The current research challenge in pure autonomic failure (PAF) lies in identifying specific biomarkers that can differentiate it from the other Lewy body disorders (Parkinson's disease, Parkinson's disease dementia, dementia with Lewy bodies) and multiple system atrophy in the early stages and predict phenoconversion trajectories to more widespread impairment. In this study, we described the natural history of our cohort of patients with PAF over five decades and validated a cluster of clinical, autonomic, and neuroimaging biomarkers that help identify clinical profiles susceptible to further neurodegeneration, working towards a biological definition of PAF. Consecutive patients with an initial diagnosis of PAF were recruited and monitored through key milestones (disease onset, first and repeat autonomic assessment, phenoconversion, and death/final contact). A subset underwent brain MRI and DaTSCAN (dopamine transporter single-photon emission CT scan). Uni- and multivariate regression analyses explored the associations among different factors, survival times, and phenoconversion, and were used to predict the probability of phenoconversion. Altogether, 281 patients with PAF were followed for a median of 10 years. Of these, 33% (91) converted to a more widespread synucleinopathy, and 41% (115) died during follow-up, of whom 53% (61) retained a PAF phenotype. Baseline cardiovascular autonomic biomarkers were key in differentiating disease trajectories and repeat testing indicated worsening of autonomic failure during the disease course. Median survival of patients with PAF was 15 years from orthostatic symptoms onset and was mostly influenced by age and the severity of orthostatic hypotension. Overall, 39% of patients had abnormal DaTSCAN results up to 7 years before phenoconversion, with 84% of these patients progressing to more widespread synucleinopathy. Male sex, older age, dream enactment behaviour and supine noradrenaline levels >200 pg/ml correlated with the risk of phenoconversion to Lewy body disorders, whereas younger age, bladder dysfunction, catheter use and dream enactment behaviour were associated with phenoconversion to multiple system atrophy. Our natural history study involves the largest single-centre longitudinal cohort of patients with an initial diagnosis of PAF and identifies robust clinical, autonomic, and neuroimaging biomarkers that, when used together, could serve as a novel and sensitive screening tool for early identification and stratification of patients at risk of phenoconversion to more widespread synucleinopathy.

Cardiovascular autonomic failure and neurogenic orthostatic hypotension (nOH) are common and disabling in Parkinson’s disease (PD) and multiple system atrophy (MSA). Recent studies have shown evidence of postganglionic autonomic denervation in MSA as well as PD. We aimed to characterise the relationship between nOH, autonomic failure and postganglionic denervation in PD and MSA. We hypothesised that postganglionic autonomic denervation contributes to the development of nOH and correlates with the severity of cardiovascular autonomic failure. We assessed 57 patients (37 PD, 20 MSA, median 64 [IQR 59–70] years) with cardiovascular autonomic testing; dynamic sweat testing; plasma noradrenaline levels; skin biopsies for quantification of intraepidermal, pilomotor and sudomotor innervation; and autonomic symptom questionnaires. Overall, 78

BackgroundPure autonomic failure (PAF) presents with progressive autonomic failure without other neurological features. Atypical presentations may lead to diagnostic uncertainty. We studied whether cutaneous phosphorylated-alpha-synuclein (p-syn) could distinguish between PAF, multiple system atrophy (MSA) and non-synucleinopathy-related autonomic failure, and examined its relationship with quantitative markers of cardiovascular autonomic failure.MethodsAll individuals underwent Composite Autonomic Symptom Score-31 autonomic questionnaires, cardiovascular autonomic testing and bilateral distal leg skin biopsies. We noted whether p-syn was present in nerves supplying autonomic adnexa, including sweat glands, blood vessels, arrector pili muscles, and subepidermal fibres, dermal fibres and nerve fascicles (maximum autonomic subscore 3, total p-syn score 6 for each sample, average calculated for both sides).Results36 individuals were studied: 11 PAF, 13 MSA and 12 non-synucleinopathy-related autonomic failure. P-syn was present in 22/22 (100%) PAF biopsies, 19/26 (73%) MSA biopsies and 0/22 (0%) non-synucleinopathy biopsies. Mean total p-syn score was significantly higher in PAF compared with MSA (median 4.5 vs 1, p<0.001). Total p-syn score >3 distinguished PAF from MSA with 100% specificity and 82% sensitivity. Autonomic p-syn subscores correlated with orthostatic intolerance ratio on tilt (ρ=0.63, p=0.0004), blood pressure recovery time following Valsalva manoeuvre (r=0.44, p=0.03) and patient-reported orthostatic intolerance (ρ=0.57, p=0.006).ConclusionCutaneous p-syn was abundant in PAF, a predominantly peripheral alpha-synucleinopathy. It is a promising biomarker to help distinguish between PAF, MSA and non-synucleinopathy-related autonomic failure to aid early diagnosis and recruitment to future clinical trials. P-syn deposition on autonomic nerves may impair control of total peripheral resistance giving rise to symptomatic orthostatic hypotension.

The cardiomyopathic and neuropathic phenotype of hereditary transthyretin amyloidosis are well recognized. Cardiovascular autonomic dysfunction is less systematically and objectively assessed. Autonomic and clinical features, quantitative cardiovascular autonomic function, and potential autonomic prognostic markers of disease progression were recorded in a cohort of individuals with hereditary transthyretin amyloidosis and in asymptomatic carriers of TTR variants at disease onset (T0) and at the time of the first quantitative autonomic assessment (T1). The severity of peripheral neuropathy and its progression was stratified with the polyneuropathy disability score. A total of 124 individuals were included (111 with a confirmed diagnosis of hereditary transthyretin amyloidosis, and 13 asymptomatic carriers of TTR variants). Symptoms of autonomic dysfunction were reported by 27

IntroductionCardiovascular autonomic failure is the hallmark finding in Pure autonomic failure (PAF) however other autonomic functions are likely to be affected. This study aims to characterise genitourinary dysfunction in PAF patients and explore their relationship with cardiovascular autonomic dysfunction.MethodsPAF patients who underwent cardiovascular autonomic testing completed self-administered questionnaires evaluating urinary and sexual symptoms and a 3-day bladder diary measuring fluid intake and urine output. Demographic, clinical features, disease duration and related medical comorbidities were assessed.Results25 PAF patients (10 males) were recruited (mean age 71+8 years; disease duration 13+8 years). 96% (24/25) reported lower urinary tract symptoms, most commonly overactive bladder symptoms (92%) followed by low stream (80%) and stress incontinence (52%). 4(16%) patients required catheterisation. 19/22 (86%) had nocturnal polyuria (NP), defined as NP index >0.3 (nocturnal urine volume/24-hour urine volume), mean NP index 0.45 (range, 0.20-0.73). There were no significant correlations between BP drops on head-up tilt, supine hypertension, respiratory sinus arrhythmia, Valsalva ratio or disease duration with the degree of nocturnal polyuria and need for catheterisation (p>0.05).ConclusionsNP and genitourinary symptoms are common in PAF. The pathophysiology of NP in PAF is likely to be multifactorial and may not only be explained by cardiovascular autonomic failure.

Objective We described autonomic features, performed quantitative cardiovascular autonomic function testing (AFT), and explored whether autonomic dysfunction could serve as a prognostic marker of disease progression in a population of variant transthyretin (ATTRv) amyloidosis. Methods Symptoms of autonomic dysfunction, neuropathic and cardiac features were collected ret- rospectively at disease onset and at the time of AFT. Autonomic failure was stratified into 3 stages. The polyneuropathy disability (PND) staging was used to stratify the severity of peripheral neuropathy and its progression rate. Results At disease onset, symptoms of autonomic dysfunction were present in 24/80 (30%) subjects, while neuropathic and cardiac symptoms were present in 51/80 (63.75%) and 17/80 (21.25%) patients respectively. 97/120 patients, who had not received any disease-modifying therapy from disease onset, were included in the final analysis. 63/97 (64.9%) patients reported symptoms of autonomic dysfunction at time of autonomic assessment (mean disease duration of 4,27 ± 3,72 [years ± SD]). Autonomic failure was present in 34/46 (73.9%) patients (not treated with antihypertensive medications). Progression rates from PND stages 1 or 2 to 3 or 4 were significantly shorter for patients with autonomic symptoms at onset, compared to patients without autonomic onset (median time 2 years; range 1-8 years vs. 5 years; range 2-12 years). Conclusion Autonomic dysfunction is an early, underestimated, and rapidly progressive feature in ATTRv amyloidosis, and it can predict faster disease progression and motor disability.

BACKGROUND AND PURPOSE:Pure autonomic failure (PAF) is a rare progressive neurodegenerative disease characterized by neurogenic orthostatic hypotension at presentation, without other neurological abnormalities. Some patients may develop other central neurological features indicative of multiple system atrophy or a Lewy body disorder. There are currently no biomarkers to assess possible central nervous system involvement in probable PAF at an early stage. A possibility is to evaluate the nigrostriatal dopaminergic degeneration by imaging of dopamine transporter with DaTscan brain imaging. The objective was to evaluate subclinical central nervous system involvement using DaTscan in PAF. METHODS:We retreospectively reviewed pure autonomic failure patients who were evaluated at the Autonomic Unit between January 2015 and August 2021 and underwent comprehensive autonomic assessment, neurological examination, brain magnetic resonance imaging and DaTscan imaging. DaTscan imaging was performed if patients presented with atypical features which did not meet the criteria for Parkinson's disease or multiple system atrophy or other atypical parkinsonism. RESULTS:In this cohort, the median age was 49.5 years at disease onset, 57.5 years at presentation, and the median disease duration was 7.5 years. Five of 10 patients had an abnormal DaTscan without neurological features meeting the criteria of an alternative diagnosis. Patients with abnormal DaTscan were predominantly males, had shorter disease duration and had more severe genitourinary symptoms. DISCUSSION:Degeneration of nigrostriatal dopaminergic neurons measured using DaTscan imaging can present in patients with PAF without concurrent signs indicating progression to widespread α-synucleinopathy. It is advocated that DaTscan imaging should be considered as part of the workup of patients with emerging autonomic failure who are considered to have PAF.

Innovative immunotherapy in the form of Immune Checkpoint Inhibitors (ICIs) has significantly improved outcomes for patients with numerous metastatic cancers. A double-edged sword, we are increasingly learning about the immune-related adverse events (irAEs) associated with use of these novel therapeu- tic agents.Here we present the case of a 53 years old woman with background of malignant melanoma of the leg and metastatic lesions to the lung and brain. She commenced treatment with dual immunotherapy with Nivolumab/Ipilimumab with subsequent resolution of both metastatic lesions.Two years following the completion of immunotherapy, she developed left sided arm and leg weakness, hemianopia, left sided Epilepsia Partialis Continua (EPC) and cognitive decline. MRI showed diffusion res- triction along the active cortex during the period of EPC that settled as AEDs suppressed clinical seizure activity. However, while there was no tumour recurrence with interval oncology MRI, there was progressive asymmetrical atrophy of the right cerebral hemisphere with associated white matter signal abnormality in keeping with Rasmussen’s encephalitis scan changes.We propose that this represents a late delayed reaction to immunotherapy, beyond the recognised encephalitis that was the likely cause of EPC. Increasing use of ICIs will likely reveal more cases.

Post-coronavirus disease 19 (COVID-19) syndrome has substantial health and economic implications. It is multi-systemic, with prevalent autonomic symptoms. Understanding presentations and potential autonomic causes may help guide treatment strategies and recovery.All patients with a suspected or confirmed history of COVID-19 infection who underwent autonomic testing between May 2020 and October 2021 were reviewed retrospectively.We evaluated 62 patients (20 male, 42 female, mean age of 41.38 ±11.52). COVID-19 was PCR confirmed in 15 patients (26%), and five (8%) required acute hospital intervention. Most common symptoms included palpitations (81%), light-headedness/dizziness (62%), dyspnoea (48%), fatigue (46%), or cognitive symptoms(33%)Autonomic testing showed normal blood pressure responses to pressor stimuli, a mean respiratory sinus arrhythmia of 18.89b/m, and Valsalva ratio of 2.09. Postural tachycardia syndrome (PoTS) was diagnosed in 12 patients, autonomically mediated syncope (AMS) in 11, neurogenic orthostatic hypotension (NOH) in two, and initial orthostatic hypotension (IOH) in seven.Normal supine and upright plasma noradrenaline levels were measured in 34 patients (mean 283.38 pg/ml supine; 472.43pg/ml tilted).Autonomic testing was reassuring (PoTS and syncope) in the majority with abnormal testing (n=32, or 52%). Further phenotyping of PoTS to exclude neuropathic pathology may be needed. IOH and OH are important considerations.

Background and Objectives Sudomotor impairment has been recognized as a key feature in differentiating Parkinson disease (PD) and multiple system atrophy–parkinsonian type (MSA-P), with the latter characterized by diffuse anhidrosis in prospective study, including patients in late stage of disease. We aimed to evaluate morphologic and functional postganglionic sudomotor involvement in patients with newly diagnosed MSA-P and PD to identify possible biomarkers that might be of help in differentiating the 2 conditions in the early stage. Methods One hundred patients with parkinsonism within 2 years from onset of motor symptoms were included in the study. At the time of recruitment, questionnaires to assess nonmotor, autonomic, and small fiber symptoms were administered, and patients underwent postganglionic sudomotor function assessment by the dynamic sweat test and punch skin biopsy from the distal leg. Skin samples were processed for indirect immunofluorescence with a panel of antibodies, including noradrenergic and cholinergic markers. The density of intraepidermal, sudomotor, and pilomotor nerve fibers was measured on confocal images with dedicated software. A follow-up visit 12 months after recruitment was performed to confirm the diagnosis. Results We recruited 57 patients with PD (M/F 36/21, age 63.5 ± 9.4 years) and 43 patients with MSA-P (M/F 27/16, age 62.3 ± 9.0 years). Clinical scales and questionnaires showed a more severe clinical picture in patients with MSA-P compared to those with PD. Sweating output and intraepidermal, pilomotor, and sudomotor nerve densities, compared to controls, were lower in both groups but with a greater impairment in patients with MSA-P. Pilomotor and sudomotor nerve density correlated with sweating function and with nonmotor clinical symptoms. A composite sudomotor parameter defined as the arithmetic product of sweat production multiplied by the density of sudomotor fibers efficiently separated the 2 populations; the receiver operating characteristics curve showed an area under the curve of 0.83. Discussion Dynamic sweat test and the quantification of cutaneous autonomic nerves proved to be a sensitive morpho-functional approach to assess the postganglionic component of the sudomotor pathway, revealing a more severe involvement in MSA-P than in PD early in the disease course. This approach can be applied to differentiate the 2 conditions early. Classification of Evidence This study provides Class II evidence that postganglionic sudomotor morpho-functional assessment accurately distinguish patients with PD from patients with MSA-P.

BackgroundSurvivors of moderate-severe traumatic brain injury (msTBI) frequently experience trouble- some unexplained somatic symptoms, which may be attributable to autonomic dysfunction.MethodsWe conducted two cohort studies. Cohort 1 comprises msTBI patients (with controls) prospec- tively recruited from a regional referral TBI outpatient clinic, in whom we assessed subjective burden of autonomic symptoms using the Composite Autonomic Symptom Score (COMPASS31) questionnaire. Cohort 2 comprises msTBI patients who had clinical autonomic function testing, retrospectively identified from referrals to a national referral autonomics unit.ResultsCohort 1 comprises 39 msTBI patients (10F:20M, median age 40 years, range 19-76), with median time since injury 19 months (range 6-299), and 44 controls (22F:22M, median age 45, range 25-71). Patients had significantly higher mean scores than controls in the weighted total COMPASS-31 score (p<0.001), and also gastrointestinal, orthostatic and secretomotor subscores (corrected p<0.05). Total COMPASS31 score inversely correlated with subjective rating of general health (p<0.001, rs=-0.84). Cohort 2 comprises 18 msTBI patients (7F:11M, median age 44 years, range 21-64), with median time between injury and testing 57.5 months (range 2-416). Clinical autonomic function testing revealed a broad spectrum of autonomic dysfunction in 13/18 patients.DiscussionOur results provide evidence for clinically relevant autonomic dysfunction after msTBI, even at the chronic stage. We advocate for routine enquiry about potential autonomic symptoms, and demons- trate the utility of formal autonomic testing in providing diagnoses.

BACKGROUND AND OBJECTIVES:Nonmotor features precede motor symptoms in many patients with multiple system atrophy (MSA). However, little is known about differences between the natural history, progression, and prognostic factors for survival in patients with MSA with nonmotor vs motor presentations. We aimed to compare initial symptoms, disease progression, and clinical features at final evaluation and investigate differences in survival and natural history between patients with MSA with motor and nonmotor presentations. METHODS:Medical records of autopsy-confirmed MSA cases at Queen Square Brain Bank who underwent both clinical examination and cardiovascular autonomic testing were identified. Clinical features, age at onset, sex, time from onset to diagnosis, disease duration, autonomic function tests, and plasma noradrenaline levels were evaluated. RESULTS:Forty-seven patients with autopsy-confirmed MSA (age 60 ± 8 years; 28 men) were identified. Time from symptom onset to first autonomic evaluation was 4 ± 2 years, and the disease duration was 7.7 ± 2.2 years. Fifteen (32%) patients presented with nonmotor features including genitourinary dysfunction, orthostatic hypotension, or REM sleep behavior disorder before developing motor involvement (median delay 1-6 years). A third (5/15) were initially diagnosed with pure autonomic failure (PAF) before evolving into MSA. All these patients had normal supine plasma noradrenaline levels (332.0 ± 120.3 pg/mL) with no rise on head-up tilt (0.1 ± 0.3 pg/mL). Patients with MSA with early cardiovascular autonomic dysfunction (within 3 years of symptom onset) had shorter survival compared with those with later onset of cardiovascular autonomic impairment (6.8 years [5.6-7.9] vs 8.5 years [7.9-9.2]; p = 0.026). Patients with early urinary catheterization had shorter survival than those requiring catheterization later (6.2 years [4.6-7.8] vs 8.5 years [7.6-9.4]; p = 0.02). The survival of patients with MSA presenting with motor and nonmotor symptoms did not differ (p > 0.05). DISCUSSION:Almost one-third of patients with MSA presented with nonmotor features, which could predate motor symptoms by up to 6 years. Cardiovascular autonomic failure and early urinary catheterization were predictors of poorer outcomes. A normal supine plasma noradrenaline level in patients presenting with PAF phenotype is a possible autonomic biomarker indicating later conversion to MSA.