Severity Of Autonomic Failure Research Articles

Autonomic Dysfunction in the Synucleinopathies.

Autonomic dysfunction is a characteristic feature in the synucleinopathies. Differences in cellular deposition and neuronal populations affected by α-synuclein aggregation influence the manifestations and severity of autonomic failure in the different synucleinopathy disorders. The Lewy body disorders (Parkinson's disease, dementia with Lewy bodies, and pure autonomic failure) have predominantly peripheral involvement, whereas multiple system atrophy chiefly manifests as central autonomic failure. Clinical and laboratory features may be useful in distinguishing the different synucleinopathies based on the pattern and severity of autonomic failure. Treatment recommendations are aimed at the underlying pathophysiology and utilize non-pharmacologic and pharmacologic approaches. This review will focus on pathophysiology, clinical manifestations, and management recommendations for autonomic failure including neurogenic orthostatic hypotension, thermoregulatory dysfunction, genitourinary dysfunction, and gastrointestinal dysfunction in the synucleinopathies.

Quantitative Scale for Grading of Cardiovascular Autonomic Reflex Tests and Small Fibers from Skin Biopsies (QASAT)

Background: Orthostatic intolerance including dizziness and syncope is common and may reflect autonomic dysfunction. Cardiovascular reflex tests (deep breathing, Valsalva maneuver and tilt test) are established diagnostic methods for evaluation of orthostatic and autonomic symptoms. Small fiber neuropathy, a frequent underlying mechanism, is evaluated by the quantitative sudomotor axonal reflex test (QSART) and skin biopsies. The comprehensive quantitative scale to grade abnormalities in these tests is lacking. Methods: This study defines the QASAT - Quantitative scale for grading of cardiovascular reflex tests using heart rate, blood pressure, n transcranial Doppler, QSART and small fibers (intrapidermal sensory and sweat gland) densities from skin biopsies. The QASAT has three main categories: cardiovascular, cerebral blood flow (includes cerebral autoregulation/vasoreactivity score) and small fiber neuropathy. QASAT was validated in 612 participants with diabetes mellitus (92), Parkinson’s disease (88), multiple system atrophy (23) and other diagnoses (409). The QASAT was compared with the Composite Autonomic Severity Score using ANOVA, correlations and sensitivity/specificity analysis. Results: Scores of heart rate variability from deep breathing, orthostatic hypotension, orthostatic cerebral blood flow, sensory and sweat gland small fiber densities were disease specific (p<0.0001) and were correlated with the severity of autonomic failure (r=0.84, p<0.0001). Autonomic, sensory and cerebral blood flow abnormalities coexist and are correlated. Initial response to slow and fast tilt, baroreflex gain, QT interval, catecholamines and spectral analysis of the heart rate failed to correlate with severity of autonomic failure and therefore were not included in QASAT. Conclusion: QASAT is an objective and validated instrument for grading of dysautonomia, associated small fiber neuropathy and cerebral blood flow. QASAT quantifies both below (bradycardia, supine/orthostatic hypotension) and above (tachycardia, supine/orthostatic hypertension) normal values. Cardiovascular tests are enhanced by scoring the cerebral hypoperfusion which underlies orthostatic symptoms. Inclusion of epidermal and sweat gland fiber density scoring improves lesion localization.

Comparison of baroreflex sensitivity with a fall and rise in blood pressure induced by the Valsalva manoeuvre

The baroreflex plays a key role in human BP (blood pressure) regulation. Its efferent limb consists of a vagal and a sympathetic component. The Valsalva manoeuvre is widely used to quantify vagal baroreflex function [BRS_vagal (vagal baroreflex sensitivity)], but most studies have focused on the R-R interval response to BP decrement, even though the subsequent response to an increment in BP is important and different. In the present study, we sought to evaluate whether BRS_vagal can be determined from BRSvagalinc (BRS_vagal derived from the rise in BP during phases III-IV of the Valsalva manoeuvre), to assess the association between BRSvagalinc and BRSvagaldec (BRS_vagal derived from the preceeding BP decrement) and to validate BRSvagalinc as an index of autonomic function. We studied patients with severe autonomic failure (n=49, 25 female), mild autonomic failure (n=25, 11 female) and matched normal controls (n=29, 15 female). BRSvagalinc and BRSvagaldec were calculated as the regression slope of R-R interval and systolic BP during phases III-IV and the early phase II of the Valsalva manoeuvre respectively, and compared these with other autonomic indices across the groups. BRSvagalinc was calculated in all subjects and correlated highly with BRSvagaldec (r=0.72, P<0.001). BRSvagalinc also correlated significantly with BP changes during phases II and IV of the Valsalva manoeuvre and sympathetic barosensitivity. BRSvagalinc was significantly different between the groups, being highest in the controls and lowest in patients with severe autonomic failure. In conclusion, vagal BRS, determined by relating R-R interval with the BP increase following phase III, is a valuable autonomic index, provides additional information about vagal baroreflex function and reflects overall severity of autonomic failure.

Recent advances in autoimmune autonomic ganglionopathy

This review highlights recent advances in our understanding of autoimmune autonomic ganglionopathy (AAG) including serological diagnosis, clinical observations, pathophysiology, and treatment. Classical AAG is a subacute disorder associated with antibodies against ganglionic acetylcholine receptors. Recent observations demonstrate that these antibodies cause a specific inhibition of synaptic transmission in autonomic ganglia and antibody levels correlate in a predictable way with severity of autonomic failure. Ganglionic acetylcholine receptor antibodies can be associated with other neurological disorders including chronic or restricted forms of autonomic dysfunction and with neurological or paraneoplastic disorders unrelated to the autonomic nervous system. Treatment of AAG is based on case reports. It is clear that AAG patients respond to immunomodulatory treatments but combination immunotherapy may be required to achieve a clinical response. Recently, additional clinical observations indicate that AAG patients may also show signs of treatment-responsive cognitive impairment. The pathophysiology and varied clinical presentation of AAG are becoming more clear. AAG is a treatable antibody-mediated disorder of autonomic ganglionic synaptic transmission. Future studies will continue to define the optimal diagnostic and therapeutic approach to autoimmune autonomic disorders.

Immunotherapy for autoimmune autonomic ganglionopathy

Purpose of review To provide an update on recent advances in the treatment of autoimmune autonomic ganglionopathy (AAG). AAG is an immune-mediated disorder characterized by prominent and selective involvement of autonomic nerve fibers or ganglia. Treatment with intravenous immunoglobulin (IVIG) or plasma exchange (PE) has been reported to be effective in single case reports and recent case series. This review summarizes current treatment options including IVIG, PE, and immunosuppressants agents, alone or in combination. Results Controlled clinical trials of immunotherapy are not available and experience with immunotherapy is confined to single case reports. Some patients with AAG seem to respond to IVIg or PE as initial therapy but often require subsequent immunosuppressive treatment to sustain or advance the improvement. Preliminary studies suggest that the most severely affected patients may need a protracted and combined treatment program to achieve clinical improvement. Summary Several recent studies suggest that IVIg, PE, and immunosuppressant agents are effective treatment for AAG. Current available treatments used as monotherapy or in combination may be efficacious and the specific regimen may depend on the severity of autonomic failure. There is preliminary evidence that novel immunosuppressant agents such as Mycophenolate mofetil (MMF) and Rituximab may be effective in certain patients who are unresponsive to IVIG or PE.

Nocturnal Blood Pressure Dipping in the Hypertension of Autonomic Failure

Blood pressure (BP) normally decreases during the night. Absence of this phenomenon (nondipping) is associated with increased cardiovascular risk. Altered autonomic and endocrine circadian rhythms are suspected to play a role. Patients with peripheral autonomic failure offer a unique opportunity to study this phenomenon, because approximately 50% develop supine hypertension despite very low autonomic function. The purpose of this study was to define the prevalence of dipping in these patients and to determine whether dipping is associated with less severe autonomic impairment or exaggerated nocturnal sodium excretion. We collected BP and urine from 8:00 pm to 8:00 am in 41 peripheral autonomic failure patients with supine hypertension. Dipping (systolic BP fall >or=10% during 12 am to 6 am from baseline [8 pm to 10 pm]) occurred in 34% of patients, with an average decrease of -44+/-4 mm Hg at 4 am. Systolic BP, averaged from 12 am to 6 am, decreased to normotensive levels in 50% (n=7) of dippers and 15% (n=7) of nondippers. There were no significant differences in the severity of autonomic failure, nocturnal diuresis, or natriuresis (0.18+/-0.01 in dippers versus 0.18+/-0.01 mEq/mg of creatinine in nondippers; P=0.522) between groups. At 8:00 am, orthostatic hypotension was similar between groups (-84/-35+/-9/4 mm Hg in dippers versus -93/-39+/-6/3 mm Hg in nondippers; P=0.356 for systolic BP). In conclusion, dipping was observed in one third of patients with peripheral autonomic failure, so that a significant percentage of patients would not require treatment for supine hypertension. Dipping was not associated with increased nocturnal urinary sodium or volume excretion or less severe autonomic failure. Thus, mechanisms independent of autonomic pathways contribute to BP dipping in these patients.

Autonomic Symptoms and Diabetic Neuropathy

The prevalence of autonomic symptoms and deficits in certain systems is known, but a comprehensive autonomic symptom profile in diabetes is not available. We aimed to estimate this using a laboratory evaluation of autonomic function and a validated self-report measure of autonomic symptoms in patients and matched control subjects from the population-based Rochester Diabetic Neuropathy Study. Participants included 231 patients with diabetes (type 1, n=83; type 2, n=148) and 245 healthy age-matched control subjects. We assessed symptoms using a validated self-report instrument (Autonomic Symptom Profile) and evaluated the severity and distribution of autonomic deficits (cardiovagal, sudomotor, adrenergic) with the objective, laboratory-based Composite Autonomic Severity Score (CASS). Autonomic symptoms were present more commonly in type 1 than in type 2 diabetes, with symptoms of orthostatic intolerance, secretomotor, urinary control, diarrhea, and sleep disturbance and pupillomotor, vasomotor, and erectile dysfunction significantly increased over healthy control subjects in type 2 diabetic patients. The prevalence of autonomic impairment was 54% in type 1 and 73% in type 2 diabetic patients. Severity of autonomic failure was mild overall (mean CASS 2.3; maximum 10), with orthostatic hypotension occurring in 8.4 and 7.4% of type 1 and 2 diabetic patients, respectively. Fourteen percent of patients had a CASS > or =5, indicating moderate to severe generalized autonomic failure. The correlation of symptoms with autonomic deficits (CASS) was better in type 1 than type 2 diabetic subjects and was weak overall. These findings indicate that autonomic symptoms and deficits are common in diabetes, but mild in severity, and that the correlation between symptom scores and deficits is overall weak in mild diabetic neuropathy, emphasizing the need to separately evaluate autonomic symptoms.

Quantitative study of lateral horn cells in 15 cases of multiple system atrophy.

Nerve cell counts of the lateral horns of the spinal cord were performed in 15 cases of multiple system atrophy (MSA) and three age- and sex-matched controls. The patients with MSA were comprised of eight with severe postural hypotension, three with orthostatic hypotension and little or no disability and four without any signs of autonomic failure. All cases of MSA had lost more than half their lateral horn cells but nerve cell loss could not be correlated with the degree of dysautonomia. These results confirm the involvement of the intermediolateral columns of the spinal cord in MSA. However, the lack of correlation between cell loss and severity of autonomic failure in our cases, suggests that lesions of other sites, such as sympathetic ganglia or the dorsal vagal nuclei, are also implicated in dysautonomia.

Somatic and autonomic function in progressive autonomic failure and multiple system atrophy.

We studied 62 consecutive patients with progressive autonomic failure (PAF) or multiple system atrophy (MSA) (26 PAF; 36 MSA). Patients were well matched in age (67 vs 66 years), duration (39 vs 36 months), and severity of autonomic failure (median values for PAF and MSA). Peripheral somatic neuropathy occurred in 2 patients with PAF and 7 patients with MSA. Postganglionic sudomotor and vasomotor functions were studied using the quantitative sudomotor axon reflex test and supine plasma norepinephrine. The extent and severity of autonomic failure were assessed by the thermoregulatory sweat test, by heart rate responses to deep breathing and the Valsalva maneuver, and by blood pressure recordings. Severe and widespread anhidrosis was found in both PAF and MSA patients. Postganglionic sudomotor failure occurred at the forearm in 50% each of PAF and MSA patients and at the foot in 69% and 66% of PAF and MSA patients, respectively. However, postganglionic sudomotor function was preserved in some patients with anhidrosis on thermoregulatory sweat test, indicating a preganglionic lesion. Vagal abnormalities were found in 77% and 81% of PAF and MSA patients. Supine plasma free norepinephrine values were significantly reduced in PAF (p less than 0.001), but not in MSA, patients. Standing plasma norepinephrine values were reduced in both PAF (p less than 0.001) and MSA (p less than 0.001) patients. We conclude the following: (1) PAF is characterized by combined postganglionic sudomotor and adrenergic failure. (2) MSA is associated with a similar frequency of postganglionic sudomotor failure, but postganglionic adrenergic denervation was uncommon. (3) Preganglionic neuron is also involved in both disorders, but more severely in MSA. (4) Somatic neuropathy may occur.

Correlation of autonomic dysfunction to CSF concentrations of noradrenaline and 3-methoxy-4-hydroxyphenylglycol in Parkinson's disease.

In order to study the role of the neurotransmitter noradrenaline (NA) and its main brain metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) in autonomic failure in Parkinson's disease (PD), an analysis of the relation of cerebrospinal fluid (CSF) NA and MHPG levels and a rating of autonomic nervous system (ANS) impairment was carried out. The mean baseline NA level in CSF of PD patients was 220.0 +/- 110.0 pg/ml, and the mean baseline MHPG level 9.9 +/- 3.9 ng/ml. These levels did not differ from those of age-matched controls. Within the group of patients with PD neither the duration of the disease nor its medication influenced the results. No correlation could be found in patients with PD between the CSF NA levels and the severity of autonomic failure, but a clear correlation was found between the CSF MHPG concentrations and the severity of autonomic failure.