Tonette L. Gehrking

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.

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. Results 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 Parkinsons 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.

Patterns of Neuropathy and Autonomic Failure in Patients With Amyloidosis

OBJECTIVE To define the clinical patterns of peripheral neuropathy and autonomic testing abnormalities in patients with amyloidosis. PATIENTS AND METHODS A retrospective chart review was conducted of 65 patients who had biopsy-proven amyloidosis and autonomic function testing between January 1, 1985, and December 31, 1997, at Mayo Clinics site in Rochester, MN. Patients were required to have neurologic evaluation, autonomic reflex screening, and tissue confirmation of amyloidosis. RESULTS We identified 5 clinical patterns of peripheral neuropathy: (1) generalized autonomic failure and polyneuropathy with pain (40 patients [62%]), (2) generalized autonomic failure and polyneuropathy without pain (11 [17%]), (3) isolated generalized autonomic failure (7 [11%]), (4) polyneuropathy without generalized autonomic failure (4 [6%]), and (5) generalized autonomic failure and small-fiber (ie, autonomic and somatic C-fiber) neuropathy (3 [5%]). Moderately severe generalized autonomic failure, involving adrenergic, cardiovagal, or sudomotor domains, was found in all patients, including those without clinically manifested autonomic failure. The diagnosis of amyloidosis was delayed in patients who did not have initial symptoms of pain or generalized autonomic failure (48 months to diagnosis in patients with polyneuropathy without autonomic failure vs 12 months to diagnosis in patients with autonomic failure and small-fiber neuropathy; P=.57). CONCLUSION Physicians should test for symptoms of generalized autonomic failure in patients who have peripheral neuropathy of unknown origin. Autonomic testing may give abnormal results in patients without overt symptoms of autonomic failure. Early recognition of autonomic failure may lead to earlier diagnosis of the underlying pathogenesis of amyloidosis, as well as earlier treatment for patients with this condition.

A randomised controlled study of the effect of cholinesterase inhibition on colon function in patients with diabetes mellitus and constipation

Objectives Chronic constipation in diabetes mellitus is associated with colonic motor dysfunction and is managed with laxatives. Cholinesterase inhibitors increase colonic motility. This study evaluated the effects of a cholinesterase inhibitor on gastrointestinal and colonic transit and bowel function in diabetic patients with constipation. Design After a 9-day baseline period, 30 patients (mean±SEM age 50±2 years) with diabetes mellitus (18 type 1, 12 type 2) and chronic constipation without defaecatory disorder were randomised to oral placebo or pyridostigmine, starting with 60 mg three times a day, increasing by 60 mg every third day up to the maximum tolerated dose or 120 mg three times a day; this dose was maintained for 7 days. Gastrointestinal and colonic transit (assessed by scintigraphy) and bowel function were evaluated at baseline and the final 3 and 7 days of treatment, respectively. Treatment effects were compared using analysis of covariance, with gender, body mass index and baseline colonic transit as covariates. Results 19 patients (63%) had moderate or severe autonomic dysfunction; 16 (53%) had diabetic retinopathy. 14 of 16 patients randomised to pyridostigmine tolerated 360 mg daily; two patients took 180 mg daily. Compared with placebo (mean±SEM 1.98±0.17 (baseline), 1.84±0.16 (treatment)), pyridostigmine accelerated (1.96±0.18 (baseline), 2.45±0.2 units (treatment), p<0.01) overall colonic transit at 24 h, but not gastric emptying or small-intestinal transit. Treatment effects on stool frequency, consistency and ease of passage were significant (p≤0.04). Cholinergic side effects were somewhat more common with pyridostigmine (p=0.14) than with placebo. Conclusions Cholinesterase inhibition with oral pyridostigmine accelerates colonic transit and improves bowel function in diabetic patients with chronic constipation. Clinical trial registration number TrialRegNo (NCT 00276406).

Pilot study of pyridostigmine in constipated patients with autonomic neuropathy

BackgroundThe effects of cholinesterase inhibitors, which increase colonic motility in health, on chronic constipation are unknown. Our aims were to evaluate the efficacy of cholinesterase inhibitors for dysautonomia and chronic constipation and to assess whether acute effects could predict the long term response.MethodsIn this single-blind study, 10 patients with autonomic neuropathy and constipation were treated with placebo (2 weeks), followed by an escalating dose of pyridostigmine to the maximum tolerated dose (i.e., 180–540 mg daily) for 6 weeks. Symptoms and gastrointestinal transit were assessed at 2 and 8 weeks. The acute effects of neostigmine on colonic transit and motility were also assessed.ResultsAt baseline, 4, 6, and 3 patients had delayed gastric, small intestinal, and colonic transit respectively. Pyridostigmine was well tolerated in most patients, improved symptoms in 4 patients, and accelerated the geometric center for colonic transit at 24 h by ≥0.7 unit in 3 patients. The effects of i.v. neostigmine on colonic transit and compliance predicted (P < 0.05) the effects of pyridostigmine on colonic transit.ConclusionsPyridostigmine improves colonic transit and symptoms in some patients with autonomic neuropathy and constipation. The motor response to neostigmine predicted the response to oral pyridostigmine.

The role of autonomic testing in the differentiation of Parkinson's disease from multiple system atrophy

Differentiation of idiopathic Parkinsons disease (PD) from multiple system atrophy (MSA) can be difficult. Methods devised to help distinguish the two disorders include standardized autonomic testing and cardiac imaging with iodine-123 meta-iodobenzylguanidine myocardial scintigraphy. MSA patients had more severe adrenergic and overall autonomic dysfunction when compared to control and PD patients. Area of anhidrosis on thermoregulatory sweat test was greater in MSA (67.4±12.42, p<0.001) versus PD patients (area of anhidrosis, 1.7±2.96). Postganglionic cardiac sympathetic innervation (iodine-123 meta-iodobenzylguanidine) expressed as heart to mediastinal ratio was significantly lower in Parkinsons disease patients (1.4±0.40, p=0.025) compared to controls (2.0±0.29), but not in multiple system atrophy (2.0±0.76). These findings indicate that autonomic dysfunction is generalized and predominantly preganglionic in multiple system atrophy, and postganglionic in Parkinsons disease. In our hands the thermoregulatory sweat test provides the best distinction between MSA and PD. However further confirmatory studies using larger patient numbers are required. Currently a combination of clinical judgment and autonomic testing is recommended to help differentiate MSA and PD.

Effect of position on valsalva maneuver: supine versus 20 degree position.

Summary: Blood pressure changes in response to the Valsalva maneuver (VM), which reflect the integrity of the baroreflex that regulates blood pressure. Performing this maneuver in the standard supine position often prevents adequate venous preload reduction, resulting in a rise rather than a fall in blood pressure, the “flat-top” Valsalva response. We determined whether performing the VM at a 20 degree angle of head-up tilt (20°) improves preload reduction, thereby reducing the frequency of flat-top responses, improving reflex vasoconstriction, and increasing the Valsalva ratio. One hundred thirty patients were evaluated in a prospective study. Each patient performed the VM in both supine and 20° positions. Flat-top responses were present in 18% of subjects when supine. Twenty degree angle of head-up tilt position reduced the flat-top response by 87%. The components of the response that are dependent on preload reduction (Valsalva ratio and phases II_E, II_L, and IV) also showed significant improvement with 20°. A 20 degree angle of tilt is sufficient to reduce venous preload, decreasing flat-top response rate and improving the Valsalva ratio and the morphology of the VM. We recommend this modification for laboratory evaluation of the VM, whenever a flat-top response is seen.

Effects of Patient-Controlled Abdominal Compression on Standing Systolic Blood Pressure in Adults With Orthostatic Hypotension

OBJECTIVE To assess the effects of patient-controlled abdominal compression on postural changes in systolic blood pressure (SBP) associated with orthostatic hypotension (OH). Secondary variables included subject assessments of their preferences and the ease-of-use. DESIGN Randomized crossover trial. SETTING Clinical research laboratory. PARTICIPANTS Adults with neurogenic OH (N=13). INTERVENTIONS Four maneuvers were performed: moving from supine to standing without abdominal compression; moving from supine to standing with either a conventional or an adjustable abdominal binder in place; application of subject-determined maximal tolerable abdominal compression while standing; and while still erect, subsequent reduction of abdominal compression to a level the subject believed would be tolerable for a prolonged period. MAIN OUTCOME MEASURES The primary outcome variable included postural changes in SBP. Secondary outcome variables included subject assessments of their preferences and ease of use. RESULTS Baseline median SBP in the supine position was not affected by mild (10mmHg) abdominal compression prior to rising (without abdominal compression: 146mmHg; interquartile range, 124-164mmHg; with the conventional binder: 145mmHg; interquartile range, 129-167mmHg; with the adjustable binder: 153mmHg, interquartile range, 129-160mmHg; P=.85). Standing without a binder was associated with an -57mmHg (interquartile range, -40 to -76mmHg) SBP decrease. Levels of compression of 10mmHg applied prior to rising with the conventional and adjustable binders blunted these drops to -50mmHg (interquartile range, -33 to -70mmHg; P=.03) and -46mmHg (interquartile range, -34 to -75mmHg; P=.01), respectively. Increasing compression to subject-selected maximal tolerance while standing did not provide additional benefit and was associated with drops of -53mmHg (interquartile range, -26 to -71mmHg; P=.64) and -59mmHg (interquartile range, -49 to -76mmHg; P=.52) for the conventional and adjustable binders, respectively. Subsequent reduction of compression to more tolerable levels tended to worsen OH with both the conventional (-61mmHg; interquartile range, -33 to -80mmHg; P=.64) and adjustable (-67mmHg; interquartile range, -61 to -84mmHg; P=.79) binders. Subjects reported no differences in preferences between the binders in terms of preference or ease of use. CONCLUSIONS These results suggest that mild (10mmHg) abdominal compression prior to rising can ameliorate OH, but further compression once standing does not result in additional benefit.

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.

Determination of vagal baroreflex sensitivity in normal subjects

Introduction: The Valsalva maneuver (VM) is used widely to quantify the sensitivity of the vagal baroreflex loop (vagal baroreflex sensitivity, BRS_v), but most studies have focused on the heart rate (HR) response to blood pressure (BP) decrement (BRS_v↓), even though the subsequent response to an increment in BP after the VM (BRS_v↑) is important and different. Methods: We evaluated recordings of HR and BP in 187 normal subjects during the VM and determined both BRS_v↑, as determined by relating HR to the BP increase after phase III and BRS_v↓. Results: BRS_v↑ was related inversely to age. In addition, BRS_v↓, age, and magnitude of phase IV were independent predictors of BRS_v↑ in a multivariate model, accounting for 47% of the variance of BRS_v↑. Conclusions: The results indicate that both BRS_v↑ and BRS_v↓ become blunted with increasing age and that these indices relate to each other. Muscle Nerve 50: 535–540, 2014