Autonomic impairment in primary lateral sclerosis.

PURPOSE: Prior studies reported evidence of autonomic involvement in motor neuron disease and suggested more severe dysfunction in upper motor neuron predominant syndromes. Hence, we sought to characterize autonomic impairment in primary lateral sclerosis. METHODS: Neurological evaluations, thermoregulatory sweat tests, and autonomic reflex screens were analyzed retrospectively in 34 primary lateral sclerosis patients (28 definite and 6 probable). Patients with other potential causes of autonomic failure and patients with autonomic testing results compromised by artifact were excluded. RESULTS: A total of 17 patients reported autonomic symptoms. Orthostatic lightheadedness was most frequent (8 patients), followed by bladder (7), bowel (5), and erectile dysfunction (3). The autonomic reflex screens of 33 patients were reviewed; 20 patients had abnormal studies. The thermoregulatory sweat tests of 19 patients were reviewed; 11 patients had abnormal studies. Composite Autonomic Severity Score was calculated for 33 patients and found abnormal in 20/33 patients (60.6%): 15/20 patients (75%) had mild impairment, and 5/20 patients (25%) had moderate impairment. The frequencies of testing abnormalities were: sudomotor 18/20 (90%), cardiovagal 9/20 (45%), and adrenergic 6/20 (30%). Sweat loss pattern analysis showed global, regional, and mixed patterns to be more common than length-dependent and distal patterns. CONCLUSION: We found evidence of frequent autonomic dysfunction in primary lateral sclerosis, which is generally of modest severity akin to prior reports for amyotrophic lateral sclerosis, but more commonly in a pattern consistent with preganglionic/ganglionic localization. This suggests that primary lateral sclerosis, as with amyotrophic lateral sclerosis, is a multisystem disease that affects the autonomic nervous system.

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.

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.

Neurofilament light chain in spinal fluid and plasma in multiple system atrophy: a prospective, longitudinal biomarker study.

PURPOSE: There is a critical need for reliable diagnostic biomarkers as well as surrogate markers of disease progression in multiple system atrophy (MSA). Neurofilament light chain (NfL) has been reported to potentially meet those needs. We therefore sought to explore the value of NfL in plasma (NfL-p) in contrast to cerebrospinal fluid (NfL-c) as a diagnostic marker of MSA, and to assess NfL-p and NfL-c as markers of clinical disease progression. METHODS: Well-characterized patients with early MSA (n = 32), Parkinson's disease (PD; n = 21), and matched controls (CON; n = 15) were enrolled in a prospective, longitudinal study of synucleinopathies with serial annual evaluations. NfL was measured using a high-sensitivity immunoassay, and findings were assessed by disease category and relationship with clinical measures of disease progression. RESULTS: Measurements of NfL-c were highly reproducible across immunoassay platforms (Pearson, r = 0.99), while correlation between NfL-c and -p was only moderate (r = 0.66). NfL was significantly higher in MSA compared with CON and PD; the separation was essentially perfect for NfL-c, but there was overlap, particularly with PD, for NfL-p. While clinical measures of disease severity progressively increased over time, NfL-c and -p remained at stable elevated levels within subjects across serial measurements. Neither change in NfL nor baseline NfL were significantly associated with changes in clinical markers of disease severity. CONCLUSIONS: These findings confirm NfL-c as a faithful diagnostic marker of MSA, while NfL-p showed less robust diagnostic value. The significant NfL elevation in MSA was found to be remarkably stable over time and was not predictive of clinical disease progression.

Neurofilament Light Chain in Spinal Fluid and Plasma in Multiple System Atrophy - A Prospective, Longitudinal Biomarker Study.

Purpose There is a critical need for reliable diagnostic biomarkers as well as surrogate markers of disease progression in multiple system atrophy (MSA). Neurofilament light chain (NfL) has been reported to potentially meet those needs. We therefore sought to explore the value of NfL in plasma (NfL-p) in contrast to CSF (NfL-c) as diagnostic marker of MSA, and to assess NfL-p and NfL-c as markers of clinical disease progression. Methods Well-characterized patients with early MSA (n=32), Parkinson's disease (PD, n=21), and matched controls (CON, n=15) were enrolled in a prospective, longitudinal study of synucleinopathies with serial annual evaluations. NfL was measured using a high sensitivity immunoassay, and findings were assessed by disease category and relationship with clinical measures of disease progression. Results Measurements of NfL-c were highly reproducible across immunoassay platforms (Pearson,r=0.99), while correlation between NfL-c and -p was only moderate (r=0.66). NfL was significantly higher in MSA compared to CON and PD; the separation was essentially perfect for NfL-c, but there was overlap, particularly with PD, for NfL-p. While clinical measures of disease severity progressively increased over time, NfL-c and -p remained at stable elevated levels within subjects across serial measurements. Neither change in NfL nor baseline NfL were significantly associated with changes in clinical markers of disease severity. Conclusions These findings confirm NfL-c as faithful diagnostic marker of MSA, while NfL-p showed less robust diagnostic value. The significant NfL elevation in MSA was found to be remarkably stable over time and was not predictive of clinical disease progression.

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.

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.

Imaging biomarkers for early multiple system atrophy.

OBJECTIVE: To systematically evaluate structural MRI and diffusion MRI features for cross-sectional discrimination and tracking of longitudinal disease progression in early multiple system atrophy (MSA). METHODS: In a prospective, longitudinal study of synucleinopathies with imaging on 14 controls and 29 MSA patients recruited at an early disease stage (15 predominant cerebellar ataxia subtype or MSA-C and 14 predominant parkinsonism subtype or MSA-P), we computed regional morphometric and diffusion MRI features. We identified morphometric features by ranking them based on their ability to distinguish MSA-C from controls and MSA-P from controls and evaluated diffusion changes in these regions. For the top performing regions, we evaluated their utility for tracking longitudinal disease progression using imaging from 12-month follow-up and computed sample size estimates for a hypothetical clinical trial in MSA. We also computed these selected morphometric features in an independent validation dataset. RESULTS: We found that morphometric changes in the cerebellar white matter, brainstem, and pons can separate early MSA-C patients from controls both cross-sectionally and longitudinally (p < 0.01). The putamen and striatum, though useful for separating early MSA-P patients from control subjects at baseline, were not useful for tracking MSA disease progression. Cerebellum white matter diffusion changes aided in capturing early disease related degeneration in MSA. INTERPRETATION: Regardless of clinically predominant features at the time of MSA assessment, brainstem and cerebellar pathways progressively deteriorate with disease progression. Quantitative measurements of these regions are promising biomarkers for MSA diagnosis in early disease stage and potential surrogate markers for future MSA clinical trials.

Neurological safety of subcutaneous tanezumab versus NSAID in patients with osteoarthritis.

OBJECTIVE: To assess the long-term neurological safety of tanezumab, a monoclonal antibody against nerve growth factor. METHODS: Patients with osteoarthritis of the hip or knee received stable doses of oral nonsteroidal anti-inflammatory drugs (NSAIDs) before study entry and during a ≤ 37-day screening period. Patients were randomized 1:1:1 to double-dummy tanezumab (2.5 mg or 5 mg, subcutaneous every 8 weeks) or oral NSAIDs (twice-daily) for 56 weeks, with a 24-week follow-up. Neurological safety evaluation focused on peripheral and sympathetic adverse events (AEs), neurologic examinations, and consultations with blinded, external diagnostic reviews. RESULTS: During the treatment period, 6.2%, 9.0%, and 4.6% of patients experienced AEs of abnormal peripheral sensation (APS) in the tanezumab 2.5 mg, 5 mg, and NSAID groups, respectively. Hypoesthesia, paresthesia, and carpal tunnel syndrome were the most common AEs of APS. Clinically significant worsening on examination occurred in <1% in any treatment group at the last study assessment. Diagnoses following external neurological consultation included mononeuropathy (1.3%, 2.1%, and 1.0%), radiculopathy (0.9%, 0.4%, and 0.5%), and polyneuropathy (0.3%, 0.5%, and 0%) in tanezumab 2.5 mg, 5 mg, and NSAID groups, respectively. AEs potentially associated with sympathetic neuropathy were reported for 1.8%, 2.3%, and 2.9% of patients in the tanezumab 2.5 mg, 5 mg, and NSAID groups, respectively. No patient was diagnosed with sympathetic neuropathy. CONCLUSION: Tanezumab had an increased incidence of AEs of APS versus NSAID; these were typically mild/moderate in severity, resolved during the study, and rarely resulted in discontinuation. Tanezumab was not associated with peripheral neuropathy and did not adversely affect the sympathetic nervous system. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02528188 (https://clinicaltrials.gov/ct2/show/NCT02528188).

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.

Small Fiber Neuropathy Incidence, Prevalence, Longitudinal Impairments, and Disability.

BACKGROUND AND OBJECTIVES: There are limited population-based data on small fiber neuropathy (SFN). We wished to determine SFN incidence, prevalence, comorbid conditions, longitudinal impairments, and disabilities. METHODS: Test-confirmed patients with SFN in Olmsted, Minnesota, and adjacent counties were compared 3:1 to matched controls (January 1, 1998-December 31, 2017). RESULTS: Ninety-four patients with SFN were identified, with an incidence of 1.3/100,000/y that increased over the study period and a prevalence of 13.3 per 100,000. Average follow-up was 6.1 years (0.7-43 years), and mean onset age was 54 years (range 14-83 years). Female sex (67%), obesity (body mass index mean 30.4 vs 28.5 kg/m2), insomnia (86% vs 54%), analgesic-opioid prescriptions (72% vs 46%), hypertriglyceridemia (180 mg/dL mean vs 147 mg/dL), and diabetes (51% vs 22%, p < 0.001) were more common (odds ratio 3.8-9.0, all p < 0.03). Patients with SFN did not self-identify as disabled with a median modified Rankin Scale score of 1.0 (range 0-6) vs 0.0 (0-6) for controls (p = 0.04). Higher Charlson comorbid conditions (median 6, range 3-9) occurred vs controls (median 3, range 1-9, p < 0.001). Myocardial infarctions occurred in 46% vs 27% of controls (p < 0.0001). Classifications included idiopathic (70%); diabetes (15%); Sjögren disease (2%); AL-amyloid (1%); transthyretin-amyloid (1%); Fabry disease (1%); lupus (1%); postviral (1%); Lewy body (1%), and multifactorial (5%). Foot ulcers occurred in 17, with 71% having diabetes. Large fiber neuropathy developed in 36%, on average 5.3 years (range 0.2-14.3 years) from SFN onset. Median onset Composite Autonomic Severity Score (CASS) was 3 (change per year 0.08, range 0-2.0). Median Neuropathy Impairment Scale (NIS) score was 2 at onset (range 0-8, change per year 1.0, range -7.9 to +23.3). NIS score and CASS change >1 point per year occurred in only AL-amyloid, hereditary transthyretin-amyloid, Fabry, uncontrolled diabetes, and Lewy body. Death after symptom onset was higher in patients with SFN (19%) vs controls (12%, p < 0.001), 50% secondary to diabetes complications. DISCUSSION: Isolated SFN is uncommon but increasing in incidence. Most patients do not develop major neurologic impairments and disability but have multiple comorbid conditions, including cardiovascular ischemic events, and increased mortality from SFN onsets. Development of large fiber involvements and diabetes are common over time. Targeted testing facilitates interventional therapies for diabetes but also rheumatologic and rare genetic forms.

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.

Alpha-Synuclein Oligomers and Neurofilament Light Chain Predict Phenoconversion of Pure Autonomic Failure.

OBJECTIVE: To explore the role of alpha-synuclein (αSyn) oligomers and neurofilament light chain (NfL) in cerebrospinal fluid (CSF) of patients with pure autonomic failure (PAF) as markers of future phenoconversion to multiple system atrophy (MSA). METHODS: Well-characterized patients with PAF (n = 32) were enrolled between June 2016 and February 2019 at Mayo Clinic Rochester and followed prospectively with annual visits to determine future phenoconversion to MSA, Parkinson's disease (PD), or dementia with Lewy bodies (DLB). ELISA was utilized to measure NfL and protein misfolding cyclic amplification (PMCA) to detect αSyn oligomers in CSF collected at baseline. RESULTS: Patients were followed for a median of 3.9 years. Five patients converted to MSA, 2 to PD, and 2 to DLB. NfL at baseline was elevated only in patients who later developed MSA, perfectly separating those from future PD and DLB converters as well as non-converters. ASyn-PMCA was positive in all but two cases (94%). The PMCA reaction was markedly different in five samples with maximum fluorescence and reaction kinetics previously described in MSA patients; all of these patients later developed MSA. INTERPRETATION: αSyn-PMCA is almost invariably positive in the CSF of patients with PAF establishing this condition as α-synucleinopathy. Both NfL and the magnitude and reaction kinetics of αSyn PMCA faithfully predict which PAF patients will eventually phenoconvert to MSA. This finding has important implications not only for prognostication, but also for future trials of disease modifying therapies, allowing for differentiation of MSA from Lewy body synucleinopathies before motor symptoms develop. ANN NEUROL 2021;89:1212-1220.

Clinical presentation and autonomic profile in Ross syndrome.

BACKGROUND: Ross syndrome is a rare disorder characterized by tonic pupils, hyporeflexia, and segmental anhidrosis. We sought to characterize the clinical presentation, associated autoimmune disorders, and autonomic profile in patients with Ross syndrome to further elucidate its pathophysiology. METHODS: We performed a retrospective chart review of all patients who underwent a thermoregulatory sweat test (TST) between 1998 and 2020 and had confirmation of the diagnosis of Ross syndrome by an autonomic disorders specialist. Standardized autonomic reflex testing was reviewed when available. RESULTS: Twenty-six patients with Ross syndrome were identified. The most common initial reported manifestation was an abnormal segmental sweating response in 16 patients (described as hyperhidrosis in 12 patients and anhidrosis in 4 patients) while a tonic pupil was the initial manifestation in 10 patients. Other commonly reported symptoms included fatigue, chronic cough, and increased urinary frequency. An associated autoimmune disorder was identified in one patient. Positive autoantibodies were found in a minority of patients often with unclear clinical significance. Distributions of anhidrosis encountered were segmental (n = 15), widespread (n = 7), and global (n = 4). Well-circumscribed small areas of preserved sweating within areas of anhidrosis were observed in the majority of patients (88.5%). Anhidrosis progressed slowly over time and sudomotor dysfunction was predominantly (post)ganglionic. Cardiovagal and adrenergic functions were preserved in most patients. CONCLUSIONS: The pattern of autonomic dysfunction in Ross syndrome is suggestive of a limited autonomic ganglioneuropathy. Sudomotor impairment is prominent and should be the focus of symptomatic management; however, clinicians should be aware of symptoms beyond the classic triad.

Dysphagia in multiple system atrophy consensus statement on diagnosis, prognosis and treatment.

Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by a combination of autonomic failure plus cerebellar syndrome and/or parkinsonism. Dysphagia is a frequent and disabling symptom in MSA and its occurrence within 5 years of motor onset is an additional diagnostic feature. Dysphagia can lead to aspiration pneumonia, a recognized cause of death in MSA. Guidelines for diagnosis and management of dysphagia in MSA are lacking. An International Consensus Conference among experts with methodological support was convened in Bologna to reach consensus statements for the diagnosis, prognosis, and treatment of dysphagia in MSA. Abnormalities of the oral and pharyngeal phases of swallowing, esophageal dysfunction and aspiration occur in MSA and worsen as the disease progresses. According to the consensus, dysphagia should be investigated through available screening questionnaires and clinical and instrumental assessment (videofluoroscopic study or fiberoptic endoscopic evaluation of swallowing and manometry) at the time of MSA diagnosis and periodically thereafter. There is evidence that dysphagia is associated with poor survival in MSA, however effective treatments for dysphagia are lacking. Compensatory strategies like diet modification, swallowing maneuvers and head postures should be applied and botulinum toxin injection may be effective in specific conditions. Percutaneous endoscopic gastrostomy may be performed when there is a severe risk of malnutrition and pulmonary complications, but its impact on survival is undetermined. Several research gaps and unmet needs for research involving diagnosis, prognosis, and treatment were identified.

Loss of putative GABAergic neurons in the ventrolateral medulla in multiple system atrophy.

STUDY OBJECTIVES: Multiple system atrophy (MSA) is associated with disturbances in cardiovascular, sleep and respiratory control. The lateral paragigantocellular nucleus (LPGi) in the ventrolateral medulla (VLM) contains GABAergic neurons that participate in control of rapid eye movement (REM) sleep and cardiovagal responses. We sought to determine whether there was loss of putative GABAergic neurons in the LPGi and adjacent regions in MSA. METHODS: Sections of the medulla were processed for GAD65/67 immunoreactivity in eight subjects with clinical and neuropathological diagnosis of MSA and in six control subjects. These putative GABAergic LPGi neurons were mapped based on their relationship to adjacent monoaminergic VLM groups. RESULTS: There were markedly decreased numbers of GAD-immunoreactive neurons in the LPGi and adjacent VLM regions in MSA. CONCLUSIONS: There is loss of GABAergic neurons in the VLM, including the LPGi in patients with MSA. Whereas these findings provide a possible mechanistic substrate, given the few cases included, further studies are necessary to determine whether they contribute to REM sleep-related cardiovagal and possibly respiratory dysregulation in MSA.

Frequency of spinocerebellar ataxia mutations in patients with multiple system atrophy.

PURPOSE: Investigate single nucleotide variants and short tandem repeats in 39 genes related to spinocerebellar ataxia in clinical and pathologically defined cohorts of multiple system atrophy. METHODS: Exome sequencing was conducted in 28 clinical multiple system atrophy patients to identify single nucleotide variants in spinocerebellar ataxia-related genes. Novel variants were validated in two independent disease cohorts: 86 clinically diagnosed multiple system atrophy patients and 166 pathological multiple system atrophy cases. Expanded repeat alleles in spinocerebellar ataxia genes were evaluated in 36 clinically diagnosed multiple system atrophy patients, and CAG/CAA repeats in TATA-Box Binding Protein (TBP, causative of SCA17) were screened in 216 clinical and pathological multiple system atrophy patients and 346 controls. RESULTS: No known pathogenic spinocerebellar ataxia single nucleotide variants or pathogenic range expanded repeat alleles of ATXN1, ATXN2, ATXN3, CACNA1A, AXTN7, ATXN8OS, ATXN10, PPP2R2B, and TBP were detected in any clinical multiple system atrophy patients. However, four novel variants were identified in four spinocerebellar ataxia-related genes across three multiple system atrophy patients. Additionally, four multiple system atrophy patients (1.6%) and one control (0.3%) carried an intermediate length 41 TBP CAG/CAA repeat allele (OR = 4.11, P = 0.21). There was a significant association between the occurrence of a repeat length of longer alleles (> 38 repeats) and an increased risk of multiple system atrophy (OR = 1.64, P = 0.03). CONCLUSION: Occurrence of TBP CAG/CAA repeat length of longer alleles (> 38 repeats) is significantly associated with increased multiple system atrophy risk. This discovery warrants further investigation and supports a possible genetic overlap of multiple system atrophy with SCA17.