The Shy Drager Syndrome/Multiple System Atrophy Support Group has an almost "Familial" relationship with the American Autonomic Society.  At the American Autonomic Society meeting in 2003, a request was made of the Support Group to begin funding a "Research Award" to support research in MSA through a donation to the American Autonomic Society.  The Research Award will be given to the best presentation directly related to MSA research presented at the annual meeting of the American Autonomic Society, on behalf of the SDS/MSA Support Group.  Board of Directors unanimously decided that this was a good way to support the research for MSA.

The 2006 recipient of the Research Award went to Dr. Peter Novak, Department of Neurology Jamaica Plain, MA. entitled Autonomic and Small Fiber Neuropathies.   research award

It is often difficult to differentiate between Shy-Drager (MSA) and other movement disorders such as Parkinson’s Disease.  Currently the best technique is to use sophisticated scans of the heart, looking for sympathetic nerves, which are intact in Shy-Drager but absent in Parkinson’s Disease and in Pure Autonomic Failure.  This technique, however, is experimental, not available in most centers, and expensive.  It would be useful for the adequate diagnosis of patients to have an easier technique.  Novak and colleagues presented a study showing that similar findings can be obtained with a simple skin biopsy (1).  They found that skin neuronal fibers were damaged in Parkinson’s patients but not in patients suffering from Shy-Drager.  These results are preliminary, but offer hope that in the future we will have a simple technique to help diagnose patients with Shy-Drager.  This presentation won the Shy-Drager Research Award.

 The Underlying Pathology in Shy-Drager

The reason why patients develop Shy-Drager is not know, but our understanding of the mechanisms involved is improving.  We now know that there is an abnormal deposit of proteins in certain areas of the brain that impair neuronal function.  A protein called alpha-synuclein is found in these precipitates not only in Shy-Drager, but also in  classic Parkinson Disease.  Shibao et al found another protein that may contribute to the abnormalities of Shy-Drager.  They found that a variant of the prion protein is found more frequently in Shy-Drager patients compared to Parkinson’s Disease (5).  This variant is associated with brain disorders, but much work is needed to understand how it contributes to Shy-Drager.  This presentation won one of three best abstract award.

            Sleep disorders are part of the clinical problems of Shy-Drager.  As mentioned above, Shy-Drager is caused by the abnormal precipitation of protein forming “Glial Cytoplasmic Inclusions – GCI” (a different form of deposits, called “Lewy Bodies”, are found in Parkinson’s Disease).  Schmeichel et al may have found CGI deposits in areas of the brain (hypothalamus) that are involved in sleep regulation (6).  This may explain the sleep problems found in Shy-Drager patients. 

 Blood Pressure Problems in Shy-Drager

            Cheshire reported that a surprisingly large percentage of patients with profound orthostatic hypotension nonetheless did not complain of symptoms (4).  The author urges physicians to measure standing blood pressures to make sure we don’t miss patients with orthostatic hypotension because of autonomic impairment.

            Patients with Shy-Drager not only have low blood pressure on standing (“orthostatic hypotension”) but also have low blood pressure after meals (“post-prandial hypotension”, see below) and at least half of them also have high blood pressure while lying down (“supine hypertension”).  Cheshire found that supine hypertension often goes unrecognized, and urges physicians to may more attention to this problem (7).

 Treatment of Blood Pressure Problems in Shy-Drager

Patients with Shy-Drager and other diseases characterized by impaired autonomic function often have a fall in blood pressure after meals.  This can worsen orthostatic hypotension (low blood pressure on standing) and increase the risk of falls in these patients.  The cause of this postprandial hypotension is the release of hormones, in response to the absorption of carbohydrates, which then lower blood pressure. Shibao and colleagues (2) showed that this postprandial hypotension can be prevented if foods are ingested with a drug called acarbose (Precose).  This drug delays the absorption of carbohydrates and the release of insulin and other hormones that may contribute to postprandial hypotension.  A 100 mg dose of acarbose, taken with meals, can help prevent the symptoms of low blood pressure after meals.  This presentation won the Streeten Travel Award for young investigators.

            Blowing against pressure (the Valsalva maneuver commonly ised to diagnosed patients with autonomic failure) causes a fall in blood pressure.  Thijs and colleagues (3) tried the opposite, having patients take in air through a device that creates a resistance to the airflow.  They found that this device improved orthostatic hypotension, and patients had less of a fall in blood pressure on standing.  This could be used to allow patients to stand with less symptoms, but it has been tried only acutely, and it is not clear how practical this approach will be in real life.

 These are the full abstracts cited above:

(1) Quantitative analysis of dermal small fibers in Parkinson’s disease and multiple system atrophy

P. Novak (1), N. Bharat Marya (2), K. Whren (2), J. Bhawan (2)

(1) Autonomic Laboratory, Dept. Neurology, Boston University School of Medicine, Boston, MA, USA; (2) Dermatopathology Section, Dept. Dermatology, Boston University School of Medicine, Boston, MA, USA

Background: Skin biopsy provides information about the small fibers. Most reported studies have focused on analysis of the sensory epidermal fibers. In this study, we evaluated autonomic and sensory nerves in the dermis in patients with multiple system atrophy (MSA) or with Parkinson’s disease complicated by autonomic dysfunction (PD-A) using dermal sheet preparations (DSP). Methods: Skin biopsies from 5 PD patients complicated by autonomic dysfunction and 5 MSA patients were analyzed. The full-dermis thickness biopsy was performed with a 3 mm diameter punch.  Samples were taken from the proximal and distal leg. DSP processing includes collagenase digestion, immunostaining with the nerve growth factor receptor p75 antibody and automatic fiber detection using phase symmetry image analysis applied on the horizontal views. Results: DSP visualizes small fibers with high contrast. Many fibers showed signs of degeneration including fragmentation, swelling, thinning and beading. The fiber density was reduced in PD-A patients (p<0.0001) compared to MSA patients. Conclusion: Digestion of skin samples by collagenase, staining with p75 antibody and use of horizontal views enables simultaneous visualization of large number of nerve fibers in dermis with high signal-to-noise ratio enabling automatic digital image analysis. Reduced small fiber density in PD-A patients suggests the presence of small fiber neuropathy in PD-A. DSP can aid in understanding the pathology of small fiber neuropathies, as with the distinction between PD and MSA.

 (2) Novel treatment for postprandial hypotension with an alpha-glucosidase inhibitor, acarbose

C. Shibao (1), A. Gamboa (1), A. Diedrich (1), C. Dossett (2), G. Farley (1), I. Biaggioni (1)

(1) Autonomic Dysfunction Center, Vanderbilt University, Nashville, TN, USA; (2) General Clinical Research Center, Vanderbilt University, Nashville, TN, USA

Postprandial hypotension (PPH), is an important clinical condition associated with syncope, fall, angina and cerebrovascular events. Those more at risk are elderly and patients with autonomic dysfunction. Because enteric glucose availability has been proposed to contribute to the pathophysiology of postprandial hypotension (PPH). We hypothesized that acarbose, an alpha-glucosidase inhibitor that decreases glucose absorption in the small intestine, would improve PPH. The effect of 100 mg of acarbose was studied in 7 patients (age 65.1±6.6 years, BMI 24.2±4.9 Kg/m2, 5 females) with pure autonomic failure in a double blind, randomized, crossover study. All participants had severe PPH, defined as a decrease in systolic blood pressure of at least 20 mm Hg within 2 hours of meal ingestion. Baseline measurements were taken for 30 minutes every 5 minutes in the supine position. The study medication (Acarbose/Placebo) was administered 20 minutes before the ingestion of a standard mixed meal consisting of 423 Kcal. Blood pressure and heart rate were monitored for 90 minutes. Neurohumoral parameters were measured at baseline, 15, 30, 45, 60 and 90 minutes of meal ingestion. During placebo the fall in systolic blood pressure was 42±9 mm Hg as compared to 20±6 mm Hg with acarbose, P<0.05. Acarbose significantly reduced plasma levels of insulin as compared to placebo (19± 3 vs 28±5 pg/ml, respectively, at 60 minutes, P=0.028). We conclude that 100 mg acarbose successfully improved postprandial hypotension in patients with severe autonomic failure, at least in part by reducing insulin levels, a known vasodilator in this condition.

 (3) Respiratory countermaneuvers in autonomic failure

R. D. Thijs (1), W. Wieling (2), J. G. van de Aardweg (3), J. G. van Dijk (1)

(1) Department of Neurology and Clinical Neurophysiology, Leiden University Medical Center, Leiden, the Netherlands (2) Department of Internal Medicine, Academic Medical Centre, Amsterdam, the Netherlands. (3) Department of Pulmonology, Medical Centre Alkmaar, Alkmaar, the Netherlands

Background: A selective inspiratory increase of impedance augments blood pressure (BP) in healthy subjects through the 'respiratory pump'. We studied whether this works in patients with autonomic failure (AF). Methods: 10 Patients with AF and 10 healthy controls were studied supine (5 minutes) and during active standing (2 minutes). Five tests were performed in a random order: normal standing (control), muscle tensing of the legs (MT), and three maneuvers aimed to selectively increase inspiratory impedance: breathing through pursed lips during inspiration (PLB), inspiratory sniffing (IS), and inspiratory obstruction through narrowing of an inspiratory valve (IO). Here, only mean arterial pressure (MAP, Finometer) and end-tidal CO₂ of the last 30 seconds standing are reported. The nonparametric Friedman’s test for repeated measures was used. Data are presented as mean±SEM relative to the control condition. Controls will be reported elsewhere. Results: The maneuvers caused significant changes of MAP (p=0.02) and end-tidal CO₂ (p=0.04). On average, IO produced an increase of MAP (7±3 mmHg) and minimal changes of end-tidal CO₂ (0.07±0.1%).  MT also caused an increase of MAP (6±2 mmHg) and minimal changes of end-tidal CO₂ (-0.02±0.1%).  PLB caused a decrease of MAP (-1±4 mmHg) and end-tidal CO₂ (-0.6±0.3%).  IS produced a decrease of MAP (-7±5 mmHg) and end-tidal CO₂ (-0.7±0.2%). In 7 patients the highest MAP was recorded during a respiratory maneuver (IO n=5; IS n=1; PLB n=1), in 2 patients during MT and in one patient during normal standing. Discussion: An external device causing an increase of inspiratory impedance is as effective as muscle tensing in preventing orthostatic hypotension in AF. The individual responses to PLB and IS varied considerably, as these maneuvers could cause hypocapnia, which may by itself reduce BP in AF. Therefore, the effectiveness of PLB and IS should be evaluated individually.

 (4) Orthostatic hypotension symptom unawareness is independent of localization of autonomic failure

W. P. Cheshire

Department of Neurology, Mayo Clinic, Jacksonville, FL, USA

Background: Symptoms of orthostatic hypotension (OH) vary greatly. Why many patients lack awareness of even substantial falls in blood pressure (BP) is unknown. Possible explanations include chronic adaptation, differences in cerebral autoregulation, or differences in afferent processing. The locus ceruleus, for example, which is impaired in multiple system atrophy (MSA), provides noradrenergic input to brain regions that integrate sensory and motor responses to stressful stimuli and increases the gain of cortical processing units that attend to novel stimuli including, perhaps, afferent signals in response to OH. Hypothesis: Symptom frequency in OH differs in central versus peripheral autonomic failure. Methods: Records of patients who underwent autonomic testing over a two-year period were reviewed. In order to compare peripheral and central autonomic failure, two diagnostic groups were selected. Inclusion criteria were OH, a diagnosis of either MSA (N=21, mean age 75, M:F 0.6) or diabetic autonomic neuropathy (DAN, N=18, mean age 65, M:F 0.6), and a composite autonomic severity score > 4. During tilt, patients were questioned regarding symptoms, and their responses were recorded. Results: Five (24%) of 21 MSA patients and 4 (22%) of 18 DAN patients were symptomatic during tilt. Symptoms included malaise, lightheadedness, and general weakness. The remaining 30 out of 39 patients were asymptomatic, despite a mean systolic BP drop of 59 mmHg for MSA and 42 mmHg for DAN. The proportions of symptomatic patients between groups was statistically insignificant. Conclusion: A surprising low proportion (23%) of patients reported symptoms during OH. The absence of symptoms did not appear to be explained by a difference in localization of autonomic failure in the central versus peripheral nervous system, since symptom unawareness was equally infrequent in MSA and DAN patients. Measurement of orthostatic BP, rather than reliance on symptoms alone, is important when evaluating autonomic failure.

 (5) Multiple system atrophy is associated with the prion protein codon 129 genotype

C. Shibao (1), E. M. Garland (1), A. Gamboa (1), C. L. Vnencak-Jones (2), V. M. Woeltz (3), J. L. Haines (4), I. Biaggioni (1)

(1) Autonomic Dysfunction Center, Vanderbilt University, Nashville, TN, USA; (2) Department of Pathology, Vanderbilt University, Nashville, TN, USA; (3) Neurology Group of Paducah, KY, USA (4) Center for Human Genetics Research and Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN, USA

Multiple system atrophy (MSA) is a neurodegenerative disorder of unknown etiology characterized by extrapyramidal, pyramidal, cerebellar, and autonomic dysfunction in any combination. We have previously reported a patient with a 3-year history of MSA who developed dementia associated with sporadic Creutzfeltd-Jakob disease (CJD). Our proband was MM homozygous for the M129V polymorphism within the prion protein gene (PRNP), a known risk factor for CJD. Objective: to test the hypothesis that homozygosity at this polymorphic site may signal a role for the prion protein in MSA. Methods and results: we conducted a case-control study to determine differences in the genotype distribution of the M129V polymorphism of PRNP in MSA in comparison to Parkinson’s disease. Review of our database yielded a total of 54 patients with a probable/definitive diagnosis of MSA following established criteria. The results of standardized autonomic function tests, plasma catecholamines and neurological evaluation were examined to ascertain the diagnosis. Our control group consisted of 54 patients with Parkinson’s disease (PD) matched by age, gender and race. Patients with PD were in Hardy-Weinberg equilibrium (HWE) (P>0.05) and had similar genotype distribution as that previously reported in US healthy controls for the M129V polymorphism. The genotype distribution in patients with MSA deviated from HWE (P<0.05), and further analysis revealed that the homozygous state was overrepresented in MSA (P=0.033, OR=2.3, 95% CI 1.07 to 5.13) as compared to PD controls. Conclusions: our findings indicate that homozygosity (MM or VV) at codon 129 of the PRNP is associated with MSA, suggesting a possible role of the prion protein in the pathogenesis of this disease.

 (6) Involvement of hypocretin neurons in multiple system atrophy and Lewy body disease

A. M. Schmeichel (1), E. E. Benarroch (1), P. A. Low (1), J. E. Parisi (2)

(1) Department of Neurology, Mayo Clinic, Rochester, MN, USA; (2) Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA

Hypocretin/orexin (Hcrt/Orx) neurons of the hypothalamus are involved in control of sleep and autonomic function, which are affected in multiple system atrophy (MSA) and Lewy body disorders (LBD). We sought to determine whether Hcrt/Orx neurons were involved in MSA and LBD. Hypothalamus was obtained from 7 subjects with neuropathologically confirmed MSA, 7 with LBD and 6 age-matched controls. Fifty micron sections were immunostained for Hcrt-1 and α-synuclein. There was a marked reduction of the numbers of Hcrt/Orx neurons compared in MSA, both compared to control and LBD cases (51±9 cells/section in MSA vs. 137±18 cells/section in controls, p < 0.001 and 97±20 cells/section in LBD, p < 0.01). There were abundant glial cytoplasmic inclusions in the area of distribution of Hcrt/Orx neurons in MSA cases. Lewy bodies were present in this area in LBD cases, but the number of neurons was relatively preserved. Loss of Hcrt/Orx neurons may contribute to sleep and autonomic disturbances of MSA. The relative preservation of these neurons in LBD indicates that sleep dysregulation in these disorders is likely multifactorial.

 (7) Bedside measurements do not reliably predict supine hypertension in autonomic failure

W. P. Cheshire

Department of Neurology, Mayo Clinic, Jacksonville, FL, USA

Background: Loss of baroreflex buffering of blood pressure (BP) can cause supine hypertension (SHTN) in patients with autonomic failure. SHTN may be associated with an increased risk of cardiovascular and cerebrovascular events. Hypothesis: Bedside measurement of supine BP predicts whether patients with autonomic failure will demonstrate SHTN in the autonomic laboratory or during ambulatory BP monitoring. Methods: Records of patients who underwent autonomic testing over a two-year period were reviewed. In order to compare peripheral and central autonomic failure, two diagnostic groups were selected. Inclusion criteria were a diagnosis of either diabetic autonomic neuropathy (DAN, N=18, mean age 65, M:F 0.6) or multiple system atrophy (MSA, N=21, mean age 75, M:F 0.6), orthostatic hypotension, and a composite autonomic severity score > 4. Initial outpatient bedside BP values were compared to values during autonomic testing and nocturnal ambulatory BP monitoring. SHTN was defined as BP > 160/90 mmHg. Results: SHTN was detected by at least one method in 22 (56%) patients (10 DAN, 12 MSA). Bedside BP measurement alone detected SHTN in only 13 (33%) patients. Of the 13 with bedside SHTN, 8 were also abnormal during autonomic testing or ambulatory monitoring. Of the 21 with normal bedside supine BP, 7 had SHTN during autonomic testing or ambulatory monitoring. All patients with nocturnal SHTN (7 of 17) during ambulatory monitoring also had SHTN either at the bedside or during autonomic testing. There were no significant differences between DAN and MSA groups. Conclusion: Measurement of BP at the bedside detected SHTN in 59% of patients with autonomic failure that were found to have SHTN by any method of assessment. Autonomic testing and ambulatory BP monitoring greatly improved the sensitivity. This disparity may be explained by intrasubject variability or by the delayed onset of SHTN upon assuming the recumbent posture.