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 eight centres (seven US-based and one 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's 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 enrolment to any diagnosis was associated with urinary and sexual dysfunction [hazard ratio (HR) 5.9, 95% confidence interval (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 enrolment. 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.

Skin Biopsy Detection of Phosphorylated α-Synuclein in Patients With Synucleinopathies.

Importance: Finding a reliable diagnostic biomarker for the disorders collectively known as synucleinopathies (Parkinson disease [PD], dementia with Lewy bodies [DLB], multiple system atrophy [MSA], and pure autonomic failure [PAF]) is an urgent unmet need. Immunohistochemical detection of cutaneous phosphorylated α-synuclein may be a sensitive and specific clinical test for the diagnosis of synucleinopathies. Objective: To evaluate the positivity rate of cutaneous α-synuclein deposition in patients with PD, DLB, MSA, and PAF. Design, Setting, and Participants: This blinded, 30-site, cross-sectional study of academic and community-based neurology practices conducted from February 2021 through March 2023 included patients aged 40 to 99 years with a clinical diagnosis of PD, DLB, MSA, or PAF based on clinical consensus criteria and confirmed by an expert review panel and control participants aged 40 to 99 years with no history of examination findings or symptoms suggestive of a synucleinopathy or neurodegenerative disease. All participants completed detailed neurologic examinations and disease-specific questionnaires and underwent skin biopsy for detection of phosphorylated α-synuclein. An expert review panel blinded to pathologic data determined the final participant diagnosis. Exposure: Skin biopsy for detection of phosphorylated α-synuclein. Main Outcomes: Rates of detection of cutaneous α-synuclein in patients with PD, MSA, DLB, and PAF and controls without synucleinopathy. Results: Of 428 enrolled participants, 343 were included in the primary analysis (mean [SD] age, 69.5 [9.1] years; 175 [51.0%] male); 223 met the consensus criteria for a synucleinopathy and 120 met criteria as controls after expert panel review. The proportions of individuals with cutaneous phosphorylated α-synuclein detected by skin biopsy were 92.7% (89 of 96) with PD, 98.2% (54 of 55) with MSA, 96.0% (48 of 50) with DLB, and 100% (22 of 22) with PAF; 3.3% (4 of 120) of controls had cutaneous phosphorylated α-synuclein detected. Conclusions and Relevance: In this cross-sectional study, a high proportion of individuals meeting clinical consensus criteria for PD, DLB, MSA, and PAF had phosphorylated α-synuclein detected by skin biopsy. Further research is needed in unselected clinical populations to externally validate the findings and fully characterize the potential role of skin biopsy detection of phosphorylated α-synuclein in clinical care.

Migraine and Autonomic Dysfunction: Which Is the Horse and Which Is the Jockey?

PURPOSE OF REVIEW: Symptoms of autonomic dysfunction are common in patients with migraine, both during and between migraine attacks. Studies evaluating objective autonomic testing in patients have found significant, though somewhat conflicting results. The purposes of this review are to summarize and interpret the key findings of these studies, including those evaluating heart rate variability, autonomic reflex testing, and functional imaging in patients with migraine. The neuroanatomy of the central autonomic network as it relates to migraine is also reviewed. RECENT FINDINGS: Several studies have evaluated autonomic balance in migraineurs, with conflicting results on the magnitude of sympathetic versus parasympathetic dysfunction. Most studies demonstrate sympathetic impairment, with a lesser degree of parasympathetic impairment. Three trends have emerged: (1) migraine with aura tends to produce more significant autonomic dysfunction than migraine without aura, (2) sympathetic impairment is more common than parasympathetic impairment, and (3) sympathetic impairment is common in the interictal period, with increased sympathetic responsiveness during the ictal period, suggesting adrenoreceptor hypersensitivity.

A case series of REM sleep behavior disorder in pure autonomic failure.

PURPOSE: Data on the prevalence of RBD in patients with PAF are limited, with discrepancies in the literature regarding prevalence. We aimed to provide further data on this association with a series of eight patients with PAF. METHODS: We reviewed the electronic medical records of all patients seen at the Stanford neurology clinics from 2012 to 2016 who were given a provisional diagnosis of PAF (343 patients), and further screened by procedure codes to identify those patients who underwent both attended video-polysomonography and autonomic testing (18 patients), and met strict exclusionary criteria (8 patients). RESULTS: The mean age of our patients was 69 years, and 63 % were women. The mean duration of autonomic symptoms was 11.2 years, and the mean duration of dream enactment was 3.75 years. All patients demonstrated evidence of adrenergic failure on autonomic testing. Five out of 8 (63 %) met diagnostic criteria for RBD, confirmed on vPSG. CONCLUSIONS: Our series supports the concept that RBD in PAF may be more common than previously reported, and that the presence of RBD suggests brainstem involvement in some cases of PAF. In addition, the timing of RBD symptoms relative to the emergence of autonomic symptoms may be useful to help distinguish these conditions.

Kleine-Levin Syndrome.

Kleine-Levin syndrome is a rare recurrent hypersomnia associated with symptoms of behavioral and cognitive impairment. This article reviews common presenting symptoms, differential diagnosis, diagnostic workup, and potential treatment options. Current updates on functional imaging studies and long-term neuropsychological studies are reviewed.

Sleep disorders in patients with postural tachycardia syndrome.

OBJECTIVE: Patients with postural tachycardia syndrome (POTS) often describe symptoms of fatigue, sleepiness, and lack of refreshing sleep. We aimed to provide further objective measures of sleep in patients with POTS. METHODS: POTS patients (n = 18) were selected based on autonomic testing and evaluation at our center. Controls (n = 16) of similar age, gender, and BMI were selected from new patients referred to the Stanford Sleep Disorders Clinic for any sleep-related complaint. All patients underwent polysomnography and completed several sleep questionnaires and a 2-week sleep diary. RESULTS: POTS patients and control subjects were of similar age (27 ± 10.2 vs. 29 ± 5.4 years, p = 0.92) and Body Mass Index (21 ± 3.8 vs. 24 ± 4.1, p = 0.14). The majority of subjects in both groups were females (72 % POTS vs. 81 % controls). POTS patients scored higher on subjective fatigue scales but not sleepiness scales. POTS patients scored in the normal range on the BDI and the "evening" category on the MEQ. Their sleep diaries were not different from controls. With the exception of mild OSA, slightly reduced %REM and prolonged REM latency, their PSG data were normal and no different from controls. CONCLUSIONS: It is unlikely that the sleep-related complaints of POTS patients are the result of a primary sleep disorder unique to POTS. We propose that a combination of factors such as body fatigue, chronic pain, and other somatic symptoms common in POTS patients might be the underlying reason for sleep-related symptoms in POTS.