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Background: The role of peripheral phosphorylated-α-Synuclein (p-α-syn) deposition on nerve degeneration in synucleinopathies is still unknown. Objective: To assess the cutaneous neural distribution of p-α-Syn deposits and its correlation with clinical data and with morphology and function of cutaneous sensory and autonomic nerves in early Parkinson’s disease (PD) and multiple system atrophy-parkinson type (MSA-p). Methods: We recruited 57 PD (F/M = 21/36; age 63.5±9.4 years) and 43 MSA-p (F/M = 16/27; age 62.3±9.0 years) patients within 2 years from motor symptoms. We applied questionnaires and clinical scales, sensory thresholds, and sudomotor testing to assess severity of motor and non-motor involvement and sensory and autonomic dysfunction. We quantified, in skin biopsy from thigh, leg, and fingertip, epidermal, pilomotor, and sudomotor nerve fibers, Meissner corpuscles and intrapapillary myelinated endings and the neural distribution of p-α-syn deposits. Results: Compared to controls, we found a cutaneous denervation paralleling functional and clinical impairment. Sensory and autonomic denervation was more severe in MSA-p than in PD. Deposits of p-α-syn were found in the majority of patients, with no significant differences among sites in both groups. Higher occurrence of p-α-syn deposits in autonomic nerves differentiated (p

Objective The objective of this study was to evaluate patients with ganglionic acetylcholine receptor antibody (gAChR-Ab) positive autoimmune autonomic ganglionopathy using a multimodal testing protocol to characterize their full clinical phenotype and explore biomarkers to quantify immunotherapy response. Methods We conducted a cohort study of 13 individuals (7 women, 21-69 years of age) with autonomic failure and gAChR-Ab >100 pM identified between 2005 and 2019. From 2018, all patients were longitudinally assessed with cardiovascular, pupillary, urinary, sudomotor, lacrimal and salivary testing, and Composite Autonomic Symptom Score (COMPASS-31) autonomic symptom questionnaires. The orthostatic intolerance ratio was calculated by dividing change in systolic blood pressure over time tolerated on head-up tilt. Eleven patients received immunotherapy. Results At first assessment, all 13 patients had cardiovascular and pupillary impairments, 7 of 8 had postganglionic sudomotor dysfunction, 9 of 11 had urinary retention and xeropthalmia, and 6 of 8 had xerostomia. After immunotherapy, there were significant improvements in orthostatic intolerance ratio (33.3 [17.8-61.3] to 5.2 [1.4-8.2], p = 0.007), heart rate response to deep breathing (1.5 [0.0-3.3] to 4.5 [3.0-6.3], p = 0.02), pupillary constriction to light (12.0 [5.5-18.0] to 19.0 [10.6-23.8]%, p = 0.02), saliva production (0.01 [0.01-0.05] to 0.08 [0.02-0.20] g/min, p = 0.03), and COMPASS-31 scores (52 to 17, p = 0.03). Orthostatic intolerance ratio correlated with autonomic symptoms at baseline (r = 0.841, p = 0.01) and following immunotherapy (r = 0.889, p = 0.02). Immunofluorescence analyses of skin samples from a patient 32 years after disease onset showed loss of nerve fibers supplying the dermal autonomic adnexa and epidermis, with clear improvements following immunotherapy. Interpretation Patients with autoimmune autonomic ganglionopathy demonstrated objective evidence of widespread sympathetic and parasympathetic autonomic failure, with significant improvements after immunotherapy. Quantitative autonomic biomarkers should be used to define initial deficits, guide therapeutic decisions, and document treatment response. ANN NEUROL 2021;89:753-768.

In this review, we describe the wide clinical spectrum of features that can be seen in multiple system atrophy (MSA) with a focus on the premotor phase and the non-motor symptoms providing an up-to-date overview of the current understanding in this fast-growing field. First, we highlight the non-motor features at disease onset when MSA can be indistinguishable from pure autonomic failure or other chronic neurodegenerative conditions. We describe the progression of clinical features to aid the diagnosis of MSA early in the disease course. We go on to describe the levels of diagnostic certainty and we discuss MSA subtypes that do not fit into the current diagnostic criteria, highlighting the complexity of the disease as well as the need for revised diagnostic tools. Second, we describe the pathology, clinical description, and investigations of cardiovascular autonomic failure, urogenital and sexual dysfunction, orthostatic hypotension, and respiratory and REM-sleep behavior disorders, which may precede the motor presentation by months or years. Their presence at presentation, even in the absence of ataxia and parkinsonism, should be regarded as highly suggestive of the premotor phase of MSA. Finally, we discuss how the recognition of the broader spectrum of clinical features of MSA and especially the non-motor features at disease onset represent a window of opportunity for disease-modifying interventions.

Background and ObjectivesNonmotor 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.MethodsMedical 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.ResultsForty-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).DiscussionAlmost 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.

Background and ObjectivesSudomotor 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.MethodsOne 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.ResultsWe 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.DiscussionDynamic 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 EvidenceThis study provides Class II evidence that postganglionic sudomotor morpho-functional assessment accurately distinguish patients with PD from patients with MSA-P.

IntroductionOrthostatic hypotension (OH) and supine hypertension (SH) are prevalent in alpha-synucle- inopathies, posing a therapeutic dilemma as OH treatment may worsen SH. We aimed to characterise SH in pure autonomic failure (PAF), multiple system atrophy (MSA), and Lewy body disorders (LBD: Parkinson’s disease and Dementia with Lewy bodies).Methods166 patients (72 PAF, 59 MSA, 35 LBD) underwent cardiovascular autonomic testing and 24hr- ambulatory blood pressure monitoring (24hr-ABPM). Demographic, clinical features, medications and cardiovascular autonomic biomarkers were compared.ResultsSH was present in more than half of patients with PAF, MSA and LBD (56%, 51% and 50%, respec- tively) without anti-hypotensive medications. Supine pre-stand BP during 24hr-ABPM detected SH with 60% sensitivity and 86% specificity [area under the curve 0.73 (95%CI 0.66-0.81)]. Supine noradrenaline levels were significantly higher in MSA vs PAF and LBD (268 vs 183 and 210 pg/ml, pConclusionsSH and nocturnal hypertension commonly co-exist and are independently associated with OH in alpha-synucleinopathies. 24hr-ABPM is useful in detecting SH in these patients. The pathophysiology of SH is likely to be heterogeneous and not entirely explained by residual sympathetic tone.

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.

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.

IntroductionCardiovascular autonomic failure and neurogenic orthostatic hypotension (nOH) are common and disabling features of Parkinson’s disease (PD) and multiple system atrophy (MSA). Compared to PD, MSA is considered a primarily central alpha-synucleinopathy.AimTo characterise the relationship between cardiovascular autonomic failure and cutaneous autonomic and somatic innervation in early PD and MSA.MethodsFifty-five patients (37 PD, 18 MSA) within 2 years of motor onset underwent: 1) cardiovascular autonomic testing 2) plasma catecholamines 3) distal leg skin biopsies for quantification of intraepider- mal (IENF), pilomotor (PNF), and sudomotor nerve fibres (SNF), and 4) COMPASS-31 autonomic symptom questionnaires.Results75% with MSA and 36% with PD had OH ≥20/10mmHg. Supine noradrenaline was significantly higher in MSA vs PD with OH (264[241-304] vs 158[154-190] pg/ml, P=.03). Compared to patients without OH, patients with OH had significantly reduced cutaneous innervation (3.1[1.3-6.0] vs 7.4[5.3-8.7] IENF/mm, P=.008; 2.8[0-8.2] vs 11.8[6.5-23.4] PNF/mm, P=.007; and 0.9[0.1-1.4] vs 1.6[1.4-1.8] nm SNF/µm3,P=.002), with no significant differences between MSA and PD with OH subgroups. Markers of cardiovas- cular autonomic failure, including severity of OH, correlated significantly with cutaneous denervation (IENF: ρ=-0.47, P=.007; PNF: ρ=-0.51, P=.004; SNF: ρ=-0.51, P=.006), and patient symptoms (COMPASS-31: ρ=0.57, P=.002).ConclusionCardiovascular autonomic failure was associated with cutaneous denervation in both MSA and PD. Postganglionic denervation may contribute to the pathophysiology of cardiovascular autonomic failure and nOH, and influence response to therapeutic agents for nOH.

The aim of this review is to outline the clinical presentation, pathophysiology and evaluation of lower urinary tract (LUT) dysfunction in Parkinson’s disease and other parkinsonian syndromes including multiple system atrophy, dementia with Lewy bodies, progressive supranuclear palsy and corticobasal degeneration. LUT dysfunction commonly occurs in neurological disorders, including patients with parkinsonian syndromes. The pattern of LUT dysfunction and its severity are variable, depending upon the site of lesion within the neural pathways. Parkinsonian syndromes are broadly divided into Parkinson’s disease (PD) and a typical parkinsonian syndromes such as multiple system atrophy (MSA), dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Different parkinsonian syndromes have distinct clinical features (e.g. dysautonomia, early dementia, supranuclear gaze palsy, higher cortical signs), and the pattern of LUT dysfunction and its severity can differ. LUT dysfunction is a common feature in patients with parkinsonian syndromes. Recognising the pattern of LUT dysfunction during the assessment of these patients can help management and possibly facilitate an earlier diagnosis.

BackgroundSurvivors of moderate-to-severe traumatic brain injury (msTBI) frequently experience troublesome unexplained somatic symptoms. Autonomic dysfunction may contribute to these symptoms. However, there is no previous study of clinical subjective and objective autonomic dysfunction in msTBI.MethodsWe present results from two groups of patients with msTBI. The first, a case–control comparative study, comprises prospectively recruited msTBI outpatients, in whom we measured burden of autonomic symptoms using the Composite Autonomic Symptom Score (COMPASS31) questionnaire. The second, a descriptive case series, comprises retrospectively identified msTBI outpatients who had formal clinical autonomic function testing at a national referral autonomics unit.ResultsGroup 1 comprises 39 patients with msTBI (10F:20M, median age 40 years, range 19–76), median time from injury 19 months (range 6–299) and 44 controls (22F:22M, median age 45, range 25–71). Patients had significantly higher mean weighted total COMPASS-31 score than controls (ps=−0.84). Group 2 comprises 18 patients with msTBI (7F:11M, median age 44 years, range 21–64), median time from injury 57.5 months (range 2–416). Clinical autonomic function testing revealed a broad spectrum of autonomic dysfunction in 13/18 patients.ConclusionsThere is clinically relevant autonomic dysfunction after msTBI, even at the chronic stage. We advocate for routine enquiry about potential autonomic symptoms, and demonstrate the utility of formal autonomic testing in providing diagnoses. Larger prospective studies are warranted, which should explore the causes and clinical correlates of post-TBI autonomic dysfunction.

The discovery of genetic links between alpha-synuclein and PD has opened unprecedented opportunities for research into a new group of diseases, now collectively known as synucleinopathies. Autonomic dysfunction, including cardiac sympathetic denervation, has been reported in familial forms of synucleinopathies that have Lewy bodies at the core of their pathogenesis. SNCA mutations and multiplications, LRRK2 disease with Lewy bodies as well as other common, sporadic forms of idiopathic PD, MSA, pure autonomic failure, and dementia with Lewy bodies have all been associated with dysautonomia. By contrast, in familial cases of parkinsonism without Lewy bodies, such as in PARK2, the autonomic profile remains normal throughout the course of the disease. The degeneration of the central and peripheral autonomic systems in genetic as well as sporadic forms of neurodegenerative synucleinopathies correlates with the accumulation of alpha-synuclein immunoreactive-containing inclusions. Given that dysautonomia has a significant impact on the quality of life of sufferers and autonomic symptoms are generally treatable, a prompt diagnostic testing and treatment should be provided. Moreover, new evidence suggests that autonomic dysfunction can be used as an outcome prediction factor in some forms of synucleinopathies or premotor diagnostic markers that could be used in the future to define further research avenues. In this review, we describe the autonomic dysfunction of genetic synucleinopathies in comparison to the dysautonomia of sporadic forms of alpha-synuclein accumulation and provide the reader with an up-to-date overview of the current understanding in this fast-growing field. © 2018 International Parkinson and Movement Disorder Society.

BACKGROUND AND PURPOSE: Twenty-four-hour ambulatory blood pressure and heart rate monitoring (24-h ABPM) can provide vital information on circadian blood pressure (BP) profiles, which are commonly abnormal in Parkinson's disease with and without autonomic failure (PD + AF and PD) and multiple system atrophy (MSA). Twenty-four-hour ABPM has not been directly compared between these disorders regarding cardiovascular autonomic function. Our aim was to determine the usefulness of 24-h ABPM with diary compared to head-up tilting (HUT) in diagnosing orthostatic hypotension (OH) in these patients. METHODS: Seventy-four patients (23 MSA, 18 PD + AF, 33 PD) underwent cardiovascular autonomic screening followed by 24-h ABPM with diary. Standing tests were included during 24-h ABPM. The sensitivity and specificity in detecting OH from the 24-h ABPM standing test were compared with HUT. RESULTS: There was no difference in OH during HUT between MSA and PD + AF (P > 0.05). There was a higher proportion of abnormal BP circadian rhythms in MSA and PD + AF compared to PD (P < 0.05) but not between MSA and PD + AF (P > 0.05). Patients were divided into groups with OH (OH+) and without OH (OH-) on HUT. Using the standing test during 24-h ABPM, a systolic BP fall of >20 mmHg showed a sensitivity and specificity of 82% and 100% (area under the curve 0.91, 95% confidence interval 0.84-0.98) in differentiating OH+ from OH-. CONCLUSIONS: Parkinson's disease with autonomic failure and MSA patients had similar circadian BP patterns suggesting that autonomic dysfunction influences abnormal BP circadian patterns similarly in these disorders. The higher sensitivity and specificity in detecting OH using a systolic BP fall of >20 mmHg compared to a diastolic BP fall of >10 mmHg during the standing test supports its usefulness to assess autonomic function in MSA and PD.

The discovery of genetic links between alpha-synuclein and PD has opened unprecedented opportunities for research into a new group of diseases, now collectively known as synucleinopathies. Autonomic dysfunction, including cardiac sympathetic denervation, has been reported in familial forms of synucleinopathies that have Lewy bodies at the core of their pathogenesis. SNCA mutations and multiplications, LRRK2 disease with Lewy bodies as well as other common, sporadic forms of idiopathic PD, MSA, pure autonomic failure, and dementia with Lewy bodies have all been associated with dysautonomia. By contrast, in familial cases of parkinsonism without Lewy bodies, such as in PARK2, the autonomic profile remains normal throughout the course of the disease. The degeneration of the central and peripheral autonomic systems in genetic as well as sporadic forms of neurodegenerative synucleinopathies correlates with the accumulation of alpha-synuclein immunoreactive-containing inclusions. Given that dysautonomia has a significant impact on the quality of life of sufferers and autonomic symptoms are generally treatable, a prompt diagnostic testing and treatment should be provided. Moreover, new evidence suggests that autonomic dysfunction can be used as an outcome prediction factor in some forms of synucleinopathies or premotor diagnostic markers that could be used in the future to define further research avenues. In this review, we describe the autonomic dysfunction of genetic synucleinopathies in comparison to the dysautonomia of sporadic forms of alpha-synuclein accumulation and provide the reader with an up-to-date overview of the current understanding in this fast-growing field. © 2018 International Parkinson and Movement Disorder Society.

BACKGROUND: According to Braak staging of Parkinson's disease (PD), detection of autonomic dysfunction would help with early diagnosis of PD. OBJECTIVE: To determine whether the autonomic nervous system is involved in the early stage of PD, we evaluated cardiovascular and sudomotor function in early untreated PD patients. METHODS: Orthostatic blood pressure regulation, heart rate variability, skin vasomotor function, and palmar sympathetic sweat responses were examined in 50 early untreated PD patients and 20 healthy control subjects. RESULTS: The mean decrease in systolic blood pressure during head-up tilt in PD patients was mildly but significantly larger than in controls (p = 0.0001). There were no differences between the 2 groups in heart rate variability, with analysis of low frequency (LF; mediated by baroreflex feedback), and high frequency (HF; mainly reflecting parasympathetic vagal) modulation. However, LF/HF, an index of sympatho-parasympathetic balance, was lower in the PD group than in controls (p = 0.02). Amplitudes of palmar sweat responses to deep inspiration (p = 0.004), mental arithmetic (p = 0.01), and exercise (p = 0.01) in PD patients were lower than in controls, with negative correlations with motor severity. Amplitudes of palmar skin vasomotor reflexes in PD patients did not differ from controls. CONCLUSIONS: Our study indicates impairment of sympathetic cardiovascular and sudomotor function with orthostatic dysregulation of blood pressure control, reduced LF/HF and reduction in palm sweat responses even in early untreated PD patients.

BackgroundNon-motor features can be presenting symptoms and often precede the motor features in patients with multiple system atrophy (MSA). However there have been no studies specifically looking at the conversion time, clinical features and survival rate in autopsy-confirmed MSA patients.MethodsMedical records of 47 autopsy-confirmed MSA cases at the Queen Square Brain Bank who underwent clinical examination and cardiovascular autonomic testing at the National Hospital for Neurology were reviewed.Results15/47 (32%, M:F/9:6) MSA patients had non-motor autonomic features as an initial presentation before developing motor symptoms. Mean pre-motor phase duration was 3 (range 1–6) years. Among these 15 patients, the most common pre-motor features (87%) were genitourinary (erectile dysfunction in 7, bladder dysfunction in 6 patients); pre-motor symptomatic orthostatic hypotension (OH) and REM sleep behavioural disorder (RBD) occurred in one patient each. 5/15 patients developed cardiovascular autonomic failure and were initially diagnosed with pure autonomic failure (PAF). There was no difference in age of onset between patients presenting with motor and pre-motor autonomic features (p=0.67) or between different pre-motor presenting features and disease duration (p>0.05).ConclusionsPre-motor autonomic features, including genitourinary, cardiovascular autonomic failure and RBD, are common presenting symptoms in MSA, accounting for almost one-third of patients. These features can predate motor symptoms by up to 6 years, or longer.

L-threo-dihydroxyphenylserine (L-DOPS) is an oral prodrug that is converted to the sympathetic neurotransmitter noradrenaline through a single-step decarboxylation by the endogenous enzyme 3,4-dihydrophenylalanine decarboxylase. DOPS can provide an exogenous source of noradrenaline to adrenergic neurons that are involved in the maintenance of blood pressure. Impaired secretion of noradrenaline at the synaptic junction can result in neurogenic orthostatic hypotension and cause faints and falls. The safety and efficacy of DOPS has been evaluated in patients with neurogenic orthostatic hypotension caused by a variety of neurological conditions that can result in autonomic failure, such as Parkinson’s disease, multiple system atrophy, pure autonomic failure and dopamine-β-hydroxylase deficiency. In this review, we include Phase II and III clinical trials undertaken that have examined the safety, efficacy and tolerability of DOPS in the treatment of neurogenic orthostatic hypotension. Drug mechanisms and pharmacology of the drug are also discussed.

Our objective was to assess the usefulness of the Scales for Outcomes in Parkinson's disease - Autonomic (SCOPA-AUT) in the differential diagnosis of Parkinsonisms and clarify its relation with 123-I-MIBG cardiac scintigraphy.A total of 112 patients with Parkinson's disease (PD), 12 with multiple system atrophy parkinsonian variant (MSA-P) and 20 with progressive supranuclear palsy (PSP) participated in the study. The following variables were collected: age, sex, age at onset, length of illness, type and dose of anti-Parkinson medication, and score on the Unified Parkinson's Disease Rating Scale. The Unified Multiple System Atrophy Rating Scale was administered to patients with MSA and the Progressive Supranuclear Palsy Rating Scale to those with PSP. Finally, the SCOPA-AUT was administered to all the patients. Cardiac 123I-MIBG SPECT scans were performed on a subset of patients (25 with PD and 5 with MSA-P).Statistically significant differences were observed (p0.01) in the SCOPA-AUT scores between patients with PD (14.75+/-8.09) and those with MSA (21.07+/-5.56), the latter having higher scores on the bowel function (20.07+/-13.40 vs 34.92+/-14.91) and urinary domains (30.21+/-21.55 vs 49.26+/-21.40) (p0.01). No correlation was found between the SCOPA-AUT score and anti-Parkinson's medication and heart:mediastinum (H/M) MIBG uptake ratio in the cardiac SPECT (at 4 h).Severity of dysautonomia as measured by the SCOPA-AUT was not correlated with clinical severity, time since onset or the H/M ratio. In the patients with PD, the only variable associated with the H/M ratio was age at onset of the disease.

In Parkinsons disease and multiple system atrophy (MSA), cardiovascular dysfunction may occur for a variety of reasons and may manifest itself through inappropriate changes and/or levels in blood pressure, heart rate and/or regional vascular perfusion in a range of situations. The early occurrence of orthostatic hypotension often leads to consideration of MSA, especially in the presence of other features of autonomic failure. Orthostatic hypotension, however, is increasingly recognised in PD, and especially with increasing age, severity of disease and as a result of drug therapy, sometimes for associated disorders. Investigation of cardiovascular autonomic dysfunction in Parkinsonism is therefore important for a variety of reasons, that include determining the precise diagnosis and in predicting prognosis. In Parkinsonian disorders, understanding the pathophysiological basis of the cardiovascular autonomic dysfunction aids targeting of therapy, improves management strategies and provides benefit for such patients.

Slowly progressive autonomic failure in adults presents a diagnostic challenge. Here we describe a patient with slowly progressive autonomic failure present for many years before any other clinically significant symptoms or signs appeared, who underwent detailed autonomic function testing, MR brain imaging and other neurological investigations on several occasions. After she developed bulbar dysfunction (causing two life-threatening choking episodes), pyramidal and sensory dysfunction, and characteristic brain imaging abnormalities were noted, a diagnosis of adult onset Alexander disease was made. GFAP sequencing demonstrated a heterozygous missense mutation (F199S) which has not been previously reported. Relatives affected by similar symptoms (orthostatic syncope and dysphagia) suggest autosomal dominant inheritance. On retrospective review, the imaging abnormalities were present from an early stage of her illness, when autonomic symptoms were present in isolation. We propose that a diagnosis of adult onset Alexander disease should be considered in cases of slowly progressive autonomic failure even in the absence of other clinical manifestations, and that awareness of the characteristic brain imaging abnormalities should allow early diagnosis which can be confirmed with genetic testing.

Non-motor symptoms are increasingly recognized in Parkinson disease (PD) and include physical as well as psychological symptoms. A psychological condition that has been well studied in PD is psychosis. Cardiovascular autonomic dysfunction in PD can include a reversed or loss of blood pressure (BP) circadian rhythm, referred to as nocturnal non-dipping. The aim of this study was to determine the relationship between 24 h ambulatory blood pressure measurements (ABPM), i.e., absence or presence of nocturnal dipping, and psychosis scores in PD.Twenty-one patiens with PD underwent 24 h ABPM using an autonomic protocol. A decrease in nocturnal mean arterial blood pressure of less than 10% was defined as non-dipping. Patients were interviewed (including the brief psychiatric rating scale; BPRS) for the assessment of psychosis.Eleven patients were dippers and 10 were non-dippers. BPRS scores were higher in non-dippers, who, on average, met the criteria for psychosis (mean non-dipper BPRS: 34.3 ± 7.3 vs mean dipper BPRS: 27.5 ± 5.3; cutoff for "mildly ill" 31). There was a correlation between BPRS scores and non-dipping, indicating that those patients who had a blunted nocturnal fall in BP were more prone to psychotic symptoms (Pearson's Correlation = 0.554, p = 0.009).These results suggest that, among PD patients, a non-dipping circadian rhythm is associated with more severe symptoms of psychosis than is a dipping circadian rhythm. This association warrants further investigation.

Non-motor symptoms are now commonly recognized in Parkinson’s Disease (PD) and can include dysautonomia. Impairment of cardiovascular autonomic function can occur at any stage of PD but is typically prevalent in advanced stages or related to (anti-parkinsonian) drugs and can result in atypical blood pressure (BP) readings and related symptoms such as orthostatic hypotension (OH) and supine hypertension. OH is usually diagnosed with a head-up-tilt test (HUT) or an (active) standing test (also known as Schellong test) in the laboratory, but 24 hour Ambulatory Blood Pressure Monitoring (ABPM) in a home setting may have several advantages, such as providing an overview of symptoms in daily life alongside pathophysiology as well as assessment of treatment interventions. This, however, is only possible if ABPM is administrated correctly and an autonomic protocol (including a diary) is followed. which will be discussed in this review. A 24hr ABPM does not only allow the detection of OH, if it is present, but also the assessment of cardiovascular autonomic dysfunction during and after various daily stimuli, such as postprandial and alcohol dependent hypotension, as well as exercise and drug induced hypotension. Furthermore, information about the circadian rhythm of BP and heart rate (HR) can be obtained and establish whether or not a patient has a fall of BP at night (i.e. ‘dipper’ vs. non-‘dipper’). The information about nocturnal BP may also allow the investigation or detection of disorders such as sleep dysfunction, nocturnal movement disorders and obstructive sleep apnea, which are common in PD. Additionally, a 24hr ABPM should be conducted to examine the effectiveness of OH therapy. This review will outline the methodology of 24 hr ABPM in PD, summarize findings of such studies in PD and briefly consider common daily stimuli that might affect 24 Hr ABPM.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterised by motor dysfunction (parkinsonism) and several non-motor features. Dysautonomia is a significant non-motor feature as well as a neuropsychiatric symptom. Autonomic dysfunction can occur even in the early stages of PD, often preceding the onset of the classic motor symptoms of PD. The patterns of autonomic features in PD are different from other parkinsonian disorders. Detection of autonomic dysfunction may therefore be helpful in diagnosing PD in the early or pre-motor stages, and/or in differentiating it from other parkinsonian disorders, such as multiple system atrophy and progressive supuranuclear palsy. The aim of this review is to describe aspects of autonomic dysfunction, including symptoms, assessment and pathophysiology, resulting from autonomic impairment in PD and other parkinsonian syndromes.

Botulism is a rare presynaptic neuromuscular junction disorder caused by potent toxins produced by the anaerobic, spore-forming, Gram-positive bacterium Clostridium botulinum. Food-borne botulism is caused by the ingestion of foods contaminated with botulinum toxin. In March 2006, there was a large outbreak of food-borne botulism associated with the ingestion of home-canned bamboo shoots in Thailand. The survival analyses for respiratory failure in these patients were studied and are reported here.A prospective observational cohort study was conducted on this outbreak. The primary outcome of interest was the time to respiratory failure. The secondary outcome was the time to weaning off ventilator. The prognostic factors associated with respiratory failure and weaning off ventilator are presented.A total of 91 in-patients with baseline clinical characteristics were included. Most cases first presented with gastrointestinal symptoms followed by neurological symptoms, the most striking of which being difficulty in swallowing. Common clinical features included ptosis, ophthalmoplegia, proximal muscle weakness, pupillary abnormality, and respiratory failure. Forty-two patients developed respiratory failure requiring mechanical ventilation and the median duration on ventilator was 14 days. The median length of hospital stay for all patients was 13.5 days. Difficulty in breathing, moderate to severe ptosis, and dilated and fixed pupils were associated with respiratory failure. Among patients who were on ventilators, a short incubation period and pupillary abnormality were associated with a longer period of mechanical ventilation. All patients had antitoxin injection and there was no mortality in this outbreak.The history of difficult breathing and the findings of moderate to severe ptosis and pupillary abnormality were associated with severe illness and respiratory failure. A long incubation time was associated with a better prognosis. Although botulism is a potentially fatal disease, there was no mortality in this outbreak. All patients had antitoxin injection and good intensive care that resulted in good clinical outcomes.

Objective: An electrophysiological study can help to confirm the diagnosis of botulism. This study was aimed at validating a simple and reliable electrodiagnostic test and at correlating the findings with clinical severity. Methods: Pre- and post-exercise single supramaximal stimulations (SSSs) were performed in 63 patients with botulism. The sensitivity and specificity of amplitude of compound muscle action potential (CMAP) and percentage increment (PI) of SSS were determined. These two parameters were then correlated with respiratory failure. The relationship between the amplitude of CMAP and PI was also studied. Results: SSS with a PI of 25% showed a sensitivity of 95.2% and a specificity of 100% in association with botulism. The area under the receiver operating characteristic (ROC) curve of CMAP and PI was associated with the respiratory failure by 0.7 and 0.6, respectively. An inverse relationship between the amplitude of CMAP and PI was also demonstrated. Conclusions: SSS is sensitive and specific in the diagnosis of botulism. There was some correlation of the findings with clinical severity. The inverse relationship between the amplitude of CMAP and PI reflects the pathophysiology of this disorder. Significance: This study has validated SSS as being a simple and reliable electrodiagnostic test for botulism.

(170.4 ± 34.2 vs 1251 ± 280.1; p = 0.0001) and total power (1045 ± 270.3 vs 4395 ± 848; p = 0.0003) in type 1 diabetic adolescents as compared to healthy controls and the high frequency HF(ms) values showed a decreasing trend (503.8 ± 763.7 vs 1747 ± 1109 ; p = 0.05 ) in the same. Conclusion: This preliminary study shows reduced HRV parameters in asymptomatic type 1 diabetic adolescents as compared to healthy controls. It can be concluded that subclinical cardiac dysautonomia is present in this group of patients.