Clinical Characteristics and Outcomes in Young-Onset Multiple System Atrophy.

BACKGROUND: Young-onset multiple system atrophy (YOMSA) is defined as the onset of multiple system atrophy (MSA) before the age of 40 years old. YOMSA is rare and there is much uncertainty of the phenotype and natural history in patients with YOMSA. OBJECTIVE: The objective is to evaluate the characteristics and disease course of patients with YOMSA. METHODS: We retrospectively reviewed medical records of patients with MSA who were evaluated at all Mayo Clinic sites from 1998 to 2021. We identified patients with YOMSA and evaluated clinical characteristics, autonomic function testing results, and disease course. RESULTS: Of 1496 patients with a diagnosis of clinically probable or clinically established MSA, 20 patients had YOMSA. The median age of onset was 39.1 (interquartile range [IQR] = 37.1, 40.1) years; 13 patients (65%) were male. MSA-parkinsonism was the most common subtype (65%). The median duration of symptom onset to YOMSA diagnosis was 4.9 (IQR = 3.7, 9) years. At the time of medical record review, 17 patients were deceased with a median survival of 8.3 (IQR = 7, 10.9) years. Univariate analysis showed that initial onset of autonomic failure predicted unfavorable survival (hazard ratio = 2.89, P = 0.04) compared to those who presented with motor impairment only at onset. At the time of YOMSA diagnosis, composite autonomic severity score was available in 19 patients with a median of 5 (IQR = 4, 6.5). CONCLUSIONS: YOMSA resembles MSA in most aspects including phenotype and prognosis, although the diagnosis is usually delayed. The presence of autonomic failure at symptom onset may be a poor predictor for survival.

The Auxiliary to the American Academy of Neurology.

The American Academy of Neurology (AAN) was founded in 1948, and the Women's Auxiliary to the AAN was founded shortly thereafter. We reviewed historical archives of the AAN and Women's Auxiliary and interviewed past Auxiliary leaders to understand the perception and roles of neurologists' spouses. The Women's Auxiliary to the AAN was originally formed for the wives of neurologist Academy members with the intention of facilitating social and intragroup relationships. The first leaders and members of the organization included some of the spouses of the original Academy founders. With the original scope to provide socialization while the men were at meetings, the male neurologists initially planned much of the Auxiliary's activities. Over time, the Auxiliary's activities shifted and became women-led; engagement in community outreach grew, subcommittees expanded, and the group engaged in supporting the AAN in achieving its goals of improving neurology education and research. The change paralleled the women's movement with educational topics during the Auxiliary's meetings evolving from topics on homemaking to business and understanding neurologic diseases. The Auxiliary was intertwined with the Academy and initiated the S. Weir Mitchell Award and the Founders Award of the AAN in 1955 and 1994 to encourage basic and clinical research in neurology, respectively. In 1982, the Auxiliary requested increased involvement in the scientific programs at the annual meetings. Reflecting societal change, the name was changed to the "Auxiliary to the AAN" in the 1970s, and in the mid-1990s to the "Alliance to the AAN" to accommodate the increasing number of male partners of neurologists. Based on interviews, the Auxiliary provided engagement, empowerment, and connection between women. The Auxiliary's activities tapered in the late 1990s, in part due to changes in women's occupations, and to the rise of women's membership and leadership within the Academy.

Phenoconversion in pure autonomic failure: a multicentre prospective longitudinal cohort study.

We aimed to describe the clinical features of patients with pure autonomic failure (PAF) preceding phenoconversion that could be useful as predictive markers for advancing α-synuclein-associated neurodegeneration of the brain. Patients diagnosed with PAF were evaluated at 8 Centers (7-US based and 1 European) and enrolled in a longitudinal observational cohort study (NCT01799915). Subjects underwent detailed assessments of motor, sleep, olfactory, cognitive, and autonomic function and were followed prospectively to determine whether they developed parkinsonism or dementia for up to 10 years. We identified incident cases of Parkinson disease (PD), dementia with Lewy bodies (DLB), or multiple system atrophy (MSA) and computed hazard ratios for phenoconversion as functions of clinical features. A total of 209 participants with PAF with a median disease duration of 6 years (IQR: 3-10) were enrolled. Of those, 149 provided follow-up information at an office or telemedicine visit. After a mean follow-up duration of 3 years, 48 (33%) participants phenoconverted (42% to PD, 35% to DLB, and 23% to MSA). Faster phenoconversion from study enrollment to any diagnosis was associated with urinary and sexual dysfunction [HR 5.9, 95%CI: 1.6-22, and HR: 3.6, 95%CI: 1.1-12] followed by subtle motor signs [HR: 2.7, 95%CI: 1.2-6], trouble swallowing [HR 2.5, 95%CI: 1.4-4.5], and changes in speech [HR:2.4, 95%CI:1.1-4.8] at enrollment. Subjects reporting deterioration of handwriting were more likely to phenoconvert to PD (HR: 2.6, 95%CI: 1.1-5.9, ) and those reporting difficulty handling utensils were more likely to phenoconvert to DLB (HR: 6.8, 95%CI: 1.2-38). Patients with a younger age of PAF onset [HR: 11, 95%CI: 2.6-46], preserved olfaction [HR: 8.7, 95%CI: 1.7-45], anhidrosis [HR: 1.8, 95%CI: 1-3.1, p=0.042], and severe urinary problems [HR 1.6, 95%CI: 1-2.5, p=0.033] were more likely to phenoconvert to MSA. The best autonomic predictor of PD was a blunted heart rate increase during the tilt-table test (HR: 6.1, 95%CI: 1.4-26). Patients with PAF have an estimated 12% (95% CI: 9%-15%) per year annual risk following study entry of phenoconverting to a manifest CNS synucleinopathy.

Sex and Gender Influence Urinary Symptoms and Management in Multiple System Atrophy.

OBJECTIVE: Multiple system atrophy (MSA) is characterized by urinary dysfunction, yet the influence of sex and gender on urinary symptoms and treatment is unclear. We sought to characterize sex and gender differences in the symptomatology, evaluation, and management of urinary dysfunction in patients with MSA. METHODS: Patients with MSA evaluated at our institution were reviewed and stratified by sex. RESULTS: While the prevalence of urinary symptoms was similar in male and female patients, incontinence was more common in females. Despite this, males and females underwent postvoid residual (PVR) measurement at similar rates. While catheterization rates were similar when PVR was measured, males were more than twice as likely to be catheterized than females in the absence of PVR measurement. CONCLUSION: Urinary symptoms are common in MSA, but their presentation differs between males and females. The difference in catheterization rates may be driven by a gender disparity in referrals for PVR, which can guide treatment.

Chorea Associated with Lamotrigine Use.

Background: Movement disorders, including chorea, have been cited as a side effect of lamotrigine use. However, the association is controversial and clinical characteristics in such cases are unclear. We sought to explore whether chorea may be associated with lamotrigine use. Methods: We performed a retrospective chart review of all patients diagnosed with chorea who had concurrent use of lamotrigine between 2000-2022. Demographic information and clinical characteristics were analyzed, including medical comorbidities and concurrent medication use. A literature search and review were conducted, with additional cases of lamotrigine-associated chorea analyzed. Results: Eight patients met the inclusion criteria for the retrospective review. In 7 patients, other causes of chorea were considered more likely. However, a 58-year-old woman with bipolar disorder on lamotrigine for mood stabilization had a clear association of chorea induced by lamotrigine. The patient was on multiple centrally active medications. Three additional cases of lamotrigine-associated chorea were identified through a literature review. In 2 of these cases, other centrally acting agents were used, and chorea was resolved with weaning lamotrigine. Discussion: Chorea is infrequently seen in the setting of lamotrigine use. In these rare cases, the presence of other centrally acting medications with lamotrigine may contribute to chorea. Highlights: Lamotrigine use is associated with movement disorders, including chorea, but the characteristics are not clearly defined. From our retrospective review, one adult had clear temporal and dose-related association between chorea and lamotrigine. We analyzed this case in conjunction with a literature review of cases of chorea associated with lamotrigine.

Nocturnal Pulse Event Frequency Is Reduced in Multiple System Atrophy.

Risk of sudden death in multiple system atrophy (MSA) is greatest during sleep with unknown mechanisms. We compared nocturnal pulse event frequency in 46 MSA patients and age-/sex-matched controls undergoing overnight pulse oximetry. Nocturnal oxyhemoglobin desaturation indices and pulse event indices (PEIs) were recorded, and relationships between pulse oximetry variables and survival were analyzed. MSA patients had lower PEI (3.1 ± 5.3 vs. 12.8 ± 10.8, p < 0.001) despite greater hypoxic burden and similar frequency of respiratory events. Nocturnal pulse events were not associated with severity of daytime autonomic failure. Two MSA patients had suspected sudden death, both with severely reduced PEI. MSA patients have fewer nocturnal pulse events compared with controls, despite similar respiratory event frequency, suggesting abnormal cardiac responses to sleep-disordered breathing. Whether this contributes to sudden death in MSA requires further study. ANN NEUROL 2023;93:205-212.

The Effects of Deep Brain Stimulation in Patients with Multiple System Atrophy.

The course of patients with multiple system atrophy (MSA) who undergo deep brain stimulation (DBS) is unclear. In a retrospective review of 1,496 patients with MSA evaluated at our institutions from 1998-2021, 12 patients underwent DBS; 9 had a diagnosis of Parkinson's disease at the time of surgery. Nine patients reported initial improvement in at least one symptom and 7 experienced overall worsening following DBS. All patients had at least one red flag sign or symptom suggesting atypical parkinsonism prior to surgery. Considering overall poor outcomes of DBS in MSA, we recommend careful consideration of red flags in patient selection.

Blood pressure changes impact corticospinal integrity and downstream gait and balance control.

Blood pressure (BP) plays an important role in white matter integrity. We sought to determine the role of intra-individual BP changes on white matter and evaluate the impact on gait speed and imbalance by sex. We identified 990 eligible participants in the population-based Mayo Clinic Study of Aging and analyzed fractional anisotropy (FA) in white matter regions. Using structural equation models (SEM), we assessed the effect of BP slope on corticospinal tract (CST) FA and downstream effects on gait speed and imbalance after age and sex effects. Of 990 participants, 438 (44%) were female with mean age of 76 years. In linear models predicting CST FA, a greater change in BP slope (0.0004; p = 0.026) and female sex (0.017; p < 0.001) were significant predictors of lower CST FA. SEMs showed that older age, female sex, and higher BP slope predicted lower CST FA, and lower CST FA predicted worse downstream motor control. Therefore, intra-individual BP slope and variability impact corticospinal tract microstructural properties of white matter with females having increased susceptibility to damage.

Women in the Mayo Clinic Department of Neurology in its early years.

The stories of early women physicians in the field of neurology are seldom discussed. Understanding the history behind women in neurology can inform our current practice and uncover the possible origins of gender disparities in academic neurology. Utilizing annual section/department reports and other primary sources, we describe the first women trainees and staff who broke gender barriers to train and work in the Mayo Clinic Department of Neurology. The department was founded in 1913 when Walter Shelden became its first consultant. It was not until the 1950s that a woman completed her neurology training and went on to practice neurology. Throughout the early years of the training program, there were no women on staff, as it was not until the 1970s when the first women were hired as consultants.

Utility of routine surface electrophysiology to screen for functional tremor prior to surgical treatment of essential tremor.

Background: Patients with functional tremor may be clinically misdiagnosed as "medication-refractory" essential tremor (ET) and referred for surgical treatment. Electrophysiology can screen for functional tremor and avoid inappropriate surgery. Objective: To report the utility of surface electrophysiology (SEMG) to screen for functional tremor in patients referred for ET surgery. Methods: Retrospective review of consecutive ET patients referred to the Mayo Clinic DBS clinic over 1.5 years. Included subjects had a clinical diagnosis of medication-refractory ET and completed presurgical workup including routine SEMG tremor study. Results: Of 87 subjects, 9 (10%) were clinically suspected of functional tremor by the DBS neurologist. Electrophysiology confirmed functional tremor features in 7/9 and ET in the other 2/9; and newly identified 5 additional cases of functional tremor. There were 12 total confirmed cases of functional tremor: isolated in 1, and mixed functional tremor and ET in 11. Of 11 mixed patients, 6 with mild functional overlay were approved for surgery. The remaining 5 patients with moderate-severe functional overlay and the single patient with isolated functional tremor were referred to the functional tremor motor retraining program. Of these, 1 patient with mixed tremor had residual disabling organic ET after program completion and was later approved for surgery. Thus, 5/87 patients (6%) avoided unnecessary surgery. Conclusions: Functional tremor may frequently overlay "medication-refractory" ET amongst patients referred for surgery, affecting 1 of 7 patients in our quaternary referral DBS center. Electrophysiology studies are useful to routinely screen patients and prevent unnecessary surgery.

Tau-PET and multimodal imaging in clinically atypical multiple system atrophy masquerading as progressive supranuclear palsy.

INTRODUCTION: Multiple system atrophy (MSA) typically presents with parkinsonism, ataxia and/or autonomic dysfunction. Occasionally, clinically atypical (ca-MSA) cases masquerade as progressive supranuclear palsy (PSP). We aimed to investigate whether different neuroimaging modalities could facilitate differentiation and whether histopathologic characteristics could explain the atypical presentation. METHODS: We identified 3 neuropathologically-defined ca-MSA patients with clinically diagnosed PSP who underwent various antemortem brain imaging: MRI and PET imaging using 11C-Pittsburgh compound B, 18F-flortaucipir, and 18F-fluorodeoxyglucose. We compared clinical features, brainstem planimetry, and radiotracer standardized uptake value ratios in ca-MSA to 10 autopsy-confirmed PSP patients and 10 healthy controls (imaging only). We also compared histologic count of neuronal loss, iron deposition and α-synuclein-immunoreactive glial cytoplasmic inclusion burden to 10 autopsy-confirmed MSA-parkinsonism (MSA-P) cases. RESULTS: Ca-MSA had better PSP Saccadic Impairment Scale scores (p = 0.003) and more frequent good levodopa response (p = 0.061) than PSP. Ca-MSA showed higher midbrain-to-pons ratio and lower Magnetic Resonance Parkinsonism Index than PSP (each, p = 0.036) and exhibited lower glucose metabolism in the putamen and globus pallidus versus PSP (p = 0.017) and controls (p = 0.007). These same regions showed higher flortaucipir uptake in ca-MSA than PSP (p = 0.007 for putamen, p = 0.049 for pallidum) and controls (p = 0.012). Lower flortaucipir retention was observed in the subthalamic nucleus versus PSP (p = 0.007). The putamen-to-subthalamic ratio distinguished ca-MSA from PSP. No histopathological differences were observed for ca-MSA versus typical MSA-P. CONCLUSION: Severity of saccadic impairment, levodopa responsiveness, MRI planimetric measurements, and different patterns of fluorodeoxyglucose and flortaucipir uptake can help improve antemortem differentiation of MSA masquerading as PSP from true PSP.

Standardized Autonomic Testing in Patients With Probable Radiation-Induced Afferent Baroreflex Failure.

Injury of the afferent limb of the baroreflex from neck radiation causes radiation-induced afferent baroreflex failure (R-ABF). Identification and management of R-ABF is challenging. We aimed to investigate the pattern of autonomic dysfunction on standardized autonomic testing in patients with probable R-ABF. We retrospectively analyzed all autonomic reflex screens performed at Mayo Clinic in Rochester, MN, between 2000 and 2020 in patients with probable R-ABF. Additional tests reviewed included ambulatory blood pressure monitoring, plasma norepinephrine, and thermoregulatory sweat test. We identified 90 patients with probable R-ABF. Median total composite autonomic severity score (range, 0-10) was 7 (interquartile range, 6-7). Cardiovascular adrenergic impairment was seen in 85 patients (94.4%), increased blood pressure recovery time after Valsalva maneuver in 71 patients (78.9%; median 17.4 seconds), and orthostatic hypotension in 68 patients (75.6%). Cardiovagal impairment was demonstrated by abnormal heart rate responses to deep breathing (79.5%), Valsalva ratio (87.2%), and vagal baroreflex sensitivity (57.9%). Plasma norepinephrine was elevated and rose appropriately upon standing (722-1207 pg/mL). Ambulatory blood pressure monitoring revealed hypertension, postural hypotension, hypertensive surges, tachycardia, and absence of nocturnal dipping. Blood pressure lability correlated with impaired vagal baroreflex function. Postganglionic sympathetic sudomotor function was normal in most cases; the most frequent thermoregulatory sweat test finding was focal neck anhidrosis (78.9%). Standardized autonomic testing in R-ABF demonstrates cardiovascular adrenergic impairment with orthostatic hypotension, blood pressure lability, and elevated plasma norepinephrine. Cardiovagal impairment is common, while sudomotor deficits are limited to direct radiation effects.

Utility of tremor electrophysiology studies.

OBJECTIVE: To determine the utility of tremor electrophysiology testing in differentiating clinically indeterminate tremor due to organic, functional, and mixed tremor types. BACKGROUND: Prior studies have shown that electrophysiological studies increase diagnostic sensitivity of tremor syndromes; however, few have examined mixed organic and functional tremors. METHODS: Patients referred for tremor to the Mayo Clinic, Rochester movement disorders lab were consecutively selected and retrospectively reviewed. Surface electromyography (EMG) recordings of upper limb muscles were performed at rest, posture, with action and distractibility tasks. RESULTS: Of 116 patients, all were clinically described as having either a resting tremor, postural tremor, action tremor, postural and action tremor, mixed resting, postural, and action tremor, or nonspecific tremulousness. Based on electrophysiological features, patients were diagnosed with organic tremor (parkinsonian, essential, mixed, rubral, cerebellar, non-specific tremulousness), functional tremor, or mixed functional and organic tremors. The median disease duration at electrophysiological confirmation of diagnosis was shorter for functional tremor at 1.5 years (IQR 1-9.3), and organic tremor at 3 years (IQR 1-15), versus mixed organic and functional tremor at 11 years (IQR 2-15) (p = 0.0422). The electrophysiology study clarified the referral/clinical diagnosis in 87 patients (75%), 26 (29.5%) of whom had functional tremor, and 61 (70.1%) had organic tremor or mixed organic/functional tremor. Variability of tremor during electrophysiology testing was associated with a change in diagnosis (p = 0.0286). CONCLUSION: Our findings show that electrophysiological assessment of tremor can be helpful in the clinical diagnosis of patients with both organic and functional tremor.

Natural History of Afferent Baroreflex Failure in Adults.

OBJECTIVE: To describe the natural history of afferent baroreflex failure (ABF) based on systematic review of clinical and laboratory data in patients with a diagnosis of ABF at Mayo Clinic Rochester. METHODS: We performed a retrospective chart review of all patients who underwent standardized autonomic reflex testing between 2000 and 2020 and had confirmation of the diagnosis of ABF by an autonomic disorders specialist. Patients were identified using a data repository of medical records. Variables included demographic, all-cause mortality, medications, ABF manifestations, comorbidities, and laboratory (autonomic testing, blood pressure monitoring, echocardiogram, brain imaging, plasma catecholamines, serum sodium level, and kidney function tests). RESULTS: A total of 104 patients with ABF were identified. Head and neck radiation was the most common etiology (86.5%), followed by neck surgery (5.8%) and other causes (7.7%). The most common findings were hypertension (87.5%), fluctuating blood pressure (78.8%), orthostatic hypotension (91.3%), syncope (58.6%), headache (22.1%), and tachycardia (20.2%). Patients commonly received antihypertensives (66.3%), pressor agents (41.3%), or a combination of both (19.2%). The median latency from completion of radiation to ABF was longer compared to the latency in the surgery group (p < 0.0001). Comorbidities, including complications from neck radiation, were frequently seen and all-cause mortality was 39.4% over a 20-year period. CONCLUSIONS: ABF should be suspected in patients with prior head and neck cancer treated by radiation or surgery who present with labile hypertension and orthostatic hypotension. Management may require both antihypertensive and pressor medications. The morbidity and mortality in ABF are high.

Autonomic dysfunction following COVID-19 infection: an early experience.

PURPOSE: Post-COVID-19 syndrome is a poorly understood aspect of the current pandemic, with clinical features that overlap with symptoms of autonomic/small fiber dysfunction. An early systematic analysis of autonomic dysfunction following COVID-19 is lacking and may provide initial insights into the spectrum of this condition. METHODS: We conducted a retrospective review of all patients with confirmed history of COVID-19 infection referred for autonomic testing for symptoms concerning for para-/postinfectious autonomic dysfunction at Mayo Clinic Rochester or Jacksonville between March 2020 and January 2021. RESULTS: We identified 27 patients fulfilling the search criteria. Symptoms developed between 0 and 122 days following the acute infection and included lightheadedness (93%), orthostatic headache (22%), syncope (11%), hyperhidrosis (11%), and burning pain (11%). Sudomotor function was abnormal in 36%, cardiovagal function in 27%, and cardiovascular adrenergic function in 7%. The most common clinical scenario was orthostatic symptoms without tachycardia or hypotension (41%); 22% of patients fulfilled the criteria for postural tachycardia syndrome (POTS), and 11% had borderline findings to support orthostatic intolerance. One patient each was diagnosed with autoimmune autonomic ganglionopathy, inappropriate sinus tachycardia, vasodepressor syncope, cough/vasovagal syncope, exacerbation of preexisting orthostatic hypotension, exacerbation of sensory and autonomic neuropathy, and exacerbation of small fiber neuropathy. CONCLUSION: Abnormalities on autonomic testing were seen in the majority of patients but were mild in most cases. The most common finding was orthostatic intolerance, often without objective hemodynamic abnormalities on testing. Unmasking/exacerbation of preexisting conditions was seen. The temporal association between infection and autonomic symptoms implies a causal relationship, which however cannot be proven by this study.