM resolution (figure 2). Six years posttreatment, she had progressive headaches and aphasia and a large cyst (figure 1C). Her symptoms resolved acutely without treatment. MRI 3 months later showed reduction of the cyst with mass effect resolution related to spontaneous fenestration in the ventricle (figure 1D).
  • Teaching NeuroImages: MR neurography for the diagnosis of hypertrophic neuropathies
    A 25-year-old woman presented with a 10-year history of frequent falls and deafness. Her mother had a similar neurologic picture. Examination showed peroneal amyotrophy, pes cavus, and hearing loss. Magnetic resonance (MR) neurography showed diffuse nerve enlargement in the lower limbs (figure). Genetic analysis revealed heterozygous mutation c.82T>C (p.Trp28Arg) in the PMP22 gene, defining diagnosis of Charcot-Marie-Tooth disease (CMT) type 1A.
  • Teaching Video NeuroImages: My weeping patient: Avoiding the pitfalls of a functional diagnosis
    A 54-year-old man presented with symptoms of a posterior circulation stroke. A right facial palsy and horizontal right end gaze nystagmus was noted. On resolution, episodes of uncontrolled weeping without a provoking stimulus was observed (video at Neurology.org). These were initially unremitting, lasting minutes, with complete resolution after 1 month. An early consideration was of a functional neurologic disorder. Subsequent MRI brain demonstrated bilateral anterior pontine infarcts (figure). It has been hypothesized that pseudobulbar affect (PBA) results from the loss of frontal cortex input to the cerebellum during emotional expression.1 This disruption in descending pathways is postulated in pontine infarcts.2 PBA should not be considered an incongruent sign.
  • Spotlight on the October 17 issue
  • An improved way to predict neurologic recovery in acute spinal cord injury
    In North America alone, spinal cord injury affects well over 1 million patients, with the average annual incidence expected to rise secondary to an increasing amount of falls in an aging population.1,2 Spinal cord injury (SCI) has detrimental health consequences that can frequently leave the injured patient with a lifetime of medical expenses exceeding $4 million.2 Although the current practice in treating SCI is to elevate a patient's mean arterial pressure (MAP) to 85–90 mm Hg for the first 7 days in an effort to maintain spinal cord perfusion, this treatment strategy has uncertain efficacy, as the actual spinal cord perfusion pressure (SCPP) remains unknown.3 In this issue of Neurology®, Squair et al.4 propose an improved treatment approach using the calculated SCPP that can provide patients with an increased likelihood of having restoration of function after an SCI.
  • Smoking cessation and secondary stroke prevention
    The 7 million adult stroke survivors in the United States remain at high risk for a recurrent stroke. The increased morbidity and cost associated with recurrent stroke, in addition to the 5% to 20% yearly stroke recurrence, support the need for additional investigations into secondary stroke prevention.1,2 Stroke prevention guidelines, whether primary or secondary, focus on risk factor control of modifiable risk factors. The American Heart Association/American Stroke Association guidelines for secondary stroke prevention indicate evidence-based risk factor control, interventional approaches, and treatment options as approaches to secondary stroke prevention.1 Risk factor control for secondary stroke prevention includes managing hypertension, diabetes mellitus, and hyperlipidemia, as well as lifestyle modifications, including weight management, alcohol consumption, and smoking cessation.3 A cornerstone of recurrent stroke reduction, and lifetime cardiovascular disease (CVD) risk, is modification of lifestyle behaviors such as abstaining from tobacco, adopting a healthy diet, and exercising regularly. While these healthy lifestyle behaviors should start in childhood and continue through one's lifetime, modifying these health behaviors after a stroke can reduce the risk of recurrent stroke and other CVD-related illnesses.3
  • Preventing burnout increases the desirability of neurology as a career
    Neurologic diseases comprise a major percentage of disease burden in the United States, and one that is predicted to increase as our population ages. The need for physicians with expertise in the recognition, diagnosis, and management of neurologic diseases also will increase. Over the next decade, the number of neurologists in the United States will grow from the current 16,000 to 18,000. However, even this number represents a predicted 20% shortfall in number of neurologists needed by 2025.1,2 Our neurology workforce therefore must increase to address this current and future need.
  • Spinal cord perfusion pressure predicts neurologic recovery in acute spinal cord injury
    Objective: To determine whether spinal cord perfusion pressure (SCPP) as measured with a lumbar intrathecal catheter is a more predictive measure of neurologic outcome than the conventionally measured mean arterial pressure (MAP). Methods: A total of 92 individuals with acute spinal cord injury were enrolled in this multicenter prospective observational clinical trial. MAP and CSF pressure (CSFP) were monitored during the first week postinjury. Neurologic impairment was assessed at baseline and at 6 months postinjury. We used logistic regression, systematic iterations of relative risk, and Cox proportional hazard models to examine hemodynamic patterns commensurate with neurologic outcome. Results: We found that SCPP (odds ratio 1.039, p = 0.002) is independently associated with positive neurologic recovery. The relative risk for not recovering neurologic function continually increased as individuals were exposed to SCPP below 50 mm Hg. Individuals who improved in neurologic grade dropped below SCPP of 50 mm Hg fewer times than those who did not improve (p = 0.012). This effect was not observed for MAP or CSFP. Those who were exposed to SCPP below 50 mm Hg were less likely to improve from their baseline neurologic impairment grade (p = 0.0056). Conclusions: We demonstrate that maintaining SCPP above 50 mm Hg is a strong predictor of improved neurologic recovery following spinal cord injury. This suggests that SCPP (the difference between MAP and CSFP) can provide useful information to guide the hemodynamic management of patients with acute spinal cord injury.
  • Comorbidity in multiple sclerosis is associated with diagnostic delays and increased mortality
    Objective: To investigate the effect of chronic comorbidity on the time of diagnosis of multiple sclerosis (MS) and on mortality in MS. Methods: We conducted a population-based, nationwide cohort study including all incident MS cases in Denmark with first MS symptom between 1980 and 2005. To investigate the time of diagnosis, we compared individuals with and without chronic comorbidity using multinomial logistic regression. To investigate mortality, we used Cox regression with time-dependent covariates, following study participants from clinical MS onset until endpoint (death) or to the end of the study, censuring at emigration. Results: We identified 8,947 individuals with clinical onset of MS between 1980 and 2005. In the study of time of diagnosis, we found statistically significant odds ratios for longer diagnostic delays with cerebrovascular comorbidity (2.01 [1.44–2.80]; <0.0005), cardiovascular comorbidity (4.04 [2.78–5.87]; <0.0005), lung comorbidity (1.93 [1.42–2.62]; <0.0005), diabetes comorbidity (1.78 [1.04–3.06]; 0.035), and cancer comorbidity (2.10 [1.20–3.67]; 0.009). In the mortality study, we found higher hazard ratios with psychiatric comorbidity (2.42 [1.67–3.01]; <0.0005), cerebrovascular comorbidity (2.47 [2.05–2.79]; <0.0005), cardiovascular comorbidity (1.68 [1.39–2.03]; <0.0005), lung comorbidity (1.23 [1.01–1.50]; 0.036), diabetes comorbidity (1.39 [1.05–1.85]; 0.021), cancer comorbidity (3.51 [2.94–4.19]; <0.0005), and Parkinson disease comorbidity (2.85 [1.34–6.06]; 0.007). Conclusions: An increased awareness of both the necessity of neurologic evaluation of new neurologic symptoms in persons with preexisting chronic disease and of optimum treatment of comorbidity in MS is critical.
  • Analysis of blood-based gene expression in idiopathic Parkinson disease
    Objective: To examine whether gene expression analysis of a large-scale Parkinson disease (PD) patient cohort produces a robust blood-based PD gene signature compared to previous studies that have used relatively small cohorts (≤220 samples). Methods: Whole-blood gene expression profiles were collected from a total of 523 individuals. After preprocessing, the data contained 486 gene profiles (n = 205 PD, n = 233 controls, n = 48 other neurodegenerative diseases) that were partitioned into training, validation, and independent test cohorts to identify and validate a gene signature. Batch-effect reduction and cross-validation were performed to ensure signature reliability. Finally, functional and pathway enrichment analyses were applied to the signature to identify PD-associated gene networks. Results: A gene signature of 100 probes that mapped to 87 genes, corresponding to 64 upregulated and 23 downregulated genes differentiating between patients with idiopathic PD and controls, was identified with the training cohort and successfully replicated in both an independent validation cohort (area under the curve [AUC] = 0.79, p = 7.13E–6) and a subsequent independent test cohort (AUC = 0.74, p = 4.2E–4). Network analysis of the signature revealed gene enrichment in pathways, including metabolism, oxidation, and ubiquitination/proteasomal activity, and misregulation of mitochondria-localized genes, including downregulation of COX4I1, ATP5A1, and VDAC3. Conclusions: We present a large-scale study of PD gene expression profiling. This work identifies a reliable blood-based PD signature and highlights the importance of large-scale patient cohorts in developing potential PD biomarkers.
  • Randomized open-label trial of dextromethorphan in Rett syndrome
    Objective: To determine safety and perform a preliminary assessment of dose-dependent efficacy of dextromethorphan in normalizing electrographic spikes, clinical seizures, and behavioral and cognitive functions in girls with Rett syndrome. Methods: We used a prospective randomized, open-label trial in fast metabolizers of dextromethorphan to examine the effect of dextromethorphan on core clinical features of Rett syndrome. Interictal spike activity and clinical seizures were determined using EEG and parent reporting. Cognitive data were obtained using the Mullen Scales of Early Learning and Vineland Adaptive Behavior Scales, while behavioral data were obtained from parent-completed checklists, the Aberrant Behavior Checklist–Community Version, and the Screen for Social Interaction. Anthropometric data were obtained according to the National Health and Nutrition Examination Survey. The Rett Syndrome Severity Scale provided a clinical global impression of the effect of dextromethorphan on clinical severity. Results: Dextromethorphan is safe for use in 3- to 15-year-old girls with Rett syndrome. Thirty-five girls were treated with 1 of 3 doses of dextromethorphan over a period of 6 months. Statistically significant dose-dependent improvements were seen in clinical seizures, receptive language, and behavioral hyperactivity. There was no significant improvement in global clinical severity as measured by the Rett Syndrome Severity Scale. Conclusions: Dextromethorphan is a potent noncompetitive antagonist of the NMDA receptor channel that is safe for use in young girls with Rett syndrome. Preliminary evidence suggests that dextromethorphan may improve some core features of Rett syndrome. Classification of evidence: This study provides Class IV evidence that dextromethorphan at various doses does not change EEG spike counts over 6 months, though precision was limited to exclude an important effect.
  • Variable course of Unverricht-Lundborg disease: Early prognostic factors
    Objective: To explore the course of Unverricht-Lundborg disease (EPM1) and identify the risk factors for severity, we investigated the time course of symptoms and prognostic factors already detectable near to disease onset. Methods: We retrospectively evaluated the features of 59 Italian patients carrying the CSTB expansion mutation, and coded the information every 5 years after the disease onset in order to describe the cumulative time-dependent probability of reaching disabling myoclonus, relevant cognitive impairment, and inability to work, and evaluated the influence of early factors using the log-rank test. The risk factors were included in a Cox multivariate proportional hazards regression model. Results: Disabling myoclonus occurred an average of 32 years after disease onset, whereas cognitive impairment occurred a little later. An age at onset of less than 12 years, the severity of myoclonus at the time of first assessment, and seizure persistence more than 10 years after onset affected the timing of disabling myoclonus and cognitive decline. Most patients became unable to work years before the appearance of disabling myoclonus or cognitive decline. Conclusions: A younger age at onset, early severe myoclonus, and seizure persistence are predictors of a more severe outcome. All of these factors may be genetically determined, but the greater hyperexcitability underlying more severe seizures and myoclonus at onset may also play a role by increasing cell damage due to reduced cystatin B activity.
  • Pretreatment behavior and subsequent medication effects in childhood absence epilepsy
    Objective: To characterize pretreatment behavioral problems and differential effects of initial therapy in children with childhood absence epilepsy (CAE). Methods: The Child Behavior Checklist (CBCL) was administered at baseline, week 16–20, and month 12 visits of a randomized double-blind trial of ethosuximide, lamotrigine, and valproate. Total problems score was the primary outcome measure. Results: A total of 382 participants at baseline, 310 participants at the week 16–20 visit, and 168 participants at the month 12 visit had CBCL data. At baseline, 8% (95% confidence interval [CI] 6%–11%) of children with CAE had elevated total problems scores (mean 52.9 ± 10.91). At week 16–20, participants taking valproic acid had significantly higher total problems (51.7 [98.3% CI 48.6–54.7]), externalizing problems (51.4 [98.3% CI 48.5–54.3]), attention problems (57.8 [98.3% CI 55.6–60.0]), and attention-deficit/hyperactivity problems (55.8 [98.3% CI 54.1–57.6]) scores compared to participants taking ethosuximide (46.5 [98.3% CI 43.4–49.6]; 45.8 [98.3% CI 42.9–48.7]; 54.6 [98.3% CI 52.4–56.9]; 53.0 [98.3% CI 51.3–54.8]). Lack of seizure freedom and elevated week 16–20 Conner Continuous Performance Test confidence index were associated with worse total problems scores. At month 12, participants taking valproic acid had significantly higher attention problems scores (57.9 [98.3% CI 55.6–60.3]) compared to participants taking ethosuximide (54.5 [95% CI 52.1–56.9]). Conclusions: Pretreatment and ongoing behavioral problems exist in CAE. Valproic acid is associated with worse behavioral outcomes than ethosuximide or lamotrigine, further reinforcing ethosuximide as the preferred initial therapy for CAE. Clinicaltrials.gov identifier: NCT00088452. Classification of evidence: This study provides Class II evidence that for children with CAE, valproic acid is associated with worse behavioral outcomes than ethosuximide or lamotrigine.
  • Comparison of symptomatic and asymptomatic persons with primary age-related tauopathy
    Objective: To conduct a clinicopathologic study to characterize clinical and neuropathologic features associated with cognitive impairment in participants with no neuritic amyloid plaques (primary age-related tauopathy [PART] definite) and sparse neuritic plaques (amyloid sparse). Methods: Using the National Alzheimer's Coordinating Center database, we identified 377 individuals who were PART definite (n = 170) or amyloid sparse (n = 207), clinically examined within 1 year of death, and autopsied at 1 of 26 National Institute on Aging–funded Alzheimer's Disease Centers. Factors associated with the odds of being symptomatic (global Clinical Dementia Rating [CDR] score >0) were identified with multivariable logistic regression. Results: PART-definite participants less often had a high Braak neurofibrillary tangle stage V or VI (4%) compared to amyloid sparse participants (28%, p < 0.001). Of the PART-definite participants, 98 were symptomatic and 72 asymptomatic according to their global CDR scores. PART-definite participants were less often symptomatic (58%) compared with amyloid sparse participants (80%, p < 0.001). Within the PART-definite group, independent predictors of symptomatic status included depression (adjusted odds ratio [aOR] 4.20, 95% confidence interval [CI] 2.15–8.19), Braak stage (aOR 1.42, 95% CI 1.04–1.95), and history of stroke (aOR 8.09, 95% CI 2.63–24.82). Within the amyloid sparse group, independent predictors of symptomatic status included education (aOR 0.80, 95% CI 0.65–0.99), Braak stage (aOR 1.91, 95% CI 1.07–3.43), and amyloid angiopathy (aOR 2.75, 95% CI 1.14–6.64). Conclusions: These findings support the hypothesis that participants with PART have an amyloid-independent dementing Alzheimer disease–like temporal lobe tauopathy.
  • Serum magnesium is associated with the risk of dementia
    Objective: To determine if serum magnesium levels are associated with the risk of all-cause dementia and Alzheimer disease. Methods: Within the prospective population-based Rotterdam Study, we measured serum magnesium levels in 9,569 participants, free from dementia at baseline (1997–2008). Participants were subsequently followed up for incident dementia, determined according to the DSM-III-R criteria, until January 1, 2015. We used Cox proportional hazard regression models to associate quintiles of serum magnesium with incident all-cause dementia. We used the third quintile as a reference group and adjusted for age, sex, Rotterdam Study cohort, educational level, cardiovascular risk factors, kidney function, comorbidities, other electrolytes, and diuretic use. Results: Our study population had a mean age of 64.9 years and 56.6% were women. During a median follow-up of 7.8 years, 823 participants were diagnosed with all-cause dementia. Both low serum magnesium levels (≤0.79 mmol/L) and high serum magnesium levels (≥0.90 mmol/L) were associated with an increased risk of dementia (hazard ratio [HR] 1.32, 95% confidence interval [CI] 1.02–1.69, and HR 1.30, 95% CI 1.02–1.67, respectively). Conclusions: Both low and high serum magnesium levels are associated with an increased risk of all-cause dementia. Our results warrant replication in other population-based studies.
  • Smoking cessation and outcome after ischemic stroke or TIA
    Objective: To assess whether smoking cessation after an ischemic stroke or TIA improves outcomes compared to continued smoking. Methods: We conducted a prospective observational cohort study of 3,876 nondiabetic men and women enrolled in the Insulin Resistance Intervention After Stroke (IRIS) trial who were randomized to pioglitazone or placebo within 180 days of a qualifying stroke or TIA and followed up for a median of 4.8 years. A tobacco use history was obtained at baseline and updated during annual interviews. The primary outcome, which was not prespecified in the IRIS protocol, was recurrent stroke, myocardial infarction (MI), or death. Cox regression models were used to assess the differences in stroke, MI, and death after 4.8 years, with correction for adjustment variables prespecified in the IRIS trial: age, sex, stroke (vs TIA) as index event, history of stroke, history of hypertension, history of coronary artery disease, and systolic and diastolic blood pressures. Results: At the time of their index event, 1,072 (28%) patients were current smokers. By the time of randomization, 450 (42%) patients had quit smoking. Among quitters, the 5-year risk of stroke, MI, or death was 15.7% compared to 22.6% for patients who continued to smoke (adjusted hazard ratio 0.66, 95% confidence interval 0.48–0.90). Conclusion: Cessation of cigarette smoking after an ischemic stroke or TIA was associated with significant health benefits over 4.8 years in the IRIS trial cohort.
  • Qualitative study of burnout, career satisfaction, and well-being among US neurologists in 2016
    Objective: To understand the experience and identify drivers and mitigating factors of burnout and well-being among US neurologists. Methods: Inductive data analysis was applied to free text comments (n = 676) from the 2016 American Academy of Neurology survey of burnout, career satisfaction, and well-being. Results: Respondents providing comments were significantly more likely to be older, owners/partners of their practice, solo practitioners, and compensated by production than those not commenting. The 4 identified themes were (1) policies and people affecting neurologists (government and insurance mandates, remuneration, recertification, leadership); (2) workload and work–life balance (workload, electronic health record [EHR], work–life balance); (3) engagement, professionalism, work domains specific to neurology; and (4) solutions (systemic and individual), advocacy, other. Neurologists mentioned workload > professional identity > time spent on insurance and government mandates when describing burnout. Neurologists' patient and clerical workload increased work hours or work brought home, resulting in poor work–life balance. EHR and expectations of high patient volumes by administrators impeded quality of patient care. As a result, many neurologists reduced work hours and call provision and considered early retirement. Conclusions: Our results further characterize burnout among US neurologists through respondents' own voices. They clarify the meaning respondents attributed to ambiguous survey questions and highlight the barriers neurologists must overcome to practice their chosen specialty, including multiple regulatory hassles and increased work hours. Erosion of professionalism by external factors was a common issue. Our findings can provide strategic direction for advocacy and programs to prevent and mitigate neurologist burnout and promote well-being and engagement.
  • Genome editing technologies and their potential to treat neurologic disease
    Genome editing refers to a process of making precise and permanent changes in the genetic code of cells, tissues, and whole organisms. The first step in this process is to program an enzyme called a nuclease to bind to a precise DNA sequence, whereby the enzyme will cut the DNA. This double-stranded break will in turn induce the cell to make a repair at that site, which will change the DNA sequence. The repair mechanism can be utilized to either knock out or introduce selected genes. Given how rapidly gene editing systems are influencing diverse applications in biomedical research, biotechnology, and agriculture,1 clinical applications in neurology to repair genetic mutations causing disease, or to incorporate genes that might be of therapeutic benefit, are on the near horizon. The following cases illustrate how such an approach may be used to develop new ex vivo (case 1) and in vivo (case 2) therapies for neurologic disease, respectively, and highlight some of the translational challenges of using these molecular reagents safely and ethically in patients.
  • Did Jules Dejerine describe AMAN at the end of the 19th century?
    Guillain-Barré syndrome (GBS) is a heterogeneous group of acute immune-mediated neuropathies, including acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor axonal neuropathy (AMAN). AMAN is an axonal subtype of GBS that has been known since the 1990s; this term was first used to describe a summer epidemic of acute ascending paralysis observed in children in northern China (and Mexico). It is pathologically characterized by noninflammatory axonal degeneration of the motor nerves (with little or no demyelination). The French neurologist Jules Dejerine (1849–1917) conducted a clinical and pathologic description of AMAN in the late 19th century. We describe his observations, which provide us with valuable information on the course of pathologic lesions in this disease.
  • Fatigable ptosis as an initial presentation of adult-onset Leigh syndrome
    A 20-year-old man presented with bilateral fatigable ptosis for 1 month. On examination, there was bilateral incomplete ptosis, which deteriorated during upward gaze and improved at rest (figure, A and B). Tests for myasthenia gravis were all negative. Brain MRI showed symmetric hyperintensities at periaqueductal gray matter on T2- and diffusion-weighted images (figure, C). CSF lactic acid was elevated. Mitochondrial genome test demonstrated a homoplasmic T9176C mutation in the MT-APT6A gene, known as pathogenic mutation of Leigh syndrome.1 In our patient, fatigable ptosis may be ascribed to the dysfunction at centrally located synapse between the nuclear complex of the third nerve and supranuclear pathways.2
  • Editors' Note
    Editors' Note: In "Ischemic lesions, blood pressure dysregulation, and poor outcomes in intracerebral hemorrhage," the authors concluded that acute blood pressure (BP) dysregulation in primary intracerebral hemorrhage (ICH) patients was associated with the development of diffusion-weighted imaging (DWI) lesions and, subsequently, worse outcomes.
  • Letter re: Ischemic Lesions, blood pressure dysregulation, and poor outcomes in intracerebral hemorrhage
    We appreciated the article by Kidwell et al.1 that showed higher first-recorded blood pressure (BP) and greater delta mean arterial pressure are associated with the development of diffusion-weighted imaging (DWI) lesions in acute intracerebral hemorrhage (ICH). The most desirable BP target and optimal antihypertensive strategy in ICH are controversial.2 The relationship between BP and outcome is more complex than simply linear, and mechanisms other than BP reduction play a role. There is accruing evidence that not only absolute BP levels but their variation over time affect ICH prognosis.3 Besides increasing the risk of hematoma enlargement, BP fluctuations could favor remote ischemia by working synergistically with preexistent burden of cerebral small angiopathy, namely leukoaraiosis and microbleeds, and influence the stroke outcome. Both systolic and diastolic BP dysregulation deserve more comprehensive assessment through the proper measures of variability, such as standard and residual deviation, variation coefficient, average real variability, and variation independent of the mean.4 In addition, time to MRI differed among DWI+ and DWI– patient subgroups, which could represent a meaningful bias: it would be appropriate to include this variable among the controlling factors of the multivariable predictive model for DWI lesions development.
  • Author response: Ischemic Lesions, blood pressure dysregulation, and poor outcomes in intracerebral hemorrhage
    We appreciate the comments by Drs. Lattanzi and Silvestrini on our article,1 and agree that further research is needed to better understand the complex relationship among blood pressure (BP) dysregulation, small vessel disease, and development of remote ischemic lesions in the setting of acute intracerebral hemorrhage.2
  • Letter re: Efficacy and safety of brivaracetam for partial-onset seizures in 3 pooled clinical studies
    We thank Dr. French1 for her Epilepsy Currents commentary on our article.2 We agree that time will tell regarding the usefulness of brivaracetam's (BRV's) addition to the antiepileptic drug (AED) armamentarium, as there is no substitute for real-world clinical experience.

Recent Issues:
  • Clinical Reasoning: A 46-year-old man with persistent hiccups, cognitive dysfunction, and imbalance
    A 46-year-old, right-handed, African American man presented to the emergency department after 1 week of persistent hiccups and 3 days of nausea and vomiting. His family member also noted that he had been experiencing right-hand tremor and gait imbalance for the last 3 months. Over the 6 months prior to presentation, the patient's coworkers had noticed that he was completing his work more slowly, that he was forgetting how to perform simple tasks, and that several times he had come to work at the wrong hours. The patient had a history of HIV diagnosed 10 years earlier and reported good adherence to an antiretroviral regimen consisting of tenofovir, emtricitabine, and atazanavir boosted by ritonavir, without any changes for several years. His viral load was undetectable when tested 8 months prior to presentation.
  • Teaching NeuroImages: Artery of Percheron thrombosis causing selective downgaze palsy
    A 47-year-old man with migraines presented with sudden onset of vertical diplopia, dysarthria, right facial weakness, and downgaze palsy (figure 1). Brain MRI revealed ischemic strokes in the midbrain periaqueductal gray, bilateral thalamic–midbrain junction, and thalamus (figure 2, A–C). Gradient echo and T1 MRI showed hypointensity in the interpeduncular fossa (figure 2, D and E). No flow could be visualized in this structure on CT angiogram or catheter angiogram, demonstrating a thrombosed artery of Percheron (figure 2, F–H). Downgaze palsy, which improved 18 months later, may result from bilateral lesions of the mesencephalic–diencephalic junction involving the rostral interstitial nucleus of the medial longitudinal fasciculus.1,2
  • Teaching NeuroImages: Spontaneous involution of symptomatic delayed tumefactive cyst following radiosurgery for AVM
    A 65-year-old woman underwent radiosurgery for a left temporal arteriovenous malformation (AVM) (figure 1A). Follow-up MRI/magnetic resonance angiography 3 years later demonstrated postradiation changes (figure 1B) and AVM resolution (figure 2). Six years posttreatment, she had progressive headaches and aphasia and a large cyst (figure 1C). Her symptoms resolved acutely without treatment. MRI 3 months later showed reduction of the cyst with mass effect resolution related to spontaneous fenestration in the ventricle (figure 1D).
  • Teaching NeuroImages: MR neurography for the diagnosis of hypertrophic neuropathies
    A 25-year-old woman presented with a 10-year history of frequent falls and deafness. Her mother had a similar neurologic picture. Examination showed peroneal amyotrophy, pes cavus, and hearing loss. Magnetic resonance (MR) neurography showed diffuse nerve enlargement in the lower limbs (figure). Genetic analysis revealed heterozygous mutation c.82T>C (p.Trp28Arg) in the PMP22 gene, defining diagnosis of Charcot-Marie-Tooth disease (CMT) type 1A.
  • Teaching Video NeuroImages: My weeping patient: Avoiding the pitfalls of a functional diagnosis
    A 54-year-old man presented with symptoms of a posterior circulation stroke. A right facial palsy and horizontal right end gaze nystagmus was noted. On resolution, episodes of uncontrolled weeping without a provoking stimulus was observed (video at Neurology.org). These were initially unremitting, lasting minutes, with complete resolution after 1 month. An early consideration was of a functional neurologic disorder. Subsequent MRI brain demonstrated bilateral anterior pontine infarcts (figure). It has been hypothesized that pseudobulbar affect (PBA) results from the loss of frontal cortex input to the cerebellum during emotional expression.1 This disruption in descending pathways is postulated in pontine infarcts.2 PBA should not be considered an incongruent sign.
  • Spotlight on the October 17 issue
  • An improved way to predict neurologic recovery in acute spinal cord injury
    In North America alone, spinal cord injury affects well over 1 million patients, with the average annual incidence expected to rise secondary to an increasing amount of falls in an aging population.1,2 Spinal cord injury (SCI) has detrimental health consequences that can frequently leave the injured patient with a lifetime of medical expenses exceeding $4 million.2 Although the current practice in treating SCI is to elevate a patient's mean arterial pressure (MAP) to 85–90 mm Hg for the first 7 days in an effort to maintain spinal cord perfusion, this treatment strategy has uncertain efficacy, as the actual spinal cord perfusion pressure (SCPP) remains unknown.3 In this issue of Neurology®, Squair et al.4 propose an improved treatment approach using the calculated SCPP that can provide patients with an increased likelihood of having restoration of function after an SCI.
  • Smoking cessation and secondary stroke prevention
    The 7 million adult stroke survivors in the United States remain at high risk for a recurrent stroke. The increased morbidity and cost associated with recurrent stroke, in addition to the 5% to 20% yearly stroke recurrence, support the need for additional investigations into secondary stroke prevention.1,2 Stroke prevention guidelines, whether primary or secondary, focus on risk factor control of modifiable risk factors. The American Heart Association/American Stroke Association guidelines for secondary stroke prevention indicate evidence-based risk factor control, interventional approaches, and treatment options as approaches to secondary stroke prevention.1 Risk factor control for secondary stroke prevention includes managing hypertension, diabetes mellitus, and hyperlipidemia, as well as lifestyle modifications, including weight management, alcohol consumption, and smoking cessation.3 A cornerstone of recurrent stroke reduction, and lifetime cardiovascular disease (CVD) risk, is modification of lifestyle behaviors such as abstaining from tobacco, adopting a healthy diet, and exercising regularly. While these healthy lifestyle behaviors should start in childhood and continue through one's lifetime, modifying these health behaviors after a stroke can reduce the risk of recurrent stroke and other CVD-related illnesses.3
  • Preventing burnout increases the desirability of neurology as a career
    Neurologic diseases comprise a major percentage of disease burden in the United States, and one that is predicted to increase as our population ages. The need for physicians with expertise in the recognition, diagnosis, and management of neurologic diseases also will increase. Over the next decade, the number of neurologists in the United States will grow from the current 16,000 to 18,000. However, even this number represents a predicted 20% shortfall in number of neurologists needed by 2025.1,2 Our neurology workforce therefore must increase to address this current and future need.
  • Spinal cord perfusion pressure predicts neurologic recovery in acute spinal cord injury
    Objective: To determine whether spinal cord perfusion pressure (SCPP) as measured with a lumbar intrathecal catheter is a more predictive measure of neurologic outcome than the conventionally measured mean arterial pressure (MAP). Methods: A total of 92 individuals with acute spinal cord injury were enrolled in this multicenter prospective observational clinical trial. MAP and CSF pressure (CSFP) were monitored during the first week postinjury. Neurologic impairment was assessed at baseline and at 6 months postinjury. We used logistic regression, systematic iterations of relative risk, and Cox proportional hazard models to examine hemodynamic patterns commensurate with neurologic outcome. Results: We found that SCPP (odds ratio 1.039, p = 0.002) is independently associated with positive neurologic recovery. The relative risk for not recovering neurologic function continually increased as individuals were exposed to SCPP below 50 mm Hg. Individuals who improved in neurologic grade dropped below SCPP of 50 mm Hg fewer times than those who did not improve (p = 0.012). This effect was not observed for MAP or CSFP. Those who were exposed to SCPP below 50 mm Hg were less likely to improve from their baseline neurologic impairment grade (p = 0.0056). Conclusions: We demonstrate that maintaining SCPP above 50 mm Hg is a strong predictor of improved neurologic recovery following spinal cord injury. This suggests that SCPP (the difference between MAP and CSFP) can provide useful information to guide the hemodynamic management of patients with acute spinal cord injury.
  • Comorbidity in multiple sclerosis is associated with diagnostic delays and increased mortality
    Objective: To investigate the effect of chronic comorbidity on the time of diagnosis of multiple sclerosis (MS) and on mortality in MS. Methods: We conducted a population-based, nationwide cohort study including all incident MS cases in Denmark with first MS symptom between 1980 and 2005. To investigate the time of diagnosis, we compared individuals with and without chronic comorbidity using multinomial logistic regression. To investigate mortality, we used Cox regression with time-dependent covariates, following study participants from clinical MS onset until endpoint (death) or to the end of the study, censuring at emigration. Results: We identified 8,947 individuals with clinical onset of MS between 1980 and 2005. In the study of time of diagnosis, we found statistically significant odds ratios for longer diagnostic delays with cerebrovascular comorbidity (2.01 [1.44–2.80]; <0.0005), cardiovascular comorbidity (4.04 [2.78–5.87]; <0.0005), lung comorbidity (1.93 [1.42–2.62]; <0.0005), diabetes comorbidity (1.78 [1.04–3.06]; 0.035), and cancer comorbidity (2.10 [1.20–3.67]; 0.009). In the mortality study, we found higher hazard ratios with psychiatric comorbidity (2.42 [1.67–3.01]; <0.0005), cerebrovascular comorbidity (2.47 [2.05–2.79]; <0.0005), cardiovascular comorbidity (1.68 [1.39–2.03]; <0.0005), lung comorbidity (1.23 [1.01–1.50]; 0.036), diabetes comorbidity (1.39 [1.05–1.85]; 0.021), cancer comorbidity (3.51 [2.94–4.19]; <0.0005), and Parkinson disease comorbidity (2.85 [1.34–6.06]; 0.007). Conclusions: An increased awareness of both the necessity of neurologic evaluation of new neurologic symptoms in persons with preexisting chronic disease and of optimum treatment of comorbidity in MS is critical.
  • Analysis of blood-based gene expression in idiopathic Parkinson disease
    Objective: To examine whether gene expression analysis of a large-scale Parkinson disease (PD) patient cohort produces a robust blood-based PD gene signature compared to previous studies that have used relatively small cohorts (≤220 samples). Methods: Whole-blood gene expression profiles were collected from a total of 523 individuals. After preprocessing, the data contained 486 gene profiles (n = 205 PD, n = 233 controls, n = 48 other neurodegenerative diseases) that were partitioned into training, validation, and independent test cohorts to identify and validate a gene signature. Batch-effect reduction and cross-validation were performed to ensure signature reliability. Finally, functional and pathway enrichment analyses were applied to the signature to identify PD-associated gene networks. Results: A gene signature of 100 probes that mapped to 87 genes, corresponding to 64 upregulated and 23 downregulated genes differentiating between patients with idiopathic PD and controls, was identified with the training cohort and successfully replicated in both an independent validation cohort (area under the curve [AUC] = 0.79, p = 7.13E–6) and a subsequent independent test cohort (AUC = 0.74, p = 4.2E–4). Network analysis of the signature revealed gene enrichment in pathways, including metabolism, oxidation, and ubiquitination/proteasomal activity, and misregulation of mitochondria-localized genes, including downregulation of COX4I1, ATP5A1, and VDAC3. Conclusions: We present a large-scale study of PD gene expression profiling. This work identifies a reliable blood-based PD signature and highlights the importance of large-scale patient cohorts in developing potential PD biomarkers.
  • Randomized open-label trial of dextromethorphan in Rett syndrome
    Objective: To determine safety and perform a preliminary assessment of dose-dependent efficacy of dextromethorphan in normalizing electrographic spikes, clinical seizures, and behavioral and cognitive functions in girls with Rett syndrome. Methods: We used a prospective randomized, open-label trial in fast metabolizers of dextromethorphan to examine the effect of dextromethorphan on core clinical features of Rett syndrome. Interictal spike activity and clinical seizures were determined using EEG and parent reporting. Cognitive data were obtained using the Mullen Scales of Early Learning and Vineland Adaptive Behavior Scales, while behavioral data were obtained from parent-completed checklists, the Aberrant Behavior Checklist–Community Version, and the Screen for Social Interaction. Anthropometric data were obtained according to the National Health and Nutrition Examination Survey. The Rett Syndrome Severity Scale provided a clinical global impression of the effect of dextromethorphan on clinical severity. Results: Dextromethorphan is safe for use in 3- to 15-year-old girls with Rett syndrome. Thirty-five girls were treated with 1 of 3 doses of dextromethorphan over a period of 6 months. Statistically significant dose-dependent improvements were seen in clinical seizures, receptive language, and behavioral hyperactivity. There was no significant improvement in global clinical severity as measured by the Rett Syndrome Severity Scale. Conclusions: Dextromethorphan is a potent noncompetitive antagonist of the NMDA receptor channel that is safe for use in young girls with Rett syndrome. Preliminary evidence suggests that dextromethorphan may improve some core features of Rett syndrome. Classification of evidence: This study provides Class IV evidence that dextromethorphan at various doses does not change EEG spike counts over 6 months, though precision was limited to exclude an important effect.
  • Variable course of Unverricht-Lundborg disease: Early prognostic factors
    Objective: To explore the course of Unverricht-Lundborg disease (EPM1) and identify the risk factors for severity, we investigated the time course of symptoms and prognostic factors already detectable near to disease onset. Methods: We retrospectively evaluated the features of 59 Italian patients carrying the CSTB expansion mutation, and coded the information every 5 years after the disease onset in order to describe the cumulative time-dependent probability of reaching disabling myoclonus, relevant cognitive impairment, and inability to work, and evaluated the influence of early factors using the log-rank test. The risk factors were included in a Cox multivariate proportional hazards regression model. Results: Disabling myoclonus occurred an average of 32 years after disease onset, whereas cognitive impairment occurred a little later. An age at onset of less than 12 years, the severity of myoclonus at the time of first assessment, and seizure persistence more than 10 years after onset affected the timing of disabling myoclonus and cognitive decline. Most patients became unable to work years before the appearance of disabling myoclonus or cognitive decline. Conclusions: A younger age at onset, early severe myoclonus, and seizure persistence are predictors of a more severe outcome. All of these factors may be genetically determined, but the greater hyperexcitability underlying more severe seizures and myoclonus at onset may also play a role by increasing cell damage due to reduced cystatin B activity.
  • Pretreatment behavior and subsequent medication effects in childhood absence epilepsy
    Objective: To characterize pretreatment behavioral problems and differential effects of initial therapy in children with childhood absence epilepsy (CAE). Methods: The Child Behavior Checklist (CBCL) was administered at baseline, week 16–20, and month 12 visits of a randomized double-blind trial of ethosuximide, lamotrigine, and valproate. Total problems score was the primary outcome measure. Results: A total of 382 participants at baseline, 310 participants at the week 16–20 visit, and 168 participants at the month 12 visit had CBCL data. At baseline, 8% (95% confidence interval [CI] 6%–11%) of children with CAE had elevated total problems scores (mean 52.9 ± 10.91). At week 16–20, participants taking valproic acid had significantly higher total problems (51.7 [98.3% CI 48.6–54.7]), externalizing problems (51.4 [98.3% CI 48.5–54.3]), attention problems (57.8 [98.3% CI 55.6–60.0]), and attention-deficit/hyperactivity problems (55.8 [98.3% CI 54.1–57.6]) scores compared to participants taking ethosuximide (46.5 [98.3% CI 43.4–49.6]; 45.8 [98.3% CI 42.9–48.7]; 54.6 [98.3% CI 52.4–56.9]; 53.0 [98.3% CI 51.3–54.8]). Lack of seizure freedom and elevated week 16–20 Conner Continuous Performance Test confidence index were associated with worse total problems scores. At month 12, participants taking valproic acid had significantly higher attention problems scores (57.9 [98.3% CI 55.6–60.3]) compared to participants taking ethosuximide (54.5 [95% CI 52.1–56.9]). Conclusions: Pretreatment and ongoing behavioral problems exist in CAE. Valproic acid is associated with worse behavioral outcomes than ethosuximide or lamotrigine, further reinforcing ethosuximide as the preferred initial therapy for CAE. Clinicaltrials.gov identifier: NCT00088452. Classification of evidence: This study provides Class II evidence that for children with CAE, valproic acid is associated with worse behavioral outcomes than ethosuximide or lamotrigine.
  • Comparison of symptomatic and asymptomatic persons with primary age-related tauopathy
    Objective: To conduct a clinicopathologic study to characterize clinical and neuropathologic features associated with cognitive impairment in participants with no neuritic amyloid plaques (primary age-related tauopathy [PART] definite) and sparse neuritic plaques (amyloid sparse). Methods: Using the National Alzheimer's Coordinating Center database, we identified 377 individuals who were PART definite (n = 170) or amyloid sparse (n = 207), clinically examined within 1 year of death, and autopsied at 1 of 26 National Institute on Aging–funded Alzheimer's Disease Centers. Factors associated with the odds of being symptomatic (global Clinical Dementia Rating [CDR] score >0) were identified with multivariable logistic regression. Results: PART-definite participants less often had a high Braak neurofibrillary tangle stage V or VI (4%) compared to amyloid sparse participants (28%, p < 0.001). Of the PART-definite participants, 98 were symptomatic and 72 asymptomatic according to their global CDR scores. PART-definite participants were less often symptomatic (58%) compared with amyloid sparse participants (80%, p < 0.001). Within the PART-definite group, independent predictors of symptomatic status included depression (adjusted odds ratio [aOR] 4.20, 95% confidence interval [CI] 2.15–8.19), Braak stage (aOR 1.42, 95% CI 1.04–1.95), and history of stroke (aOR 8.09, 95% CI 2.63–24.82). Within the amyloid sparse group, independent predictors of symptomatic status included education (aOR 0.80, 95% CI 0.65–0.99), Braak stage (aOR 1.91, 95% CI 1.07–3.43), and amyloid angiopathy (aOR 2.75, 95% CI 1.14–6.64). Conclusions: These findings support the hypothesis that participants with PART have an amyloid-independent dementing Alzheimer disease–like temporal lobe tauopathy.
  • Serum magnesium is associated with the risk of dementia
    Objective: To determine if serum magnesium levels are associated with the risk of all-cause dementia and Alzheimer disease. Methods: Within the prospective population-based Rotterdam Study, we measured serum magnesium levels in 9,569 participants, free from dementia at baseline (1997–2008). Participants were subsequently followed up for incident dementia, determined according to the DSM-III-R criteria, until January 1, 2015. We used Cox proportional hazard regression models to associate quintiles of serum magnesium with incident all-cause dementia. We used the third quintile as a reference group and adjusted for age, sex, Rotterdam Study cohort, educational level, cardiovascular risk factors, kidney function, comorbidities, other electrolytes, and diuretic use. Results: Our study population had a mean age of 64.9 years and 56.6% were women. During a median follow-up of 7.8 years, 823 participants were diagnosed with all-cause dementia. Both low serum magnesium levels (≤0.79 mmol/L) and high serum magnesium levels (≥0.90 mmol/L) were associated with an increased risk of dementia (hazard ratio [HR] 1.32, 95% confidence interval [CI] 1.02–1.69, and HR 1.30, 95% CI 1.02–1.67, respectively). Conclusions: Both low and high serum magnesium levels are associated with an increased risk of all-cause dementia. Our results warrant replication in other population-based studies.
  • Smoking cessation and outcome after ischemic stroke or TIA
    Objective: To assess whether smoking cessation after an ischemic stroke or TIA improves outcomes compared to continued smoking. Methods: We conducted a prospective observational cohort study of 3,876 nondiabetic men and women enrolled in the Insulin Resistance Intervention After Stroke (IRIS) trial who were randomized to pioglitazone or placebo within 180 days of a qualifying stroke or TIA and followed up for a median of 4.8 years. A tobacco use history was obtained at baseline and updated during annual interviews. The primary outcome, which was not prespecified in the IRIS protocol, was recurrent stroke, myocardial infarction (MI), or death. Cox regression models were used to assess the differences in stroke, MI, and death after 4.8 years, with correction for adjustment variables prespecified in the IRIS trial: age, sex, stroke (vs TIA) as index event, history of stroke, history of hypertension, history of coronary artery disease, and systolic and diastolic blood pressures. Results: At the time of their index event, 1,072 (28%) patients were current smokers. By the time of randomization, 450 (42%) patients had quit smoking. Among quitters, the 5-year risk of stroke, MI, or death was 15.7% compared to 22.6% for patients who continued to smoke (adjusted hazard ratio 0.66, 95% confidence interval 0.48–0.90). Conclusion: Cessation of cigarette smoking after an ischemic stroke or TIA was associated with significant health benefits over 4.8 years in the IRIS trial cohort.
  • Qualitative study of burnout, career satisfaction, and well-being among US neurologists in 2016
    Objective: To understand the experience and identify drivers and mitigating factors of burnout and well-being among US neurologists. Methods: Inductive data analysis was applied to free text comments (n = 676) from the 2016 American Academy of Neurology survey of burnout, career satisfaction, and well-being. Results: Respondents providing comments were significantly more likely to be older, owners/partners of their practice, solo practitioners, and compensated by production than those not commenting. The 4 identified themes were (1) policies and people affecting neurologists (government and insurance mandates, remuneration, recertification, leadership); (2) workload and work–life balance (workload, electronic health record [EHR], work–life balance); (3) engagement, professionalism, work domains specific to neurology; and (4) solutions (systemic and individual), advocacy, other. Neurologists mentioned workload > professional identity > time spent on insurance and government mandates when describing burnout. Neurologists' patient and clerical workload increased work hours or work brought home, resulting in poor work–life balance. EHR and expectations of high patient volumes by administrators impeded quality of patient care. As a result, many neurologists reduced work hours and call provision and considered early retirement. Conclusions: Our results further characterize burnout among US neurologists through respondents' own voices. They clarify the meaning respondents attributed to ambiguous survey questions and highlight the barriers neurologists must overcome to practice their chosen specialty, including multiple regulatory hassles and increased work hours. Erosion of professionalism by external factors was a common issue. Our findings can provide strategic direction for advocacy and programs to prevent and mitigate neurologist burnout and promote well-being and engagement.
  • Genome editing technologies and their potential to treat neurologic disease
    Genome editing refers to a process of making precise and permanent changes in the genetic code of cells, tissues, and whole organisms. The first step in this process is to program an enzyme called a nuclease to bind to a precise DNA sequence, whereby the enzyme will cut the DNA. This double-stranded break will in turn induce the cell to make a repair at that site, which will change the DNA sequence. The repair mechanism can be utilized to either knock out or introduce selected genes. Given how rapidly gene editing systems are influencing diverse applications in biomedical research, biotechnology, and agriculture,1 clinical applications in neurology to repair genetic mutations causing disease, or to incorporate genes that might be of therapeutic benefit, are on the near horizon. The following cases illustrate how such an approach may be used to develop new ex vivo (case 1) and in vivo (case 2) therapies for neurologic disease, respectively, and highlight some of the translational challenges of using these molecular reagents safely and ethically in patients.
  • Did Jules Dejerine describe AMAN at the end of the 19th century?
    Guillain-Barré syndrome (GBS) is a heterogeneous group of acute immune-mediated neuropathies, including acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor axonal neuropathy (AMAN). AMAN is an axonal subtype of GBS that has been known since the 1990s; this term was first used to describe a summer epidemic of acute ascending paralysis observed in children in northern China (and Mexico). It is pathologically characterized by noninflammatory axonal degeneration of the motor nerves (with little or no demyelination). The French neurologist Jules Dejerine (1849–1917) conducted a clinical and pathologic description of AMAN in the late 19th century. We describe his observations, which provide us with valuable information on the course of pathologic lesions in this disease.
  • Fatigable ptosis as an initial presentation of adult-onset Leigh syndrome
    A 20-year-old man presented with bilateral fatigable ptosis for 1 month. On examination, there was bilateral incomplete ptosis, which deteriorated during upward gaze and improved at rest (figure, A and B). Tests for myasthenia gravis were all negative. Brain MRI showed symmetric hyperintensities at periaqueductal gray matter on T2- and diffusion-weighted images (figure, C). CSF lactic acid was elevated. Mitochondrial genome test demonstrated a homoplasmic T9176C mutation in the MT-APT6A gene, known as pathogenic mutation of Leigh syndrome.1 In our patient, fatigable ptosis may be ascribed to the dysfunction at centrally located synapse between the nuclear complex of the third nerve and supranuclear pathways.2
  • Editors' Note
    Editors' Note: In "Ischemic lesions, blood pressure dysregulation, and poor outcomes in intracerebral hemorrhage," the authors concluded that acute blood pressure (BP) dysregulation in primary intracerebral hemorrhage (ICH) patients was associated with the development of diffusion-weighted imaging (DWI) lesions and, subsequently, worse outcomes.
  • Letter re: Ischemic Lesions, blood pressure dysregulation, and poor outcomes in intracerebral hemorrhage
    We appreciated the article by Kidwell et al.1 that showed higher first-recorded blood pressure (BP) and greater delta mean arterial pressure are associated with the development of diffusion-weighted imaging (DWI) lesions in acute intracerebral hemorrhage (ICH). The most desirable BP target and optimal antihypertensive strategy in ICH are controversial.2 The relationship between BP and outcome is more complex than simply linear, and mechanisms other than BP reduction play a role. There is accruing evidence that not only absolute BP levels but their variation over time affect ICH prognosis.3 Besides increasing the risk of hematoma enlargement, BP fluctuations could favor remote ischemia by working synergistically with preexistent burden of cerebral small angiopathy, namely leukoaraiosis and microbleeds, and influence the stroke outcome. Both systolic and diastolic BP dysregulation deserve more comprehensive assessment through the proper measures of variability, such as standard and residual deviation, variation coefficient, average real variability, and variation independent of the mean.4 In addition, time to MRI differed among DWI+ and DWI– patient subgroups, which could represent a meaningful bias: it would be appropriate to include this variable among the controlling factors of the multivariable predictive model for DWI lesions development.
  • Author response: Ischemic Lesions, blood pressure dysregulation, and poor outcomes in intracerebral hemorrhage
    We appreciate the comments by Drs. Lattanzi and Silvestrini on our article,1 and agree that further research is needed to better understand the complex relationship among blood pressure (BP) dysregulation, small vessel disease, and development of remote ischemic lesions in the setting of acute intracerebral hemorrhage.2
  • Letter re: Efficacy and safety of brivaracetam for partial-onset seizures in 3 pooled clinical studies
    We thank Dr. French1 for her Epilepsy Currents commentary on our article.2 We agree that time will tell regarding the usefulness of brivaracetam's (BRV's) addition to the antiepileptic drug (AED) armamentarium, as there is no substitute for real-world clinical experience.
  • Clinical Reasoning: A 55-year-old man with rapidly progressive dementia and parkinsonism
    A 55-year-old right-handed man presented with a history of rapidly progressive apathy and behavior changes, speech loss, bladder and bowel incontinence, and gait loss in the previous month. He had been diagnosed with depression 7 months before and tried to commit suicide with carbon monoxide poisoning 2 months before, needing treatment in a hyperbaric chamber, with a good recovery. He had no history of other comorbidities and an unremarkable family history. At the first neurologic evaluation at our department, he presented with marked apathy and mutism, pseudobulbar affect, marked frontal release signs, generalized rigidity with hypomimia, global hyperreflexia with a left extensor plantar reflex, infrequent generalized myoclonus, and gait apraxia. Basic laboratory tests including electrolytes, complete blood count, carboxyhemoglobin, and liver function tests and CT scan had normal results. He had been medicated with lorazepam and mirtazapine but abandoned medication 2 weeks after the suicide attempt. He denied drug use or substantial alcohol consumption.
  • Teaching NeuroImages: Interferon-induced psoriasis flare in a multiple sclerosis case remits with dimethyl fumarate
    A 26-year-old woman with a history of psoriasis diagnosed with relapsing-remitting multiple sclerosis (Expanded Disability Status Scale score 1) received SC interferon β-1a as first-line treatment. Interferon was discontinued 4 months later, following a dramatic psoriasis flare with plaques in upper and lower extremities (figure, A–C) and manifestation of Koebner phenomenon along abdominal injection sites (figure, C). Switch to oral dimethyl fumarate (DMF) resulted in complete remission within 14 months (figure, D–F), and the patient remained relapse-free for the last 3 years under DMF treatment. Our case is consistent with the association of multiple sclerosis with psoriasis1 and the overlapping efficacy of fumaric acid esters in both conditions.2
  • Teaching NeuroImages: Giant cell arteritis presenting with acute ischemic strokes due to diffuse intracranial stenoses
    A 72-year-old woman with unremarkable medical history was admitted with acute ischemic strokes (AIS) in multiple arterial distributions in anterior and posterior circulation (figure 1A and supplemental data at Neurology.org). Elevated erythrocyte sedimentation rate (98 mm/h) prompted the evaluation of superficial temporal arteries (STA) with duplex sonography (halo sign; figure 1B) and contrast angiography (right STA [figure 2A] and multiple intracranial arterial stenoses [figure 2, A–D]). STA biopsy confirmed the diagnosis of giant cell arteritis (GCA; figure 1, C and D).
  • Teaching NeuroImages: Spinocerebellar ataxia type 3 presenting with a cock-walk gait phenotype
    A 22-year-old woman presented with a 4-year history of progressive gait disturbance and slurred speech. Examination disclosed ataxia, nystagmus, pyramidal signs, bradykinesia, and feet dystonia with a cock-walk gait pattern (video at Neurology.org). There was no weakness of ankle dorsiflexion or plantar flexion. Family history was remarkable for ataxia. MRI showed mild pontocerebellar atrophy (figure). Genetic testing confirmed spinocerebellar ataxia type 3 (SCA3; 34/77 alleles). There were poor responses to levodopa, anticholinergic drugs, and botulinum toxin.
  • Spotlight on the October 10 issue
  • Some light in the shadows of atrial fibrillation and stroke: To look or not to look
    In ischemic stroke, the diagnostic workup determines the best preventive strategy. However, cryptogenic stroke accounts for about 20%–40% of all strokes.1 For these patients, the best preventive treatment remains unknown, and most guidelines recommend risk factor modification and antiplatelet therapy. Given the substantial recurrence rate for cryptogenic stroke, this is not a comfortable situation: just try to tell your stroke patients, "After all these tests, I do not have any clue why you had a stroke"; and about the treatment, "Just take an aspirin and cross fingers you do not have another one."
  • Preventing multiple sclerosis: To (take) vitamin D or not to (take) vitamin D?
    Over 2 million persons worldwide have multiple sclerosis (MS),1 and the burden of the disease for affected individuals and society is substantial. A recent study estimated that by 2031, 133,635 Canadians would be living with MS, and that the direct costs of their care would reach a staggering $2 billion annually.2 Therefore, identifying modifiable risk factors for MS remains vitally important. Researchers still seek to firmly demonstrate a causal role for vitamin D, a biologically plausible etiologic factor which is modifiable. Vitamin D receptors are ubiquitous, being expressed on immune cells and in the CNS; immune responses are affected by variations in 25-hydroxyvitamin D (25[OH]D) levels; and 1,25-dihydroxycholecaliferol can prevent the emergence of experimental autoimmune encephalomyelitis,3,4 an animal model of demyelinating disease. However, epidemiologic studies have often been hindered by the inability to demonstrate temporality; that is, that the exposure to inadequate 25(OH)D occurred before the onset of MS.
  • HIV-related cognitive decline despite viral suppression and complex confounds in American women
    In this issue of Neurology®, the Women's Interagency HIV Study (WIHS)1 presents a longitudinal analysis of its American cohort. The cohort is unique because it is large and representative of contemporary women with or at risk of HIV infection the United States. The cohort is ethnically diverse, composed of a substantial number who are economically disadvantaged, and includes participants with mental health issues, including alcohol/drug use (most women report past use of alcohol and recreational drugs, and between 7% and 18% are current users). There were few differences between the women who completed and those who did not complete the study; however, each of the differing characteristics was still well represented for the participants who completed the study (Hispanic ethnicity, smoking, marijuana and efavirenz use, better adherence with combination antiretroviral therapy [cART], shorter duration of ART use, higher CD4+ T cell count).
  • Striving to improve the quality of stroke care in the USA
    Compelling evidence indicates that the organization and delivery of stroke care makes a difference in the chances of patients surviving, their level of disability, and the chances of further strokes. Most evidence-based interventions do not require expensive high-technology medicine but rather need well-organized basic care delivered by people with expertise in stroke. Yet there are many places in the world, including parts of the United States, where high-quality care cannot be guaranteed, resulting in higher than necessary levels of mortality and morbidity.
  • Franz Gerstenbrand, Dr med (1924-2017)
    Franz Gerstenbrand was born on September 6, 1924, in Hof, North Moravia. He attended elementary and high school in Nikolsburg in Südmähren. In 1942, he was in the German armed forces, and after the Second World War he studied medicine at the University of Vienna, earning a doctorate in 1950. Under Hans Hoff, the head of the Department of Neurology of the University Hospital Vienna, he finished his specialization in neurology and psychiatry. At that time, his special interests were neurotrauma, prolonged coma after severe brain damage, spinal cord injury, and the early diagnosis of brain damage in child neurology. In 1967, Gerstenbrand published an article on habilitation in the traumatic apallic syndrome that attracted worldwide attention, and was, for many years, a standard work in German-speaking neurology.
  • Relevance of supraventricular runs detected after cerebral ischemia
    Objective: Prolonged ECG monitoring after stroke frequently reveals short paroxysmal atrial fibrillation (pAF) and supraventricular (SV) runs. The minimal duration of atrial fibrillation (AF) required to induce cardioembolism, the relevance of SV runs, and whether short pAF results from cerebral damage itself are currently being debated. We aimed to study the relevance of SV runs and short pAF detected by prolonged Holter ECG after cerebral ischemia during long-term follow-up. Methods: Analysis is from the prospective Find-AF trial (ISRCTN46104198). We included patients with acute cerebral ischemia. Those without AF on admission received 7-day Holter ECG monitoring. We differentiated patients with AF on admission (AF-adm), with pAF (>30 seconds), with SV runs (>5 beats but <30 seconds in a 24-hour ECG interval), and without SV runs (controls). During follow-up, those with baseline pAF received another 7-day Holter ECG to examine AF persistence. Results: A total of 254 of 281 initially included patients were analyzed (mean age 70.0 years, 45.3% female). Forty-three (16.9%) had AF-adm. A total of 211 received 7-day Holter ECG monitoring: 27 (12.8%) had pAF, 67 (31.8%) had SV runs, and 117 (55.5%) were controls. During a mean 3.7 years of follow-up, the SV runs group had more recurrent strokes (p = 0.04) and showed numerically more novel AF (12% vs 5%, p = 0.09) than the controls. Seventy-five percent of the patients with manifest pAF detected after cerebral ischemia still had AF during follow-up (50% paroxysmal, 50% persisting/permanent). Conclusions: Patients with cerebral ischemia and SV runs had more recurrent strokes and numerically more novel AF during follow-up and could benefit from further prolonged ECG monitoring. pAF detected after stroke is not a temporal phenomenon.
  • CSF inflammatory response after intraventricular hemorrhage
    Objective: To investigate the temporal pattern and relevant associations of CSF inflammatory measures after intraventricular hemorrhage (IVH). Methods: We analyzed prospectively collected CSF cell counts and protein and glucose levels from participants in the Clot Lysis Evaluation of Accelerated Resolution of IVH phase III (CLEAR III) trial. Corrected leukocyte count and cell index were calculated to adjust for CSF leukocytes attributable to circulating blood. Data were chronologically plotted. CSF inflammatory measures (daily, mean, median, maximum, and cases with highest quartile response) were correlated with initial IVH volume, IVH clearance rate, thrombolytic treatment, bacterial infection, and adjudicated clinical outcome at 30 and 180 days. Results: A total of 11,376 data points of CSF results from 464 trial participants were analyzed. Measures of CSF inflammatory response evolved during the resolution of IVH. This was significantly more pronounced with initial IVH volume exceeding 20 mL. Intraventricular alteplase was associated with a significantly augmented inflammatory response compared to saline, even after correcting for initial IVH volume. There was an association but nonpredictive correlation of CSF inflammation measures with culture-positive CSF bacterial infection. None of the CSF inflammatory measures, including cases with upper quartile inflammatory response, was associated with a significant detrimental effect on 30 or 180 days functional outcome or mortality after multivariate adjustment for measures of disease severity. Conclusions: Aseptic CSF inflammation after IVH is primarily dependent on the volume of initial bleed. Thrombolysis intensifies the inflammatory response, with no apparent detrimental effect on clinical outcome. Clinicaltrials.gov identifier: NCT00784134.
  • Outcome after stroke thrombolysis in patients >80 years treated within 3 hours vs >3-4.5 hours
    Objective: To determine outcomes and risks of IV thrombolysis (IVT) in patients with acute ischemic stroke (AIS) >80 years of age within 3 hours compared to >3 to 4.5 hours recorded in the Safe Implementation of Treatment in Stroke (SITS) International Stroke Thrombolysis Registry. Methods: A total of 14,240 (year 2003–2015) patients >80 years of age with AIS were treated with IVT ≤4.5 hours of stroke onset (3,558 in >3–4.5 hours). Of these, 8,658 (2,157 in >3–4.5 hours) were treated otherwise according to the European Summary of Product Characteristics (EU SmPC) criteria for alteplase. Outcomes were 3-month functional independence (modified Rankin Scale score 0–2), mortality, and symptomatic intracerebral hemorrhage (SICH)/SITS. Results were compared between the groups treated in >3 to 4.5 and ≤3 hours. Results: Median age was 84 years; 61% were female in both groups. Median NIH Stroke Scale score was 12 vs 14 in the >3- to 4.5- and ≤3-hour group, respectively. Three-month functional independence was 34% vs 35% (adjusted odds ratio [aOR] 0.78, 95% confidence interval [CI] 0.69–0.89, p < 0.001); mortality was 31% vs 32% (aOR 1.10, 95% CI 0.97–1.25, p = 0.13); and SICH/SITS was 2.7% vs 1.6% (aOR 1.72, 95% CI 1.25–2.35, p = 0.001). In EU SmPC–compliant patients, 3-month functional independence was 36 vs 37% (aOR 0.79, 95% CI 0.68–0.92, p = 0.002), mortality was 29% vs 29.6% (aOR 1.10, 95% CI 0.95–1.28, p = 0.20), and SICH/SITS was 2.7% vs 1.6% (aOR 1.62, 95% CI 1.12–2.34, p = 0.01). Conclusions: In this observational study, unselected patients >80 years of age treated with IVT after 3 hours vs earlier had a slightly higher rate of SICH and similar unadjusted functional outcome but poorer adjusted outcome. The absolute difference between the treatment groups is small, and elderly patients should not be denied IVT in the later time window solely because of age without other contraindications.
  • Nonlinear temporal dynamics of cerebral small vessel disease: The RUN DMC study
    Objective: To investigate the temporal dynamics of cerebral small vessel disease (SVD) by 3 consecutive assessments over a period of 9 years, distinguishing progression from regression. Methods: Changes in SVD markers of 276 participants of the Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Imaging Cohort (RUN DMC) cohort were assessed at 3 time points over 9 years. We assessed white matter hyperintensities (WMH) volume by semiautomatic segmentation and rated lacunes and microbleeds manually. We categorized baseline WMH severity as mild, moderate, or severe according to the modified Fazekas scale. We performed mixed-effects regression analysis including a quadratic term for increasing age. Results: Mean WMH progression over 9 years was 4.7 mL (0.54 mL/y; interquartile range 0.95–5.5 mL), 20.3% of patients had incident lacunes (2.3%/y), and 18.9% had incident microbleeds (2.2%/y). WMH volume declined in 9.4% of the participants during the first follow-up interval, but only for 1 participant (0.4%) throughout the whole follow-up. Lacunes disappeared in 3.6% and microbleeds in 5.7% of the participants. WMH progression accelerated over time: including a quadratic term for increasing age during follow-up significantly improved the model (p < 0.001). SVD progression was predominantly seen in participants with moderate to severe WMH at baseline compared to those with mild WMH (odds ratio [OR] 35.5, 95% confidence interval [CI] 15.8–80.0, p < 0.001 for WMH progression; OR 5.7, 95% CI 2.8–11.2, p < 0.001 for incident lacunes; and OR 2.9, 95% CI 1.4–5.9, p = 0.003 for incident microbleeds). Conclusions: SVD progression is nonlinear, accelerating over time, and a highly dynamic process, with progression interrupted by reduction in some, in a population that on average shows progression.
  • 25-Hydroxyvitamin D deficiency and risk of MS among women in the Finnish Maternity Cohort
    Objective: To determine whether and to what extent vitamin D deficiency is associated with multiple sclerosis (MS) risk. Methods: We conducted a prospective nested case-control study among women in the Finnish Maternity Cohort (FMC). The FMC had 1.8 million stored serum samples taken during the pregnancies of over 800,000 women at the time of this study. Through linkages with hospital and prescription registries, we identified 1,092 women with MS diagnosed between 1983 and 2009 with at least 1 serum sample collected prior to date of MS diagnosis; ≥2 serum samples were available for 511 cases. Cases were matched to up to 3 controls (n = 2,123) on date of birth (±2 years) and area of residence. 25-Hydroxyvitamin D (25[OH]D) levels were measured using a chemiluminescence assay. We used conditional logistic regression adjusted for year of sample collection, gravidity, and parity to estimate relative risks (RRs) and 95% confidence intervals (CIs). Results: A 50 nmol/L increase in 25(OH)D was associated with a 39% reduced risk of MS (RR 0.61, 95% CI 0.44–0.85), p = 0.003. Women with 25(OH)D levels <30 nmol/L had a 43% higher MS risk (RR 1.43, 95% CI 1.02–1.99, p = 0.04) as compared to women with levels ≥50 nmol/L. In women with ≥2 samples, MS risk was 2-fold higher in women with 25(OH)D <30 nmol/L as compared to women with 25(OH)D ≥50 nmol/L (RR 2.02, 95% CI 1.18–3.45, p = 0.01). Conclusions: These results directly support vitamin D deficiency as a risk factor for MS and strengthen the rationale for broad public health interventions to improve vitamin D levels.
  • Reversibility of the effects of natalizumab on peripheral immune cell dynamics in MS patients
    Objective: To characterize the reversibility of natalizumab-mediated changes in pharmacokinetics/pharmacodynamics in patients with multiple sclerosis (MS) following therapy interruption. Methods: Pharmacokinetic/pharmacodynamic data were collected in the Safety and Efficacy of Natalizumab in the Treatment of Multiple Sclerosis (AFFIRM) (every 12 weeks for 116 weeks) and Randomized Treatment Interruption of Natalizumab (RESTORE) (every 4 weeks for 28 weeks) studies. Serum natalizumab and soluble vascular cell adhesion molecule–1 (sVCAM-1) were measured using immunoassays. Lymphocyte subsets, α4-integrin expression/saturation, and vascular cell adhesion molecule–1 (VCAM-1) binding were assessed using flow cytometry. Results: Blood lymphocyte counts (cells/L) in natalizumab-treated patients increased from 2.1 x 109 to 3.5 x 109. Starting 8 weeks post last natalizumab dose, lymphocyte counts became significantly lower in patients interrupting treatment than in those continuing treatment (3.1 x 109 vs 3.5 x 109; p = 0.031), plateauing at prenatalizumab levels from week 16 onward. All measured cell subpopulation, α4-integrin expression/saturation, and sVCAM changes demonstrated similar reversibility. Lymphocyte counts remained within the normal range. Ex vivo VCAM-1 binding to lymphocytes increased until 16 weeks after the last natalizumab dose, then plateaued, suggesting reversibility of immune cell functionality. The temporal appearance of gadolinium-enhancing lesions was consistent with pharmacodynamic marker reversal. Conclusions: Natalizumab's effects on peripheral immune cells and pharmacodynamic markers were reversible, with changes starting 8 weeks post last natalizumab dose; levels returned to those observed/expected in untreated patients 16 weeks post last dose. This reversibility differentiates natalizumab from MS treatments that require longer reconstitution times. Characterization of the time course of natalizumab's biological effects may help clinicians make treatment sequencing decisions. Classification of evidence: This study provides Class III evidence that the pharmacodynamic markers of natalizumab are reversed 16 weeks after stopping natalizumab.
  • Cognitive trajectories over 4 years among HIV-infected women with optimal viral suppression
    Objective: To determine whether persistent viral suppression alters cognitive trajectories among HIV-infected (HIV+) women on combination antiretroviral therapy (cART) by investigating performance longitudinally in uninfected (HIV–) and 3 groups of HIV+ women: those with consistent viral suppression after continuous cART use (VS), those without consistent virologic suppression despite continuous cART use (NVS), and those without consistent virologic suppression after intermittent cART use (Int NVS). Methods: Two hundred thirty-nine VS, 220 NVS, 172 Int NVS, and 301 HIV– women from the Women's Interagency HIV Study (WIHS) completed neuropsychological testing every 2 years for 3 visits between 2009 and 2013. Mixed-effects regressions were used to examine group differences on continuous T scores and categorical measures of impairment (T score <40). Results: On global function, VS women demonstrated lower scores and were more likely to score in the impaired range than HIV– women (p = 0.01). These differences persisted over time (group x time, p > 0.39). VS women demonstrated lower learning and memory scores than HIV– women (p < 0.05) and lower attention/working memory and fluency scores than HIV– and NVS women (p < 0.05). Group differences in scores persisted over time. Categorically, VS women were more likely to be impaired on attention/working memory and executive function than HIV– women (p < 0.05). On motor skills, VS and NVS women showed a greater decline and were more likely to be impaired than HIV– women (p < 0.05). Conclusions: Cognitive difficulties remain among HIV+ women despite persistent viral suppression. In some instances, VS women are worse than NVS women, reinforcing the need for novel adjunctive therapies to attenuate cognitive problems.
  • Optical coherence tomography identifies outer retina thinning in frontotemporal degeneration
    Objective: Whereas Alzheimer disease (AD) is associated with inner retina thinning visualized by spectral-domain optical coherence tomography (SD-OCT), we sought to determine if the retina has a distinguishing biomarker for frontotemporal degeneration (FTD). Methods: Using a cross-sectional design, we examined retinal structure in 38 consecutively enrolled patients with FTD and 44 controls using a standard SD-OCT protocol. Retinal layers were segmented with the Iowa Reference Algorithm. Subgroups of highly predictive molecular pathology (tauopathy, TAR DNA–binding protein 43, unknown) were determined by clinical criteria, genetic markers, and a CSF biomarker (total tau: β-amyloid) to exclude presumed AD. We excluded eyes with poor image quality or confounding diseases. SD-OCT measures of patients (n = 46 eyes) and controls (n = 69 eyes) were compared using a generalized linear model accounting for intereye correlation, and correlations between retinal layer thicknesses and Mini-Mental State Examination (MMSE) were evaluated. Results: Adjusting for age, sex, and race, patients with FTD had a thinner outer retina than controls (132 vs 142 μm, p = 0.004). Patients with FTD also had a thinner outer nuclear layer (ONL) (88.5 vs 97.9 μm, p = 0.003) and ellipsoid zone (EZ) (14.5 vs 15.1 μm, p = 0.009) than controls, but had similar thicknesses for inner retinal layers. The outer retina thickness of patients correlated with MMSE (Spearman r = 0.44, p = 0.03). The highly predictive tauopathy subgroup (n = 31 eyes) also had a thinner ONL (88.7 vs 97.4 μm, p = 0.01) and EZ (14.4 vs 15.1 μm, p = 0.01) than controls. Conclusions: FTD is associated with outer retina thinning, and this thinning correlates with disease severity.
  • REM sleep behavior disorder is related to enteric neuropathology in Parkinson disease
    Objective: To determine whether REM sleep behavior disorder (RBD) in Parkinson disease (PD) is associated with lesions and dysfunctions of the autonomic nervous system by evaluating enteric phosphorylated α-synuclein histopathology (PASH) and permeability. Methods: A total of 45 patients with PD were included in this cross-sectional study. RBD was diagnosed on the basis of a standardized clinical interview and confirmed by polysomnography. For each patient, 5 biopsies were taken at the junction between the sigmoid and descending colon during the course of a rectosigmoidoscopy. For the detection of enteric PASH, 2 colonic biopsies were analyzed by immunohistochemistry with antibodies against phosphorylated α-synuclein and PGP9.5 in 43 patients (2 patients were excluded because only 1 biopsy was available). The paracellular permeability and transcellular permeability were evaluated by measuring sulfonic acid and horseradish peroxidase flux, respectively, in the 3 remaining biopsies mounted in Ussing chambers. Results: Enteric PASH was more frequent in the subgroup of patients with PD with RBD compared to patients without RBD (18 of 28, 64.3%, vs 2 of 15, 13.3%, respectively, p < 0.01). No differences were observed in intestinal permeability between patients with PD with and without RBD. Conclusions: Patients with PD and RBD have a greater frequency of synuclein pathology in the enteric nervous system, suggesting that RBD is associated with widespread synuclein neuropathology.
  • Quality improvement in neurology: Stroke and Stroke Rehabilitation Quality Measurement Set update
    Stroke is the fifth leading cause of death in the United States and the second leading cause of disability worldwide.1,2 "On average, every 40 seconds, someone in the United States has a stroke, and someone dies of one approximately every 4 minutes."3 Each year, nearly 800,000 people experience stroke, with up to 185,000 experiencing recurrent stroke events.3 Strokes occur at any age, and risk increases with age.4 Nearly half of older stroke survivors experience moderate to severe disability.5
  • Giuliano Vanghetti and the innovation of "cineplastic operations"
    Objective: Developing functional artificial limbs for amputees has been a centuries-old challenge in medicine. We review the mechanical and neurologic principles of "cineplastic operations" and "plastic motors" used to restore movements in prostheses, with special attention to the work of Giuliano Vanghetti. Methods: We evaluated original publications describing cineplastic operations, biographic information, writings, drawings, and unpublished letters from the Vanghetti library, preserved in Empoli, Italy, and performed a bibliographic search and comparison for similar procedures in the literature. Results: Vanghetti's method for cineplastic operations differs from similar previous methods, being the first aimed at exploiting natural movements of the remnant muscles to activate the mechanical prosthesis, and the first to do so by directly connecting the prosthesis to the residual muscles and tendons. This represented a frame-changing innovation for that time and paved the way for current neuroprosthetic approaches. The first description of the method was published in 1898 and human studies started in 1900. The results of these studies were presented in 1905 and published in 1906 in Plastic and Kinematic Prosthesis. A German surgeon, Ferdinand Sauerbruch, often acknowledged as the inventor of the method, published his first results in 1915. Conclusions: Vanghetti was the first to accurately perform and describe cineplastic operations for patients following an upper arm amputation. He considered the neurologic implications of the problem and, perhaps in an effort to provide more appropriate proprioceptive feedback, he intuitively applied the prostheses so that they were functionally activated by the muscles of the proximal stump.
  • Sex differences in the prevalence of genetic mutations in FTD and ALS: A meta-analysis
    Objective: To conduct a meta-analysis that investigates sex differences in the prevalence of mutations in the 3 most common genes that cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)—chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN), or microtubule-associated protein tau (MAPT)—in patients clinically diagnosed with these conditions. Methods: MEDLINE, EMBASE, and PsycINFO databases were searched (inception to June 30, 2016). Studies of patients with FTD or ALS that reported the number of men and women with and without mutations of interest were selected. Female to male pooled risk ratios (RR) and 95% confidence intervals (CI) for each mutation were calculated using random-effects models. Results: Thirty-two articles reporting 12,784 patients with ALS (including 1,244 C9orf72 mutation carriers) revealed a higher prevalence of female patients with C9orf72-related ALS (RR 1.16, 95% CI 1.04–1.29). Twenty-three articles reporting 5,320 patients with FTD (including 488 C9orf72 mutation carriers) revealed no sex differences in C9orf72-related FTD (RR 0.95, 95% CI 0.81–1.12). Thirty-six articles reporting 3,857 patients with FTD (including 369 GRN mutation carriers) revealed a higher prevalence of female patients with GRN-related FTD (RR 1.33, 95% CI 1.09–1.62). Finally, 21 articles reporting 2,377 patients with FTD (including 215 MAPT mutation carriers) revealed no sex difference in MAPT-related FTD (RR 1.21, 95% CI 0.95–1.55). Conclusions: Higher female prevalence of C9orf72 hexanucleotide repeat expansions in ALS and GRN mutations in FTD suggest that sex-related risk factors might moderate C9orf72 and GRN-mediated phenotypic expression.
  • Swallowing-induced displacement of the carotid artery as a risk of stroke: Flip-flop phenomenon
    A 70-year-old man without cerebrovascular risk factors was admitted to our hospital with amaurosis fugax of the right eye. Diffusion MRI showed an acute asymptomatic brain infarct in the right frontal lobe cortex, and carotid duplex ultrasound revealed movement of the right internal carotid artery (ICA), with a hypoechoic plaque at its origin, in contact with the hyoid bone during head rotation and swallowing (figure).
  • Job negotiation
    There are many who will find this poem Difficult to understand. And many who, thank God, Will not.
  • TIPIC syndrome
    A 31-year-old woman presented with left acute cervical pain. Cervical imaging showed a large pericarotid infiltration (figure 1). A diagnosis of transient perivascular inflammation of the carotid artery (TIPIC) syndrome was made. The patient received steroids with full clinical recovery 12 days after onset. The follow-up ultrasound showed striking decrease of the perivascular infiltration, confirming the diagnosis (figure 2).
  • Editors' Note
    Editors' Note: In a survey of US American Academy of Neurology member neurologists who had finished training, Busis et al. found that approximately 60% had at least one symptom of burnout. Burnout was strongly associated with decreased career satisfaction, while meaningful work and job autonomy were associated with increased satisfaction.
  • Letter re: Burnout, career satisfaction, and well-being among US neurologists in 2016
    From a recent workforce survey, Busis et al.1 reported that 63% of neurologists in clinical practice had at least one symptom of burnout. Burnout and percentage of clinical practice time were associated with decreased professional satisfaction. However, meaningful work and job autonomy were associated with increased satisfaction.
  • Letter re: Burnout, career satisfaction, and well-being among US neurologists in 2016
    Busis et al.1 investigated the prevalence and factors that contribute to burnout, career satisfaction, and well-being in US neurologists. Within the last decade, there has been growing interest in considering factors defined at multiple levels in psychological and health research; multilevel analysis emerged as a way to partly address this need by allowing simultaneous examination of group-level and individual-level factors.2 Given that doctors do not live in a social vacuum, without emotional, cognitive, and behavioral influences, but are active members of working groups with lead roles in health care organizations, a shift of methodology was proposed: multilevel analyses, when applied in burnout research, examine data from people in different groups but working in the same organization, and examine how they influence each other emotionally, by treating obtained data from the subordinates group as nested within actual data from their leaders.3,4 The choice of binary logistic regressions with only individual-level variables neglects the influence of other important variables on emotions and, thus, is restrictive.4 This is evident in findings that support that specific personality-related characteristics of doctors in charge of a hospital clinic predict better burnout than other demographic or individual-level variables.5
  • Letter re: Burnout, career satisfaction, and well-being among US neurologists in 2016
    I heard the excellent Presidential Plenary Address by Dr. Terrence Cascino at the 2017 American Academy of Neurology (AAN) meeting. The focus of the AAN on this issue, especially early retirement, is to be applauded, but the emphasis on work–life balance and yoga is misplaced. The term burnout is demeaning to our colleagues.
  • Letter re: Burnout, career satisfaction, and well-being among US neurologists in 2016
    The study by Busis et al.1 of 1,671 US neurologist survey respondents revealed that burnout was common among all neurology practice settings and subspecialties. During Dr. Cascino's 2017 Presidential Plenary Address, he presented a figure from a larger survey of US physicians in general that correlated the percentage of physicians with burnout identified by specialty with the percentage satisfied with their work–life balance.2 This graph seemed to indicate that neurology was among the specialties with the greatest degree of burnout and the least satisfaction with work–life balance.2
  • Letter re: Burnout, career satisfaction, and well-being among US neurologists in 2016
    I read with interest the article on burnout among US neurologists.1 There are 2 additional factors contributing to burnout that the authors fail to address. One is the electronization of medicine. Electronization is a term used to describe the process of taking an item or process from paper-based form and electronically producing it, mainly to increase profitability and efficiency. We now have electronic health records (EHR) available on laptop, iPad, and cell phone. Patients can email physicians through the myconnect portal on the EHR, contact physicians through work email, or, in some instances, text physicians on cell phones. Frequently, these calls and emails are for nonemergency reasons, but since we are always connected, we are obligated to answer. One leaves the office or the hospital, but does not leave work behind. We are always on call. Doctors lost their right and battle to disconnect. Second, the authors mention the importance of implementing physician-friendly national policies that decrease regulatory burden but do not discuss the burden and stress on physicians caused by ever-increasing mandatory continuing medical education requirements and maintenance of certification requirements.
  • Author response: Burnout, career satisfaction, and well-being among US neurologists in 2016
    We thank Bagot et al. for their comments. Burnout, career satisfaction, and well-being in neurologists who practice telemedicine is important to study as this practice model becomes more common.
  • Increased brain-predicted aging in treated HIV disease
  • Teaching NeuroImages: Figure of 8: The clue to the diagnosis of AMPD2 pontocerebellar hypoplasia (PCH9)
    A 2-year-old girl, born after uneventful pregnancy from healthy nonconsanguineous parents, presented with failure to thrive, microcephaly, facial dysmorphism, strabismus, nystagmus, axial hypotonia, lower limb spasticity/hyperreflexia, dystonic movements, and no active postures. Since the first months of life, developmental delay without any motor skills acquisition, drug-resistant epilepsy, and progressive spasticity had emerged. Neuroimaging revealed pontocerebellar hypoplasia with the figure of 8 midbrain appearance (figure), a distinctive sign for PCH8 or AMPD2 deficiency.1,2 Sanger sequencing of the adenosine monophosphate deaminase 2 enzyme gene (AMPD2) revealed the first compound heterozygous mutation (c.1664C>T; c.1112+1 G>A). The patient died at age 3 years due to respiratory insufficiency.
  • Teaching NeuroImages: Rare cause of Horner syndrome in Loeys-Dietz syndrome
    A 36-year-old woman with Loeys-Dietz syndrome presented with left eye ptosis, anisocoria, and shoulder pain. The diagnosis of left-sided Horner syndrome was made (figure 1). The patient had a known left subclavian artery aneurysm with percutaneous stent graft placement. CT angiography revealed a large left subclavian aneurysm sac, consistent with endoleak type I (figure 2). Horner syndrome and shoulder pain improved following common carotid to axillary artery bypass in addition to thoracic endovascular aortic repair surgery.
  • Teaching NeuroImages: Typical neuroimaging features in high-altitude cerebral edema
    A 61-year-old man presented with thunderclap headache followed by loss of consciousness, 2 days after arriving in Atacama Desert, Andes Mountains, Chile, at 4,000 meters. Examination showed coma. Mechanical ventilation was necessary. He had progressive improvement after transfer to low altitudes. Brain MRI showed diffuse vasogenic edema and microhemorrhages (figure), and high-altitude cerebral edema (HACE) was diagnosed.
  • Teaching Video NeuroImages: Spastic ataxia syndrome: The Friedreich-like phenotype of ARSACS
    A 24-year-old Chilean man with slowly progressive ataxia since age 2 presented with spastic ataxia, hyperreflexia, pes cavus, axonal polyneuropathy, incomplete right-bundle branch block on ECG, and impaired glucose tolerance test, suggesting Friedreich ataxia (figure; video at Neurology.org). However, the combination of hyperreflexia and cerebellar (rather than cervical cord) atrophy with T2-weighted linear hypointensity in the pons on brain MRI suggested autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). Biallelic mutations were found (c.4492C>T p.[R1498X] and c.2388dupA p.[L797Ifs*4]) in the SACS gene (NCBI sequence NM_001278055). ARSACS is the second most common cause of autosomal recessive spastic ataxia syndrome (SACS mutations account for 37% of Friedreich-negative cases)1 and should be considered in any population with suggestive MRI abnormalities.2
  • Teaching Video NeuroImages: Palsy of conjugate horizontal gaze and face due to isolated abducens nuclear infarction
    A 58-year-old woman presented leftward conjugate gaze palsy and left facial nerve palsy of a peripheral pattern due to acute infarction restricted to the area of left abducens nucleus (figure, A–C; video at Neurology.org).
  • Spotlight on the October 3 issue
  • Biomarkers for early detection of Parkinson disease: A scent of consistency with olfactory dysfunction
    There are approximately 1,000 genes involved in odor recognition and 347 that code for functional receptors. This enables our distinguishing of approximately 4,000–10,000 distinct odorous ligands, a scientific discovery that earned a Nobel Prize in 2004.1 The olfactory nerve (CN1) contains 6–10 million receptor cells whose ciliated dendrites and cell bodies are contained within a specialized (neuro)epithelium located within the posterior nasal cavity (figure).2 These olfactory receptor cells are interspersed with sustentacular cells for stability of the epithelium and basal cells (stem cells) that provide a regenerative capacity. Also in residence are the Bowman glands, which secrete and maintain the mucous layer upon the cilia that float just beneath the (neuro)epithelium. This mucous contains several proteins that may help metabolize xenobiotics and support epithelial integrity (e.g., mucin, lysozyme, amylase, immunoglobulin G).2 Once an odorant enters the nose, it interacts with the receptors located on the surface of the olfactory cilia and a chemical signature generates a crescendo of action potentials in the olfactory neuron axon (figure). These project to higher brain regions involved in conscious thought processes and the limbic system, generating the emotional, motivational, and memory context.3 Olfactory dysfunction presenting as hyposmia impairs the satisfaction gained from foods and inhibits the detection of environmental hazards (e.g., toxins, fire, spoiled foods, and natural gas leaks). Diminished olfactory inputs also dampen the neural/cephalic phase of digestion responsible for stimulating exocrine secretions in the mouth (e.g., amylase), stomach (e.g., hydrochloric acid, digestive enzymes), and small intestine (e.g., lipase).4,5 These secretions facilitate the absorption and assimilation of micronutrients and fatty acids and contribute to the nature of the microbiome in the host by governing the gut pH.6
  • The yin and yang of gastrostomy in the management of ALS: Friend or foe?
    Though we do not yet have a cure for amyotrophic lateral sclerosis (ALS), we can provide treatment, and the host of medical and other interventions provided by ALS specialists and multidisciplinary care teams increases survival and substantially improves quality of life for patients and their families. Dysphagia is one of the most consequential symptoms in ALS, and ultimately affects the majority of patients. It causes dehydration, weight loss, choking, and chronic aspiration, which substantially increase the risk of potentially fatal aspiration pneumonia. Weight loss alone worsens progression and survival in ALS,1 presumably because caloric deficit due to dysphagia promotes muscle catabolism, adding to underlying muscle loss from motor neuron death, thereby accelerating weakness and decline. In attempts to circumvent this cascade, enteral tube feeding has been used in the management of ALS for many years, principally via percutaneous endoscopic gastrostomy (PEG).2 However, gastrostomy tube placement can be hazardous in advanced cases, as impaired respiratory function may increase the risk of respiratory arrest during sedation, as well as ventilator dependence postoperatively. Consequently, gastrostomy tubes are typically only recommended for those patients having forced vital capacity (FVC) >50% of the predicted normal value.3,4
  • Amyloid-PET in cerebral amyloid angiopathy: Detecting vascular amyloid deposits, not just blood
    Sporadic cerebral amyloid angiopathy (CAA) is a common age-related cerebral small vessel disease characterized by progressive deposition of amyloidal protein made up of (with rare exception) amyloid-β (Aβ) in the media and adventitia of cortical and leptomeningeal vessels.1 Lobar intracerebral hemorrhage (ICH) represents a late, often devastating manifestation of the disease, leading to high mortality, poor functional outcome, and dementia. Definite CAA diagnosis requires a full postmortem neuropathologic examination. However, brain MRI can help to diagnose CAA during life by detecting hemorrhagic lesions such as lobar cerebral microbleeds and cortical superficial siderosis. The modified Boston criteria include these MRI hemorrhagic markers and show a sensitivity of 95% and a specificity of 82% for probable CAA diagnosis.2 These hemorrhagic lesions may represent late and irreversible steps in the pathways leading from vascular dysfunction to brain injury. In vivo detection of vascular amyloidal protein might help early diagnosis of CAA.
  • Sickle cell disease and the unmet challenges of neurologic complications
    Sometimes an important scientific report is more notable for what it cannot tell us than for what it can. In this issue of Neurology®, Noubiap and colleagues1 provide a comprehensive, well-conducted systematic meta-analysis of the neurologic complications of sickle cell disease (SCD) that incorporates rigorous design and advanced analytic methods to delineate in substantial detail what is known about the prevalence of neurologic injury among people with SCD in Africa—where over half the world's population of people with SCD reside. As one might expect, based upon what is known from more medically developed regions of the world, stroke, seizures, and headache are common. Data within the African meta-analysis offer some insights into why the stroke prevalence rates identified are more similar to populations from advanced medical settings than expected, given the lack of universal availability of the 2 best tried and proven modalities of both primary and secondary stroke prevention—adequate maintenance of low sickle cell hemoglobin levels through regular transfusion and hydroxyurea in resource-impoverished areas of Africa.
  • Olfaction and incident Parkinson disease in US white and black older adults
    Objective: To investigate olfaction in relation to incident Parkinson disease (PD) in US white and black older adults. Methods: The study included 1,510 white (mean age 75.6 years) and 952 black (75.4 years) participants of the Health, Aging, and Body Composition study. We evaluated the olfaction of study participants with the Brief Smell Identification Test (BSIT) in 1999–2000. We retrospectively adjudicated PD cases identified through August 31, 2012, using multiple data sources. We used multivariable Cox models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: During an average of 9.8 years of follow-up, we identified a total of 42 incident PD cases, including 30 white and 12 black participants. Overall, poor sense of smell, as indicated by a lower BSIT score, was associated with higher risk of PD. Compared with the highest tertile of BSIT (t3), the HR was 1.3 (95% CI 0.5–3.6) for the second tertile (t2) and 4.8 (95% CI 2.0–11.2) for the lowest tertile (t1) (ptrend < 0.00001). Further analyses revealed significant associations for incident PD in both the first 5 years of follow-up (HRt1/[t2+t3] 4.2, 95% CI 1.7–10.8) and thereafter (HRt1/[t2+t3] 4.1, 95% CI 1.7–9.8). This association appeared to be stronger in white (HRt1/[t2+t3] 4.9, 95% CI 2.3–10.5) than in black participants (HRt1/[t2+t3] 2.5, 95% CI 0.8–8.1), and in men (HRt1/[t2+t3] 5.4, 95% CI 2.3–12.9) than in women (HRt1/[t2+t3] 2.9, 95% CI 1.1–7.8). Conclusions: Poor olfaction predicts PD in short and intermediate terms; the possibility of stronger associations among men and white participants warrants further investigation.
  • A predictive model to identify Parkinson disease from administrative claims data
    Objective: To use administrative medical claims data to identify patients with incident Parkinson disease (PD) prior to diagnosis. Methods: Using a population-based case-control study of incident PD in 2009 among Medicare beneficiaries aged 66–90 years (89,790 cases, 118,095 controls) and the elastic net algorithm, we developed a cross-validated model for predicting PD using only demographic data and 2004–2009 Medicare claims data. We then compared this model to more basic models containing only demographic data and diagnosis codes for constipation, taste/smell disturbance, and REM sleep behavior disorder, using each model's receiver operator characteristic area under the curve (AUC). Results: We observed all established associations between PD and age, sex, race/ethnicity, tobacco smoking, and the above medical conditions. A model with those predictors had an AUC of only 0.670 (95% confidence interval [CI] 0.668–0.673). In contrast, the AUC for a predictive model with 536 diagnosis and procedure codes was 0.857 (95% CI 0.855–0.859). At the optimal cut point, sensitivity was 73.5% and specificity was 83.2%. Conclusions: Using only demographic data and selected diagnosis and procedure codes readily available in administrative claims data, it is possible to identify individuals with a high probability of eventually being diagnosed with PD.
  • Polycystic kidney disease is significantly associated with dementia risk
    Objective: Data on the risk of neurodegenerative diseases, including Alzheimer disease (AD) and Parkinson disease (PD), in patients with polycystic kidney disease (PKD) are lacking. Methods: A total of 4,229 patients who were aged ≥20 years and had received a diagnosis of PKD were included in the PKD cohort. For each PKD case identified, 1 participant aged ≥20 years without a history of PKD, dementia, or PD was selected from the comparison cohort. For each patient with PKD, the corresponding controls were selected 1:1 on the basis of the nearest propensity score calculated using logistic regression. Results: The incidence density rates of dementia were 4.31 and 2.50 per 1,000 person-years in the PKD and control cohorts, respectively. A 2.04-fold higher risk of dementia was observed in patients with PKD than in controls (adjusted hazard ratio [aHR] 2.04; 95% confidence interval [CI] 1.46–2.85). Regarding the risk of different dementia subtypes, including AD and vascular dementia (VaD), the aHR for AD and presenile dementia was 2.71 (95% CI 1.08–6.75) and that for VaD was 0.90 (95% CI 0.43–1.87) in patients with PKD compared with controls, after adjustment for age, sex, and comorbidities. Compared with controls, the risk of PD increased by 1.78-fold (95% CI 1.14–2.79) in patients with PKD. Conclusions: In clinical practice, health care professionals should be aware of the risk of neurodegenerative diseases in patients with PKD.
  • Subjective memory complaints in preclinical autosomal dominant Alzheimer disease
    Objective: To cross-sectionally study subjective memory complaints (SMC) in autosomal dominant Alzheimer disease (ADAD). Methods: We examined self-reported and study partner–based SMC in 52 young, cognitively unimpaired individuals from a Colombian kindred with early-onset ADAD. Twenty-six carried the PSEN-1 E280A mutation, averaging 7 years of age younger than the kindred's expected clinical onset. Twenty-six were age-matched noncarriers. Participants also underwent structural MRI and cognitive testing. Results: Self-reported SMC were greater in carriers than noncarriers (p = 0.02). Study partner–based SMC did not differ between groups (p = 0.21), but in carriers increased with age (r = 0.66, p < 0.001) and decreased with hippocampal volume (r = –0.35, p = 0.08). Conclusions: Cognitively unimpaired PSEN-1 carriers have elevated SMC. Self-reported SMC may be a relatively early indicator of preclinical AD, while partner- reported SMC increases later in preclinical AD, closer to clinical onset.
  • Antibody-associated CNS syndromes without signs of inflammation in the elderly
    Objective: To report the CNS syndromes of patients ≥60 years of age with antibodies against neuronal surface antigens but no evidence of brain MRI and CSF inflammatory changes. Methods: This was a retrospective clinical analysis of patients with antibodies against neuronal surface antigens who fulfilled 3 criteria: age ≥60 years, no inflammatory abnormalities in brain MRI, and no CSF pleocytosis. Antibodies were determined with reported techniques. Results: Among 155 patients ≥60 years of age with neurologic syndromes related to antibodies against neuronal surface antigens, 35 (22.6%) fulfilled the indicated criteria. The median age of these 35 patients was 68 years (range 60–88 years). Clinical manifestations included faciobrachial dystonic seizures (FBDS) in 11 of 35 (31.4%) patients, all with LGI1 antibodies; a combination of gait instability, brainstem dysfunction, and sleep disorder associated with IgLON5 antibodies in 10 (28.6%); acute confusion, memory loss, and behavioral changes suggesting autoimmune encephalitis (AE) in 9 (25.7%; 2 patients with AMPAR, 2 with NMDAR, 2 with GABAbR, 2 with LGI1, and 1 with CASPR2 antibodies); and rapidly progressive cognitive deterioration in 5 (14.3%; 3 patients with IgLON5 antibodies, 1 with chorea; 1 with DPPX antibody–associated cerebellar ataxia and arm rigidity; and 1 with CASPR2 antibodies). Conclusions: In patients ≥60 years of age, the correct identification of characteristic CNS syndromes (FBDS, anti-IgLON5 syndrome, AE) should prompt antibody testing even without evidence of inflammation in MRI and CSF studies. Up to 15% of the patients developed rapidly progressive cognitive deterioration, which further complicated the differential diagnosis with a neurodegenerative disorder.
  • Long-term risk of seizures in adult survivors of sepsis
    Objective: To examine the association between sepsis and the long-term risk of seizures. Methods: We conducted a retrospective population-based cohort study using administrative claims data from all emergency department visits and hospitalizations at nonfederal acute care hospitals in California, Florida, and New York from 2005 to 2013. Using previously validated diagnosis codes, we identified all adult patients hospitalized with sepsis. Our outcome was any emergency department visit or hospitalization for seizure. Poisson regression and demographic data were used to calculate age-, sex-, and race-standardized incidence rate ratios (IRR). To confirm our findings, we used a matched cohort of hospitalized patients without sepsis for comparison and additionally assessed claims data from a nationally representative 5% sample of Medicare beneficiaries. Results: We identified 842,735 patients with sepsis. The annual incidence of seizure was 1.29% (95% confidence interval [CI] 1.27%–1.30%) in patients with sepsis vs 0.16% (95% CI 0.16%–0.16%) in the general population (IRR 4.98; 95% CI 4.92–5.04). A secondary analysis using matched hospitalized patients confirmed these findings (IRR 4.33; 95% CI 4.13–4.55), as did a separate analysis of Medicare beneficiaries, in whom we found a similar strength of association (IRR 2.72; 95% CI 2.60–2.83), as we did in patients ≥65 years of age in our primary statewide data (IRR 2.83; 95% CI 2.78–2.88). Conclusions: We found that survivors of sepsis faced a significantly higher long-term risk of seizures than both the general population and other hospitalized patients. Our findings suggest that sepsis is associated with pathways that lead to permanent neurologic sequelae.
  • Causal inference methods to study gastric tube use in amyotrophic lateral sclerosis
    Objective: To estimate effects of gastric tube (G-tube) on survival and quality of life (QOL) in people with amyotrophic lateral sclerosis (ALS) correcting for confounding by indication inherent in nonrandomized observational data. Methods: To complement a recent causal inference analysis, which concluded that G-tube placement increases the hazard of death, permanent assisted ventilation, or tracheostomy by 28%, we fit causal inference models on a different sample of 481 patients with ALS enrolled in a recent clinical trial of ceftriaxone. Forward selection identified predictors of G-tube placement. Effects of G-tube on survival and QOL were estimated using structural nested models and marginal structural models, accounting for predictors of G-tube treatment. Results: Forced vital capacity and the total score and bulbar subscale of the revised ALS Functional Rating Scale best predicted G-tube placement. Correcting for these confounders, G-tube placement decreased survival time by 46% (p < 0.001) and had no effect on QOL (p = 0.078). Sensitivity survival analyses varied in significance, but none revealed a survival benefit. Conclusions: In the absence of randomization, causal inference methods are necessary to correct for time-varying confounding. G-tube placement may have a negative effect on survival with no QOL-related benefit for people with ALS. A randomized controlled trial is warranted to further evaluate the efficacy of this widely used intervention. Clinicaltrials.gov identifier: NCT00349622. Classification of evidence: This study provides Class III evidence that for patients with ALS, G-tube placement decreases survival time and does not affect QOL.
  • Amyloid-PET in sporadic cerebral amyloid angiopathy: A diagnostic accuracy meta-analysis
    Objective: To perform a meta-analysis synthesizing evidence of the value and accuracy of amyloid-PET in diagnosing patients with sporadic cerebral amyloid angiopathy (CAA). Methods: In a PubMed systematic literature search, we identified all case-control studies with extractable data relevant for the sensitivity and specificity of amyloid-PET positivity in symptomatic patients with CAA (cases) vs healthy participants or patients with spontaneous deep intracerebral hemorrhage (ICH) (control groups). Using a hierarchical (multilevel) logistic regression model, we calculated pooled diagnostic test accuracy. Results: Seven studies, including 106 patients with CAA (>90% with probable CAA) and 151 controls, were eligible and included in the meta-analysis. The studies were of moderate to high quality and varied in several methodological aspects, including definition of PET-positive and PET-negative cases and relevant cutoffs. The sensitivity of amyloid-PET for CAA diagnosis ranged from 60% to 91% and the specificity from 56% to 90%. The overall pooled sensitivity was 79% (95% confidence interval [CI] 62–89) and specificity was 78% (95% CI 67–86) for CAA diagnosis. A predefined subgroup analysis of studies restricted to symptomatic patients presenting with lobar ICH CAA (n = 58 vs 86 controls) resulted in 79% sensitivity (95% CI 61–90%) and 84% specificity (95% CI 65–93%). In prespecified bivariate diagnostic accuracy meta-analysis of 2 studies using 18F-florbetapir-PET, the sensitivity for CAA-ICH diagnosis was 90% (95% CI 76–100%) and specificity was 88% (95% CI 74–100%). Conclusions: Amyloid-PET appears to have moderate to good diagnostic accuracy in differentiating patients with probable CAA from cognitively normal healthy controls or patients with deep ICH. Given that amyloid-PET labels both cerebrovascular and parenchymal amyloid, a negative scan might be useful to rule out CAA in the appropriate clinical setting.
  • Functional impairments for outcomes in a randomized trial of unruptured brain AVMs
    Objective: To investigate the effects of medical vs interventional management on functional outcome in A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA). Methods: We used the initial results of a nonblinded, randomized, controlled, parallel-group trial involving adults ≥18 years of age with an unruptured brain arteriovenous malformation (AVM) to compare the effects of medical management (MM) with or without interventional therapy (IT) on functional impairment, defined by a primary outcome of death or symptomatic stroke causing modified Rankin Scale (mRS) score ≥2. ARUBA closed recruitment on April 15, 2013. Results: After a median of 33.3 months of follow-up (interquartile range 16.3–49.8 months), of the 223 enrolled in the trial, those in the MM arm were less likely to experience primary outcomes with an mRS score ≥2 than those who underwent IT. The results applied for both those as randomized (MM n = 109 vs IT n = 114) (hazard ratio [HR] 0.25, 95% confidence interval [CI] 0.11–0.57, p = 0.001) and as treated (MM n = 125 vs IT n = 98) (HR 0.10, 95% CI 0.04–0.28, p < 0.001). Functional impairment for the outcomes showed no significant difference by Spetzler-Martin grade for MM but was more frequent with increasing grades for IT (p < 0.001). Conclusion: Death or stroke with functional impairment in ARUBA after a median follow-up of 33 months was significantly lower for those in the MM arm both as randomized and as treated compared with those with IT. Functional severity of outcomes was lower in the MM arm, regardless of Spetzler-Martin grades. ClinicalTrials.gov identifier: NCT00389181. Classification of evidence: This study provides Class II evidence that for adults with unruptured brain AVMs, interventional management compared to MM increases the risk of disability and death over 3 years.
  • Reducing placebo exposure in trials: Considerations from the Research Roundtable in Epilepsy
    The randomized controlled trial is the unequivocal gold standard for demonstrating clinical efficacy and safety of investigational therapies. Recently there have been concerns raised about prolonged exposure to placebo and ineffective therapy during the course of an add-on regulatory trial for new antiepileptic drug approval (typically ~6 months in duration), due to the potential risks of continued uncontrolled epilepsy for that period. The first meeting of the Research Roundtable in Epilepsy on May 19–20, 2016, focused on "Reducing placebo exposure in epilepsy clinical trials," with a goal of considering new designs for epilepsy regulatory trials that may be added to the overall development plan to make it, as a whole, safer for participants while still providing rigorous evidence of effect. This topic was motivated in part by data from a meta-analysis showing a 3- to 5-fold increased rate of sudden unexpected death in epilepsy in participants randomized to placebo or ineffective doses of new antiepileptic drugs. The meeting agenda included rationale and discussion of different trial designs, including active-control add-on trials, placebo add-on to background therapy with adjustment, time to event designs, adaptive designs, platform trials with pooled placebo control, a pharmacokinetic/pharmacodynamic approach to reducing placebo exposure, and shorter trials when drug tolerance has been ruled out. The merits and limitations of each design were discussed and are reviewed here.
  • Neurologic complications of sickle cell disease in Africa: A systematic review and meta-analysis
    Objective: To summarize prevalence data on the neurologic complications of sickle cell disease (SCD) in Africa. Methods: We searched EMBASE, PubMed, and African Index Medicus to identify all relevant articles published from inception to May 31, 2016. Each study was reviewed for methodologic quality. A random-effects model was used to estimate the prevalence of neurologic complications of SCD across studies. Results: Thirty-one studies were included. Methodologic quality was high or moderate in 90% of studies. Stroke, conditional and abnormal cerebral blood flow, seizures, and headache were the complications most frequently reported, with overall prevalence rates of 4.2%, 10.6%, 6.1%, 4.4%, and 18.9%, respectively. Some complications, like silent brain infarcts, peripheral neuropathies, neurocognitive deficits, or moyamoya disease, have been rarely or not studied at all in the African setting. Incidence data were scarce and of poor quality. Conclusions: The burden of neurologic complications of SCD is important in Africa and most likely underestimated. A better evaluation of this burden requires larger prospective studies using standard up-to-date screening methods. Accessibility to diagnostic tools such as neuroimaging, transcranial Doppler, EEG, and neuropsychological evaluation, as well as to preventive and therapeutic interventions and trained health care providers, should be improved in routine clinical practice.
  • Procoagulant imbalance in premenopausal women with chronic migraine
    Migraine has been associated with an increased risk for stroke, especially in young women.1 Among the pathophysiologic mechanisms linking migraine and stroke, coagulation abnormalities have been regarded as a logical link.2
  • Spinal epidural gas mimicking lumbar disc herniation
    A 73-year-old woman presented with acute lower back pain and right sensory radicular L4 syndrome. Spinal MRI showed a cranially shifted T2-hypointense mass suspicious for disc herniation in the L3/4 segment with compression of the right nerve root L4 (figure 1). Due to atypical morphology, CT was performed and disclosed an intraspinal epidural gas bubble mimicking disc herniation on MRI (figure 2). In association with coexisting intravertebral vacuum disc phenomenon (figure 2B), it appears likely that the gas gained access to the epidural space after annulus fibrosus rupture.1 Vacuum disc phenomenon results from the accumulation of gas (mostly nitrogen) within the crevices of the disc as it degenerates.1
  • Serpiginous cranial arterial calcification in uremia
    A 65-year-old man with chronic kidney disease (CKD) on hemodialysis presented with a subcortical stroke. Unenhanced CT scan of the brain revealed widespread arterial calcification, notably involving the carotid siphons (figure 1) and external carotid artery branches (figure 2, A and B). Vascular calcification in CKD closely resembles ossification, and may involve the intima (as in atherosclerosis) or more commonly the media.1 Both patterns of calcification are associated with increased cardiovascular mortality, though no specific treatment has been shown to modify this risk.2 This example is particularly striking for the serpiginous appearance of the affected arteries.
  • Editors' Note
    Editors' Note: In "Prolonged sleep duration as a marker of early neurodegeneration predicting incident dementia," Westwood et al. found an association between long sleep duration and incident dementia. Liguori et al. propose obstructive sleep apnea (OSA) as a possible link between increased sleep duration and neurodegeneration.
  • Letter re: Prolonged sleep duration as a marker of early neurodegeneration predicting incident dementia
    Westwood et al.1 demonstrated that long sleep duration could represent a marker of early neurodegeneration leading to dementia. There is evidence of an interplay between sleep and cognition.2 In particular, sleep disturbances are related to the occurrence of dementia by altering brain processes active during sleep.2 The observation by Westwood et al. adds to the literature on sleep and neurodegeneration.3 However, the absence of polysomnographic recordings leaves an unresolved question: why are neurodegenerative processes promoted by long sleep duration?
  • Author response: Prolonged sleep duration as a marker of early neurodegeneration predicting incident dementia
    We thank Liguori et al. for the interest in our article, which demonstrated an association between long sleep duration and incident dementia.1 We did not examine the underlying mechanisms; these require investigation.
  • Letter re: Prolonged sleep duration as a marker of early neurodegeneration predicting incident dementia
    I read with interest the article by Westwood et al.,1 which implicated prolonged sleep duration as a potential marker of early-onset neurodegeneration and subsequent dementia. There is possibly a pivotal role of fragmented, and thereby disturbed, sleep hygiene in patients with obstructive sleep apnea. These patients spend minimal time of their sleep in the REM phase, which is crucial for clearance of metabolic waste, especially β-amyloid plagues, through the paravascular pathways in the brain.2 This is accountable for early neurodegenerative processes. Further studies monitoring total time spent in each phase of sleep and neuroimaging for confirming deposition of amyloid plagues would further provide supportive cues in solving this issue.
  • Author response: Prolonged sleep duration as a marker of early neurodegeneration predicting incident dementia
    We thank Dr. Munakomi for the letter regarding our recent article on prolonged sleep duration as a potential marker of early-onset neurodegeneration and subsequent dementia.1 We agree it is important to unpack the associations between sleep and Alzheimer disease (AD). The fascinating study by Xie et al.2 demonstrated that the rate of β-amyloid clearance is increased during sleep. However, the role of REM sleep or sleep hygiene in the neurodegenerative process is unclear. In the experiments of Xie et al.,2 sleep was characterized by an increased prevalence of delta wave activity, typical of deep sleep as compared with REM sleep. In cross-sectional studies,3,4 REM sleep was reduced in patients with dementia and cognitive impairment. However, dementia is associated with comorbidities that can affect sleep, and associations between sleep and AD may be bidirectional.5 Prospective studies are needed to investigate the association between sleep architecture and the future risk of AD and dementia; this is a project that we are currently pursuing using home-based polysomnography and prospective follow-up for incident dementia in the Framingham Heart Study.
  • Doctors without weapons: "You people are pathetic"
    "How can you come to a war and not bring a weapon? Every soldier must have a weapon. That's the rule!" My boss was emphatic. "You people are pathetic."
  • Clinical Reasoning: A case of altered mental status, not otherwise specified
    A 33-year-old right-handed woman presented with a 1-week history of rapid cognitive decline. The behavioral changes emerged gradually, with the first sign marked by erratic driving resulting in arrest. The patient was nonchalant about the detainment, which was out of character. In the preceding week, she had a precipitous decline in cognitive abilities, including a loss of interest in grooming, emotional outbursts, fecal and urinary incontinence, difficulty performing household chores, and jerky movements of her arms and legs impairing her ability to walk.
  • Mystery Case: Diagnostic challenges in a young patient with hypereosinophilia
    A 48-year-old woman with recent diagnosis of nonischemic cardiomyopathy and longstanding history of asthma and allergic rhinitis without additional vascular risk factors had intermittent chest pain and dyspnea for 6 weeks, treated with antibiotics and oral steroids without benefit. Subsequently, she developed bilateral leg edema, orthopnea, and chest pain, and was hospitalized twice at another institution. Transthoracic echocardiogram (TTE) demonstrated an ejection fraction (EF) of 30%. Cardiac catheterization was normal. CT of the chest showed a large pericardial effusion (~300 mL) and bilateral pleural effusions. She had urgent pericardiocentesis and right thoracentesis, and was transferred to our institution for further evaluation and care.
  • Teaching NeuroImages: Wallerian degeneration in evolving pediatric stroke
    An 8-year-old girl presented with acute hemiparesis and facial palsy. MRI demonstrated right middle cerebral artery territory infarction (figure, A and B), secondary to traumatic dissection. Following discharge, multiple visits for nonspecific neurologic symptoms prompted repeat short-term imaging, initially concerning for right midbrain infarction (figure, C–H).
  • Teaching Video NeuroImages: Olivary enlargement and pharyngeal nystagmus
    A 77-year-old woman diagnosed with a pontine cavernoma developed progressive difficulty swallowing. A videofluoroscopic swallowing study showed low-frequency rhythmic contractions of the soft palate and upper larynx (video at Neurology.org). Brain MRI revealed hypertrophy in the right inferior olivary nucleus (figure).
  • Multiple sclerosis, inflammation in the brain, and mood
    In their study, "Neuroinflammation drives anxiety and depression in relapsing-remitting multiple sclerosis," Dr. Rossi et al.1 investigated the relationship between mood and inflammation. They did this by looking at a group of people who have multiple sclerosis (MS). It has long been observed that inflammation occurs in the brains and spinal cords of people with a specific kind of MS called relapsing-remitting MS.
  • Spotlight on the September 26 issue
  • Dietary sodium intake: An etiologic dead end in multiple sclerosis
    Multiple sclerosis (MS) is a disease of complex etiology with many unknown, hidden elements. Apart from strong genetic influence working at population and individual levels, environmental factors are important as they are essential to understanding and explaining the true increase in incidence observed in many places since the middle of the 20th century.1,2 In recent decades, environmental factors, some of them associated with lifestyle, have been elaborated, e.g., cigarette smoking, obesity, and vitamin D shortage3 and other dietary factors.4 Among possible factors attracting recent attention is dietary sodium intake. Sodium chloride induces pathogenic TH17 cells and thereby is a possible risk factor for autoimmune diseases.5 One study has shown that high dietary salt intake in patients with MS is associated with a higher relapse rate and a greater risk of developing new MRI lesions,6 but another study failed to find an association between sodium excretion and disease activity in MS.7 This has laid the ground for studies of high dietary salt intake as a possible risk factor for MS on a population level.
  • X-linked myotubular myopathy: Living longer and awaiting treatment
    The congenital myopathies (CMs) are a cluster of genetic disorders affecting myofiber structure and function. The salient clinical features are hypotonia, weakness, and motor impairment. The presentation varies from the most severe impairment in the newborn to a range of phenotypes in infancy ("floppy baby"), childhood, or occasionally adulthood. The prevalence of CMs is 1:26,000 children (birth to 17 years).1 The CMs were named on the basis of distinctive morphologic abnormalities seen on muscle biopsy: nemaline myopathy, with rods due to protein accumulation; core myopathy, with cores or multiminicores devoid of oxidative enzyme activity; centronuclear myopathy, with abnormal centrally placed nuclei; and congenital fiber-type disproportion, with a predominance of small type 1 fibers. Specific clinical features, e.g., ophthalmoparesis and facial, bulbar, and respiratory weakness, and muscle MRI can point toward a specific diagnosis.2 Standard-of-care guidelines for the CMs were published in 2012.3
  • Stem cell transplantation in Krabbe disease: New truths discovered and opinions change
    ...Institutions must go hand in hand with the progress of the human mind. As that becomes more developed, more enlightened, as new discoveries are made, new truths discovered and manners and opinions change, with the change of circumstances, institutions must advance also to keep pace with the times. —Thomas Jefferson, July 12, 1816
  • Aneurysm rupture: Another reason to abstain from smoking
    Smoking independently increases risk for aneurysm rupture and aneurysm formation.1,2 It may weaken the wall of intracranial aneurysms due to inflammation, making them more vulnerable to trigger factors and therefore to rupture.3 Previous studies have assessed the effect of current smoking. In this issue of Neurology®, Can et al.4 assess the effect of both smoking intensity and duration on intracranial aneurysm rupture.
  • No association between dietary sodium intake and the risk of multiple sclerosis
    Objective: To prospectively investigate the association between dietary sodium intake and multiple sclerosis (MS) risk. Methods: In this cohort study, we assessed dietary sodium intake by a validated food frequency questionnaire administered every 4 years to 80,920 nurses in the Nurses' Health Study (NHS) (1984–2002) and to 94,511 in the Nurses' Health Study II (NHSII) (1991–2007), and calibrated it using data from a validation study. There were 479 new MS cases during follow-up. We used Cox proportional hazards models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the effect of energy-adjusted dietary sodium on MS risk, adjusting also for age, latitude of residence at age 15, ancestry, body mass index at age 18, supplemental vitamin D intake, cigarette smoking, and total energy intake in each cohort. The results in both cohorts were pooled using fixed effects models. Results: Total dietary intake of sodium at baseline was not associated with MS risk (highest [medians: 3.2 g/d NHS; 3.5 g/d NHSII] vs lowest [medians: 2.5 g/d NHS; 2.8 g/d NHSII] quintile: HRpooled 0.98, 95% CI 0.74–1.30, p for trend = 0.75). Cumulative average sodium intake during follow-up was also not associated with MS risk (highest [medians: 3.3 g/d NHS; 3.4 g/d NHSII] vs lowest [medians: 2.7 g/d NHS; 2.8 g/d NHSII] quintile: HRpooled 1.02, 95% CI 0.76–1.37, p for trend = 0.76). Comparing more extreme sodium intake in deciles yielded similar results (p for trend = 0.95). Conclusions: Our findings suggest that higher dietary sodium intake does not increase the risk of developing MS.
  • Epstein-Barr virus, cytomegalovirus, and multiple sclerosis susceptibility: A multiethnic study
    Objective: To determine whether Epstein-Barr virus (EBV) or cytomegalovirus (CMV) seropositivity is associated with multiple sclerosis (MS) in blacks and Hispanics and to what extent measures of the hygiene hypothesis or breastfeeding could explain these findings. EBV and CMV have been associated with MS risk in whites, and the timing and frequency of both viruses vary by factors implicated in the hygiene hypothesis. Methods: Incident cases of MS or its precursor, clinically isolated syndrome (CIS), and matched controls (blacks, 111 cases/128 controls; Hispanics, 173/187; whites, 235/256) were recruited from the membership of Kaiser Permanente Southern California. Logistic regression models accounted for HLA-DRB1*1501 status, smoking, socioeconomic status, age, sex, genetic ancestry, and country of birth. Results: Epstein-Barr nuclear antigen-1 (EBNA-1) seropositivity was independently associated with an increased odds of MS/CIS in all 3 racial/ethnic groups (p < 0.001 for blacks and whites, p = 0.02 for Hispanics). In contrast, CMV seropositivity was associated with a lower risk of MS/CIS in Hispanics (p = 0.004) but not in blacks (p = 0.95) or whites (p = 0.96). Being born in a low/middle-income country was associated with a lower risk of MS in Hispanics (p = 0.02) but not after accounting for EBNA-1 seropositivity. Accounting for breastfeeding did not diminish the association between CMV and MS in Hispanics. Conclusions: The consistency of EBNA-1 seropositivity with MS across racial/ethnic groups and between studies points to a strong biological link between EBV infection and MS risk. The association between past CMV infection and MS risk supports the broader hygiene hypothesis, but the inconsistency of this association across racial/ethnic groups implies noncausal associations.
  • Neuroinflammation drives anxiety and depression in relapsing-remitting multiple sclerosis
    Objective: To explore the inflammatory processes in the pathogenesis of psychiatric symptoms and the prognostic value of psychiatric comorbidities in multiple sclerosis (MS). Methods: Four hundred five patients with relapsing-remitting (RR) MS underwent psychiatric evaluation by means of Beck Depression Inventory II (BDI-II) and State/Trait Anxiety Inventory (STAI-Y). The inflammatory activity level was assessed by MRI. In a subset of 111 treatment-naive patients, CSF levels of proinflammatory cytokines were determined. Correlation and regression analyses were performed to determine associations between variables. Results: Relapsing patients demonstrated greater values of STAI-state and BDI-II compared with remitting patients but comparable trait-anxiety scores. There were no significant differences in psychometric parameters between relapsing and asymptomatic MRI-active patients, highlighting the effect of subclinical inflammation on mood disturbances. A significant reduction of STAI-state and BDI-II scores was recorded, along with the subsiding of neuroinflammation. Interleukin-2 CSF levels were found to correlate with STAI-state, while tumor necrosis factor-α and interleukin-1β correlated with BDI-II. Because emotional disorders were associated with subclinical inflammation, variations of the psychometric profile were able to detect subclinical reactivation earlier. In line with this, high STAI-state values considerably predicted the possibility of disease reactivation. Conclusions: Mood alterations are induced by intrathecal inflammation, even though not clinically apparent, and are able to predict inflammatory reactivations in RRMS. Inflammation is therefore a biological event, not less important than the traditional psychosocial factors, involved in mood disorders.
  • High frequency of gastrointestinal manifestations in myotonic dystrophy type 1 and type 2
    Objective: To analyze gastrointestinal (GI) manifestations, their progression over time, and medications being used to treat GI symptoms in a large cohort of patients with myotonic dystrophy types 1 (DM1) and 2 (DM2). Methods: We analyzed patient-reported data and medical records in a national registry cohort at baseline and 5 years. Results: At baseline, the majority of patients reported trouble swallowing in DM1 (55%; n = 499 of 913) and constipation in DM2 (53%; n = 96 of 180). Cholecystectomy occurred in 16.5% of patients with DM1 and 12.8% of patients with DM2, on average before 45 years of age. The use of medications indicated for gastroesophageal reflux disease was reported by 22.5% of DM1 and 18.9% of patients with DM2. Greater risk of a GI manifestation was associated with higher body mass index and longer disease duration in DM1 and female sex in DM2. At the 5-year follow-up, the most common new manifestations were trouble swallowing in patients with DM1 and constipation in patients with DM2. Conclusions: GI manifestations were common in both DM1 and DM2, with a relatively high frequency of gallbladder removal in DM1 and DM2 occurring at a younger age compared to normative data in the literature. Studies are needed to determine the pathomechanism of how sex, weight gain, and duration of disease contribute to GI manifestations and how these manifestations affect quality of life and clinical care for patients with DM1 and DM2.
  • A natural history study of X-linked myotubular myopathy
    Objective: To define the natural history of X-linked myotubular myopathy (MTM). Methods: We performed a cross-sectional study that included an online survey (n = 35) and a prospective, 1-year longitudinal investigation using a phone survey (n = 33). Results: We ascertained data from 50 male patients with MTM and performed longitudinal assessments on 33 affected individuals. Consistent with existing knowledge, we found that MTM is a disorder associated with extensive morbidities, including wheelchair (86.7% nonambulant) and ventilator (75% requiring >16 hours of support) dependence. However, unlike previous reports and despite the high burden of disease, mortality was lower than anticipated (approximate rate 10%/y). Seventy-six percent of patients with MTM enrolled (mean age 10 years 11 months) were alive at the end of the study. Nearly all deaths in the study were associated with respiratory failure. In addition, the disease course was more stable than expected, with few adverse events reported during the prospective survey. Few non–muscle-related morbidities were identified, although an unexpectedly high incidence of learning disability (43%) was noted. Conversely, MTM was associated with substantial burdens on patient and caregiver daily living, reflected by missed days of school and lost workdays. Conclusions: MTM is one of the most severe neuromuscular disorders, with affected individuals requiring extensive mechanical interventions for survival. However, among study participants, the disease course was more stable than predicted, with more individuals surviving infancy and early childhood. These data reflect the disease burden of MTM but offer hope in terms of future therapeutic intervention.
  • Developmental outcomes of cord blood transplantation for Krabbe disease: A 15-year study
    Objective: To describe long-term outcomes of children with early-infantile Krabbe disease who underwent hematopoietic stem cell transplantation (HSCT) in the first 7 weeks of life. Methods: In this prospective longitudinal study, evaluations performed at baseline and follow-up included brain imaging, neurodiagnostic tests, and neurobehavioral evaluations. Results: Of the 18 patients in this study (11 girls, 7 boys; mean follow-up 9.5 years, range 4–15), 5 died (3 of peritransplant complications, 1 of a surgical complication unrelated to Krabbe disease, 1 of disease progression). One of the surviving patients has normal cognitive function and 10 continue to develop cognitive skills at a slightly slower rate than normal. All surviving patients continue to gain receptive language skills, with 7 falling within the normal range. Ten patients receive speech therapy, and 2 of these patients require augmentative communication devices. Gross motor development varies widely, but 3 patients can walk independently, and 7 walk with assistive devices. Spasticity ranges from mild to severe, and 12 patients wear orthotics. Fine motor skills are generally preserved. Brain myelination and atrophy stabilized in 8 patients, improved in 4 patients, and worsened in 1 patient. Nerve conduction velocities initially improved but continue to be abnormal in most patients. Conclusions: The surviving patients function at a much higher level than untreated children or symptomatic children who underwent HSCT. These results show that early HSCT changes the natural history of this disease by improving both lifespan and functional abilities. Classification of evidence: This study provides Class IV evidence that for children with early-infantile Krabbe disease, early HSCT improves lifespan and functional abilities.
  • Brain network efficiency is influenced by the pathologic source of corticobasal syndrome
    Objective: To apply network-based statistics to diffusion-weighted imaging tractography data and detect Alzheimer disease vs non-Alzheimer degeneration in the context of corticobasal syndrome. Methods: In a cross-sectional design, pathology was confirmed by autopsy or a pathologically validated CSF total tau-to-β-amyloid ratio (T-tau/Aβ). Using structural MRI data, we identify association areas in fronto-temporo-parietal cortex with reduced gray matter density in corticobasal syndrome (n = 40) relative to age-matched controls (n = 40). Using these fronto-temporo-parietal regions of interest, we construct structural brain networks in clinically similar subgroups of individuals with Alzheimer disease (n = 21) or non-Alzheimer pathology (n = 19) by linking these regions by the number of white matter streamlines identified in a deterministic tractography analysis of diffusion tensor imaging data. We characterize these structural networks using 5 graph-based statistics, and assess their relative utility in classifying underlying pathology with leave-one-out cross-validation using a supervised support vector machine. Results: Gray matter density poorly discriminates between Alzheimer disease and non-Alzheimer pathology subgroups with low sensitivity (57%) and specificity (52%). In contrast, a statistic of local network efficiency demonstrates very good discriminatory power, with 85% sensitivity and 84% specificity. Conclusions: Our results indicate that the underlying pathologic sources of corticobasal syndrome can be classified more accurately using graph theoretical statistics derived from patterns of white matter network organization in association cortex than by regional gray matter density alone. These results highlight the importance of a multimodal neuroimaging approach to diagnostic analyses of corticobasal syndrome.
  • Sex differences in Alzheimer risk: Brain imaging of endocrine vs chronologic aging
    Objective: This observational multimodality brain imaging study investigates emergence of endophenotypes of late-onset Alzheimer disease (AD) risk during endocrine transition states in a cohort of clinically and cognitively normal women and age-matched men. Methods: Forty-two 40- to 60-year-old cognitively normal women (15 asymptomatic perimenopausal by age [CNT], 13 perimenopausal [PERI], and 14 postmenopausal [MENO]) and 18 age- and education-matched men were examined. All patients had volumetric MRI, 18F-fluoro-2-deoxyglucose (FDG)–PET (glucose metabolism), and Pittsburgh compound B–PET scans (β-amyloid [Aβ] deposition, a hallmark of AD pathology). Results: As expected, the MENO group was older than the PERI and CNT groups. Otherwise, groups were comparable on clinical and neuropsychological measures and APOE4 distribution. Compared to CNT women and to men, and controlling for age, PERI and MENO groups exhibited increased indicators of AD endophenotype, including hypometabolism, increased Aβ deposition, and reduced gray and white matter volumes in AD-vulnerable regions (p < 0.001). AD biomarker abnormalities were greatest in MENO, intermediate in PERI, and lowest in CNT women (p < 0.001). Aβ deposition was exacerbated in APOE4-positive MENO women relative to the other groups (p < 0.001). Conclusions: Multimodality brain imaging indicates sex differences in development of the AD endophenotype, suggesting that the preclinical AD phase is early in the female aging process and coincides with the endocrine transition of perimenopause. These data indicate that the optimal window of opportunity for therapeutic intervention in women is early in the endocrine aging process.
  • 1H-MRS metabolites and rate of {beta}-amyloid accumulation on serial PET in clinically normal adults
    Objective: To assess whether noninvasive proton magnetic resonance spectroscopy (1H-MRS) tissue metabolite measurements at baseline can predict an increase in the rate of β-amyloid (Aβ) accumulation on serial PET in clinically normal (CN) older adults. Methods: Consecutive participants aged 60 years and older (n = 594) from the Mayo Clinic Study of Aging who were CN at baseline and who underwent 1H-MRS from the posterior cingulate voxel and longitudinal 11C-Pittsburgh compound B (PiB)–PET were included. The rate of Aβ accumulation by serial cortical PiB standardized uptake value ratios was estimated as a function of baseline 1H-MRS metabolite ratios and time using mixed-effect models adjusted for age, sex, and APOE 4. Effect of APOE 4 on the relationship between baseline MRS and an increased rate of Aβ accumulation was also assessed. Results: Among all participants, a higher myo-inositol (mI)/creatine (p = 0.011) and a lower N-acetylaspartate/mI (p = 0.006) at baseline were associated with an increased Aβ accumulation over time after adjusting for age, sex, and APOE 4. APOE 4 did not modify the association of baseline 1H-MRS metabolite ratios and rate of Aβ accumulation. However, APOE 4 carriers accumulated Aβ faster than noncarriers regardless of the baseline Aβ load (p = 0.001). Conclusion: Among CN older adults, early metabolic alterations on 1H-MRS and APOE 4 status are independently associated with an increased rate of Aβ accumulation. Our findings could have important implications for early diagnosis and identification of individuals for secondary prevention trials, because an increased rate of Aβ accumulation in CN older adults may confer a higher risk for cognitive decline and mild cognitive impairment.
  • Effect of informed consent on patient characteristics in a stroke thrombolysis trial
    Objective: To determine whether the manner of consent, i.e., informed consent by patients themselves or informed consent by proxy, affects clinical characteristics of samples of acute stroke patients enrolled in clinical trials. Methods: We analyzed the manner of obtaining informed consent in the first 1,005 patients from WAKE-UP, an investigator-initiated, randomized, placebo-controlled trial of MRI-based thrombolysis in stroke patients with unknown time of symptom onset running in 6 European countries. Patients providing informed consent by themselves were compared with patients enrolled by proxy consent. Baseline clinical measures were compared between groups. Results: In 359 (35.7%) patients, informed consent was by proxy. Patients with proxy consent were older (median 71 vs 66 years, p < 0.0001) and had a higher frequency of arterial hypertension (58.2% vs 43.4%, p < 0.0001). They showed higher scores on the NIH Stroke Scale (median 11 vs 5, p < 0.0001) and more frequently aphasia (73.7% vs 20.0%, p < 0.0001). The rate of proxy consent varied among countries (p < 0.0001), ranging from 77.1% in Spain to 1.2% in Denmark. Conclusions: Patients recruited by proxy consent were older, had more severe strokes, and had higher prevalence of aphasia than those with capacity to give personal consent. Variations in the manner of consent across countries may influence trial results. Clinicaltrials.gov and Clinicaltrialsregister.eu identifiers: NCT01525290 (clinicaltrials.gov); 2011-005906-32 (clinicaltrialsregister.eu).
  • Comment: Capacity, consent, and country in acute stroke research
    As a general principle, any research involving humans requires voluntary participation based on informed consent.1 This also applies to enrollment in clinical trials und usually requires participants to give written informed consent after having received detailed information about potential benefits and risks as well as alternative treatment options, and after having had adequate time for consideration. Trials in acute stroke, however, present several challenges to this approach. Reperfusion therapies in acute stroke show a clear time-dependent effect, being more effective the earlier treatment is started, or reperfusion achieved.2,3 Both routine care and clinical trials in acute stroke are carried out under pressure of time. Thus, time available for consideration is very short. In addition, the brain injury commonly compromises language function, awareness of neurologic deficits, conscious level, and physical abilities, including vision and writing, relevant to the usual consent process. Since most stroke patients lack capacity to provide consent,4,5 alternative approaches are needed,6,7 and the bias introduced by systematic exclusion of certain subgroups of stroke patients, e.g., those with aphasia, has been reviewed critically.8
  • Association of intracranial aneurysm rupture with smoking duration, intensity, and cessation
    Objective: Although smoking is a known risk factor for intracranial aneurysm (IA) rupture, the exact relationship between IA rupture and smoking intensity and duration, as well as duration of smoking cessation, remains unknown. Methods: In this case-control study, we analyzed 4,701 patients with 6,411 IAs diagnosed at the Brigham and Women's Hospital and Massachusetts General Hospital between 1990 and 2016. We divided individuals into patients with ruptured aneurysms and controls with unruptured aneurysms. We performed univariable and multivariable logistic regression analyses to determine the association between smoking status and ruptured IAs at presentation. In a subgroup analysis among former and current smokers, we assessed the association between ruptured aneurysms and number of packs per day, duration of smoking, and duration since smoking cessation. Results: In multivariable analysis, current (odds ratio [OR] 2.21, 95% confidence interval [CI] 1.89–2.59) and former smoking status (OR 1.56, 95% CI 1.31–1.86) were associated with rupture status at presentation compared with never smokers. In a subgroup analysis among current and former smokers, years smoked (OR 1.02, 95% CI 1.01–1.03) and packs per day (OR 1.46, 95% CI 1.25–1.70) were significantly associated with ruptured aneurysms at presentation, whereas duration since cessation among former smokers was not significant (OR 1.00, 95% CI 0.99–1.02). Conclusions: Current cigarette smoking, smoking intensity, and smoking duration are significantly associated with ruptured IAs at presentation. However, the significantly increased risk persists after smoking cessation, and smoking cessation does not confer a reduced risk of aneurysmal subarachnoid hemorrhage beyond that of reducing the cumulative dose.
  • Thalamic deep brain stimulation for tremor in Parkinson disease, essential tremor, and dystonia
    Objective: To report on the long-term outcomes of deep brain stimulation (DBS) of the thalamic ventral intermediate nucleus (VIM) in Parkinson disease (PD), essential tremor (ET), and dystonic tremor. Methods: One hundred fifty-nine patients with PD, ET, and dystonia underwent VIM DBS due to refractory tremor at the Grenoble University Hospital. The primary outcome was a change in the tremor scores at 1 year after surgery and at the latest follow-up (21 years). Secondary outcomes included the relationship between tremor score reduction over time and the active contact position. Tremor scores (Unified Parkinson's Disease Rating Scale-III, items 20 and 21; Fahn, Tolosa, Marin Tremor Rating Scale) and the coordinates of the active contacts were recorded. Results: Ninety-eight patients were included. Patients with PD and ET had sustained improvement in tremor with VIM stimulation (mean improvement, 70% and 66% at 1 year; 63% and 48% beyond 10 years, respectively; p < 0.05). There was no significant loss of stimulation benefit over time (p > 0.05). Patients with dystonia exhibited a moderate response at 1-year follow-up (41% tremor improvement, p = 0.027), which was not sustained after 5 years (30% improvement, p = 0.109). The more dorsal active contacts' coordinates in the right lead were related to a better outcome 1 year after surgery (p = 0.029). During the whole follow-up, forty-eight patients (49%) experienced minor side effects, whereas 2 (2.0%) had serious events (brain hemorrhage and infection). Conclusions: VIM DBS is an effective long-term (beyond 10 years) treatment for tremor in PD and ET. Effects on dystonic tremor were modest and transient. Classification of evidence: This provides Class IV evidence. It is an observational study.
  • Abdominal tremor in thyrotoxicosis
    Hyperthyroidism is a common medical condition in the general population and neurologic symptoms can be the first presentation. Neurologic manifestations include cognitive abnormalities and seizures, movement disorders such as chorea and tremors, and peripheral nervous system conditions including myopathy and neuropathy. Tremor, usually limb tremor, has been observed in 78% of patients with thyrotoxicosis.1 Here we report isolated abdominal tremor, reminiscent but different from belly dancer’s dyskinesia, in a patient with thyrotoxicosis.
  • Benefit of dual-energy CT iodine overlay technique for T1-hyperintense brain lesion
    A 47-year-old woman was admitted for radiation therapy of a left frontal glioblastoma, resected 2 months prior. On enhanced MRI, it was difficult to identify the tumor enhancement due to intrinsic T1 hyperintensity, possibly related to postoperative hemorrhage1 (figure, A–C). However, the iodine overlay image derived from the dual-energy CT technique (figure, D) was revealing: subsequent surgical resection confirmed residual tumor cells along the region that showed the elevated iodine concentration (figure, E). The dual-energy CT iodine overlay technique may be particularly useful in the evaluation of a T1-hyperintense lesion.2
  • Editors' Note
    Editors' Note: In the article "High hypothetical interest in physician-assisted death in multiple sclerosis," the opinions of persons with multiple sclerosis (MS) regarding physician-assisted death (PAD) were assessed. Investigators surveyed participants in the North American Research Committee on Multiple Sclerosis Registry regarding PAD.
  • Letter re: High hypothetical interest in physician-assisted death in multiple sclerosis
    Reading the article by Marrie et al.1 reminded me of Leo Alexander's horrifying report, which was published as the lead article in a 1949 issue of the New England Journal of Medicine (NEJM).2 As an expert at the Nuremberg trial, Alexander carefully reviewed the extensive medical records left behind by the Nazi regime. In the NEJM article,2 he mentioned one of the Nazi propaganda movies, I Accuse, which depicted the life history of a woman with multiple sclerosis. In the movie, the woman's husband, a doctor, finally kills her to the accompaniment of soft piano music rendered by a sympathetic colleague in an adjoining room. After describing extensively unimaginable cruelty, Alexander concluded
  • Letter re: Physician-assisted death in chronic neurologic diseases
    I read with interest the editorial by Drs. Bernat and McQuillen1 on physician-assisted death (PAD) in chronic neurologic disease. I fully support their view that "physicians have a concurrent duty to respect our patients' liberty-based right to determine themselves what constitutes their best outcome." However, it is important to remember that, among legislative criteria granting the right to practice PAD, there are 4 requirements: requests must be voluntary, persistent, well-thought, and well-informed.2 Also, and perhaps more importantly, I do not agree that in the Netherlands and Belgium "voluntary active euthanasia now far surpasses PAD in frequency,"1 because, at least in Belgium, assisted suicide is not possible and voluntary active euthanasia is the only legalized PAD (unlike in Canada, Switzerland, and some US states).3
  • Letter re: High hypothetical interest in physician-assisted death in multiple sclerosis and Physician-assisted death in chronic neurologic diseases
    I read with interest the editorial by Drs. Bernat and McQuillen,1 accompanying the article by Marrie et al.2 I share some of the concerns highlighted in the editorial, but want to highlight the other side of the argument.
  • Author response: High hypothetical interest in physician-assisted death in multiple sclerosis
    We appreciate Dr. Masdeu's interest in our article,1 and Dr. Sethi's comments on our article and the related editorial by Drs. Bernat and McQuillen.2
  • Author response: Physician-assisted death in chronic neurologic diseases
    We thank Dr. Bier for the correction that the law in Belgium allows only active euthanasia and not physician-assisted death (PAD). Our statement remains true that, in the Netherlands, where both activities are lawful, active euthanasia is more commonly practiced than PAD.1
  • White matter microstructure, cognition, and molecular markers in fragile X premutation females

Ahead of Print:
  • Amyloid PET scan: Staging beyond reading?
    The advent of in vivo β-amyloid (Aβ) PET imaging has revolutionized the field of Alzheimer disease (AD). The opportunity to visualize, during life, one of the main neuropathologic hallmarks of the disease, i.e., Aβ deposition, has yielded considerable hope for diagnosis and treatment efficacy. From a clinical perspective, although the presence of Aβ deposition in the brain is not a sufficient criterion for AD dementia diagnosis, Aβ PET imaging is used to support or rule out the diagnosis, especially in patients with a complicated clinical course.1 Moreover, Aβ PET imaging is a powerful tool for clinical trials to enrich the sample for Aβ-positive participants, and to evaluate treatment effects on Aβ deposition. Finally, Aβ PET imaging has provided a unique opportunity to assess how Aβ deposition relates to cognitive and functional decline, brain atrophy, and hypometabolism, both cross-sectionally and longitudinally.
  • Randomized study of IV prochlorperazine plus diphenhydramine vs IV hydromorphone for migraine
    Objective:To determine outcomes among patients with migraine in the emergency department (ED) who receive IV hydromorphone vs IV prochlorperazine + diphenhydramine.Methods:This study was conducted in 2 EDs in New York City. Patients who met international criteria for migraine were eligible for participation if they had not used an opioid within the previous month. Clinicians, participants, investigators, and research personnel were blinded to treatment. Patients were randomized in blocks of 4. Participants received hydromorphone 1 mg or prochlorperazine 10 mg + diphenhydramine 25 mg. Diphenhydramine was administered to prevent akathisia, a common side effect of IV prochlorperazine. The primary outcome was sustained headache relief, defined as achieving a headache level of mild or none within 2 hours of medication administration and maintaining that level for 48 hours without the requirement of rescue medication. A planned interim analysis was conducted once 48-hour data were available for 120 patients.Results:The trial was halted by the data monitoring committee after 127 patients had been enrolled. The primary outcome was achieved in the prochlorperazine arm by 37 of 62 (60%) participants and in the hydromorphone arm by 20 of 64 (31%) participants (difference 28%, 95% confidence interval 12–45, number needed to treat 4, 95% confidence interval 2–9).Conclusions:IV hydromorphone is substantially less effective than IV prochlorperazine for the treatment of acute migraine in the ED and should not be used as first-line therapy.ClinicalTrials.gov identifier:NCT02389829.Classification of evidence:This study provides Class I evidence that for patients in the ED with migraine, IV prochlorperazine + diphenhydramine is superior to IV hydromorphone.
  • Serum neurofilament light is sensitive to active cerebral small vessel disease
    Objective:To explore whether serum neurofilament light chain protein (NfL) levels are increased in patients with MRI-confirmed recent small subcortical infarcts (RSSI) compared to healthy controls and to determine the subsequent course and determinants of NfL levels in a longitudinal manner.Methods:In a prospectively collected group of symptomatic patients with an RSSI (n = 79, mean age 61 ± 11 years, 67% male), we analyzed brain MRI and serum NfL using a Single Molecule Array (Simoa) assay at baseline and at 3 and 15 months after stroke. Community-dwelling healthy age- and sex-matched individuals with comparable severity of MRI white matter hyperintensities (WMH) (n = 53) served as controls.Results:Patients with an RSSI had higher NfL baseline levels compared to controls (73.45 vs 34.59 pg/mL, p < 0.0001), and they were increasingly higher with the time from stroke symptom onset to blood sampling (median 4 days, range 1–11 days, rs = 0.51, p < 0.0001). NfL levels remained increased at the 3-month follow-up but returned to normal at 15 months after stroke. NfL levels were associated with RSSI size and baseline WMH severity and were especially high in patients with new, clinically silent cerebral small vessel disease (CSVD)–related lesions at follow-up.Conclusions:Serum NfL is increased in patients with an RSSI and the occurrence of new CSVD-related MRI lesions, even when clinically silent. This suggests NfL as a blood biomarker for active CSVD.
  • In vivo staging of regional amyloid deposition
    Objectives:To estimate a regional progression pattern of amyloid deposition from cross-sectional amyloid-sensitive PET data and evaluate its potential for in vivo staging of an individual's amyloid pathology.Methods:Multiregional analysis of florbetapir (18F-AV45)–PET data was used to determine individual amyloid distribution profiles in a sample of 667 participants from the Alzheimer's Disease Neuroimaging Initiative cohort, including cognitively normal older individuals (CN) as well as patients with mild cognitive impairment and Alzheimer disease (AD) dementia. The frequency of regional amyloid positivity across CN individuals was used to construct a 4-stage model of progressing amyloid pathology, and individual distribution profiles were used to evaluate the consistency of this hierarchical stage model across the full cohort.Results:According to a 4-stage model, amyloid deposition begins in temporobasal and frontomedial areas, and successively affects the remaining associative neocortex, primary sensory-motor areas and the medial temporal lobe, and finally the striatum. Amyloid deposition in these brain regions showed a highly consistent hierarchical nesting across participants, where only 2% exhibited distribution profiles that deviated from the staging scheme. The earliest in vivo amyloid stages were mostly missed by conventional dichotomous classification approaches based on global florbetapir-PET signal, but were associated with significantly reduced CSF Aβ42 levels. Advanced in vivo amyloid stages were most frequent in patients with AD and correlated with cognitive impairment in individuals without dementia.Conclusions:The highly consistent regional hierarchy of PET-evidenced amyloid deposition across participants resembles neuropathologic observations and suggests a predictable regional sequence that may be used to stage an individual's progress of amyloid pathology in vivo.
  • Adding quantitative muscle MRI to the FSHD clinical trial toolbox
    Objective:To add quantitative muscle MRI to the clinical trial toolbox for facioscapulohumeral muscular dystrophy (FSHD) by correlating it to clinical outcome measures in a large cohort of genetically and clinically well-characterized patients with FSHD comprising the entire clinical spectrum.Methods:Quantitative MRI scans of leg muscles of 140 patients with FSHD1 and FSHD2 were assessed for fatty infiltration and TIRM hyperintensities and were correlated to multiple clinical outcome measures.Results:The mean fat fraction of the total leg musculature correlated highly with the motor function measure, FSHD clinical score, Ricci score, and 6-minute walking test (correlation coefficients –0.845, 0.835, 0.791, –0.701, respectively). Fat fraction per muscle group correlated well with corresponding muscle strength (correlation coefficients up to –0.82). The hamstring muscles, adductor muscles, rectus femoris, and gastrocnemius medialis were affected most frequently, also in early stage disease and in patients without leg muscle weakness. Muscle involvement was asymmetric in 20% of all muscle pairs and fatty infiltration within muscles showed a decrease from distal to proximal of 3.9%. TIRM hyperintense areas, suggesting inflammation, were found in 3.5% of all muscles, with and without fatty infiltration.Conclusions:We show a strong correlation between quantitative muscle MRI and clinical outcome measures. Muscle MRI is able to detect muscle pathology before clinical involvement of the leg muscles. This indicates that quantitative leg muscle MRI is a promising biomarker that captures disease severity and motor functioning and can thus be included in the FSHD trial toolbox.
  • Association between percent decline in serum total homocysteine and risk of first stroke
    Objective:To examine whether a change in serum total homocysteine (tHcy) levels is associated with first stroke risk in a post hoc analysis of the China Stroke Primary Prevention Trial (CSPPT).Methods:We analyzed 16,867 participants of the CSPPT with tHcy measurements at both baseline and exit visits. The primary outcome was first stroke. The secondary outcome was a composite of cardiovascular events consisting of cardiovascular death, myocardial infarction, and stroke. The percent decline in tHcy was calculated as [(baseline tHcy – exit tHcy)/baseline tHcy x 100].Results:Over the median treatment duration of 4.5 years, participants who developed a first stroke had a significantly lower percent decline in tHcy (β = –5.7; 95% confidence interval [CI] –8.8 to –2.6) compared to their counterparts. A 20% tHcy decline was associated with a reduction in stroke risk of 7% (hazard ratio [HR] 0.93; 95% CI 0.90–0.97). When percent decline in tHcy was assessed as tertiles, a significantly lower stroke risk was found in those in tertiles 2–3 (HR 0.79; 95% CI 0.64–0.97) compared with participants in tertile 1. Similar results were observed for the composite of cardiovascular events. The beneficial effect associated with greater tHcy reduction was observed across strata for age, sex, treatment group (with vs without folic acid), MTHFR C677T genotypes, baseline tHcy and serum folate levels, and blood pressure control.Conclusions:Percent lowering in tHcy was significantly associated with a reduction in first stroke risk in Chinese adults with hypertension, and if further confirmed, may serve as a useful indicator for folic acid treatment efficacy on stroke prevention.Clinicaltrials.gov identifier:NCT00794885.
  • Optimal deep brain stimulation site and target connectivity for chronic cluster headache
    Objective:To investigate the mechanism of action of deep brain stimulation for refractory chronic cluster headache and the optimal target within the ventral tegmental area.Methods:Seven patients with refractory chronic cluster headache underwent high spatial and angular resolution diffusion MRI preoperatively. MRI-guided and MRI-verified electrode implantation was performed unilaterally in 5 patients and bilaterally in 2. Volumes of tissue activation were generated around active lead contacts with a finite-element model. Twelve months after surgery, voxel-based morphometry was used to identify voxels associated with higher reduction in headache load. Probabilistic tractography was used to identify the brain connectivity of the activation volumes in responders, defined as patients with a reduction of ≥30% in headache load.Results:There was no surgical morbidity. Average follow-up was 34 ± 14 months. Patients showed reductions of 76 ± 33% in headache load, 46 ± 41% in attack severity, 58 ± 41% in headache frequency, and 51 ± 46% in attack duration at the last follow-up. Six patients responded to treatment. Greatest reduction in headache load was associated with activation in an area cantered at 6 mm lateral, 2 mm posterior, and 1 mm inferior to the midcommissural point of the third ventricle. Average responders' activation volume lay on the trigeminohypothalamic tract, connecting the trigeminal system and other brainstem nuclei associated with nociception and pain modulation with the hypothalamus, and the prefrontal and mesial temporal areas.Conclusions:We identify the optimal stimulation site and structural connectivity of the deep brain stimulation target for cluster headache, explicating possible mechanisms of action and disease pathophysiology.
  • Infliximab for the treatment of CNS sarcoidosis: A multi-institutional series
    Objective:To describe clinical and imaging responses in neurosarcoidosis to infliximab, a monoclonal antibody against tumor necrosis factor–α.Methods:Investigators at 6 US centers retrospectively identified patients with CNS sarcoidosis treated with infliximab, including only patients with definite or probable neurosarcoidosis following rigorous exclusion of other causes.Results:Of 66 patients with CNS sarcoidosis (27 definite, 39 probable) treated with infliximab for a median of 1.5 years, the mean age was 47.5 years at infliximab initiation (SD 11.7, range 24–71 years); 56.1% were female; 62.1% were white, 37.0% African American, and 3% Hispanic. Sarcoidosis was isolated to the CNS in 19.7%. Using infliximab doses ranging from 3 to 7 mg/kg every 4–8 weeks, MRI evidence of a favorable treatment response was observed in 82.1% of patients with imaging follow-up (n = 56), with complete remission of active disease in 51.8% and partial MRI improvement in 30.1%; MRI worsened in 1 patient (1.8%). There was clinical improvement in 77.3% of patients, with complete neurologic recovery in 28.8%, partial improvement in 48.5%, clinical stability in 18.2%, worsening in 3%, and 1 lost to follow-up. In 16 patients in remission when infliximab was discontinued, the disease recurred in 9 (56%), typically in the same neuroanatomic location.Conclusions:Most patients with CNS sarcoidosis treated with infliximab exhibit favorable imaging and clinical treatment responses, including some previously refractory to other immunosuppressive treatments.Classification of evidence:This study provides Class IV evidence that for patients with CNS sarcoidosis infliximab is associated with favorable imaging and clinical responses.
  • GABA alterations in pediatric sport concussion
    Objective:To evaluate whether frontal-lobe magnetic resonance spectroscopy measures of -aminobutyric acid (GABA) would be altered in a sample of adolescents scanned after sport concussion because mild traumatic brain injury is often associated with working memory problems.Methods:Eleven adolescents (age 14–17 years) who had sustained a first-time sport concussion were studied with MRI/magnetic resonance spectroscopy within 23 to 44 days after injury (mean 30.4 ± 6.1 days). Age- and sex-matched healthy controls, being seen for sports-related injuries not involving the head and with no history of concussion, were also examined. GABA/creatine + phosphocreatine (Cre) was measured in left-sided frontal lobe and central posterior cingulate regions. The frontal voxel was positioned to overlap with patient-specific activation on a 1-back working memory task.Results:Increased GABA/Cre was shown in the frontal lobe for the concussed group. A decreased relationship was observed in the parietal region. High correlations between GABA/Cre and task activation were observed for the control group in the frontal lobe, a relationship not shown in the concussed participants.Conclusions:GABA/Cre appears increased in a region colocalized with working memory task activation after sport concussion. Further work extending these results in larger samples and at time points across the injury episode will aid in refining the clinical significance of these observations.
  • Longitudinal CSF biomarkers in patients with early Parkinson disease and healthy controls
    Objective:To analyze longitudinal levels of CSF biomarkers in drug-naive patients with Parkinson disease (PD) and healthy controls (HC), examine the extent to which these biomarker changes relate to clinical measures of PD, and identify what may influence them.Methods:CSF α-synuclein (α-syn), total and phosphorylated tau (t- and p-tau), and β-amyloid 1–42 (Aβ42) were measured at baseline and 6 and 12 months in 173 patients with PD and 112 matched HC in the international multicenter Parkinson's Progression Marker Initiative. Baseline clinical and demographic variables, PD medications, neuroimaging, and genetic variables were evaluated as potential predictors of CSF biomarker changes.Results:CSF biomarkers were stable over 6 and 12 months, and there was a small but significant increase in CSF Aβ42 in both patients with patients with PD and HC from baseline to 12 months. The t-tau remained stable. The p-tau increased marginally more in patients with PD than in HC. α-syn remained relatively stable in patients with PD and HC. Ratios of p-tau/t-tau increased, while t-tau/Aβ42 decreased over 12 months in patients with PD. CSF biomarker changes did not correlate with changes in Movement Disorder Society–sponsored revision of the Unified Parkinson’s Disease Rating Scale motor scores or dopamine imaging. CSF α-syn levels at 12 months were lower in patients with PD treated with dopamine replacement therapy, especially dopamine agonists.Conclusions:These core CSF biomarkers remained stable over 6 and 12 months in patients with early PD and HC. PD medication use may influence CSF α-syn. Novel biomarkers are needed to better profile progressive neurodegeneration in PD.
  • Weighting and standardization of frequencies to determine prevalence of AD imaging biomarkers
    Objective:To estimate the prevalence of elevated brain amyloid and reduced cortical thickness (as a marker for neurodegeneration) in a defined population.Methods:Mayo Clinic Study of Aging participants underwent MRI to assess a composite Alzheimer disease (AD) signature cortical thickness measure and PET to assess brain amyloid accumulation. Participants were characterized as having elevated amyloid (A+/A–), reduced cortical thickness (N+/N–), and A+N+, A+N–, A–N+, or A–N–. The prevalence of AD biomarkers was derived by adjusting for nonparticipation and standardizing to the Olmsted County, Minnesota, population.Results:Among 1,646 participants without dementia (mean age 70.8 years; 53.2% men), the prevalence (95% confidence interval) of amyloidosis was 21.1% (19.1%–23.2%): women, 24.3%; men, 17.5%. The prevalence of reduced cortical thickness was 28.9% (26.4%–31.5%): women, 27.9%; men, 30.2%. The prevalence estimates of biomarker categories were as follows: A–N–: 61.4%; A+N–: 9.7%; A–N+: 17.4%; and A+N+: 11.5%, and varied by sex and by APOE 4 carrier status. In men, prevalence estimates were as follows: A–N–: 62.6%; A+N–: 7.3%; A–N+: 19.9%; and A+N+: 10.2%. In women, prevalence estimates were as follows: A–N–: 60.4%; A+N–: 11.7%; A–N+: 15.3%; and A+N+: 12.6%. In 4 carriers, prevalence estimates were as follows: A–N–: 54.6%; A+N–: 16.6%; A–N+: 12.4%; and A+N+: 16.4%. In non-4 carriers, prevalence estimates were as follows: A–N–: 63.3%; A+N–: 6.9%; A–N+: 19.9%; and A+N+: 10.0%.Conclusions:These prevalence estimates are important for understanding age-related trends in amyloid positivity and AD signature cortical thickness in the population, and for potentially projecting the future burden of biomarkers in elderly persons.
  • Effect of concussion and blast exposure on symptoms after military deployment
    Objective:To examine whether blast exposure alone and blast-associated concussion result in similar neurologic and mental health symptoms.Methods:A 14-item questionnaire was administered to male US Marines on their return from deployment in Iraq and/or Afghanistan.Results:A total of 2,612 Marines (median age 22 years) completed the survey. Of those, 2,320 (88.9%) reported exposure to ≥1 blast during their current and/or prior deployments. In addition, 1,022 (39.1%) reported ≥1 concussion during the current deployment, and 731 (28.0%) had experienced at least 1 prior lifetime concussion. Marines were more likely to have sustained a concussion during the current deployment if they had a history of 1 (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.2–2.0) or ≥1 (OR 2.3, 95% CI 1.7–3.0) prior concussion. The most common symptoms were trouble sleeping (38.4%), irritability (37.9%), tinnitus (33.8%), and headaches (33.3%). Compared to those experiencing blast exposure without injury, Marines either experiencing a concussion during the current deployment or being moved or injured by a blast had an increased risk of postinjury symptoms.Conclusions:There appears to be a continuum of increasing total symptoms from no exposure to blast exposure plus both current deployment concussion and past concussion. Concussion had a greater influence than blast exposure alone on the presence of postdeployment symptoms. A high blast injury score can be used to triage those exposed to explosive blasts for evaluation.
  • Increasing prevalence of vascular risk factors in patients with stroke: A call to action
    Objective:To evaluate trends in prevalence of cardiovascular risk factors (hypertension, diabetes, dyslipidemia, smoking, and drug abuse) and cardiovascular diseases (carotid stenosis, chronic renal failure [CRF], and coronary artery disease [CAD]) in acute ischemic stroke (AIS) in the United States.Methods:We used the 2004–2014 National Inpatient Sample to compute weighted prevalence of each risk factor in hospitalized patients with AIS and used joinpoint regression to evaluate change in prevalence over time.Results:Across the 2004–2014 period, 92.5% of patients with AIS had ≥1 risk factor. Overall age- and sex-adjusted prevalence of hypertension, diabetes, dyslipidemia, smoking, and drug abuse were 79%, 34%, 47%, 15%, and 2%, respectively, while those of carotid stenosis, CRF, and CAD were 13%, 12%, and 27%, respectively. Risk factor prevalence varied by age (hypertension: 44% in 18–39 years vs 82% in 60–79 years), race (diabetes: Hispanic 49% vs white 30%), and sex (drug abuse: men 3% vs women 1.4%). Using joinpoint regression, prevalence of hypertension increased annually by 1.4%, diabetes by 2%, dyslipidemia by 7%, smoking by 5%, and drug abuse by 7%. Prevalence of CRF, carotid stenosis, and CAD increased annually by 13%, 6%, and 1%, respectively. Proportion of patients with multiple risk factors also increased over time.Conclusions:Despite numerous guidelines and prevention initiatives, prevalence of hypertension, diabetes, dyslipidemia, smoking, and drug abuse in AIS increased across the 2004–2014 period. Proportion of patients with carotid stenosis, CRF, and multiple risk factors also increased. Enhanced risk factor modification strategies and implementation of evidence-based recommendations are needed for optimal stroke prevention.
  • Big data trends in stroke epidemiology in the United States: But are they good data?
    Based on prior epidemiologic studies in the United States, approximately 80% of first-time strokes can be explained by modifiable risk factors such as hypertension, and therefore optimal control or elimination of known risk factors might prevent these strokes.1 Campaigns such as the American Heart Association (AHA) initiative, Life's Simple 7, have set ambitious goals for optimal cardiovascular and stroke risk factor control; in addition, a wealth of online resources are available for an increasingly health-conscious society.2 There are indeed some glimmers of hope. Efforts to prevent stroke, in large part from emphasis on improved detection and behavioral and pharmacologic treatment of risk factors, have led to substantial declines in stroke incidence and mortality in Western countries over the last several decades.3
  • Meta-analysis of pharmacogenetic interactions in amyotrophic lateral sclerosis clinical trials
    Objective:To assess whether genetic subgroups in recent amyotrophic lateral sclerosis (ALS) trials responded to treatment with lithium carbonate, but that the treatment effect was lost in a large cohort of nonresponders.Methods:Individual participant data were obtained from 3 randomized trials investigating the efficacy of lithium carbonate. We matched clinical data with data regarding the UNC13A and C9orf72 genotype. Our primary outcome was survival at 12 months. On an exploratory basis, we assessed whether the effect of lithium depended on the genotype.Results:Clinical data were available for 518 of the 606 participants. Overall, treatment with lithium carbonate did not improve 12-month survival (hazard ratio [HR] 1.0, 95% confidence interval [CI] 0.7–1.4; p = 0.96). Both the UNC13A and C9orf72 genotype were independent predictors of survival (HR 2.4, 95% CI 1.3–4.3; p = 0.006 and HR 2.5, 95% CI 1.1–5.2; p = 0.032, respectively). The effect of lithium was different for UNC13A carriers (p = 0.027), but not for C9orf72 carriers (p = 0.22). The 12-month survival probability for UNC13A carriers treated with lithium carbonate improved from 40.1% (95% CI 23.2–69.1) to 69.7% (95% CI 50.4–96.3).Conclusions:This study incorporated genetic data into past ALS trials to determine treatment effects in a genetic post hoc analysis. Our results suggest that we should reorient our strategies toward finding treatments for ALS, start focusing on genotype-targeted treatments, and standardize genotyping in order to optimize randomization and analysis for future clinical trials.
  • Radiographic and symptomatic brain ischemia in CEA and CAS: A systematic review and meta-analysis
    Objective:In a systematic review, we compared ratio of new periprocedural radiographic brain ischemia (RBI) to the number of strokes and TIAs among patients undergoing carotid endarterectomy (CEA) and carotid artery stenting (CAS).Methods:We searched 5 databases for entries related to brain ischemia in CEA or CAS from inception through September 2015. We included articles with CEA or CAS and systematic performance of preprocedural and postprocedural brain MRI and reporting of RBI and stroke incidence. We calculated a symptomatic risk ratio of number of strokes and TIAs to RBI. Random effects models were used.Results:Fifty-nine studies (5,431 participants) met the inclusion criteria. There were 22 cohorts in CEA, 34 in CAS with distal protection, 8 in CAS with proximal protection, 9 in CAS without protection, and 9 in CAS with unspecified devices. Overall, 30.7% (95% confidence interval [CI] 26.6%–34.7%) had RBI, while 3.2% (95% CI 2.6%–3.8%) had clinical strokes or TIAs, with a stroke and TIA to RBI weighted ratio of 0.18 (95% CI 0.15–0.22). CEA had lower incidence of RBI compared to CAS (13.0% vs 37.4%) and also lower number of strokes and TIAs (1.8% vs 4.1%). The stroke and TIA to RBI ratio did not differ across 5 different types of carotid interventions (p = 0.58).Conclusions:One in 5 persons with periprocedural radiographic brain ischemia during CEA and CAS had strokes and TIAs. The stable ratio of stroke and TIA to radiographic ischemia suggests that MRI ischemia could serve as a surrogate measure of periprocedural risk.
  • Volumetric brain changes in migraineurs from the general population
    Objective:To assess volumetric brain changes in migraineurs from the general population compared with controls.Methods:Structural brain changes in migraineurs from the general population-based MRI Cerebral Abnormalities in Migraine, an Epidemiologic Risk Analysis (CAMERA)-2 observational cohort study were assessed by state-of-the-art voxel-based morphometry. T1-weighted MRIs of 84 migraineurs (52 with aura, 32 without aura) and 35 headache-free controls were evaluated. Regional volumes were compared voxelwise, corrected for age, sex, and total intracranial volume, with region-of-interest and whole-brain analyses.Results:In region-of-interest analyses, migraineurs showed decreased gray matter volume in the visual areas V3 and V5 of the right occipital cortex compared to controls (p < 0.05, familywise error correction). Post hoc analyses revealed that similar changes were present regardless of migraine aura status, disease activity (>1 year attack-free [inactive] vs ≥1 attack within the last year [active] and attack frequency [≤1 (low) vs ≥1 attack per month [high]). In exploratory whole-brain analyses (p < 0.001, uncorrected for multiple comparisons), we identified additional structural differences in migraineurs in other cortical and subcortical areas, including white matter tracts, that are particularly involved in visual processing.Conclusions:Migraineurs from the general population showed small volumetric brain changes, mainly in cortical areas involved in visual motion processing, compared to controls. The presence of morphologic changes regardless of the presence of migraine aura or disease activity suggests that migraines with and without aura share common pathophysiologic pathways and suggests that these changes are (partially) irreversible or might have been present throughout life.
  • Population-based study of home-time by stroke type and correlation with modified Rankin score
    Objective:To describe home-time, stratified by stroke type, in a complete population and to determine its correlation with modified Rankin Scale (mRS) scores.Methods:We used linked administrative data to derive home-time in all patients admitted for a cerebrovascular event in Alberta, Canada, between 2012 and 2016. Home-time is the number of days spent outside a health institution in the first 90 days after index hospitalization. We used negative binomial regression, adjusted for age, sex, Charlson comorbidity index, and hospital location, to determine the association between home-time and stroke type. In 552 patients enrolled in 4 acute ischemic stroke clinical trials, we used multivariable ordinal logistic regression analysis to determine the association between home-time and mRS score at 90 days.Results:Among 15,644 patients (n = 10,428 with ischemic stroke, n = 1,415 with intracerebral hemorrhage, n = 760 with subarachnoid hemorrhage, n = 3,041 with TIA), patients with TIA have the longest home-time, almost triple the number of days at home compared to patients with intracerebral hemorrhage (incidence rate ratio 2.85, 95% confidence interval [CI] 2.58–3.15). Among clinical trial ischemic stroke patients, longer home-time was associated with a lower mRS score at 90 days (adjusted common odds ratio 1.04, 95% CI 1.04–1.05).Conclusions:We showed that home-time is an objective and graded indicator that is correlated with disability after stroke. It is obtainable from administrative data, applicable to different stroke types, and a valuable outcome indicator in population-based health services research.
  • TRMT5 mutations are associated with features of complex hereditary spastic paraparesis
    Mitochondrial DNA (mtDNA) encodes for 22 tRNAs (mt-tRNA) that undergo posttranscriptional modification.1,2 A specific nucleotide adjacent to the anticodon of mt-tRNA (position 37) is methylated (m1G37) to enhance translational efficiency/fidelity.3 The gene tRNA methyltransferase 5 (TRMT5) encodes a protein involved in m1G37 formation for some mitochondrial tRNAs3,4 and has been associated with combined oxidative phosphorylation deficiency 26 (COXPD26) (OMIM 616539).
  • Longitudinal decline of driving safety in Parkinson disease
    Objective:To longitudinally assess and predict on-road driving safety in Parkinson disease (PD).Methods:Drivers with PD (n = 67) and healthy controls (n = 110) drove a standardized route in an instrumented vehicle and were invited to return 2 years later. A professional driving expert reviewed drive data and videos to score safety errors.Results:At baseline, drivers with PD performed worse on visual, cognitive, and motor tests, and committed more road safety errors compared to controls (median PD 38.0 vs controls 30.5; p < 0.001). A smaller proportion of drivers with PD returned for repeat testing (42.8% vs 62.7%; p < 0.01). At baseline, returnees with PD made fewer errors than nonreturnees with PD (median 34.5 vs 40.0; p < 0.05) and performed similar to control returnees (median 33). Baseline global cognitive performance of returnees with PD was better than that of nonreturnees with PD, but worse than for control returnees (p < 0.05). After 2 years, returnees with PD showed greater cognitive decline and larger increase in error counts than control returnees (median increase PD 13.5 vs controls 3.0; p < 0.001). Driving error count increase in the returnees with PD was predicted by greater error count and worse visual acuity at baseline, and by greater interval worsening of global cognition, Unified Parkinson's Disease Rating Scale activities of daily living score, executive functions, visual processing speed, and attention.Conclusions:Despite drop out of the more impaired drivers within the PD cohort, returning drivers with PD, who drove like controls without PD at baseline, showed many more driving safety errors than controls after 2 years. Driving decline in PD was predicted by baseline driving performance and deterioration of cognitive, visual, and functional abnormalities on follow-up.
  • Successful motor mapping with transcranial magnetic stimulation in an infant: A case report
    Accurate assessment of motor function is critical, particularly in the context of presurgical functional mapping. There are a few noninvasive tools available for preoperative motor mapping in older children and adults undergoing surgery for brain tumor or refractory epilepsy including fMRI, magnetoencephalography (MEG), and transcranial magnetic stimulation (TMS).1,2 However, assessing motor function is challenging in very young children. Direct cortical stimulation, a standard procedure in adults, is associated with a high incidence of intraoperative seizures, and is often unsuccessful in young children.3,4 Alternately, noninvasive motor mapping using MEG and fMRI attempted during sleep or under sedation primarily localize the somatosensory cortex from which the location of motor cortex is inferred.5,6 Furthermore, these methods have a low success rate (~25%) and have risks associated with sedation.6 However, TMS has the advantage of mapping the motor cortex directly without requiring sedation. We have previously reported on successful mapping of the motor cortex in young children aged between 17 and 35 months.7 Here we describe a case of an 11-month-old infant who is, to our knowledge, the youngest person to undergo successful presurgical motor mapping with TMS.
  • Alzheimer dementia's other victim: The spouse
    Editor's Note: The initial portion of this essay is an excerpt from the author's book (Before I Forget: Love, Hope, Help, and Acceptance in our Fight Against Alzheimer's. Copyright © 2016 by B. Smith, Dan Gasby, and Michael Shnayerson. Published by Harmony Books, an imprint of Penguin Random House LLC), reprinted with permission. Following this excerpt is an update from the events chronicled in the book.
  • Subjective cognitive decline and {beta}-amyloid burden predict cognitive change in healthy elderly
    Objective:To assess in a longitudinal study whether subjective cognitive decline (SCD) and brain β-amyloid (Aβ) contribute unique information to cognitive decline.Methods:One hundred thirty-six healthy elderly from the Berkeley Aging Cohort Study were followed up for a mean of 4 years. SCD and affective measures were generated from the Geriatric Depression Scale (GDS) with factor analysis on data from a larger set of 347 healthy, nondepressed (GDS <11) elderly individuals. Cognition was summarized with previously validated factor scores. Pittsburgh compound B (PiB)-PET scans were acquired to determine the presence (PiB+) or absence (PiB–) of Aβ pathology. Mixed models were used to assess the independent and interactive effects of SCD, affective features, PiB status, and time on cognition, with adjustment for demographic variables.Results:SCD score demonstrated good construct validity compared to an existing measure of subjective memory and was partially explained by several lower-order measurements. Mixed models revealed that SCD interacted with PiB status to predict change in episodic memory and global cognition over time, with adjustment for affective features. PiB+ individuals with more severe SCD demonstrated the steepest cognitive decline. Worse SCD predicted faster decline in working memory independently of PiB status. No such effects were seen for affective scores when adjusted for SCD.Conclusions:PiB+ individuals with SCD are at greatest risk of cognitive decline. Evidence for amyloid alone is not sufficient to indicate risk of rapid cognitive decline in healthy elderly. Effects of GDS on cognitive decline in nondepressed cohorts may be driven by SCD rather than subsyndromal depression.
  • Clinical outcomes of asleep vs awake deep brain stimulation for Parkinson disease
    Objective:To compare motor and nonmotor outcomes at 6 months of asleep deep brain stimulation (DBS) for Parkinson disease (PD) using intraoperative imaging guidance to confirm electrode placement vs awake DBS using microelectrode recording to confirm electrode placement.Methods:DBS candidates with PD referred to Oregon Health & Science University underwent asleep DBS with imaging guidance. Six-month outcomes were compared to those of patients who previously underwent awake DBS by the same surgeon and center. Assessments included an "off"-levodopa Unified Parkinson’s Disease Rating Scale (UPDRS) II and III, the 39-item Parkinson's Disease Questionnaire, motor diaries, and speech fluency.Results:Thirty participants underwent asleep DBS and 39 underwent awake DBS. No difference was observed in improvement of UPDRS III (+14.8 ± 8.9 vs +17.6 ± 12.3 points, p = 0.19) or UPDRS II (+9.3 ± 2.7 vs +7.4 ± 5.8 points, p = 0.16). Improvement in "on" time without dyskinesia was superior in asleep DBS (+6.4 ± 3.0 h/d vs +1.7 ± 1.2 h/d, p = 0.002). Quality of life scores improved in both groups (+18.8 ± 9.4 in awake, +8.9 ± 11.5 in asleep). Improvement in summary index (p = 0.004) and subscores for cognition (p = 0.011) and communication (p < 0.001) were superior in asleep DBS. Speech outcomes were superior in asleep DBS, both in category (+2.77 ± 4.3 points vs –6.31 ± 9.7 points (p = 0.0012) and phonemic fluency (+1.0 ± 8.2 points vs –5.5 ± 9.6 points, p = 0.038).Conclusions:Asleep DBS for PD improved motor outcomes over 6 months on par with or better than awake DBS, was superior with regard to speech fluency and quality of life, and should be an option considered for all patients who are candidates for this treatment.Clinicaltrials.gov identifier:NCT01703598.Classification of evidence:This study provides Class III evidence that for patients with PD undergoing DBS, asleep intraoperative CT imaging–guided implantation is not significantly different from awake microelectrode recording–guided implantation in improving motor outcomes at 6 months.
  • Prediction of work resumption and sustainability up to 1 year after mild traumatic brain injury
    Objective:To study return to work (RTW) after mild traumatic brain injury (mTBI) at several intervals after injury and to predict RTW on the basis of occupational factors in addition to demographic, personality, and injury-related factors at 6 and 12 months after injury.Methods:This was a prospective cohort study (UPFRONT study, n = 1,151) of patients with mTBI admitted to the emergency department. Patients received questionnaires at 2 weeks and 3, 6, and 12 months after injury. RTW was divided into 3 levels: complete (cRTW), partial (pRTW), and no RTW.Results:Rates of cRTW increased from 34% at 2 weeks to 77% at 12 months after injury, pRTW varied from 8% to 16% throughout the year. Logistic regression (complete vs incomplete RTW) demonstrated that apart from previously identified predictors such as demographics (e.g., age and education) and injury characteristics (e.g., cause and severity of injury) and indicators of psychological distress, occupational factors were of influence on work resumption after 6 months (area under the curve [AUC] = 0.82), At 12 months, however, the model was based solely on the presence of extracranial injuries and indicators of maladaptation after injury (AUC = 0.81).Conclusions:RTW after mTBI is a gradual process, with varying levels of RTW throughout the first year after injury. Different predictors were relevant for short- vs long-term work resumption, with occupational factors influencing short-term RTW. However, for both short- and long-term RTW, posttraumatic complaints and signs of psychological distress early after injury were relevant predictors, allowing early identification of patients at risk for problematic work resumption.
  • Is virtual reality a useful adjunct to rehabilitation after spinal cord injury?
    Spinal cord injury (SCI) has devastating effects on the CNS, leading to disruption of various neuromuscular, sensory, and autonomic pathways. However, the changes induced in the nervous system extend well beyond the tracts and neurons directly disrupted starting soon after the injury.1 There is substantial neural plasticity that takes place throughout the CNS, including the cortex.2 Trying to improve function and pain after a peripheral injury by intervening at the cortical level has been explored since the mid-1990s with classic mirror box therapy for phantom limb pain.3
  • To sleep or not to sleep during deep brain stimulation surgery for Parkinson disease?
    In functional stereotactic neurosurgery, precise placement of lesions or deep brain stimulation (DBS) electrodes is paramount. From the beginning of the specialty, electrical stimulation of the brain target prior to lesioning, and confirmation of accuracy of targeting by postoperative imaging, have been critical.1 Two schools subsequently evolved: one using macroelectrode stimulation in the awake patient with careful on-table assessment and one using microelectrode recording (MER) to map out boundaries of the target followed by microstimulation to assess efficacy and avoid side effects. For many, the latter technique was adopted as the gold standard, but the evidence to support the superior efficacy or better safety of this stance was lacking.2
  • Virtual reality improves embodiment and neuropathic pain caused by spinal cord injury
    Objective:To investigate changes in body ownership and chronic neuropathic pain in patients with spinal cord injury (SCI) using multisensory own body illusions and virtual reality (VR).Methods:Twenty patients with SCI with paraplegia and 20 healthy control participants (HC) participated in 2 factorial, randomized, repeated-measures design studies. In the virtual leg illusion (VLI), we applied asynchronous or synchronous visuotactile stimulation to the participant's back (either immediately above the lesion level or at the shoulder) and to the virtual legs as seen on a VR head-mounted display. We tested the effect of the VLI on the sense of leg ownership (questionnaires) and on perceived neuropathic pain (visual analogue scale pain ratings). We compared illusory leg ownership with illusory global body ownership (induced in the full body illusion [FBI]), by applying asynchronous or synchronous visuotactile stimulation to the participant's back and the back of a virtual body as seen on a head-mounted display.Results:Our data show that patients with SCI are less sensitive to multisensory stimulations inducing illusory leg ownership (as compared to HC) and that leg ownership decreased with time since SCI. In contrast, we found no differences between groups in global body ownership as tested in the FBI. VLI and FBI were both associated with mild analgesia that was only during the VLI specific for synchronous visuotactile stimulation and the lower back position.Conclusions:The present findings show that VR exposure using multisensory stimulation differently affected leg vs body ownership, and is associated with mild analgesia with potential for SCI neurorehabilitation protocols.
  • Thrombolysis in acute ischemic stroke in patients with dementia: A Swedish registry study
    Objective:To compare access to intravenous thrombolysis (IVT) for acute ischemic stroke (AIS) and its outcomes in patients with and without dementia.Methods:This was a longitudinal cohort study of the Swedish dementia and stroke registries. Patients with preexisting dementia who had AIS from 2010 to 2014 (n = 1,356) were compared with matched patients without dementia (n = 6,755). We examined access to thrombolysis and its outcomes at 3 months (death, residency, and modified Rankin Scale [mRS] score). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated with logistic and ordinal logistic regression.Results:The median age at stroke onset was 83 years in both groups. IVT was administered to 94 (7.0%) patients with dementia and 639 (9.5%) patients without dementia. The OR of receiving IVT was 0.68 (95% CI 0.54–0.86) for patients with dementia. When the analysis was repeated exclusively among patients independent in everyday activities, dementia status was no longer significant (OR 0.79, 95% CI 0.60–1.06). However, differences persisted in patients ≤80 years of age (OR 0.58, 95% CI 0.36–0.94). In patients who received thrombolysis, the incidence of symptomatic intracerebral hemorrhage (sICH; 7.4% vs 7.3%) and death at 3 months (22.0% vs 18.8%) did not differ significantly between the 2 groups. However, mRS score and accommodation status were worse among patients with dementia after 3 months in adjusted analyses (both p < 0.001). Unfavorable outcomes with an mRS score of 5 to 6 were doubled in patients with dementia (56.1% vs 28.1%).Conclusions:Younger patients with dementia and AIS are less likely to receive IVT. Among patients receiving thrombolysis, there are no differences in sICH or death, although patients with dementia have worse accommodation and functional outcomes at 3 months.
  • Prevalence and clinical features of neuromyelitis optica spectrum disorders in northern Japan
    Objective:To clarify the prevalence and clinical characteristics of neuromyelitis optica spectrum disorders (NMOSD) in Japan and compare them with those in other ethnic populations.Methods:Data processing sheets were sent to all related institutions in northern Japan and were collected from April to May 2016. Prevalence was determined on March 31, 2016, using the 2015 International Panel for NMO Diagnosis criteria.Results:The crude prevalence was 4.1/100,000 (95% confidence interval 2.2–6.9) for NMOSD in northern Japan, with a significantly higher number of female than male patients (female: male 12:2). The positivity for anti-aquaporin-4 antibody was 78.6%, and the mean age at onset was 45.2 years. All patients were subjected to preventive therapy in the form of treatment with steroids or immunosuppressive agents.Conclusions:Our results showed that the prevalence of NMOSD in the Japanese population is similar to that in Caucasians.
  • Polycystic kidney disease among 4,436 intracranial aneurysm patients from a defined population
    Objective:To define the association of autosomal dominant polycystic kidney disease (ADPKD) with the characteristics of aneurysmal subarachnoid hemorrhage (aSAH) and unruptured intracranial aneurysm (IA) disease.Methods:We fused data from the Kuopio Intracranial Aneurysm database (n = 4,436 IA patients) and Finnish nationwide registries into a population-based series of 53 IA patients with ADPKD to compare the aneurysm- and patient-specific characteristics of IA disease in ADPKD and in the general IA population, and to identify risks for de novo IA formation.Results:In total, there were 33 patients with ADPKD with aSAH and 20 patients with ADPKD with unruptured IAs. The median size of ruptured IAs in ADPKD was significantly smaller than in the general population (6.00 vs 8.00 mm) and the proportion of small ruptured IAs was significantly higher (31% vs 18%). Median age at aSAH was 42.8 years, 10 years younger than in the general IA population. Multiple IAs were present in 45% of patients with ADPKD compared to 28% in the general IA population. Cumulative risk of de novo IA formation was 1.3% per patient-year (vs 0.2% in the general IA population). Hazard for de novo aneurysm formation was significantly elevated in patients with ADPKD (Cox regression hazard ratio 7.7, 95% confidence interval 2.8–20; p < 0.0005).Conclusions:Subarachnoid hemorrhage occurs at younger age and from smaller IAs in patients with ADPKD and risk for de novo IAs is higher than in the general Eastern Finnish population. ADPKD should be considered as an indicator for long-term angiographic follow-up in patients with diagnosed IAs.
  • The social and economic burden of frontotemporal degeneration
    Objective:To quantify the socioeconomic burden of frontotemporal degeneration (FTD) compared to previously published data for Alzheimer disease (AD).Methods:A 250-item internet survey was administered to primary caregivers of patients with behavioral-variant FTD (bvFTD), primary progressive aphasia, FTD with motor neuron disease, corticobasal syndrome, or progressive supranuclear palsy. The survey included validated scales for disease staging, behavior, activities of daily living, caregiver burden, and health economics, as well as investigator-designed questions to capture patient and caregiver experience with FTD.Results:The entire survey was completed by 674 of 956 respondents (70.5%). Direct costs (2016 US dollars) equaled $47,916 and indirect costs $71,737, for a total annual per-patient cost of $119,654, nearly 2 times higher than reported costs for AD. Patients ≥65 years of age, with later stages of disease, and with bvFTD correlated with higher direct costs, while patients <65 years of age and men were associated with higher indirect costs. An FTD diagnosis produced a mean decrease in household income from $75,000 to $99,000 12 months before diagnosis to $50,000 to $59,999 12 months after diagnosis, resulting from lost days of work and early departure from the workforce.Conclusions:The economic burden of FTD is substantial. Counting productivity-related costs, per-patient costs for FTD appear to be greater than per-patient costs reported for AD. There is a need for biomarkers for accurate and timely diagnosis, effective treatments, and services to reduce this socioeconomic burden.
  • Polycystic kidney disease and intracranial aneurysms: Some answers, but many questions remain
    Unruptured intracranial aneurysms (UIA) occur in about 2%–3% of the population. Several medical conditions are associated with a UIA presence, including autosomal dominant polycystic kidney disease (ADPKD). Clinicians and patients want to know the risk of aneurysm growth, rupture, or de novo development, predictors of clinical outcomes, and the optimal initial and follow-up screening for individuals with UIA and ADPKD. Such data are unavailable. The recent American Heart Association–American Stroke Association statement on UIAs recommends that patients with familial risk and patients with conditions in which aneurysms are prevalent such as ADPKD be offered screening.1 The evidence for this recommendation comes from cross-sectional studies of screening in patients with clinically diagnosed ADPKD and follow-up for aneurysmal subarachnoid hemorrhage (aSAH) with substantial variation in prevalence estimates. A few studies, with a small sample size, have clinical and radiologic follow-up for aSAH, aneurysmal change, or new aneurysm development.
  • Female sex, early-onset hypertension, and risk of dementia
    Objective:To evaluate the association of early-adulthood and mid-adulthood hypertension with dementia in men and women.Methods:We evaluated 5,646 members of a diverse integrated health care delivery system who had clinical examinations and health survey data from 1964 to 1973 (mean age 32.7 years; early adulthood) and 1978–1985 (mean age 44.3 years; mid-adulthood) and were members as of January 1, 1996 (mean age 59.8 years). Hypertension categories based on measurements of blood pressure (BP) and change in hypertension categories between the 2 examinations (e.g., onset hypertension) were used to predict dementia incidence from January 1, 1996, to September 30, 2015. Cox proportional hazard models were adjusted for demographics, vascular comorbidities, and hypertension treatment; inverse probability weighting accounted for differential attrition between first BP measurement and start of follow-up.Results:A total of 532 individuals (9.4%) were diagnosed with dementia. Early adulthood hypertension was not associated with dementia, though effect estimates were elevated among women. Mid-adulthood hypertension was associated with 65% (95% confidence interval [CI] 1.25–2.18) increased dementia risk among women but not men. Onset of hypertension in mid-adulthood predicted 73% higher dementia risk in women (95% CI 1.24–2.40) compared to stable normotensive. There was no evidence that hypertension or changes in hypertension increased dementia risk among men.Conclusions:Though midlife hypertension was more common in men, it was only associated with dementia risk in women. Sex differences in the timing of dementia risk factors have important implications for brain health and hypertension management.
  • Change in multimodal MRI markers predicts dementia risk in cerebral small vessel disease
    Objective:To determine whether MRI markers, including diffusion tensor imaging (DTI), can predict cognitive decline and dementia in patients with cerebral small vessel disease (SVD).Methods:In the prospective St George's Cognition and Neuroimaging in Stroke study, multimodal MRI was performed annually for 3 years and cognitive assessments annually for 5 years in a cohort of 99 patients with SVD, defined as symptomatic lacunar stroke and confluent white matter hyperintensities (WMH). Progression to dementia was determined in all patients. Progression of WMH, brain volume, lacunes, cerebral microbleeds, and a DTI measure (the normalized peak height of the mean diffusivity histogram distribution) as a marker of white matter microstructural damage were determined.Results:Over 5 years of follow-up, 18 patients (18.2%) progressed to dementia. A significant change in all MRI markers, representing deterioration, was observed. The presence of new lacunes, and rate of increase in white matter microstructural damage on DTI, correlated with both decline in executive function and global functioning. Growth of WMH and deterioration of white matter microstructure on DTI predicted progression to dementia. A model including change in MRI variables together with their baseline values correctly classified progression to dementia with a C statistic of 0.85.Conclusions:This longitudinal prospective study provides evidence that change in MRI measures including DTI, over time durations during which cognitive change is not detectable, predicts cognitive decline and progression to dementia. It supports the use of MRI measures, including DTI, as useful surrogate biomarkers to monitor disease and assess therapeutic interventions.
  • Traumatic brain injury may not increase the risk of Alzheimer disease
    Traumatic brain injury (TBI) commonly occurs in civilian and military populations. Some epidemiologic studies previously have associated TBI with an increased risk of Alzheimer disease (AD). Recent clinicopathologic and biomarker studies have failed to confirm the relationship of TBI to the development of AD dementia or pathologic changes, and suggest that other neurodegenerative processes might be linked to TBI. Additional studies are required to determine the long-term consequences of TBI.
  • The beginning of precision medicine in ALS?: Treatment to fit the genes
    Amyotrophic lateral sclerosis (ALS) affects approximately 1 in 400 adults of western European ancestry, making it the most common degenerative disease of the motor neuron network. ALS has a mean age at onset of 65 and 85%–90% of cases occur sporadically. Ten to fifteen percent of cases have a recognized genetic contribution, usually in known ALS gene-carrying families.1 In populations of European extraction, the commonest cause of familial ALS, accounting for up to 40% of familial cases, is the C9orf72 hexanucleotide repeat expansion.2 C9orf72 has a broader associated phenotype including frontotemporal dementia and a more rapid clinical progression. Men with spinal-onset disease have a lower median age at onset and drive the more rapid clinical progression.2 Other gene variants also associate with earlier age at onset and more rapid progression; for example, the A4V variant mutated SOD1 gene.3
  • Association of metabolic syndrome and change in Unified Parkinson's Disease Rating Scale scores
    Objective:To explore the association between metabolic syndrome and the Unified Parkinson’s Disease Rating Scale (UPDRS) scores and, secondarily, the Symbol Digit Modalities Test (SDMT).Methods:This is a secondary analysis of data from 1,022 of 1,741 participants of the National Institute of Neurological Disorders and Stroke Exploratory Clinical Trials in Parkinson Disease Long-Term Study 1, a randomized, placebo-controlled trial of creatine. Participants were categorized as having or not having metabolic syndrome on the basis of modified criteria from the National Cholesterol Education Program Adult Treatment Panel III. Those who had the same metabolic syndrome status at consecutive annual visits were included. The change in UPDRS and SDMT scores from randomization to 3 years was compared in participants with and without metabolic syndrome.Results:Participants with metabolic syndrome (n = 396) compared to those without (n = 626) were older (mean [SD] 63.9 [8.1] vs 59.9 [9.4] years; p < 0.0001), were more likely to be male (75.3% vs 57.0%; p < 0.0001), and had a higher mean uric acid level (men 5.7 [1.3] vs 5.3 [1.1] mg/dL, women 4.9 [1.3] vs 3.9 [0.9] mg/dL, p < 0.0001). Participants with metabolic syndrome experienced an additional 0.6- (0.2) unit annual increase in total UPDRS (p = 0.02) and 0.5- (0.2) unit increase in motor UPDRS (p = 0.01) scores compared with participants without metabolic syndrome. There was no difference in the change in SDMT scores.Conclusions:Persons with Parkinson disease meeting modified criteria for metabolic syndrome experienced a greater increase in total UPDRS scores over time, mainly as a result of increases in motor scores, compared to those who did not. Further studies are needed to confirm this finding.ClinicalTrials.gov identifier:NCT00449865.
  • Can lifestyle modification slow progression of Parkinson disease?
    Parkinson disease (PD), similar to other neurodegenerative conditions, is characterized by relentless clinical progression with gradual worsening of both motor and nonmotor features. Potential neuroprotective therapies focusing on aspects of neurodegeneration in PD such as impaired mitochondrial function with abnormalities of oxidative phosphorylation, increased oxidative stress, and suppressed neuroinflammation, have failed to alter the clinical course of PD.1,2 New insights into PD pathophysiology have identified potential molecular targets, including accumulation and potential prion-like spreading of aggregates containing misfolded α-synuclein protein.3 These therapies are only approaching clinical testing, and their true therapeutic potential remains unknown. Even if successful, they are many years away from clinical availability. Thus, at present, we do not have any proven pharmacologic options to modify the progressive decline of patients with PD.
  • A phase 3 randomized placebo-controlled trial of tadalafil for Duchenne muscular dystrophy
    Objective:To conduct a randomized trial to test the primary hypothesis that once-daily tadalafil, administered orally for 48 weeks, lessens the decline in ambulatory ability in boys with Duchenne muscular dystrophy (DMD).Methods:Three hundred thirty-one participants with DMD 7 to 14 years of age taking glucocorticoids were randomized to tadalafil 0.3 mg·kg–1·d–1, tadalafil 0.6 mg·kg–1·d–1, or placebo. The primary efficacy measure was 6-minute walk distance (6MWD) after 48 weeks. Secondary efficacy measures included North Star Ambulatory Assessment and timed function tests. Performance of Upper Limb (PUL) was a prespecified exploratory outcome.Results:Tadalafil had no effect on the primary outcome: 48-week declines in 6MWD were 51.0 ± 9.3 m with placebo, 64.7 ± 9.8 m with low-dose tadalafil (p = 0.307 vs placebo), and 59.1 ± 9.4 m with high-dose tadalafil (p = 0.538 vs placebo). Tadalafil also had no effect on secondary outcomes. In boys >10 years of age, total PUL score and shoulder subscore declined less with low-dose tadalafil than placebo. Adverse events were consistent with the known safety profile of tadalafil and the DMD disease state.Conclusions:Tadalafil did not lessen the decline in ambulatory ability in boys with DMD. Further studies should be considered to confirm the hypothesis-generating upper limb data and to determine whether ambulatory decline can be slowed by initiation of tadalafil before 7 years of age.Clinicaltrials.gov identifier:NCT01865084.Classification of evidence:This study provides Class I evidence that tadalafil does not slow ambulatory decline in 7- to 14-year-old boys with Duchenne muscular dystrophy.
  • Effects of acute intermittent hypoxia on hand use after spinal cord trauma: A preliminary study
    Objective:To test the hypothesis that daily acute intermittent hypoxia (AIH) combined with hand opening practice improves hand dexterity, function, and maximum hand opening in persons with chronic, motor-incomplete, cervical spinal cord injury.Methods:Six participants completed the double-blind, crossover study. Participants received daily (5 consecutive days) AIH (15 episodes per day: 1.5 minutes of fraction of inspired oxygen [FIo2] = 0.09, 1-minute normoxic intervals) followed by 20 repetitions of hand opening practice and normoxia (sham, FIo2 = 0.21) + hand opening practice. Hand dexterity and function were quantified with Box and Block and Jebsen-Taylor hand function tests. We also recorded maximum hand opening using motion analyses and coactivity of extensor digitorum and flexor digitorum superficialis muscles using surface EMG.Results:Daily AIH + hand opening practice improved hand dexterity, function, and maximum hand opening in all participants. AIH + hand opening practice improved Box and Block Test scores vs baseline in 5 participants (p = 0.057) and vs sham + hand opening practice in all 6 participants (p = 0.016). All participants reduced Jebsen-Taylor Hand Function Test (JTHF) time after daily AIH + hand opening practice (–7.2 ± 1.4 seconds) vs baseline; 4 of 6 reduced JTHF time vs sham + hand opening practice (p = 0.078). AIH + hand opening practice improved maximum hand aperture in 5 of 6 participants (8.1 ± 2.7 mm) vs baseline (p = 0.018) and sham + hand opening practice (p = 0.030). In 5 participants, daily AIH–induced changes in hand opening were accompanied by improved EMG coactivity (p = 0.029).Conclusions:This report suggests the need for further study of AIH as a plasticity "primer" for task-specific training in spinal cord injury rehabilitation. Important clinical questions remain concerning optimal AIH dosage, patient screening, safety, and effect persistence.ClinicalTrials.gov identifier:NCT01272336.
  • Anti-cytosolic 5'-nucleotidase 1A (cN1A) autoantibodies in motor neuron diseases
    Inclusion body myositis (IBM) is the most common acquired muscle disease in patients older than 50 years. Asymmetric weakness and early involvement of quadriceps and forearm flexors are key clinical features. Muscle biopsy remains the gold standard diagnostic test, which has high specificity, but low sensitivity.1 In addition to the canonical pathologic features of IBM, upregulation of major histocompatibility complex class I and accumulation of various proteins (p62, SMI-31, and TDP-43) have been adopted to the 2011 European Neuromuscular Center diagnostic criteria for IBM.1 The recent identification of anti-cytosolic 5'-nucleotidase 1A (cN1A) autoantibodies by immunoblotting in patients with IBM has raised the question whether we should incorporate these particular antibodies into the diagnostic criteria for IBM.2,3 Anti-cN1A antibodies may be positive several years predating the IBM diagnosis.3 The clinical features of patients with motor neuron disease (MND) with lower motor neuron findings could resemble those of patients with IBM, given their common age group and asymmetry in muscle weakness and atrophy. Here I present 2 patients with MND who had positive anti-cN1A antibodies.
  • Oral antidiabetic drugs and dementia risk: Does treatment matter?
    As the population ages, dementia grows as a public health problem. The rising life expectancy and the aging of the so-called baby boomer cohort translate to a substantial number of people reaching ages of high risk for age-related conditions like dementia. As a major cause of disability and dependency in elderly people, dementia puts social and economic burden on patients and their families and affects health care systems worldwide. In the absence of a cure, primary prevention will have the largest effect on the reduction of dementia occurrence.1 Thus, public health research should focus on the identification of modifiable risk factors for dementia. Diabetes mellitus is an established risk factor for dementia. Patients with diabetes have an increased risk for any dementia, Alzheimer disease, and vascular dementia.2 The exact mechanisms of cognitive impairment in diabetic patients remain unknown. The main contributors to diabetes-associated cognitive decline include hyperglycemia, decreased insulin secretion, obesity, increased oxidative stress, and inflammation.3 Diabetes not only promotes neurodegeneration but also induces cerebrovascular pathologies such as stroke, which in turn are further risk factors for dementia.4 Furthermore, patients with diabetes often have other comorbidities such as high blood pressure and cardiovascular disease that may contribute to the development of dementia. About 12%–14% of US adults have diabetes.5 An effective treatment could prevent harmful effects of diabetes on cognition. Several studies have examined the association of different antidiabetic medications and cognitive function. Results from epidemiologic studies conflict. Some found protective effects of oral antidiabetic medications such as metformin on dementia risk; others detected deleterious effects.6,7
  • Caffeine as symptomatic treatment for Parkinson disease (Cafe-PD): A randomized trial
    Objective:To assess effects of caffeine on Parkinson disease (PD).Methods:In this multicenter parallel-group controlled trial, patients with PD with 1–8 years disease duration, Hoehn & Yahr stages I–III, on stable symptomatic therapy were randomized to caffeine 200 mg BID vs matching placebo capsules for 6–18 months. The primary research question was whether objective motor scores would differ at 6 months (Movement Disorder Society–sponsored Unified Parkinson's Disease Rating Scale [MDS-UPDRS]–III, Class I evidence). Secondary outcomes included safety and tolerability, motor symptoms (MDS-UPDRS-II), motor fluctuations, sleep, nonmotor symptoms (MDS-UPDRS-I), cognition (Montreal Cognitive Assessment), and quality of life.Results:Sixty patients received caffeine and 61 placebo. Caffeine was well-tolerated with similar prevalence of side effects as placebo. There was no improvement in motor parkinsonism (the primary outcome) with caffeine treatment compared to placebo (difference between groups –0.48 [95% confidence interval –3.21 to 2.25] points on MDS-UPDRS-III). Similarly, on secondary outcomes, there was no change in motor signs or motor symptoms (MDS-UPDRS-II) at any time point, and no difference on quality of life. There was a slight improvement in somnolence over the first 6 months, which attenuated over time. There was a slight increase in dyskinesia with caffeine (MDS-UPDRS-4.1+4.2 = 0.25 points higher), and caffeine was associated with worse cognitive testing scores (average Montreal Cognitive Assessment = 0.66 [0.01, 1.32] worse than placebo).Conclusion:Caffeine did not provide clinically important improvement of motor manifestations of PD (Class I evidence). Epidemiologic links between caffeine and lower PD risk do not appear to be explained by symptomatic effects.Clinicaltrials.gov identifier:NCT01738178.Classification of evidence:This study provides Class I evidence that for patients with PD, caffeine does not significantly improve motor manifestations.
  • Virtually reducing fall risk in Parkinson disease
    Falls are common and often represent devastating events for patients with advanced Parkinson disease (PD). Prospective studies report that 70% of people with PD have at least one fall in a year, and that 39% fall recurrently. Falls have serious consequences (fractures and other injury, hospital admission, fear of falls, and an increase in caregiver burden).1,2 The few available treatment options are not highly effective.
  • Metformin vs sulfonylurea use and risk of dementia in US veterans aged >=65 years with diabetes
    Objective:To determine whether metformin is associated with a lower incidence of dementia than sulfonylureas.Methods:This was a retrospective cohort study of US veterans ≥65 years of age with type 2 diabetes who were new users of metformin or a sulfonylurea and had no dementia. Follow-up began after 2 years of therapy. To account for confounding by indication, we developed a propensity score (PS) and used inverse probability of treatment weighting (IPTW) methods. Cox proportional hazards models estimated the hazard ratio (HR) of incident dementia.Results:We identified 17,200 new users of metformin and 11,440 new users of sulfonylureas. Mean age was 73.5 years and mean HbA1c was 6.8%. Over an average follow-up of 5 years, 4,906 cases of dementia were diagnosed. Due to effect modification by age, all analyses were conducted using a piecewise model for age. Crude hazard ratio [HR] for any dementia in metformin vs sulfonylurea users was 0.67 (95% confidence interval [CI] 0.61–0.73) and 0.78 (95% CI 0.72–0.83) for those <75 years of age and ≥75 years of age, respectively. After PS IPTW adjustment, results remained significant in veterans <75 years of age (HR 0.89; 95% CI 0.79–0.99), but not for those ≥75 years of age (HR 0.96; 95% CI 0.87–1.05). A lower risk of dementia was also seen in the subset of younger veterans who had HbA1C values ≥7% (HR 0.76; 95% CI 0.63–0.91), had good renal function (HR 0.86; 95% CI 0.76–0.97), and were white (HR 0.87; 95% CI 0.77–0.99).Conclusions:After accounting for confounding by indication, metformin was associated with a lower risk of subsequent dementia than sulfonylurea use in veterans <75 years of age. Further work is needed to identify which patients may benefit from metformin for the prevention of dementia.
  • UFM1 founder mutation in the Roma population causes recessive variant of H-ABC
    Objective:To identify the gene defect in patients with hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) who are negative for TUBB4A mutations.Methods:We performed homozygosity mapping and whole exome sequencing (WES) to detect the disease-causing variant. We used a Taqman assay for population screening. We developed a luciferase reporter construct to investigate the effect of the promoter mutation on expression.Results:Sixteen patients from 14 families from different countries fulfilling the MRI criteria for H-ABC exhibited a similar, severe clinical phenotype, including lack of development and a severe epileptic encephalopathy. The majority of patients had a known Roma ethnic background. Single nucleotide polymorphism array analysis in 5 patients identified one large overlapping homozygous region on chromosome 13. WES in 2 patients revealed a homozygous deletion in the promoter region of UFM1. Sanger sequencing confirmed homozygosity for this variant in all 16 patients. All patients shared a common haplotype, indicative of a founder effect. Screening of 1,000 controls from different European Roma panels demonstrated an overall carrier rate of the mutation of 3%–25%. Transfection assays showed that the deletion significantly reduced expression in specific CNS cell lines.Conclusions:UFM1 encodes ubiquitin-fold modifier 1 (UFM1), a member of the ubiquitin-like family involved in posttranslational modification of proteins. Its exact biological role is unclear. This study associates a UFM1 gene defect with a disease and sheds new light on possible UFM1 functional networks.
  • Deciphering neurodegeneration: A paradigm shift from focality to connectivity
    "Wet or dry" is the fundamental dichotomy of biomarker research, referring to biofluid vs imaging-based approaches. Biomarker development in neurodegeneration has gained unprecedented momentum in recent years. Despite the substantial diagnostic advantages of molecular PET and biofluid markers, accurate prognostic indicators and sensitive monitoring markers are urgently required both for clinical trial designs and individualized patient care.
  • COL4A2 is associated with lacunar ischemic stroke and deep ICH: Meta-analyses among 21,500 cases and 40,600 controls
    Objective:To determine whether common variants in familial cerebral small vessel disease (SVD) genes confer risk of sporadic cerebral SVD.Methods:We meta-analyzed genotype data from individuals of European ancestry to determine associations of common single nucleotide polymorphisms (SNPs) in 6 familial cerebral SVD genes (COL4A1, COL4A2, NOTCH3, HTRA1, TREX1, and CECR1) with intracerebral hemorrhage (ICH) (deep, lobar, all; 1,878 cases, 2,830 controls) and ischemic stroke (IS) (lacunar, cardioembolic, large vessel disease, all; 19,569 cases, 37,853 controls). We applied data quality filters and set statistical significance thresholds accounting for linkage disequilibrium and multiple testing.Results:A locus in COL4A2 was associated (significance threshold p < 3.5 x 10–4) with both lacunar IS (lead SNP rs9515201: odds ratio [OR] 1.17, 95% confidence interval [CI] 1.11–1.24, p = 6.62 x 10–8) and deep ICH (lead SNP rs4771674: OR 1.28, 95% CI 1.13–1.44, p = 5.76 x 10–5). A SNP in HTRA1 was associated (significance threshold p < 5.5 x 10–4) with lacunar IS (rs79043147: OR 1.23, 95% CI 1.10–1.37, p = 1.90 x 10–4) and less robustly with deep ICH. There was no clear evidence for association of common variants in either COL4A2 or HTRA1 with non-SVD strokes or in any of the other genes with any stroke phenotype.Conclusions:These results provide evidence of shared genetic determinants and suggest common pathophysiologic mechanisms of distinct ischemic and hemorrhagic cerebral SVD stroke phenotypes, offering new insights into the causal mechanisms of cerebral SVD.
  • Disparate effects of training on brain activation in Parkinson disease
    Objective:To compare the effects of 2 forms of exercise, i.e., a 6-week trial of treadmill training with virtual reality (TT + VR) that targets motor and cognitive aspects of safe ambulation and a 6-week trial of treadmill training alone (TT), on brain activation in patients with Parkinson disease (PD).Methods:As part of a randomized controlled trial, patients were randomly assigned to 6 weeks of TT (n = 17, mean age 71.5 ± 1.5 years, disease duration 11.6 ± 1.6 years; 70% men) or TT + VR (n = 17, mean age 71.2 ± 1.7 years, disease duration 7.9 ± 1.4 years; 65% men). A previously validated fMRI imagery paradigm assessed changes in neural activation pretraining and post-training. Participants imagined themselves walking in 2 virtual scenes projected in the fMRI: (1) a clear path and (2) a path with virtual obstacles. Whole brain and region of interest analyses were performed.Results:Brain activation patterns were similar between training arms before the interventions. After training, participants in the TT + VR arm had lower activation than the TT arm in Brodmann area 10 and the inferior frontal gyrus (cluster level familywise error–corrected [FWEcorr] p < 0.012), while the TT arm had lower activation than TT + VR in the cerebellum and middle temporal gyrus (cluster level FWEcorr p < 0.001). Changes in fall frequency and brain activation were correlated in the TT + VR arm.Conclusions:Exercise modifies brain activation patterns in patients with PD in a mode-specific manner. Motor-cognitive training decreased the reliance on frontal regions, which apparently resulted in improved function, perhaps reflecting increased brain efficiency.
  • Brain network connectivity differs in early-onset neurodegenerative dementia
    Objective:To investigate functional brain network architecture in early-onset Alzheimer disease (EOAD) and behavioral variant frontotemporal dementia (bvFTD).Methods:Thirty-eight patients with bvFTD, 37 patients with EOAD, and 32 age-matched healthy controls underwent 3D T1-weighted and resting-state fMRI. Graph analysis and connectomics assessed global and local functional topologic network properties, regional functional connectivity, and intrahemispheric and interhemispheric between-lobe connectivity.Results:Despite similarly extensive cognitive impairment relative to controls, patients with EOAD showed severe global functional network alterations (lower mean nodal strength, local efficiency, clustering coefficient, and longer path length), while patients with bvFTD showed relatively preserved global functional brain architecture. Patients with bvFTD demonstrated reduced nodal strength in the frontoinsular lobe and a relatively focal altered functional connectivity of frontoinsular and temporal regions. Functional connectivity breakdown in the posterior brain nodes, particularly in the parietal lobe, differentiated patients with EOAD from those with bvFTD. While EOAD was associated with widespread loss of both intrahemispheric and interhemispheric functional correlations, bvFTD showed a preferential disruption of the intrahemispheric connectivity.Conclusions:Disease-specific patterns of functional network topology and connectivity alterations were observed in patients with EOAD and bvFTD. Graph analysis and connectomics may aid clinical diagnosis and help elucidate pathophysiologic differences between neurodegenerative dementias.
  • Caffeine and PD--Time to consider other interventions
    Multiple studies have consistently linked the use of caffeine, an adenosine antagonist, to a lower risk of Parkinson disease (PD). The combined relative risk in a recent meta-analysis was 0.67 (95% confidence interval [CI] 0.58, 0.76).1 The mechanism for this robust finding is unclear. Although a neuroprotective effect is possible,2,3 there are other explanations, including reverse causality (prodromal PD reduces tolerability, benefit, or desire for caffeine), symptomatic benefit (caffeine treats motor symptoms, so delays diagnosis), or residual confounding by another factor (e.g., the Parkinson personality or changes in reward mechanisms).
  • Neurolymphomatosis of the thoracic sympathetic chain
    Neurolymphomatosis (NL) is defined as lymphomatous invasion of cranial or peripheral nerves by non-Hodgkin lymphoma (NHL). While most cases of NL are due to secondary dissemination from systemic or CNS sites, in rare cases it can be the primary manifestation of the malignancy.1–3 Early recognition of the disease and its precise neuroanatomic localization is critical for successful treatment.
  • Neurogranin, a synaptic protein, is associated with memory independent of Alzheimer biomarkers
    Objective:To determine the association between synaptic functioning as measured via neurogranin in CSF and cognition relative to established Alzheimer disease (AD) biomarkers in neurologically healthy older adults.Methods:We analyzed CSF concentrations of neurogranin, β-amyloid (Aβ42), phosphorylated tau (p-tau), and total tau (t-tau) among 132 neurologically normal older adults (mean 64.5, range 55–85), along with bilateral hippocampal volumes and a measure of episodic memory (Auditory Verbal Learning Test, delayed recall). Univariable analyses examined the relationship between neurogranin and the other AD-related biomarkers. Multivariable regression models examined the relationship between neurogranin and delayed recall, adjusting for age and sex, and interaction terms (neurogranin x AD biomarkers).Results:Higher neurogranin concentrations were associated with older age ( = 0.20, p = 0.02), lower levels of p-tau and t-tau, and smaller hippocampal volumes (p < 0.03), but not with CSF Aβ42 (p = 0.18). In addition, CSF neurogranin demonstrated a significant relationship with memory performance independent of the AD-related biomarkers; individuals with the lowest CSF neurogranin concentrations performed better on delayed recall than those with medium or high CSF neurogranin concentrations (p < 0.01). Notably, CSF p-tau, t-tau, and Aβ42 and hippocampal volumes were not significantly associated with delayed recall scores (p > 0.40), and did not interact with neurogranin to predict memory (p > 0.10).Conclusions:Synaptic dysfunction (assessed via neurogranin) may be an early pathologic process in age-related neurodegeneration, and a sensitive marker of age-related cognitive abilities, potentially preceding or even acting independently from AD pathogenesis. Synaptic functioning may be a useful early marker of cognitive aging and possibly a target for future brain aging interventions.
  • Mixed neuropathologies and associations with domain-specific cognitive decline
    Objective:To test whether decline in specific cognitive domains associated with Alzheimer disease neuropathologic change (ADNC) is modified by co-occurrence of other neuropathologies such as Lewy body disease (LBD) or vascular brain injury (VBI).Methods:Data came from 1,603 autopsied participants evaluated at US Alzheimer's Disease Centers. Standardized z scores in memory, attention, language, and executive function were derived from neuropsychological test scores assessed at each annual visit. Multivariable linear mixed-effects models assessed associations between neuropathologies and longitudinal trajectories of domain scores.Results:Compared to other participants, those with ADNC + LBD generally had worse cognitive trajectories, particularly lower initial executive function and faster attention decline. Participants with ADNC + VBI typically had less impairment and slower decline. Interactions were significant between LBD and ADNC for memory (p = 0.046) and between VBI and ADNC for language (p = 0.03); decline was slower than expected if these neuropathologies acted additively on the rate of decline. In secondary models, these interactions were limited to those with high ADNC (but not intermediate ADNC). In a subset of 260 participants with data on microinfarct location, cortical and subcortical microinfarcts were associated with decline in memory, language, and executive function in those without ADNC, but this effect was reduced among those with ADNC.Conclusions:ADNC + LBD (but not ADNC + VBI) was associated with poorer executive function and attention compared to other pathology groupings. However, the effect of co-occurring pathologies on cognitive trajectories may depend on the severity of ADNC. Future studies using antemortem biomarkers should seek to replicate these neuropathologic observations.
  • EDITORIAL EXPRESSION OF CONCERN: Herpes zoster as a risk factor for stroke and TIA: A retrospective cohort study in the UK
    With regard to the research article "Herpes zoster as a risk factor for stroke and TIA: A retrospective cohort study in the UK" by J. Breuer et al. (Neurology® 2014;82:206–212; published ahead of print January 2, 2014), we are publishing this Expression of Concern to alert readers that errors of data presentation have been uncovered since publication. The authors are preparing a corrected version of the paper.
  • 4-Aminopyridine toxicity with unintentional overdose in four patients with multiple sclerosis
  • Cortical demyelination in PML and MS: Similarities and differences
    ABSTRACT Objective: To characterize pathologic changes in the cerebral cortex of patients with multiple sclerosis (MS) and progressive multifocal leukoencephalopathy (PML). Methods: Autopsy brain tissue was obtained from 13 patients with PML, 4 patients with MS, 2 patients with HIV encephalopathy, and 1 subject without neurologic pathology. Immunohistochemistry for myelin proteins, inflammatory cells, and neurofilaments was performed to evaluate the distribution of cortical lesions, their inflammatory activity, and neuritic pathology. Confocal microscopy was applied to examine pathologic changes in neurites in PML cortex. Results: Leukocortical, intracortical, and subpial patterns of cortical demyelination were represented in MS brain tissue. In PML brain tissue intracortical and leukocortical but not subpial lesions were observed. Cortical lesions in PML and MS contained fewer inflammatory cells than demyelinated areas in the white matter. Neuritic pathology in cortical PML lesions was represented by dystrophic and transected neurites. Pathologic modifications in neuritic processes in PML were more evident in highly inflamed white matter than in gray matter areas of demyelination, reminiscent of previous reports of neuritic pathology in MS. JC virus-infected cells were associated with PML white matter, leukocortical and intracortical lesions. Conclusions: Cortical pathology represents a distinct feature of progressive multifocal leukoencephalopathy. Similarities and differences with regard to multiple sclerosis cortical pathology were noted and may be informative regarding the pathogenesis of both disorders.
  • Plasma amyloid {beta} protein is elevated in late-onset Alzheimer disease families
    ABSTRACT Objective: Plasma Aβ levels are elevated in early onset Alzheimer disease (AD) caused by autosomal dominant mutations. Our objective was to determine whether similar genetic elevations exist in late onset AD (LOAD). Methods: We measured plasma Aβ in first-degree relatives of patients with LOAD in a cross-sectional series and in extended LOAD families. We screened these subjects for pathogenic mutations in early onset AD genes and determined their ApoE genotypes. Results: Plasma Aβ is significantly elevated in the LOAD first-degree relatives in comparison to unrelated controls and married-in spouses. These elevations are not due to ApoE 4 or pathogenic coding mutations in the known early onset AD genes. Conclusions: The findings provide strong evidence for the existence of novel, as yet unknown genetic factors that affect late onset Alzheimer disease by increasing Aβ.
  • Clinical trial outcome in neuropathic pain. Relationship to study characteristics
    Abstract Background: Several recent randomized clinical trials have found that the medications being evaluated for neuropathic pain did not significantly differ from placebo for the primary efficacy endpoint, despite encouraging results from prior preclinical and clinical studies. It is unclear whether these trials were unsuccessful because the medications truly lack efficacy or whether characteristics of the trials compromised the demonstration of treatment benefits. Objective: To identify factors associated with positive (i.e., favors medication) vs negative outcomes of placebo-controlled neuropathic pain trials. Methods: We examined study characteristics associated with positive vs negative clinical trial outcomes for neuropathic pain treatments using the information provided in a comprehensive meta-analysis and additional ratings for 106 clinical trials. Results: Univariate analyses indicated that the results of medication vs placebo comparisons were more likely to be positive when medication response rates were greater, placebo response rates were lower, and studies were published earlier. In a multivariate analysis performed to identify independent contributions of study characteristics to trial outcomes, greater medication response, reduced placebo response, and larger sample sizes were each uniquely associated with positive outcomes. In addition, greater medication response rates and parallel groups designs were each independently associated with greater placebo response rates. Conclusions: The results suggest that study characteristics may contribute to the outcomes of clinical trials of treatments for neuropathic pain and provide an impetus for investigating strategies for decreasing placebo response rates and thereby possibly increasing the likelihood of positive outcomes in trials of efficacious treatments.
  • Perfusion fMRI detects deficits in regional CBF during memory-encoding tasks in MCI subjects
    ABSTRACT Objective: To determine how memory-encoding tasks elicit functional perfusion change in subjects with amnestic mild cognitive impairment (aMCI). Methods: Twelve subjects with aMCI and 14 age-matched cognitively normal (CN) subjects were recruited for this study. Arterial spin-labeling perfusion MRI (ASL-MRI) was employed to measure regional cerebral blood flow (CBF) during both control and encoding task conditions. Results: Experimental results demonstrated that hypoperfusion occurred in the right precuneus and cuneus in the aMCI group, and not the CN group, during the control state. During the memory-task performance, the difference in these regional hypoperfusion areas extended to the posterior cingulate. These regional perfusion rates correlated with the Mini-Mental State Examination and the Rey Auditory Verbal Learning Test scores. In addition, a CBF percentage increase (22.7%) occurred in the right parahippocampus region during the memory-encoding task performance in the CN group, with approximately no change in the aMCI group. Conclusion: Subjects with amnestic mild cognitive impairment had significant regional cerebral hypoperfusion and lacked the dynamic capability to modulate their regional cerebral blood flow responses to the challenge of the functional tasks.

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Weekly podcast of content from Neurology®, the official journal of the American Academy of Neurology.

  • Delayed Recall - July 2017
    In this month's Delayed Recall episode, we are featuring four interviews by Dr. Kait Nevel on the topic of neuro-oncology. In the first interview, Dr. Nevel speaks with Dr. Jennie Taylor about neuro-oncology and seizures. In the second, she discusses intracranial pressure with Dr. Mariza Daras. These interviews originally appeared in the March 7 and March 14 episodes, respectively. Next, Dr. Nevel and Dr. Lisa DeAngelis talk about metastatic diseases in neurology, in a segment that appeared in the March 21 episode. Last, Dr. Nevel discusses gliomas with Dr. David Schiff in an interview from March 28.
  • July 4 2017 Issue
    Show description/summary:1) Intake of dairy foods and risk of Parkinson disease 2) Topic of the Month: Immunotherapies in neurology This podcast begins and closes with Dr. Robert Gross, Editor-in-Chief, briefly discussing highlighted articles from the July 4, 2017 issue of Neurology. In the first segment, Dr. Michelle Fullard talks with Dr. Katherine C. Hughes about her paper on intake of dairy foods and risk of Parkinson disease. In the second part of the podcast, Dr. Stacey Clardy focuses her interview with Dr. Dennis Bourdette on new immunotherapies in neurology. Disclosures can be found at Neurology.org.DISCLOSURES: Dr. Fullard has received training support from NIH. Dr. Hughes received research support from the U.S. Department of Defense. Dr. Clardy received research support from Western Institute for Biomedical Research (WIBR). Dr. Bourdette serves as an editorial board member on Neurology®, receives funding for travel from the National Multiple Sclerosis Society, the Consortium of MS Centers, and the Paralyzed Veterans of America; consults with Magellan Health and is a patient consultant for Best Doctors, Inc.; has a patent and a second patent pending for drug treatments of multiple sclerosis; and serves as a PI for the National MS Society.
  • July 11 2017 Issue
    Show description/summary:1) Neurology® Neuroimmunology & Neuroinflammation: Antiepileptic drug therapy in patients with Autoimmune Epilepsy3) Topic of the Month: immunotherapy in neurologyThis podcast begins and closes with Dr. Robert Gross, Editor-in-Chief, briefly discussing highlighted articles from the July 11, 2017 issue of Neurology. In the first segment, Dr. Lara Marcuse talks with Dr. Anteneh Feyissa about his Neurology: Neuroimmunology & Neuroinflammation paper on antiepileptic drug therapy in patients with autoimmune epilepsy. In the second part of the podcast Dr. Stacey Clardy focuses her interview with Dr. Jeffrey A. Cohen on new immunotherapies in neurology. Disclosures can be found at Neurology.org.DISCLOSURES: Dr. Clardy received research support from Western Institute for Biomedical Research (WIBR). Dr. Cohen has served on scientific advisory boards for Adamas, Celgene, Genentech, Genzyme/Sanofi, Merck, and Novartis; serves as co-editor for Multiple Sclerosis Journal; receives publishing royalties from Multiple Sclerosis Therapeutics (Cambridge University Press, 4th ed., 2011); and has received research support form the Department of Defense, NIH, National MS Society, and Consortium of MS Centers. All other participants report no disclosures.
  • July 18 2017 Issue
    Show description/summary:1) Diagnosis of DWI-negative acute ischemic stroke: a meta-analysis 2) Topic of the Month: Multiple sclerosis therapeutics and pediatric multiple sclerosis patientsThis podcast begins and closes with Dr. Robert Gross, Editor-in-Chief, briefly discussing highlighted articles from the July 18, 2017 issue of Neurology. In the first segment, Dr. Kevin Barrett talks with Dr. Brian L. Edlow about his paper on the diagnosis of DWI-negative acute ischemic stroke: a meta-analysis. In the second part of the podcast Dr. Stacey Clardy focuses her interview with Dr. Emmanuelle Waubant on MS therapeutics and pediatric MS patients. Disclosures can be found at Neurology.org.DISCLOSURES:Dr. Barrett has served on the editorial boards of both Neurology® and The Neurohospitalist; receives publishing royalities from the book Stroke; and receives research support from NINDS.Dr. Edlow receives research support from Guger Technologies, NIH, American Academy of Neurology/American Brain Foundation, and the James S. McDonnell Foundation.Dr. Clardy received research support from Western Institute for Biomedical Research (WIBR).Dr. Waubant volunteers on a Novartis advisory board; serves on the editorial board of Annals of Clinical and Translational Neurology; serves as editor of MSARD; receives royalties from the publication of the book Demyelinating disorders of the central nervous system in childhood; and receives research support from Roche, Novartis, NIH, National MS Society, and Race to Erase MS.
  • July 25 2017 Issue
    Show description/summary:1) Neurology and the Humanities: Discovering the patient within2) Topic of the Month: immunosuppressants in neurologyIn the first segment, Dr. Ted Burns talks with Dr. Richard Morton about his Neurology and the Humanities paper, “Discovering the Patient Within.” In the second part of the podcast, Dr. Stacey Clardy focuses her interview with Dr. Anne Cross on immunosuppressants in neurology. Disclosures can be found at Neurology.org.DISCLOSURES:Dr. Burns serves as a section editor for the Neurology® podcast; serves on advisory boards for Argenx, UCB, and CSL Behring; receives travel or speaker honoraria from Argenx and Alexion; and received support for consulting from UCB Pharma and CSL Behring.Dr. Morton reports no disclosures. Dr. Clardy has received research support from Western Institute for Biomedical Research (WIBR).Dr. Cross has served on advisory boards for Roche and Genentech; has served on editorial boards for Brain Pathology, Journal of Neuroimmunology, and Annals of Clinical Translational Neurology; receives research support from Roche, Teva Neuroscience, OBOE, NIH, Barnes-Jewish Hospital Foundation, and Conrad N Hilton Foundation; consults with Biogen, Sanofi-Aventis/Genzyme, Novartis, Teva Neuroscience, Gerson Lehrman Group, Guidepoint Global, LLC, AbbVie, EMD Serono, Genentech, and Bayer; and receives honoraria from Projects in Knowledge, Prime Education, Inc., Race to Erase MS, Conrad N. Hilton Foundation, and WebMD.
  • August 1 2017 Issue
    Show description/summary:1) On being sick: Musings about kindness, side effects, and slowing down2) Resident & Fellow Section Update: Annual Writing AwardIn the first segment, Dr. Alberto Espay talks with Dr. Ted Burns about his Special Editorial, “On being sick: Musings about kindness, side effects, and slowing down.” In the second part of the podcast, Dr. Andy Southerland focuses his interview with Dr. John Millichap on the annual Resident & Fellow writing award. Disclosures can be found at Neurology.org.DISCLOSURES:Dr. Espay serves as Associate Editor for the Journal of Clinical Movement Disorders; serves as an editorial board member of Parkinsonism and Related Disorders and The European Neurological Journal; serves on the scientific advisory board for Solvay Pharmaceuticals, Inc. (now Abbvie), Chelsea Therapeutics International, Ltd., Teva Pharmaceutical Industries Ltd., Impax, Merz Pharmaceuticals, Inc., Pfizer Inc, Solstice Neurosciences, Eli Lilly and Company, ACADIA Pharmaceuticals, Inc. and USWorldMeds; is a consultant for Chelsea Therapeutics International, Ltd., Solvay Pharmaceuticals, Inc. (now Abbvie), ACADIA Pharmaceuticals, Inc., Cynapsus and Lundbeck, Inc; receives royalties for publications of books from Lippincott, Williams & Wilkins and Cambridge University Press; serves on the speakers' bureau of UCB, Teva Pharmaceutical Industries Ltd., American Academy of Neurology and Movement Disorders Society; receives research support from the CleveMed/Great Lake Neurotechnilogies, Michael J. Fox Foundation and the NIH.Dr. Burns serves as Podcast Editor for Neurology®; and has received research support for consulting activities with UCB, CSL Behring, Walgreens and Alexion Pharmaceuticals, Inc. All other participants report no disclosures.Dr. Southerland serves as Podcast Editor for Neurology; receives research support from the American Heart Association-American Stroke Association National Clinical Research Program, American Academy of Neurology, American Board of Psychiatry and Neurology, Health Resources Services Administration and the NIH; has a provisional patent application titled: “Method, system and computer readable medium for improving treatment times for rapid evaluation of acute stroke via mobile telemedicine;” and gave legal expert review.Dr. Millichap has received speaker honoraria from Invitae; serves on the editorial board for Neurology and Pediatric Neurology Briefs; receives publishing royalties from BMJ Best Practice and UpToDate; and has received research support from UCB Pharma, Thrasher Research Fund, and Citizens United for Research in Epilepsy.
  • August 8 2017 Issue
    Show description/summary:1) Neurology® Clinical Practice: Barriers and Facilitators to ER Physician Use of the Test and Treatment for BPPV2) What’s Trending: New crowd-funding research initiative from ABFIn the first segment, Dr. Jim Siegler talks with Dr. Kevin Kerber and Dr. William Meurer about their Neurology® Clinical Practice article on ER physician use of the test and treatment for benign paroxysmal positional vertigo. In the second part of the podcast, Dr. Andy Southerland focuses his interview with Dr. Robert Griggs and Jane Ransom on the new crowd-funding research initiative from the American Brain Foundation. Disclosures can be found at Neurology.org.DISCLOSURES: Dr. Siegler serves on the Resident and Fellow Section Team for Neurology, and has received research support from NIH (U10 StrokeNet grant, 2017-2018).Jane Ransom is Executive Director of the American Brain Foundation.Dr. Kerber received funding for travel from Elsevier Inc. and the American Academy of Neurology; receives royalties from the publication of the book Clinical Neurophysiology of the Vestibular System, 4th edition; is a consultant for the American Academy of Neurology, University of California San Francisco (including work on a project funded by AstraZeneca), and Best Doctors, Inc.; receives research support from the NIH; received speaker honoraria from American Academy of Neurology and University of California San Francisco and loan repayment award from the NIH; reviewed legal records of Phil Pearsons, MD, JD and National Medical Consultants.Dr. Meurer serves as Decision Editor for the Annals of Emergency Medicine; serves as Methodology Statistics Reviewer for Academic Emergency Medicine; and has received research support from the Massey Foundation for TBI research. Dr. Griggs has served on scientific advisory boards for National Hospital Queen Square, Marathon Pharmaceuticals, Taro Pharmaceuticals, and Sarepta Pharmaceuticals; has served on the data monitoring and safety board for PTC Therapeutics, Inc.; serves on the editorial board for NeuroTherapeutics and Current Treatment Opinions in Neurology; serves as Correspondence Editor for Neurology; receives publishing royalties from Andreoli and Carpenter’s Cecil Essentials of Medicine (Eighth Edition, Elsevier), Cecil Textbook of Medicine (multiple editions, Elsevier), and Evaluation and Treatment of Myopathies (2014, Oxford); has consulted for Marathon, PTC Therapeutics, Sarepta, Taro Pharmaceuticals, Idera Pharmaceuticals, and Strongbridge Pharmaceuticals; receives data royalties and research support from Taro Pharmaceuticals and Marathon Pharmaceuticals; has received research support from NINDS (T32 NS07338, 5U01NS061799, 1R13NS084687), the FDA (R01 FD003923), Parent Project Muscular Dystrophy, Inc., and the Muscular Dystrophy Association; and is the recent past Chair of Executive Committee of the Muscle Study Group.
  • August 15 2017 Issue
    Show description/summary:1) Quality improvement in neurology: Inpatient and emergency care quality measure set executive summary 2) Neurology Today: Incidental findings and normal variants on MRI of the brain in adults for primary headachesIn the first segment, Dr. Jason Crowell talks with Dr. Paul Vespa about his paper on quality improvement in inpatient and emergency neurologic care. In the second part of the podcast, Dr. Teshamae Monteith focuses her interview with Dr. Randolph Evans on a Neurology Today® story about incidental findings and normal variants on brain MRI for primary headache in adults. Disclosures can be found at Neurology.org.DISCLOSURES: Dr. Vespa serves on scientific advisory boards for Intouch Health, Edge Pharmaceuticals, and Sage Pharmaceuticals; serves on editorial boards for Critical Care Medicine, Neurocritical Care, and Surgical Neurology International; has consulted for General Electric and Neuren; receives research support from NINDS; holds stock in Intouch Health and stock options in Pfizer; and gave expert testimony about brain trauma.Dr. Monteith serves as an editorial advisory board member for Neurology Now and receives research support from the NIH.Dr. Crowell and Dr. Evans report no disclosures.
  • August 22 2017 Issue
    Show description/summary:1) Oral fluoroquinolones and risk of secondary pseudotumor cerebri syndrome2) Neurology Today: FDA Approves Edaravone for ALS: Phase 3 Trial Finds It Slows ProgressionThis podcast begins and closes with Dr. Robert Gross, Editor-in-Chief, briefly discussing highlighted articles from the August 22, 2017 issue of Neurology. In the first segment, Dr. Halley Alexander talks with Mr. Mohit Sodhi about his paper on oral fluoroquinolones and risk of secondary pseudotumor cerebri syndrome. In the second part of the podcast, Dr. Kelly Gwathmey focuses her interview with Dr. Terry Heiman-Patterson on a Neurology Today® story about the FDA-approval of edaravone for the treatment of ALS. Disclosures can be found at Neurology.org.DISCLOSURES: All participants report no disclosures.
  • August 29 2017 Issue
    Show description/summary:1) Prognostic relevance of MOG antibodies in children with an acquired demyelinating syndrome2) What’s Trending: CTE and American football playersThis podcast begins and closes with Dr. Robert Gross, Editor-in-Chief, briefly discussing highlighted articles from the August 29, 2017 issue of Neurology. In the first segment, Dr. Nicholas Brenton talks with Dr. Kevin Rostásy about his paper on the prognostic relevance of MOG antibodies in children with an acquired demyelinating syndrome. In the second part of the podcast, Dr. Jason Crowell focuses his interview with Dr. Jesse Mez on chronic traumatic encephalopathy and American football players. Disclosures can be found at Neurology.org.DISCLOSURES: Dr. Rostásy serves on a scientific advisory board for Novartis regarding a fingolimod project, and has received speaker honoraria for Merck-Serono.Dr. Smith serves on the Celegene data monitoring committee; serves as editor for NeuroLearn; has consulted for Regenesis, Allergan, and Viromed; and receives research support from Impeto Medical, and NIDDK (DK064814), NINDS (U10NS077305 and U10NS086606).All other participants report no disclosures.
  • Delayed Recall - September 2017
    The first interview in this month’s Delayed Recall episode is from March 17, 2015; in this interview, Dr. Howard Goodkin and Dr. Robert Stern discuss the effect that age of first exposure to football has on later-life cognitive impairment in former NFL players. The second interview, from August 29, 2017, is a discussion between Dr. Jason Crowell and Dr. Jesse Mez about a July 2017 JAMA paper on occurrence of CTE in American football players. In the third interview, Dr. Christopher Giza speaks with Dr. John Hart about Dr. Hart’s paper regarding depressive symptoms and white matter dysfunction in retired NFL players with concussion history. This interview originally appeared in the July 1, 2013 episode. The fourth and final interview is a discussion between Dr. Ted Burns and former NFL player Ben Utecht, regarding Mr. Utecht’s Sept 23, 2014 editorial, “Concussed.”
  • September 5 2017 Issue
    Show description/summary:1) Longitudinal diffusion changes following postoperative delirium in older people without dementia2) What’s Trending: Poor sleep is associated with CSF biomarkers of amyloid pathology in cognitively normal adultsThis podcast begins and closes with Dr. Robert Gross, Editor-in-Chief, briefly discussing highlighted articles from the September 5, 2017 issue of Neurology. In the first segment, Dr. Pearce Korb talks with Dr. Michele Cavallari and Dr. David Alsop about their paper on longitudinal diffusion changes following postoperative delirium in people without dementia. In the second part of the podcast, Dr. Jeff Burns focuses his interview with Dr. Barbara Bendlin on poor sleep and biomarkers of amyloid pathology in cognitively normal adults. Disclosures can be found at Neurology.org.DISCLOSURES: Dr. Alsop serves as associate editor for Magnetic Resonance in Medicine; has received research support from GE Healthcare Technologies, NIH (P01 AG031720, R01 MH080729, R01 NS047029, R21 EB014471, R01 CA169470, P20 DK108276, R44 DK111260); and receives royalty payments for Patent 7,545,142 (arterial spin labeling with pulsed radio frequency sequences) and from GE Healthcare, Philips Healthcare, Siemens Medical, Hitachi Medical, and Animage Technology.Dr. Cavallari has received research support from NIA (P01AG03172).Dr. Burns has served on the DSMB for NIH-funded trials (non-profit entities); serves on the editorial board for Journal of Alzheimer's Disease; has consulted for Grifols, USA; has served on Eli Lilly Amyvid Speaker's Bureau; and has received research support from Eli Lilly, Avid Radiopharmaceuticals, Toyama Chemical Company, Merck, Biogen, AbbVie, Novartis, vTv Therapeutics, Janssen, and NIH (R01AG058557, R01AG053312, R01AG034614, R01AG03367, R01AG043962, P30AG035982, U10NS077356, UL1TR000001). Dr. Bendlin serves as associate editor for Journal of Alzheimer's Disease; and has received research support from NIH/NIA (Alzheimer's Disease Connectome Project, U01AG051216, P50 AG033514, R01AG037639, R56AG052698, R21AG053738, P50 AG033514, 1U54AI117924).Dr. Korb reports no disclosures.
  • September 12 2017 Issue
    Show description/summary:1) National randomized controlled trial of virtual house calls for Parkinson disease2) Neurology Today: Interview with Joseph Safdieh, the new Editor-in-Chief of Neurology Today®This podcast begins and closes with Dr. Robert Gross, Editor-in-Chief, briefly discussing highlighted articles from the September 12, 2017 issue of Neurology. In the first segment, Dr. Jeff Ratliff talks with Dr. Ray Dorsey about his paper on virtual house calls for Parkinson disease. In the second part of the podcast, Dr. Andy Southerland interviews Dr. Joseph Safdieh about Dr. Safdieh’s new position as Editor in Chief of Neurology Today. Disclosures can be found at Neurology.org.DISCLOSURES: Dr. Ratliff has received a speaker honorarium from Haverford College.Dr. Dorsey has served on the scientific advisory boards of Shire Pharmaceuticals and Huntington's Disease Society of America; has received travel funding and/or honoraria from the American Academy of Neurology and the American Neurological Association; has served on the editorial boards of the Journal of Huntington's Disease, HD Insights, and Digital Biomarkers; has been a consultant for 23andMe, Abbott Nutrition, Abbvie, Amgen, Biogen, Clintrex, GlaxoSmithKline, Grand Rounds, Lundbeck MC10, MedAvante, Medico Legal services, NIH/NINDS Optio, Shire, Sunovion Pharma, Teva, UCB, Voyager Therapeutics, State of Georgia, Mednick Associates, and Putnam Associates; has performed clinical practice, including telemedicine, as a movement disorder neurologist; has received research support from Abbvie, AMC Health, Avid Radiopharmaceuticals, BioMarin, GlaxoSmithKline, Great Lakes Neurotechnologies, Lundbeck, Medtronic, Prana Biotechnology, Raptor Pharmaceuticals, Roche, Teva Pharmaceuticals, National Institute of Neurological Disorders and Stroke, Patient-Centered Outcomes Research Institute, University of California Irvine, Duke University, Burroughs Wellcome Fund, Davis Phinney Foundation, Michael J. Fox Foundation, Safra Foundation, Greater Rochester Health Foundation, Huntington Study Group, and National Science Foundation; holds Grand Rounds and BlackFlynn stock options; and has received compensation for expert testimony.Dr. Southerland serves as Podcast Editor for Neurology; receives research support from the American Heart Association-American Stroke Association National Clinical Research Program, American Academy of Neurology, American Board of Psychiatry and Neurology, Health Resources Services Administration and the NIH; has a provisional patent application titled: “Method, system and computer readable medium for improving treatment times for rapid evaluation of acute stroke via mobile telemedicine;” and gave legal expert review.Dr. Safdieh has served on the scientific advisory board for Upsher Smith; is the Editor-in-Chief of Neurology Today, has received publishing royalties from Elsevier, and has performed consultant work regarding legal proceedings.
  • September 19 2017 Issue
    Show description/summary:1) Medication-overuse headache: An entrenched idea in need of scrutiny 2) What’s Trending: DAWN TrialThis podcast begins and closes with Dr. Robert Gross, Editor-in-Chief, briefly discussing highlighted articles from the September 19th, 2017 issue of Neurology. In the first segment, Dr. Alex Menze talks with Dr. Elizabeth Loder about her paper on medication overuse headache. In the second part of the podcast, Dr. Kevin Barrett focuses his interview with Dr. Tudor Jovin on the DAWN trial on Trevo thrombectomy for acute ischemic stroke. Disclosures can be found at Neurology.org.DISCLOSURES: Dr. Menze reports no disclosures.Dr. Loder has received travel funding from the American Headache Society and American Migraine Foundation and The British Medical Journal; has served on the editorial boards of The British Medical Journal, Cephalalgia, and Headache; receives publishing royalties from Cambridge University Press; and has received research support from Harvard Medical School.Dr. Barrett serves on the editorial boards of Neurology and Neurohospitalist; receives publishing royalties from Wiley-Blackwell; and has received research support from NINDS.Dr. Jovin has served on the Codman Neurovascular Data Safety Monitoring Board; has received travel funding from Stryker Neurovascular and Fundacio Ictus; and holds stock/stock options in Silk Road Medical, Anaconda, and Blockade Medical.
  • September 26 2017 Issue
    Show description/summary:1) Neurology® Genetics: ExACtly zero or once: A clinically helpful guide to assessing genetic variants in mild epilepsies 2) What’s Trending: Orphan drug pricingThis podcast begins and closes with Dr. Robert Gross, Editor-in-Chief, briefly discussing highlighted articles from the September 26, 2017 issue of Neurology. In the first segment, Dr. Jim Kiely talks with Dr. Samuel Berkovic about his Neurology® Genetics paper on assessing genetic variants in mild epilepsies. In the second part of the podcast, Dr. Jason Crowell focuses his interview with Dr. Gordon Smith on orphan drug pricing. Disclosures can be found at Neurology.org.DISCLOSURES: Dr. Kiely is employed at InTouch Health Physician Services as a teleneurologist, and holds stock with InTouch Health. Dr. Berkovic serves on scientific advisory board for UCB Pharma and Eisai Australia; has served on editorial boards for Brain, Epileptic Disorders, and Lancet Neurology; is an investor listed on a Bionomics Inc patent on diagnostic testing using SCN1A gene (WO2006/133508), and is an investor on a pending patent for a therapeutic compound related to a genetic cause of familial epilepsy with mental retardation in females (WO61/010176); receives research support from UCB, SciGen, and Eisai Australia, the National Health and Medical Research Council of Australia (Program Grant #1091593; 2016-2020), and NINDS (U01 NS077367-01; 2011-2014).Dr. Smith serves on the Celegene data monitoring committee; serves as editor for NeuroLearn; has consulted for Regenesis, Allergan, and Viromed; and receives research support from Impeto Medical, and NIDDK (DK064814), NINDS (U10NS077305 and U10NS086606).Dr. Crowell reports no disclosures.
  • Delayed Recall - October 2017
    This special Delayed Recall episode is the second installment of our new Practice Current segment. In this episode, Dr. Luca Bartolini speaks with neuromyelitis optica (NMO) experts Dr. Tarso Adoni and Dr. Michael Levy. They discuss the results of a recent Practice Current (a section of Neurology® Clinical Practice) survey regarding NMO treatment, and share their thoughts on best practices. This is the first appearance of this interview in the podcast.
  • October 3 2017 Issue
    Show description/summary:1) Functional impairments for outcomes in a randomized trial of of unruptured brain AVMs2) What’s Trending: Hurricane Harvey and patient care in TexasThis podcast begins and closes with Dr. Robert Gross, Editor-in-Chief, briefly discussing highlighted articles from the October 3, 2017, issue of Neurology. In the first segment, Dr. Andrew Southerland talks with Dr. JP Mohr about his paper on functional impairment outcome measurements in a randomized trial of unruptured brain arteriovenous malformations. In the second part of the podcast, Dr. Jason Crowell focuses his interview with Dr. Aziz Shaibani on Hurricane Harvey and its effect on patient care in Texas. Disclosures can be found at Neurology.org.DISCLOSURES: Dr. Southerland serves as Podcast Editor for Neurology; receives research support from the American Heart Association-American Stroke Association National Clinical Research Program, American Academy of Neurology, American Board of Psychiatry and Neurology, Health Resources Services Administration and the NIH; has a provisional patent application titled: “Method, system and computer readable medium for improving treatment times for rapid evaluation of acute stroke via mobile telemedicine;” and gave legal expert review.Dr. Mohr serves as Associate Editor for History of Stroke and Cerebrovascular Disease; has consulted for Schering-Plough; has given expert testimony on unruptured brain AVMs; and has received research support from NINDS associated with the ARUBA trial. Dr. Crowell reports no disclosures.Dr. Shaibani is President-Elect for the Texas Neurology Society.
  • October 10 2017 Issue
    Show description/summary:1) Quality improvement in neurology: Stroke and stroke rehabilitation quality measurement set update2) Neurology Today® paper on Parkinson disease and autoimmunityIn the first segment, Dr. Dan Ackerman talks with Dr. Gene Latorre about his paper on the updated quality measurement set for stroke and stroke rehabilitation. In the second part of the podcast, Dr. Alberto Espay focuses his interview with Dr. David Sulzer on Parkinson disease and autoimmunity. Disclosures can be found at Neurology.org.DISCLOSURES: Dr. Espay serves as Associate Editor for the Journal of Clinical Movement Disorders; serves as an editorial board member of Parkinsonism and Related Disorders and The European Neurological Journal; serves on the scientific advisory board for Solvay Pharmaceuticals, Inc. (now Abbvie), Chelsea Therapeutics International, Ltd., Teva Pharmaceutical Industries Ltd., Impax, Merz Pharmaceuticals, Inc., Pfizer Inc, Solstice Neurosciences, Eli Lilly and Company, ACADIA Pharmaceuticals, Inc. and USWorldMeds; is a consultant for Chelsea Therapeutics International, Ltd., Solvay Pharmaceuticals, Inc. (now Abbvie), ACADIA Pharmaceuticals, Inc., Cynapsus and Lundbeck, Inc; receives royalties for publications of books from Lippincott, Williams & Wilkins and Cambridge University Press; serves on the speakers' bureau of UCB, Teva Pharmaceutical Industries Ltd., American Academy of Neurology and Movement Disorders Society; receives research support from the CleveMed/Great Lake Neurotechnilogies, Michael J. Fox Foundation and the NIH.All other participants report no disclosures.
  • October 17 2017 Issue
    Show description/summary:1) Qualitative study of burnout, career satisfaction, and well-being among US neurologists in 20162) What’s Trending: gene editing in human embryosThis podcast begins and closes with Dr. Robert Gross, Editor-in-Chief, briefly discussing highlighted articles from the October 17, 2017, issue of Neurology. In the first segment, Dr. Pearce Korb talks with Dr. Janis Miyasaki about her paper on burnout, career satisfaction and well-being among US neurologists. In the second part of the podcast, Dr. Jason Crowell focuses his interview with Dr. Shoukhrat Mitalipov on gene editing in human embryos for correction of a pathogenic mutation.DISCLOSURES: Dr. Miyasaki has received honoraria from Davis Phinny Foundation, Sunovion, and NINDS; receives publishing royalties from “Up to Date: Psychogenic Movement Disorders;” has consulted for Cynapsus and GE; has served on a scientific advisory board for Parkinson Society Canada; and has received research support from Allergan, PCORI, and Parkinson Alberta.Dr. Mitalipov holds patents for Primate Totipotent and Pluripotent Stem Cells Produced by Somatic Cell Nuclear Transfer (U.S. patent No. 7,972,849), Human Pluripotent Stem Cells Produced by Somatic Cell Nuclear Transfer (U.S. Patent No. 9,546,383), and Methods for Mitochondrial DNA Replacement in Oocytes (U.S. Patent No. 9434921); has patents pending for Metabolic rescue in pluripotent cells from subjects with mitochondrial DNA disease (Application Number: 62192358), Generation of human oocytes by polar body transfer” (Application 62/419,638), and Mitochondrial Replacement in Human Oocytes Carrying Pathogenic Mitochondrial DNA Mutations (Application 62427546); has consulted for Flagship VentureLabs; and has received research support from NIH/NIA, Burroughs Wellcome Fund, and Foundation Leducq.Dr. Korb and Dr. Crowell report no disclosures.

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