Does Head Tremor Predict Postural Instability After Bilateral Thalamic Stimulation in Essential Tremor?

Essential tremor (ET) may present with head tremor (HT), of presumed cerebellar nature. Deep brain stimulation (DBS) targeting the ventral intermediate (Vim) nucleus of the thalamus is a highly effective therapy for medication-refractory ET. However, stimulation-related side effects may include cerebellar abnormalities, such as postural instability. This retrospective cohort study evaluated the risk of post-Vim DBS postural instability (primary outcome measure) in patients with versus without head tremor (HT vs. nHT). The primary outcome measure, namely post-DBS postural instability, was assessed in both groups using a Wilcoxon rank sum t-test. The time to postural instability was determined using Cox proportional hazards regression analysis adjusted for age and sex. Out of 30 patients analyzed during the follow up period, there was similar postural instability detected in HT (9/14, 64%) and nHT patients (11/16, 69%) at 24 months post-Vim DBS (p=0.82), adjusted hazard ratio[aHR]=0.82, p=0.69). These data suggest that the presence or absence of HT does not have an impact on postural instability after bilateral Vim DBS in patients with ET.

Diagnostic Uncertainties in Tremor.

The approach and diagnosis of patients with tremor may be challenging for clinicians. According to the most recent consensus statement by the Task Force on Tremor of the International Parkinson Movement Disorder Society, the differentiation between action (i.e., kinetic, postural, intention), resting, and other task- and position-specific tremors is crucial to this goal. In addition, patients with tremor must be carefully examined for other relevant features, including the topography of the tremor, since it can involve different body areas and possibly associate with neurological signs of uncertain significance. Following the characterization of major clinical features, it may be useful to define, whenever possible, a particular tremor syndrome and to narrow down the spectrum of possible etiologies. First, it is important to distinguish between physiological and pathological tremor, and, in the latter case, to differentiate between the underlying pathological conditions. A correct approach to tremor is particularly relevant for appropriate referral, counseling, prognosis definition, and therapeutic management of patients. The purpose of this review is to outline the possible diagnostic uncertainties that may be encountered in clinical practice in the approach to patients with tremor. In addition to an emphasis on a clinical approach, this review discusses the important ancillary role of neurophysiology and innovative technologies, neuroimaging, and genetics in the diagnostic process.

Immigrant Neurologists in the Physician-Scientist Pipeline: An Intervenable Stenosis.

Immigrant neurologists on a visa make up one-fourth of our neurology resident workforce. In this article, we describe the challenges faced by them in pursuit of a career as physician-scientists. We highlight the key role that immigration status plays in various aspects of research advancement early along the neurology pipeline, pertaining to clinical career decisions and the associated delay in achieving these milestones. We conclude with a call to action to address these key roadblocks, which would have the additional potential benefit of improving inclusion and diversity in clinical and translational science. ANN NEUROL 2021;90:542-545.

Rivastigmine in Parkinson's Disease Dementia with Orthostatic Hypotension.

OBJECTIVE: The purpose of this study was to evaluate if the cognitive benefit of rivastigmine is affected by the presence of orthostatic hypotension (OH) in patients with Parkinson's disease dementia (PDD). METHODS: We conducted a post hoc analysis on 1,047 patients with PDD from 2 randomized controlled trials comparing rivastigmine versus placebo at week 24 (n = 501) and rivastigmine patch versus capsule at week 76 (n = 546). A drop ≥ 20 mm Hg in systolic blood pressure (SBP) or ≥ 10 in diastolic blood pressure (DBP) upon standing classified subjects as OH positive (OH+); otherwise, OH negative (OH-). The primary end point was the Alzheimer's Disease Assessment Scale - Cognitive subscale (ADAS-Cog) at week 24 and the Mattis Dementia Rating Scale (MDRS) at week 76, using intention-to-treat with retrieved dropout at week 24 and observed cases at week 76, consistent with the original analyses. RESULTS: Overall safety was comparable between OH+ (n = 288, 27.5%) and OH- (n = 730, 69.7%), except for higher frequency of syncope (9.2%) in the OH+ placebo arm. The placebo-adjusted effect of rivastigmine on ADAS-Cog at week 24 was 5.6 ± 1.2 for OH+ and 1.9 ± 0.9 in OH- (p = 0.0165). Among subjects with OH, the MDRS change from baseline at week 76 was higher for rivastigmine capsules versus patch (10.6 ± 2.9 vs -1.5 ± 3.0, p = 0.031). The overall prevalence of OH was lower for rivastigmine than placebo at week 24 (28.3% vs 44.6%, p = 0.0476). INTERPRETATION: The cognitive benefit from rivastigmine is larger in patients with PDD with OH, possibly mediated by a direct antihypotensive effect. ANN NEUROL 2021;89:91-98.

APOE4 Allele, Sex, and Dementia Risk in Parkinson's Disease: Lessons From a Longitudinal Cohort.

INTRODUCTION: The effect of APOE4 allele on dementia risk is well established in Alzheimer's disease and Parkinson's disease (PD). However, it is unknown if sex modifies this relationship. We sought to determine the effect of sex on the relationship between APOE4 status and incident cognitive decline in PD. METHODS: Data from the prospectively collected longitudinal National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS) and Neuropathology Data Set (NDS) were analyzed. The NACC develops and maintains data from approximately 29 National Institutes of Aging-funded Alzheimer's Disease Research Centers. Further details may be found at the NACC web site (www.alz.washington.edu). The visit at which diagnosis of PD was made was termed the baseline visit. All patients with a PD diagnosis but without dementia at the baseline visit were included in the analyses. RESULTS: Presence of APOE4 allele was associated with higher odds (OR = 7.4; P < .001) of subsequent diagnosis of dementia and with a faster time to developing dementia (P = .04). Those with APOE4 allele were more likely to have neuropathology associated with Alzheimer's disease than those without APOE4 allele. We did not find any difference by sex. There were no differences between Lewy body pathology or neuron loss in the substantia nigra between the 2 groups. Sex was not associated with dementia risk in PD (OR = 0.53, P = .15) or with the time to dementia onset (P = .22). Sex did not modify the relationship between the APOE4 allele and dementia onset in PD patients (P = .12). CONCLUSIONS: APOE4 allele status in PD may be a predictor of cognitive decline in PD but does not appear to be modified by sex.

Lessons learned from the syndrome of oculopalatal tremor.

The syndrome of oculopalatal tremor (OPT) featuring the olivo-cerebellar hypersychrony leads to disabling pendular nystagmus and palatal myoclonus. This rare disorder provides valuable information about the motor physiology and offers insights into the mechanistic underpinning of common movement disorders. This focused review summarizes the last decade of OPT research from our laboratory and addresses three critical questions: 1) How the disease of inferior olive affects the physiology of motor learning? We discovered that our brain's ability to compensate for the impaired motor command and implement errors to correct future movements could be affected if the cerebellum is occupied in receiving and transmitting the meaningless signal. A complete failure of OPT patients to adapt to change in rapid eye movements (saccades) provided proof of this principle. 2) Whether maladaptive olivo-cerebellar circuit offers insight into the mechanistic underpinning of the common movement disorder, dystonia, characterized by abnormal twisting and turning of the body part. We discovered that the subgroup of patients who had OPT also had dystonia affecting the neck, trunk, limbs, and face. We also found that the subjects who had tremor predominant neck dystonia (without OPT) also had impaired motor learning on a long and short timescale, just like those with OPT. Altogether, our studies focused on dystonia suggested the evidence for the maladaptive olive-cerebellar system. 3) We discovered that the OPT subjects had difficulty in perceiving the direction of their linear forward motion, i.e., heading, suggesting that olivo-cerebellar hypersynchrony also affects perception.

Tremor-Dominant Cervical Dystonia: a Cerebellar Syndrome.

The objective of this study is to examine the role of the cerebellum in the tremor-dominant subtype of cervical dystonia (CD). CD patients with head tremor at onset (Tr-CD) were age- and sex-matched to CD patients without head tremor at onset (nTr-CD). All patients were evaluated for cerebellar disability using the Scale for the Assessment and Rating of Ataxia (SARA), gait variability using ProtoKinetics Zeno Walkway, and cerebellar volume analysis extracted from brain magnetic resonance imaging (MRI) using a semiquantitative scale. Compared to nTr-CD (n = 10, median age, 70.5 years), Tr-CD patients (n = 10, 71.5 years) exhibited higher median SARA scores (9 vs 7.5, p = 0.03) and greater median gait variability index (131 vs 124, p = 0.03). SARA scores inversely correlated with cerebellar volume in all patients (- 0.4, p = 0.04). Tr-CD patients exhibited greater superior vermian atrophy than nTr-CD patients (p = 0.01). Head tremor at onset heralds a CD subtype with prominent axial cerebellar disability and atrophy of the superior vermis of the cerebellum.

Impaired Saccade Adaptation in Tremor-Dominant Cervical Dystonia-Evidence for Maladaptive Cerebellum.

We examined the role of the cerebellum in patients with tremor-dominant cervical dystonia by measuring the adaptive capacity of rapid reflexive eye movements (saccades). We chose the saccade adaptation paradigm because, unlike other motor learning paradigms, the real-time modification of saccades cannot "wait" for the sensory (visual) feedback. Instead, saccades rely primarily on the internal reafference modulated by the cerebellum. The saccade adaptation happens over fast and slow timescales. The fast timescale has poor retention of learned response, while the slow timescale has strong retention. Cerebellar defects resulting in loss of function affect the fast timescale but the slow timescale of saccade adaptation is retained. In contrast, maladaptive cerebellar disorders feature the absence of both fast and slow timescales. We were able to measure both timescales using noninvasive oculography in 6 normal individuals. In contrast, both timescales were absent in 12 patients with tremor-dominant cervical dystonia. These findings are consistent with maladaptive cerebellar outflow as a putative pathophysiological basis for tremor-dominant cervical dystonia.

Progressive Ataxia with Hemiplegic Migraines: a Phenotype of CACNA1A Missense Mutations, Not CAG Repeat Expansions.

We report a 52-year-old woman presenting with autosomal dominant progressive cerebellar ataxia and familial hemiplegic migraine type 1 whose genetic evaluation, negative for spinocerebellar ataxia (SCA) types 1, 2, 3, and 6, revealed instead a heterozygous pathogenic missense mutation in CACNA1A (NM_001127221:c.1748G > A:p.Arg583Gln). A systematic literature review showed that Arg583Gln is associated predominantly with progressive ataxia combined with episodic disorders (overwhelmingly hemiplegic migraine) whereas Thr666Met, the other most common CACNA1A missense mutation, with a combination of progressive ataxia and episodic disorders in half the cases and episodic disorders only in the other half. While uncertainties remain in the genotype-phenotype correlation of all CACNA1A mutations, the accumulated evidence suggests that that the co-occurrence of hemiplegic migraine and autosomal dominant progressive cerebellar ataxia should guide the clinician to test for CACNA1A missense mutation rather than CAG expansions or truncating mutations.

Predictive modeling of spread in adult-onset isolated dystonia: Key properties and effect of tremor inclusion.

BACKGROUND AND PURPOSE: Several clinical and demographic factors relate to anatomic spread of adult-onset isolated dystonia, but a predictive model is still lacking. The aims of this study were: (i) to develop and validate a predictive model of anatomic spread of adult-onset isolated dystonia; and (ii) to evaluate whether presence of tremor associated with dystonia influences model predictions of spread. METHODS: Adult-onset isolated dystonia participants with focal onset from the Dystonia Coalition Natural History Project database were included. We developed two prediction models, one with dystonia as sole disease manifestation ("dystonia-only") and one accepting dystonia OR tremor in any body part as disease manifestations ("dystonia OR tremor"). Demographic and clinical predictors were selected based on previous evidence, clinical plausibility of association with spread, or both. We used logistic regressions and evaluated model discrimination and calibration. Internal validation was carried out based on bootstrapping. RESULTS: Both predictive models showed an area under the curve of 0.65 (95% confidence intervals 0.62-0.70 and 0.62-0.69, respectively) and good calibration after internal validation. In both models, onset of dystonia in body regions other than the neck, older age, depression and history of neck trauma were predictors of spread. CONCLUSIONS: This predictive modeling of spread in adult-onset isolated dystonia based on accessible predictors (demographic and clinical) can be easily implemented to inform individuals' risk of spread. Because tremor did not influence prediction of spread, our results support the argument that tremor is a part of the dystonia syndrome, and not an independent or coincidental disorder.

Clinical and Demographic Characteristics of Upper Limb Dystonia.

BACKGROUND: Knowledge of characteristics in upper limb dystonia remains limited, derived primarily from small, single-site studies. OBJECTIVE: The objective of this study was to characterize demographic and clinical characteristics of upper limb dystonia from the Dystonia Coalition data set, a large, international, multicenter resource. METHODS: We evaluated clinical and demographic characteristics of 367 participants with upper limb dystonia from onset, comparing across subcategories of focal (with and without dystonia spread) versus nonfocal onset. RESULTS: Focal onset occurred in 80%; 67% remained focal without spread. Task specificity was most frequent in this subgroup, most often writer's cramp and affecting the dominant limb (83%). Focal onset with spread was more frequent in young onset (<21 years). Focal onset occurred equally in women and men; nonfocal onset affected women disproportionately. CONCLUSIONS: Upper limb dystonia distribution, focality, and task specificity relate to onset age and likelihood of regional spread. Observations may inform clinical counseling and design, execution, and interpretation of future studies. © 2020 International Parkinson and Movement Disorder Society.

Pimavanserin use in a movement disorders clinic: a single-center experience.

BACKGROUND: Parkinson's disease psychosis (PDP) is a disabling non-motor symptom of Parkinson's disease (PD) that is challenging to treat. Dopamine receptor blockers (DRB) are used to treat PDP, though these may be associated with adverse effects, including worsening of Parkinsonism. Pimavanserin, a selective 5-HT2A receptor inverse agonist, was recently FDA-approved for treatment of PDP; however, there is limited information on its long-term use in PDP patients. METHODS: A retrospective chart review of patients prescribed pimavanserin was performed in August, 2017. Data on demographics, psychotic features, sleep, and adverse effects was collected using a semi-structured telephone interview with patients or caregivers. Hallucination severity (HS) was quantified as mild (< 1 episode/week), moderate (1/week to < 1/day), or severe (daily/continuous). RESULTS: Seventeen patients consented to participate in the study; 16 were diagnosed with PDP, 1 with Lewy body dementia. Fourteen had co-morbid cognitive impairment/dementia. The mean duration of Parkinsonism was 11.8 ± 8.0 years, with 2.6 ± 1.9 years of psychosis. Eleven of the seventeen patients reported improvement of hallucinations of which 5/8 were initiated on pimavanserin monotherapy, and 6/9 reported improvement of HS with combination of DRB. Six of nine patients prescribed DRB were able to discontinue this medication after introduction of pimavanserin. Four patients discontinued medications (2, no benefit; 1, spontaneous resolution; 1, cost). No major side effects were reported, and two patients noted subjective improvement of sleep. CONCLUSION: In our series based on a small sample size, pimavanserin is well-tolerated and effective as both monotherapy and adjuvant treatment for moderate to severe. This medication can facilitate reduction or cessation of DRB medication.

Dialysis Requiring Acute Kidney Injury in Acute Cerebrovascular Accident Hospitalizations.

BACKGROUND AND PURPOSE: The epidemiology of dialysis requiring acute kidney injury (AKI-D) in acute ischemic stroke (AIS) and intracerebral hemorrhage (ICH) admissions is poorly understood with previous studies being from a single center or year. METHODS: We used the Nationwide Inpatient Sample to evaluate the yearly incidence trends of AKI-D in hospitalizations with AIS and ICH from 2002 to 2011. We also evaluated the trend of impact of AKI-D on in-hospital mortality and adverse discharge using adjusted odds ratios (aOR) after adjusting for demographics and comorbidity indices. RESULTS: We extracted a total of 3,937,928 and 696,754 hospitalizations with AIS and ICH, respectively. AKI-D occurred in 1.5 and 3.5 per 1000 in AIS and ICH admissions, respectively. Incidence of admissions complicated by AKI-D doubled from 0.9/1000 to 1.7/1000 in AIS and from 2.1/1000 to 4.3/1000 in ICH admissions. In AIS admissions, AKI-D was associated with 30% higher odds of mortality (aOR, 1.30; 95% confidence interval, 1.12-1.48; P<0.001) and 18% higher odds of adverse discharge (aOR, 1.18; 95% confidence interval, 1.02-1.37; P<0.001). Similarly, in ICH admissions, AKI-D was associated with twice the odds of mortality (aOR, 1.95; 95% confidence interval, 1.61-2.36; P<0.01) and 74% higher odds of adverse discharge (aOR, 1.74; 95% confidence interval, 1.34-2.24; P<0.01). Attributable risk percent of mortality was high with AKI-D (98%-99%) and did not change significantly over the study period. CONCLUSIONS: Incidence of AKI-D complicating hospitalizations with cerebrovascular accident continues to grow and is associated with increased mortality and adverse discharge. This highlights the need for early diagnosis, better risk stratification, and preparedness for need for complex long-term care in this vulnerable population.

Hope vs. Hype I: Spreading alpha-synuclein explains cognitive deficits in Parkinson disease.

The Parkinson Study Group (PSG) gathered North American experts in Parkinson disease during the 9th Annual Symposium on "Shaping the Management of Parkinson Disease: Debating Current Controversies". Debaters were tasked with agree or disagree positions to a particular prompt. This is the first in three-part series of "Hype vs. Hope" debates involving current trends and advances in Parkinson disease. With the prompt of "Spreading alpha-synuclein explains cognitive deficits in Parkinson disease," Dr. Kelly Mills, MD, MHS was tasked with the "agree" stance and Dr. Abhimanyu Mahajan, MD, MHS was tasked with the "disagree" stance. The following point-of-view article is an adaptation of this debate.

Opinion & Special Articles: Navigating Your First Academic Job Search. Pearls, Pitfalls, and Lessons Learned

Most graduating neurology residents plan to pursue an academic career after completing residency or fellowship training. Although a career in academic neurology has many benefits, the path to finding the right first academic job can be challenging. For many, this may be their first professional job, and finding an ideal academic position requires a tailored approach, focus, timeline, and scope. In this article, we outline a roadmap for navigating the first academic job search after neurology training and share pearls and pitfalls related to the job search.

Understanding Anxiety in Cervical Dystonia: An Imaging Study.

BACKGROUND: Anxiety may precede motor symptoms in cervical dystonia (CD) and is associated with an earlier onset of dystonia. Our understanding of anxiety in CD is inadequate. OBJECTIVE: To investigate brain networks associated with anxiety in CD. METHODS: Twenty-six subjects with idiopathic CD underwent MRI Brain without contrast. Correlational tractography was derived using Diffusion MRI connectometry. Quantitative Anisotropy (QA) was used in deterministic diffusion fiber tracking. Correlational tractography was then used to correlate QA with State-Trait Anxiety Inventory (STAI) state (STAI-S) and trait (STAI-T) subscales. RESULTS: Connectometry analysis showed direct correlation between state anxiety and QA in tracts from amygdala to thalamus/ pulvinar bilaterally, and trait anxiety and QA in tracts from amygdala to motor cortex, sensorimotor cortex and parietal association area bilaterally (FDR ≤0.05). CONCLUSION: Our efforts to map anxiety to brain networks in CD highlight the role of the amygdala in the pathophysiology of anxiety in CD.

Recalibrating the Why and Whom of Animal Models in Parkinson Disease: A Clinician's Perspective.

Animal models have been used to gain pathophysiologic insights into Parkinson's disease (PD) and aid in the translational efforts of interventions with therapeutic potential in human clinical trials. However, no disease-modifying therapy for PD has successfully emerged from model predictions. These translational disappointments warrant a reappraisal of the types of preclinical questions asked of animal models. Besides the limitations of experimental designs, the one-size convergence and oversimplification yielded by a model cannot recapitulate the molecular diversity within and between PD patients. Here, we compare the strengths and pitfalls of different models, review the discrepancies between animal and human data on similar pathologic and molecular mechanisms, assess the potential of organoids as novel modeling tools, and evaluate the types of questions for which models can guide and misguide. We propose that animal models may be of greatest utility in the evaluation of molecular mechanisms, neural pathways, drug toxicity, and safety but can be unreliable or misleading when used to generate pathophysiologic hypotheses or predict therapeutic efficacy for compounds with potential neuroprotective effects in humans. To enhance the translational disease-modification potential, the modeling must reflect the biology not of a diseased population but of subtypes of diseased humans to distinguish What data are relevant and to Whom.

Sex Differences in Dystonia.

BACKGROUND: Prior studies have indicated that female individuals outnumber male individuals for certain types of dystonia. Few studies have addressed factors impacting these sex differences or their potential biological mechanisms. OBJECTIVES: To evaluate factors underlying sex differences in the dystonias and explore potential mechanisms for these differences. METHODS: Data from individuals with various types of dystonia were analyzed in relation to sex. Data came from two different sources. One source was the Dystonia Coalition database, which contains predominantly idiopathic adult-onset focal and segmental dystonias. The second source was the MDSGene database, which contains predominantly early-onset monogenic dystonias. RESULTS: The 3222 individuals from the Dystonia Coalition included 71% female participants and 29% male participants for an overall female-to-male ratio (F:M) of 2.4. This ratio varied according to body region affected and whether dystonia was task-specific. The female predominance was age-dependent. Sex did not have a significant impact on co-existing tremor, geste antagoniste, depression or anxiety. In the 1377 individuals from the MDSGene database, female participants outnumbered male participants for some genes (GNAL, GCH1, and ANO3) but not for other genes (THAP1, TH, and TOR1A). CONCLUSIONS: These results are in keeping with prior studies that have indicated female individuals outnumber male individuals for both adult-onset idiopathic and early onset monogenic dystonias. These results extend prior observations by revealing that sex ratios depend on the type of dystonia, age, and underlying genetics.