Thomas C. Chelimsky

A cytoarchitectonic and histochemical study of nucleus basalis and associated cell groups in the normal human brain

Several recent studies have reported loss of neurons in the nucleus basalis in Alzheimers disease. However, few detailed studies of the normal distribution of these neurons in the human brain have appeared. We have used Nissl staining and acetylcholinesterase histochemical staining of the human basal forebrain, alone or in combination to identify the organization of the nucleus basalis and associated cell groups, (or collectively, the magnocellular basal nucleus) in the normal human brain. The magnocellular basal nucleus includes a series of clusters of neurons and scattered perikarya extending from the medial septum and diagonal band nucleus rostrally, through the substantia innominata to the furthest caudal extent of the globus pallidus. This distribution is similar to that which has been described in the monkey. Furthermore, acetylcholinesterase-positive fibers in the human brain are seen in the two major pathways that have been identified as carrying magnocellular basal nucleus axons to the cerebral cortex in other species. These observations suggest that the topographic organization of the magnocellular basal projection to cerebral cortex in other species probably exists in man as well. It will therefore be important in future studies of the fate of these neurons in neurological degenerative diseases to assess the loss of neurons in the different components of the magnocellular basal nucleus in relation to the clinical evidence for dysfunction in the cortical areas which they innervate.

Natural history of multiple system atrophy in the USA: a prospective cohort study

Background Multiple system atrophy (MSA) is a rare, fatal neurodegenerative disorder exhibiting a combination of parkinsonism and/or cerebellar ataxia with autonomic failure. We report the first North American prospective natural history study of MSA, and the effects of phenotype and autonomic failure on prognosis. Methods 175 subjects with probable MSA, both MSA-P and MSA-C, were recruited and prospectively followed for 5 years with evaluations every 6 months in 12 centers. Natural history was evaluated by Kaplan-Meier survival analysis. We compared MSA-P with MSA-C and evaluated predictors of outcome. These subjects were evaluated with UMSARS I (a functional score of symptoms and ability to undertake activities of daily living), UMSARS II (neurological motor evaluation), and the Composite Autonomic Symptoms Scale (COMPASS)-select (a measure of autonomic symptoms and autonomic functional status. Findings Mean age of symptom onset was 63.4 (SD 8.57) years. Median survival from symptom onset by Kaplan-Meier analysis was 9.8 years (95% CI 8.8-10.7). Subjects with severe symptomatic autonomic failure (symptomatic orthostatic hypotension, urinary incontinence) at diagnosis had a worse prognosis, surviving 8.0 years (95% CI, 6.5-9.5, n=62) while remaining subjects survived a median of 10.3 years (95% CI, 9.3-11.4, n=113). At baseline MSA-P (n=126) and MSA-C (n=49) were not different in symptoms and function, UMSARS I, 25.2 (8.08) vs 24.6 (8.34), p=0.835; UMSARS II, 26.4 (8.77) vs 25.4 (10.51), p=0.7635; COMPASS_select), 43.5 (18.66) vs 42.8 (19.56), p=0.835. Progression, evaluated by change in UMSARS I, UMSARS II, COMPASS_select over the next 5 years, was not significantly different between MSA-P and MSA-C. Median time to death from enrollment baseline was 1.8 (95% CI, 0.9-2.7) years. Interpretation Probable MSA represents late-stage disease with short survival. Natural history of MSA-P and MSA-C are similar. Severe symptomatic autonomic failure at diagnosis is associated with worse prognosis. Funding National Institutes of Health (P01 NS044233), Mayo CTSA (UL1 TR000135), the Kathy Shih Memorial Foundation, and Mayo funds.

Autonomic nervous system testing may not distinguish multiple system atrophy from Parkinson’s disease

Background: Formal laboratory testing of autonomic function is reported to distinguish between patients with Parkinson’s disease and those with multiple system atrophy (MSA), but such studies segregate patients according to clinical criteria that select those with autonomic dysfunction for the MSA category. Objective: To characterise the profiles of autonomic disturbances in patients in whom the diagnosis of Parkinson’s disease or MSA used criteria other than autonomic dysfunction. Methods: 47 patients with parkinsonism and autonomic symptoms who had undergone autonomic laboratory testing were identified and their case records reviewed for non-autonomic features. They were classified clinically into three diagnostic groups: Parkinson’s disease (19), MSA (14), and uncertain (14). The performance of the patients with Parkinson’s disease was compared with that of the MSA patients on five autonomic tests: RR variation on deep breathing, heart rate changes with the Valsalva manoeuvre, tilt table testing, the sudomotor axon reflex test, and thermoregulatory sweat testing. Results: None of the tests distinguished one group from the other with any statistical significance, alone or in combination. Parkinson’s disease and MSA patients showed similar patterns of autonomic dysfunction on formal testing of cardiac sympathetic and parasympathetic, vasomotor, and central and peripheral sudomotor functions. Conclusions: This study supports the clinical observation that Parkinson’s disease is often indistinguishable from MSA when it involves the autonomic nervous system. The clinical combination of parkinsonism and dysautonomia is as likely to be caused by Parkinson’s disease as by MSA. Current clinical criteria for Parkinson’s disease and MSA that direct patients with dysautonomia into the MSA group may be inappropriate.

Efficacy and safety of rifampicin for multiple system atrophy: a randomised, double-blind, placebo-controlled trial

BACKGROUND No available treatments slow or halt progression of multiple system atrophy, which is a rare, progressive, fatal neurological disorder. In a mouse model of multiple system atrophy, rifampicin inhibited formation of α-synuclein fibrils, the neuropathological hallmark of the disease. We aimed to assess the safety and efficacy of rifampicin in patients with multiple system atrophy. METHODS In this randomised, double-blind, placebo-controlled trial we recruited participants aged 30-80 years with possible or probable multiple system atrophy from ten US medical centres. Eligible participants were randomly assigned (1:1) via computer-generated permuted block randomisation to rifampicin 300 mg twice daily or matching placebo (50 mg riboflavin capsules), stratified by subtype (parkinsonian vs cerebellar), with a block size of four. The primary outcome was rate of change (slope analysis) from baseline to 12 months in Unified Multiple System Atrophy Rating Scale (UMSARS) I score, analysed in all participants with at least one post-baseline measurement. This study is registered with ClinicalTrials.gov, number NCT01287221. FINDINGS Between April 22, 2011, and April 19, 2012, we randomly assigned 100 participants (50 to rifampicin and 50 to placebo). Four participants in the rifampicin group and five in the placebo group withdrew from study prematurely. Results of the preplanned interim analysis (n=15 in each group) of the primary endpoint showed that futility criteria had been met, and the trial was stopped (the mean rate of change [slope analysis] of UMSARS I score was 0.62 points [SD 0.85] per month in the rifampicin group vs 0.47 points [0.48] per month in the placebo group; futility p=0.032; efficacy p=0.76). At the time of study termination, 49 participants in the rifampicin group and 50 in the placebo group had follow-up data and were included in the final analysis. The primary endpoint was 0.5 points (SD 0.7) per month for rifampicin and 0.5 points (0.5) per month for placebo (difference 0.0, 95% CI -0.24 to 0.24; p=0.82). Three (6%) of 50 participants in the rifampicin group and 12 (24%) of 50 in the placebo group had one or more serious adverse events; none was thought to be related to treatment. INTERPRETATION Our results show that rifampicin does not slow or halt progression of multiple system atrophy. Despite the negative result, the trial does provide information that could be useful in the design of future studies assessing potential disease modifying therapies in patients with multiple system atrophy. FUNDING National Institutes of Health, Mayo Clinic Center for Translational Science Activities, and Mayo Funds.

Autonomic abnormalities in cyclic vomiting syndrome.

Background: Although cyclic vomiting syndrome (CVS) is associated with migraine, and migraine in turn is associated with orthostatic tachycardia, few studies have explored the association of CVS and autonomic dysfunction. We describe the results of autonomic testing in 6 children with characteristic CVS. Patients and Methods: All patients fully met the established criteria for the diagnosis of CVS, were well hydrated, and were beyond their episode of vomiting. We performed 3 tests of cardiovascular function and 1 sudomotor test, using standard previously published methods. Results: The findings were surprisingly uniform, with normal cardiovascular responses to deep breathing and to the Valsalva maneuver in all patients, a significant increase in heart rate (>30 beats per minute) with tilt testing, and a vasodepressor tendency in 2 patients. Interestingly, abdominal pain occurred at blood pressure nadir in both these patients and in a third patient without the vasodepressor findings but who described syncope clinically. Sudomotor test results were abnormal in all 6 patients, with reduced responses in 5 of 6 and exaggerated responses in the 6th. All 6 patients reported a personal or family history of migraine headaches. Conclusions: CVS is associated with remarkably uniform primarily sympathetic autonomic dysfunction, affecting mainly the vasomotor and sudomotor systems, and compatible with an underlying autonomic neuropathy. The occurrence of symptoms during tilt testing in half the patients suggests that these findings may play a true pathophysiologic role. A vagally modulated sympathetic effect is postulated as the best mechanistic model to account for all current physiologic data on cyclic vomiting and gastroparesis.

PUDENDAL NERVE INJURY ASSOCIATED WITH AVID BICYCLING

Perineal and penile numbness is a frequent complaint of avid male bicyclists. It is currently believed to be caused by cycling induced transient ischemia from pressure on perineal neurovasculature while riding, which results in temporary numbness. We report electromyographic evidence of bilateral pudendal nerve injury associated with excessive bicycling. This condition may be associated with male erectile dysfunction if the penile blood supply is compromised.

Hypotension Unawareness in Profound Orthostatic Hypotension

BACKGROUND Clinicians depend on history given by the patients when considering the diagnosis of orthostatic hypotension. METHODS Patients with a decrease in systolic blood pressure more than 60 mm Hg from baseline during a head-up tilt table test were included. They were classified according to their symptoms during the head-up tilt table test. Localization of the cause of orthostatic hypotension was sought in each of these groups. RESULTS Eighty-eight (43%) patients had typical symptoms, 49 (24%) had atypical symptoms, and 68 (33%) were asymptomatic. The average decrease in systolic blood pressure was 88 mm Hg, 87.5 mm Hg, and 89.8 mm Hg in the typical, atypical, and asymptomatic groups, respectively (P=.81). Patients reported severe dizziness with a similar frequency as lower extremity discomfort. Backache and headache also were common atypical complaints. Patients with peripheral cause of dysautonomia were able to sustain the longest upright position during the head-up tilt table test (21 minutes, compared with central dysautonomia [15 minutes]) (P=.005). There was no correlation between the cause of dysautonomia and the occurrence of symptoms during the head-up tilt table test (P=.58). CONCLUSION A third of the patients with severe orthostatic hypotension are completely asymptomatic during the head-up tilt table test, and another quarter have atypical complaints that would not lead physicians toward the diagnosis of orthostatic hypotension. These findings suggest that they might not provide adequate information in diagnosing profound orthostatic hypotension in a subset of patients with this disorder.

α-Adrenergic supersensitivity of the sudomotor nerve in complex regional pain syndrome

α‐adrenoreceptor supersensitivity in many tissues has been described in patients with complex regional pain syndrome type I (CRPS I). Because excessive sweating of the affected limb is an important feature of CRPS I, we investigated whether this supersensitivity also occurs in the sudomotor system. We compared the sweat response to iontophoresis of an α‐adrenergic agent (phenylephrine) in 4 patients with acute CRPS I and 3 patients with resolved CRPS I with that in 9 control subjects using the methodology of the quantitative sudomotor axon reflex test (QSART). A significantly higher sweat response was observed in the affected limb of patients with acute CRPS I compared to their unaffected limb (p = 0.03), to control subjects (p > 0.018), and to the affected or unaffected limbs of patients with resolved CRPS I (p = 0.02), whose sweat response was not significantly different from that of control subjects. We conclude that the abnormal response in patients with acute CRPS I is most likely mediated by an axon reflex and that α‐adrenoreceptor supersensitivity occurs in the presynaptic portion of the postganglionic sudomotor axon. This supersensitivity is reversed when CRPS I resolves. Ann Neurol 2001;49:453–459

Incidence and Mortality Rates of Syncope in the United States

PURPOSE Syncope is a common cause of hospitalization in the US. The main objective of this study is to determine the incidence and mortality rates when patients are admitted with a principle diagnosis of syncope. METHODS An observational cross-sectional study included patients with the principle diagnosis of syncope identified from the National Inpatient Sample database for the years 2000-2005. Incidence rate of syncope was adjusted according to the US Census data. In-hospital mortality and its predictors were identified by a logistic regression analysis, and Cochran-Armitage test was used for trend analysis. RESULTS After data cleansing, 305,932 patients were included in the analysis. Adjusted incidence rate of syncope varied between 0.80 and 0.93 per 1000 person-years and was unchanged over the years included in the analysis. Overall mortality rate is 0.28%, a trend that has not changed over the years (P=0.07). The odds ratio (OR) of death increased with age, becoming more prominent after age 40 years. Hospital mortality is higher in men (OR 1.49; 95% confidence interval [CI], 1.30-1.71) and in patients with higher comorbidity index (OR 1.39; 95% CI, 1.20-1.62) for moderate, and (OR 4.14; 95% CI, 3.05-5.61) for severe comorbidity index. The median cost of hospitalization is

Natural history of multiple system atrophy in the USA

8579, which increased by 3- to 11-fold if patients had a cardiac pacemaker or implantable cardioverter-defibrillator. CONCLUSIONS Syncope remains a common cause of hospital admission. The hospital mortality rate for syncope is low. A better definition and a nationally implemented care path for syncope diagnosis could provide a substantial cost savings.