Association of innervation-adjusted alpha-synuclein in arrector pili muscles with cardiac noradrenergic deficiency in autonomic synucleinopathies.

BACKGROUND: Autonomic synucleinopathies feature deposition of the protein alpha-synuclein (AS) in neurons [e.g., Lewy body neurogenic orthostatic hypotension (nOH)] or glial cells (multiple system atrophy, MSA). AS in skin biopsies might provide biomarkers of these diseases; however, this approach would be complicated or invalidated if there were substantial loss of AS-containing nerves. We report AS content in arrector pili muscles in skin biopsies after adjustment for local innervation in patients with Lewy body nOH or MSA. Cardiac sympathetic neuroimaging by myocardial 18F-dopamine positron emission tomography (PET) was done to examine pathophysiological correlates of innervation-adjusted AS. METHODS: Thirty-one patients (19 Lewy body nOH, 12 MSA) underwent thoracic 18F-dopamine PET and skin biopsies. AS signal intensity analyzed by immunofluorescence microscopy was adjusted for innervation by the ratio of AS to protein gene product (PGP) 9.5, a pan-axonal marker (Harvard lab site), or the ratio of AS to tyrosine hydroxylase (TH), an indicator of catecholaminergic neurons (NIH lab site). RESULTS: The Lewy body nOH group had higher ratios of AS/PGP 9.5 or log AS/TH than did the MSA group (0.89 ± 0.05 vs. 0.66 ± 0.04, -0.13 ± 0.05 vs. -1.60 ± 0.33; p < 0.00001 each). All 19 Lewy body patients had AS/PGP 9.5 > 0.8 or log AS/TH > 1.2 and had myocardial 18F-dopamine-derived radioactivity < 6000 nCi-kg/cc-mCi, the lower limit of normal. Two MSA patients (17%) had increased AS/PGP or log AS/TH, and two (17%) had low 18F-dopamine-derived radioactivity. CONCLUSIONS: Lewy body forms of nOH are associated with increased innervation-adjusted AS in arrector pili muscles and neuroimaging evidence of myocardial noradrenergic deficiency.

Multiple system atrophy: Building a global community - 30years of advocacy efforts.

Multiple system atrophy (MSA) is a rare, progressive and ultimately fatal neurodegenerative disease with no known cause and no available disease modifying treatment. Known previously by various names including Shy-Drager Syndrome, olivopontocerebellar atrophy (OPCA) and striatonigral degeneration, MSA can be classified simultaneously as a movement disorder, an autonomic disorder, a cerebellar ataxia and an atypical parkinsonian disorder. Despite scholarly attempts to better describe the disease, awareness among medical practitioners about multiple system atrophy as a diagnostic possibility has been slow to catch on. As a result, patients often go undiagnosed for many years or are largely misdiagnosed as Parkinson's disease. The non-homogeneous clinical presentation of MSA and years of confusing nomenclature have all contributed to a lack of awareness of the disease among healthcare professionals as well as the public. This lack of awareness has amplified the unmet needs of MSA patients and other stakeholders. Since the 1980s there has been a growing advocacy effort directed at this rare disease from advocacy groups, grassroots supporters, healthcare professionals and research networks. These stakeholders are beginning to unite their efforts and attack the disease from a global perspective in the hopes of improving outcomes for MSA patients in the future.

[Evaluation of autonomic nervous function by assessing baroreceptor reflex].

The autonomic nervous functional tests assessing baroreceptor reflex (BR) were described. I. Head-up tilt test: Sympathetic nervous function is activated and alginine-vasopressin is secreted through the BR. Orthostatic hypotension is induced by BR dysfunction. II. Spectral analysis of heart and blood pressure: High-frequency power in R-R interval variability indicates parasympathetic function and low-frequency power may reflect BR function. Low-frequency power in blood pressure may indicate sympathetic nervous function. However, spectral analysis of them can not detect a sympathetic nervous hyperfunction. III. Baroreceptor sensitivity during the Valsalva maneuver: Baroreceptor sensitivity is obtained from the correlation of systolic blood pressure and RR interval. It decreases in early stage of Parkinson's disease. IV. Correlation of heart rate and blood pressure: The correlation of them may reflect qualitative differences in the central autonomic dysfunction.

Skin sympathetic fiber α-synuclein deposits: a potential biomarker for pure autonomic failure.

OBJECTIVE: This study aimed to test whether peripheral α-synuclein staining might be useful for pure autonomic failure (PAF) diagnosis, helping to differentiate degenerative from acquired peripheral autonomic neuropathy. METHODS: We studied 21 patients with chronic peripheral autonomic neuropathy showing sympathetic and parasympathetic involvement as confirmed by cardiovascular reflexes and microneurography from the peroneal nerve. Twelve patients showed a specific cause of neuropathy (acquired autonomic neuropathy) whereas 9 had no specific acquired causes fulfilling the diagnostic criteria for PAF. Fifteen matched healthy subjects served as controls. Subjects underwent skin biopsy from thigh and leg to study skin innervation and phosphorylated α-synuclein deposits in the peripheral axons. RESULTS: Somatic and autonomic skin innervations were significantly decreased in patients with peripheral autonomic neuropathy compared to controls. No differences were found between acquired autonomic neuropathy and PAF. The deposits of α-synuclein were not found in controls but served to distinguish acquired from degenerative autonomic peripheral neuropathy: all patients with PAF showed α-synuclein deposits, which were absent in patients with acquired autonomic neuropathy. Colocalization study disclosed α-synuclein neuritic inclusions in the postganglionic sympathetic adrenergic and cholinergic nerve fibers. CONCLUSIONS: Our study demonstrated that a search for neuritic inclusions of phosphorylated α-synuclein in the skin sympathetic nerve fibers could provide a sensitive in vivo biomarker for degenerative peripheral autonomic neuropathy and may shed more light on the pathogenesis of PAF.

Confounders of vasovagal syncope: orthostatic hypotension.

A syncope evaluation should start by identifying potentially life-threatening causes, including valvular heart disease, cardiomyopathies, and arrhythmias. Most patients who present with syncope, however, have the more benign vasovagal (reflex) syncope. A busy syncope practice often also sees patients with neurogenic orthostatic hypotension presenting with syncope or severe recurrent presyncope. Recognition of these potential confounders of syncope might be difficult without adequate knowledge of their presentation, and this can adversely affect optimal management. This article reviews the presentation of the vasovagal syncope confounder and the putative pathophysiology of orthostatic hypotension, and suggests options for nonpharmacologic and pharmacologic management.

Autopsy confirmed multiple system atrophy cases: Mayo experience and role of autonomic function tests.

BACKGROUND: Multiple system atrophy (MSA) is a sporadic progressive neurodegenerative disorder characterised by autonomic failure, manifested as orthostatic hypotension or urogenital dysfunction, with combinations of parkinsonism that is poorly responsive to levodopa, cerebellar ataxia and corticospinal dysfunction. Published autopsy confirmed cases have provided reasonable neurological characterisation but have lacked adequate autonomic function testing. OBJECTIVES: To retrospectively evaluate if the autonomic characterisation of MSA is accurate in autopsy confirmed MSA and if consensus criteria are validated by autopsy confirmation. METHODS: 29 autopsy confirmed cases of MSA evaluated at the Mayo Clinic who had undergone formalised autonomic testing, including adrenergic, sudomotor and cardiovagal functions and Thermoregulatory Sweat Test (TST), from which the Composite Autonomic Severity Score (CASS) was derived, were included in the study. PATIENT CHARACTERISTICS: 17 men, 12 women; age of onset 57±8.1 years; disease duration to death 6.5±3.3 years; first symptom autonomic in 18, parkinsonism in seven and cerebellar in two. Clinical phenotype at first visit was MSA-P (predominant parkinsonism) in 18, MSA-C (predominant cerebellar involvement) in eight, pure autonomic failure in two and Parkinson's disease in one. Clinical diagnosis at last visit was MSA for 28 cases. Autonomic failure was severe: CASS was 7.2±2.3 (maximum 10). TST% was 65.6±33.9% and exceeded 30% in 82% of patients. The most common pattern was global anhidrosis. Norepinephrine was normal supine (203.6±112.7) but orthostatic increment of 33.5±23.2% was reduced. Four clinical features (rapid progression, early postural instability, poor levodopa responsiveness and symmetric involvement) were common. CONCLUSION: The pattern of severe and progressive generalised autonomic failure with severe adrenergic and sudomotor failure combined with the clinical phenotype is highly predictive of MSA.

A review of orthostatic blood pressure regulation and its association with mood and cognition.

AIMS: This paper will review literature that examines the psychological and neuropsychological correlates of orthostatic blood pressure regulation. RESULTS: The pattern of change in systolic blood pressure in response to the shift from supine to upright posture reflects the adequacy of orthostatic regulation. Orthostatic integrity involves the skeletal muscle pump, neurovascular compensation, neurohumoral effects and cerebral flow regulation. Various physiological states and disease conditions may disrupt these mechanisms. Clinical and subclinical orthostatic hypotension has been associated with impaired cognitive function, decreased effort, reduced motivation and increased hopelessness as well as dementia, diabetes mellitus, and Parkinson's disease. Furthermore, inadequate blood pressure regulation in response to orthostasis has been linked to increased depression and anxiety as well as to intergenerational behavioral sequalae. CONCLUSIONS: Identifying possible causes and consequences of subclinical and clinical OH are critical in improving quality of life for both children and older adults.

The Orthostatic Hypotension Questionnaire (OHQ): validation of a novel symptom assessment scale.

BACKGROUND: There is no widely accepted validated scale to assess the comprehensive symptom burden and severity of neurogenic orthostatic hypotension (NOH). The Orthostatic Hypotension Questionnaire (OHQ) was developed, with two components: the six-item symptoms assessment scale and a four-item daily activity scale to assess the burden of symptoms. Validation analyses were then performed on the two scales and a composite score of the OHQ. METHODS: The validation analyses of the OHQ were performed using data from patients with NOH participating in a phase IV, double blind, randomized, cross over, placebo-controlled trial of the alpha agonist midodrine. Convergent validity was assessed by correlating OHQ scores with clinician global impression scores of severity as well as with generic health questionnaire scores. Test-retest reliability was evaluated using intraclass correlation coefficients at baseline and crossover in a subgroup of patients who reported no change in symptoms across visits on a patient global impression scores of change. Responsiveness was examined by determining whether worsening or improvement in the patients' underlying disease status produced an appropriate change in OHQ scores. RESULTS: Baseline data were collected in 137 enrolled patients, follow-up data were collected in 104 patients randomized to treatment arm. Analyses were conducted using all available data. The floor and ceiling effects were minimal. OHQ scores were highly correlated with other patient reported outcome measures, indicating excellent convergent validity. Test-retest reliability was good. OHQ scores could distinguish between patients with severe and patients with less severe symptoms and responded appropriately to midodrine, a pressor agent commonly used to treat NOH. CONCLUSION: These findings provide empirical evidence that the OHQ can accurately evaluate the severity of symptoms and the functional impact of NOH as well as assess the efficacy of treatment.

Orthostatic hypotension is differentially associated with the cerebellar versus the parkinsonian variant of multiple system atrophy: a comparative study.

Orthostatic hypotension (OH) is a cardinal feature of autonomic failure in multiple system atrophy (MSA); however, there are few comparative data on OH in the motor subtypes of MSA. In the present retrospective study, postural blood pressure drop after 3 min of standing was determined in 16 patients with the cerebellar variant of MSA (MSA-C) and in 17 patients with the Parkinson variant (MSA-P). Twenty idiopathic Parkinson's disease (IPD) patients matched for age, sex, disease duration and dopaminergic therapy served as control group. OH frequency and severity were more pronounced in MSA-C followed by MSA-P and IPD. Differences in brainstem pathology are likely to account for the tight association of MSA-C and OH. A simple standing test should be obligatory in the work-up of patients with sporadic late-onset ataxias.

Investigation of autonomic function in idiopathic REM sleep behavior disorder.

Idiopathic REM sleep behavior disorder (iRBD) has been suggested as an early "pre-motor" stage of Parkinson's disease (PD) in a significant proportion of cases. We investigated autonomic function in 15 consecutive iRBD patients and compared these findings to PD patients and healthy controls. All participants underwent cardiovascular autonomic function testing, and were rated on the COMPASS scale. Symptomatic orthostatic hypotension was present in two iRBD patients, two PD patients and none of the healthy controls. In the tilt table examination, blood pressure changes were similar between iRBD patients and healthy controls. In the PD group, blood pressure drops were more pronounced. In the orthostatic standing test, iRBD patients had higher blood pressure changes than healthy controls. Highest drops were found in PD. Valsalva ratio was lower in iRBD and PD compared to healthy controls. Total COMPASS score was higher in iRBD compared to healthy controls. Highest scores were found in PD. These results support the presence of autonomic dysfunction in iRBD. On several measures, dysfunction was intermediate between healthy controls and PD consistent with the concept that iRBD can be manifestation of synuclein-associated neurodegenerative disorders. Follow-up studies are needed to determine whether iRBD patients with dysfunction on several autonomic domains are at particular risk for developing one of these diseases.

ß-1 and ß-2 adrenergic receptor polymorphism and association with cardiovascular response to orthostatic screening.

Variation in the beta-1 and beta-2 adrenergic receptor genes (ADRB1 and ADRB2, respectively) may influence cardiovascular reactivity including orthostatic stress. We tested this hypothesis in a head-up tilt (HUT) screening protocol in healthy young adults without history of syncope. Following brachial arterial catheter insertion, 120 subjects (age 18-40, 72 females, Caucasian) underwent 5min 60° HUT. Polymorphisms tested were: Ser49/Gly and Arg389/Gly in ADRB1; and Arg16/Gly, Gln27/Glu, and Thr164/Ile in ADRB2. Three statistical models (recessive, dominant, additive) were evaluated using general linear models with analysis for each physiologic variable. A recessive model demonstrated a significant association between Arg16/Gly and: absolute supine and upright HR; HUT-induced change in cardiac index (CI), stroke index (SI) and systemic vascular resistance (SVR); and supine and upright norepinephrine values. Blood pressure was not influenced by genotype. Fewer associations were present for other polymorphisms: Ser49/Gly and the change in SI (dominant model), and Arg389/Gly and supine and HUT norepinephrine (additive model). We conclude that in this population, there is a robust association between Arg16/Gly and HUT responses, such that 2 copies of Arg16 increase supine and upright HR, and greater HUT-induced decreases in CI and SI, with greater increases in SVR and norepinephrine. ADRB1 gene variation appears to impact SI and plasma NE levels but not HR. Whether ADRB2 gene variation is ultimately disease-causing or disease-modifying, this study suggests an association between Arg16/Gly and postural hemodynamics, with sympathetic noradrenergic activity affected in a similar direction. This may have implications in the development of orthostatic disorders.

Presentation, diagnosis, and management of multiple system atrophy in Europe: final analysis of the European multiple system atrophy registry.

Multiple system atrophy (MSA) is a Parkinson's Disease (PD)-like α-synucleinopathy clinically characterized by dysautonomia, parkinsonism, cerebellar ataxia, and pyramidal signs in any combination. We aimed to determine whether the clinical presentation of MSA as well as diagnostic and therapeutic strategies differ across Europe and Israel. In 19 European MSA Study Group centres all consecutive patients with a clinical diagnosis of MSA were recruited from 2001 to 2005. A standardized minimal data set was obtained from all patients. Four-hundred thirty-seven MSA patients from 19 centres in 10 countries were included. Mean age at onset was 57.8 years; mean disease duration at inclusion was 5.8 years. According to the consensus criteria 68% were classified as parkinsonian type (MSA-P) and 32% as cerebellar type (MSA-C) (probable MSA: 72%, possible MSA: 28%). Symptomatic dysautonomia was present in almost all patients, and urinary dysfunction (83%) more common than symptomatic orthostatic hypotension (75%). Cerebellar ataxia was present in 64%, and parkinsonism in 87%, of all cases. No significant differences in the clinical presentation were observed between the participating countries. In contrast, diagnostic work up and therapeutic strategies were heterogeneous. Less than a third of patients with documented orthostatic hypotension or neurogenic bladder disturbance were receiving treatment. This largest clinical series of MSA patients reported so far shows that the disease presents uniformly across Europe. The observed differences in diagnostic and therapeutic management including lack of therapy for dysautonomia emphasize the need for future guidelines in these areas.

[Shy-Drager syndrome]. / Shyuv-Drageruv syndrom.

Shy-Drager syndrome is a rare neurological disease with a poor prognosis causing a generalised autonomy dysfunction. The disorder is also known as multiple system atrophy, the orthostatic hypotension syndrome or Shy-McGee-Drager syndrome. Patients have mainly dysautonomic symptoms. Patients suffer from orthostatic hypotension, bradycardia, anhidrosis, failure of accommodation, sialoporia, low tears secretion, gastrointestinal dysmotility and incomplete emptying of the urinary bladder. Neuropathological examination of patient's brains demonstrated neurodegenerative changes of the structures of central nervous system, mainly of brainstem. The Shy-Drager syndrome results from striatonigral and olivo-ponto-cerebellar atrophy and from accumulation of alpha-synuclein in these structures. The patients suffering from the Shy-Drager syndrome are very often misdiagnosed because of overlap of symptomatology with psychiatric and psychosomatic diseases. It is also very difficult to make the diagnosis because of complexity of symptoms. The prognosis of Shy-Drager syndrome is very poor; patients are markedly disabled and have shorter survival.

The close relationship between life-threatening breathing disorders and urine storage dysfunction in multiple system atrophy.

Survival of multiple system atrophy (MSA) depends on whether a variety of sleep-related breathing problems as well as autonomic failure (AF) occur. Since the brainstem lesions that cause respiratory and autonomic dysfunction overlap with each other, these critical manifestations might get worse in parallel. If so, the detection of AF, which is comparatively easy, might be predictive of a latent life-threatening breathing disorder. In 15 patients with MSA, we performed autonomic function tests composed of postural challenges and administered a questionnaire on bladder condition, as well as polysomnography and laryngoscopy during wakefulness and under anesthesia. Polysomnographic variables such as the apnea-hypopnea index (AHI) and oxygen saturation (SpO(2)) and the findings of laryngoscopy were compared with the degree of cardiac and urinary autonomic dysfunction. AHI, mean SpO(2) and the lowest SpO(2) showed significant correlations with urine storage dysfunction. In addition, patients with vocal cord abductor paralysis (VCAP) or central sleep apnea (CSA) contributing to nocturnal sudden death had more severe storage disorders than those without. On the other hand, no significant relationship between polysomnographic variables and orthostatic hypotension was observed except in the case of mean SpO(2). These results indicate that life-threatening breathing disorders have a close relationship with AF, and especially urine storage dysfunction. Therefore, longitudinal assessment of deterioration of the storage function might be useful for predicting the latent progress of VCAP and CSA.

Chiari drop attacks: surgical decompression and the role of tilt table testing.

BACKGROUND: Chiari I malformation (CM1) is characterized by impaired CSF flow through the foramen magnum. Dysfunctional autonomic cardiovascular regulation may result in syncope. Syncope may be the primary presenting symptom of CM1: a syndrome termed Chiari drop attack. It has been postulated that Chiari drop attack is secondary to dysautonomia caused by hindbrain compression. There has been recent debate regarding the association between CM1, dysautonomia and Chiari drop attack. METHODS: We selected patients with Chiari drop attacks who had negative workups for cardiac syncope, followed by tilt table testing and subsequent surgical decompression. We report test results and clinical outcomes following CM1 decompression. RESULTS: Ten patients met the inclusion criteria: 5 patients had positive and 5 negative tilt table tests. Following decompression, 7 had symptomatic improvement or resolution and 3 failed to improve. The sensitivity and specificity of the tilt table test for detecting clinical improvement with surgical decompression was 43 and 33%, respectively. Tilt table testing had 40% accuracy in predicting clinical response to decompression. CONCLUSIONS: In this short series, surgical decompression of CM1 has a high success rate (70%) for patients with Chiari drop attacks. Tilt table testing has poor predictive value in judging the clinical response to surgical decompression and is not a useful test to guide surgical decision- making.

Prospective differentiation of multiple system atrophy from Parkinson disease, with and without autonomic failure.

OBJECTIVE: To report preliminary results of a prospective ongoing study of multiple system atrophy (MSA) and Parkinson disease (PD), with a large subset of patients with PD with autonomic failure (25%), to evaluate autonomic indices that distinguish MSA from PD. METHODS: We used consensus criteria, detailed autonomic studies (Composite Autonomic Symptom Scale, Composite Autonomic Scoring Scale, thermoregulatory sweat test, and plasma catecholamines), and functional scales (Unified MSA Rating Scale [UMSARS] I-IV and Hoehn-Yahr grading) on a prospective, repeated, and ongoing basis. RESULTS: We report the results of a study on 52 patients with MSA (mean [SD], age, 61.1 [7.8] years; body mass index (calculated as weight in kilograms divided by height in meters squared), 27.2 [4.6]; Hoehn-Yahr grade, 3.2 [0.9]; UMSARS I score, 21.5 [7.4]; and UMSARS II score, 22.7 [9.0]) and 29 patients with PD, including PD with autonomic failure (mean [SD], age, 66.0 [8.1] years; body mass index, 26.6 [5.5]; Hoehn-Yahr grade, 2.2 [0.8]; UMSARS I score, 10.4 [6.1]; and UMSARS II score, 13.0 [5.9]). Autonomic indices were highly significantly more abnormal in MSA than PD (P < .001) for the Composite Autonomic Scoring Scale (5.9 [1.9] vs 3.3 [2.3], respectively), Composite Autonomic Symptom Scale (54.4 [21.8] vs 24.7 [20.5], respectively), and thermoregulatory sweat test (percentage anhidrosis, 57.4% [35.2%] vs 9.9% [17.7%], respectively). These differences were sustained and greater at 1-year follow-up, indicating a greater rate of progression of dysautonomia in MSA than PD. CONCLUSIONS: The severity, distribution, and pattern of autonomic deficits at study entry will distinguish MSA from PD, and MSA from PD with autonomic failure. These differences continue and are increased at follow-up. Our ongoing conclusion is that autonomic function tests can separate MSA from PD. Autonomic indices support the notion that the primary lesion in PD is ganglionic and postganglionic, while MSA is preganglionic.

Acute autonomic, sensory and motor neuropathy: successful treatment with IVIg.

Acute autonomic, sensory and motor neuropathy (AASMN) is a rare peripheral nerve disorder characterized by prominent dysautonomia with somatic sensory and motor impairment. Dysautonomia in AASMN is intractable even with corticosteroid therapy or plasmapheresis. Here we report a case of AASMN with severe orthostatic hypotension. Although the effectiveness of corticosteroid was insufficient, high dose intravenous immunoglobulin therapy (IVIg) was effective for not only sensorimotor symptoms but also autonomic symptoms. This is the first case of AASMN showing favorable responses to IVIg treatment, suggesting that IVIg should be considered when corticosteroid therapy or plasmapheresis is ineffective or insufficient.

Orthostatic hypotension associated with an epidermoid tumor of the IV ventricle.

We report the case of a 32-year-old man with an epidermoid tumor of the fourth ventricle. About 14 years later, he showed a tumor recurrence which was removed. After this procedure the patient complained of presyncopal and syncopal crisis while attempting to stand or walk. On examination, severe orthostatic hypotension was confirmed and autonomic tests were abnormal. The brain MRI showed a tetraventricular hydrocephalus predominating in the fourth ventricle. A ventriculo-peritoneal shunt was performed, and after surgery the orthostatic intolerance improved. We believe that hydrocephalus has probably been a contributory factor to orthostatic hypotension, and suggest expanding testing for dysautonomia in patients with hydrocephalus.

Falls, faints, fits and funny turns.

In this practically oriented review, we will outline the clinical approach of patients with falls due to an impairment or loss of consciousness. Following a set of definitions, we describe the salient clinical features of disorders leading to such falls. Among falls caused by true loss of consciousness, we separate the clinical characteristics of syncopal falls (due to reflex syncope, hypovolemia, orthostatic hypotension or cardiac syncope) from falls due to other causes of transient unconsciousness, such as seizures. With respect to falls caused by an apparent loss of consciousness, we discuss the presentation of cataplexy, drop attacks, and psychogenic falls. Particular emphasis will be laid upon crucial features obtained by history taking for distinguishing between the various conditions that cause or mimic a transient loss of consciousness.