C. J. Mathias

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 Parkinsons 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.

A novel TRK A (NTRK1) mutation associated with hereditary sensory and autonomic neuropathy type V.

A boy with recurrent pyrexial episodes from early life sustained a painless ankle injury and was found to have a calcaneus fracture and, later, neuropathic joint degeneration of the tarsus. Examination revealed distal loss of pain and temperature sensation and widespread anhidrosis. Sural nerve biopsy demonstrated severe reduction in small‐caliber myelinated fiber density but only modest reduction in unmyelinated axons, the pattern of type V hereditary sensory and autonomic neuropathy (HSAN V). DNA analysis showed that he was homozygous for a mutation in the NTRK1/high‐affinity nerve growth factor (TrkA) gene, his parents being heterozygous. Mutations in this gene are known to be responsible for HSAN IV (congenital insensitivity to pain with anhidrosis). The two disorders are therefore likely to be allelic. Ann Neurol 2001;49:521–525

The European Multiple System Atrophy-Study Group (EMSA-SG)

Summary.Introduction. The European Multiple System Atrophy-Study Group (EMSA-SG) is an academic network comprising 23 centers across Europe and Israel that has constituted itself already in January 1999. This international forum of established experts under the guidance of the University Hospital of Innsbruck as coordinating center is supported by the 5th framework program of the European Union since March 2001 (QLK6-CT-2000-00661). Objectives. Primary goals of the network include (1) a central Registry for European multiple system atrophy (MSA) patients, (2) a decentralized DNA Bank, (3) the development and validation of the novel Unified MSA Rating Scale (UMSARS), (4) the conduction of a Natural History Study (NHS), and (5) the planning or implementation of interventional therapeutic trials. Methods. The EMSA-SG Registry is a computerized data bank localized at the coordinating centre in Innsbruck collecting diagnostic and therapeutic data of MSA patients. Blood samples of patients and controls are recruited into the DNA Bank. The UMSARS is a novel specific rating instrument that has been developed and validated by the EMSA-SG. The NHS comprises assessments of basic anthropometric data as well as a range of scales including the UMSARS, Unified Parkinson’s Disease Rating Scale (UPDRS), measures of global disability, Red Flag list, MMSE (Mini Mental State Examination), quality of live measures, i.e. EuroQoL 5D (EQ-5D) and Medical Outcome Study Short Form (SF-36) as well as the Beck Depression Inventory (BDI). In a subgroup of patients dysautonomic features are recorded in detail using the Queen Square Cardiovascular Autonomic Function Test Battery, the Composite Autonomic Symptom Scale (COMPASS) and measurements of residual urinary volume. Most of these measures are repeated at 6-monthly follow up visits for a total study period of 24 months. Surrogate markers of the disease progression are identified by the EMSA-SG using magnetic resonance and diffusion weighted imaging (MRI and DWI, respectively). Results. 412 patients have been recruited into the Registry so far. Probable MSA-P was the most common diagnosis (49% of cases). 507 patients donated DNA for research. 131 patients have been recruited into the NHS. There was a rapid deterioration of the motor disorder (in particular akinesia) by 26.1% of the UMSARS II, and – to a lesser degree – of activities of daily living by 16.8% of the UMSARS I in relation to the respective baseline scores. Motor progression was associated with low motor or global disability as well as low akinesia or cerebellar subscores at baseline. Mental function did not deteriorate during this short follow up period. Conclusion. For the first time, prospective data concerning disease progression are available. Such data about the natural history and prognosis of MSA as well as surrogate markers of disease process allow planning and implementation of multi-centre phase II/III neuroprotective intervention trials within the next years more effectively. Indeed, a trial on growth hormone in MSA has just been completed, and another on minocycline will be completed by the end of this year.

Safety and tolerability of growth hormone therapy in multiple system atrophy: A double-blind, placebo-controlled study

The objective of this study was to investigate tolerability and possible neurotrophic effects of growth hormone (GH) in treatment of multiple system atrophy (MSA). In this double‐blind pilot study, MSA patients were randomized to recombinant human growth hormone (r‐hGH, n = 22), 1 mg every second day (6 months) followed by alternating daily injections of 1 mg and 0.5 mg (6 months), or matched placebo (n = 21). Safety analysis demonstrated no obvious between‐group differences. In both groups, there was progressive worsening of Unified Parkinsons Disease Rating Scale total score, which tended to be less in r‐hGH‐treated patients (12.9% at 6 months, 25.3% at 12 months) than in placebo (17.0% and 35.7%). Similarly, there was a trend to less worsening in Unified MSA Rating Scale total score with r‐hGH (13.2% and 21.2%) than with placebo (21.1% and 36.5%). Cardiovascular reflex autonomic testing also tended to show less deterioration with r‐hGH than with placebo at 12 months. However, 95% CI did not indicate treatment differences for any efficacy measures. In conclusion, r‐hGH administration in MSA patients for up to 1 year appears safe and might influence disease symptoms, signs and, possibly, progression. The results support further studies utilizing higher doses in more patients.

Selegiline-induced postural hypotension in Parkinson's disease: A longitudinal study on the effects of drug withdrawal

The United Kingdom Parkinsons Disease Research Group (UKPDRG) trial found an increased mortality in patients with Parkinsons disease (PD) randomized to receive 10 mg selegiline per day and L‐dopa compared with those taking L‐dopa alone. Recently, we found that therapy with selegiline and L‐dopa was associated with selective systolic orthostatic hypotension which was abolished by withdrawal of selegiline. This unwanted effect on postural blood pressure was not the result of underlying autonomic failure. The aims of this study were to confirm our previous findings in a separate cohort of patients and to determine the time course of the cardiovascular consequences of stopping selegiline in the expectation that this might shed light on the mechanisms by which the drug causes orthostatic hypotension.

Progression of dysautonomia in multiple system atrophy: a prospective study of self-perceived impairment

To assess severity and progression of self‐perceived dysautonomia and their impact on health‐related quality of life (Hr‐QoL) in multiple system atrophy (MSA), twenty‐seven patients were recruited by the European MSA Study Group (EMSA‐SG). At baseline, all patients completed the Composite Autonomic Symptom Scale (COMPASS) and the 36 item Short Form Health Survey (SF‐36), and they were assessed using the 3‐point global disease severity scale (SS‐3) and the Unified MSA Rating Scale (UMSARS). After 6u2003months follow‐up, the self completed COMPASS Change Scale (CCS), the SF‐36, SS‐3, and UMSARS were obtained. MSA patients showed marked self‐perceived dysautonomia at baseline visit and pronounced worsening of dysautonomia severity on the CCS at follow‐up. Severity and progression of dysautonomia did not correlate with age, disease duration, motor impairment and overall disease severity at baseline. There were no significant differences between genders and motor subtypes. Baseline COMPASS scores were, however, inversely correlated with SF‐36 scores. Progression of self‐perceived dysautonomia did not correlate with global disease progression. Hr‐QoL scores were stable during follow‐up. This is the first study to investigate self‐perceived dysautonomia severity in MSA and its evolution over time. Our data suggest that dysautonomia should be recognized as a key target for therapeutic intervention in MSA.

Measuring health‐related quality of life in MSA: The MSA‐QoL

The objective of this study was to develop a new patient‐reported outcome measure for patients with multiple system atrophy (MSA) and to test its psychometric properties. There were three stages. First, a pool of potential scale items was generated from in‐depth patient interviews. Second, these items were administered, in the form of a questionnaire, to a sample of people with MSA and traditional psychometric methods used to develop a rating scale satisfying standard criteria for reliability and validity. Third, the psychometric properties of the rating scale were examined in a second sample. In stage one, a pool of 105 items was generated from 20 patient interviews. In stage two, a scale with three subscales (motor, 14 items; nonmotor, 12 items; emotional/social functioning, 14 items), satisfying standard criteria for reliability and validity, was developed from the response data of 317 patients with MSA (response rate 71%). In stage three, the scale was examined in 286 people with MSA. Missing data were low, scores in both subscales were evenly distributed, and floor and ceiling effects were small. Reliability was high (Cronbachs alpha 0.83–0.93; test‐retest ICC 0.88–0.92). Validity was supported by the interscale correlations (r = 0.47–0.59), known group differences, and the magnitude and pattern of correlations with four other rating scales, disease severity, and disease duration. In conclusion, the patient‐rated MSA health‐related Quality of life scale (MSA‐QoL) may be a suitable patient‐reported scale for use in clinical trials and studies in MSA.

Abnormal cardiovascular responses to carotid sinus massage also occur in vasovagal syncope – implications for diagnosis and treatment

Background and purpose:u2002 Carotid sinus massage (CSM) is commonly used to identify carotid sinus hypersensitivity (CSH) as a possible cause for syncope, especially in older patients. However, CSM itself could provoke classical vasovagal syncope (VVS) in pre disposed subjects.

Twenty-four-hour ambulatory blood pressure and heart rate profiles in diagnosing orthostatic hypotension in Parkinson's disease and multiple system atrophy.

Twenty‐four‐hour ambulatory blood pressure and heart rate monitoring (24‐h ABPM) can provide vital information on circadian blood pressure (BP) profiles, which are commonly abnormal in Parkinsons disease with and without autonomic failure (PD + AF and PD) and multiple system atrophy (MSA). Twenty‐four‐hour ABPM has not been directly compared between these disorders regarding cardiovascular autonomic function. Our aim was to determine the usefulness of 24‐h ABPM with diary compared to head‐up tilting (HUT) in diagnosing orthostatic hypotension (OH) in these patients.

Small fibre neuropathy and Collagen IV reduction in Postural Tachycardia Syndrome and Joint Hypermobility Syndrome

Doppler is conducted in POTS patients with family history of MALS and persistent gastric symptoms. Peak systolic velocity (PSV), End Diastolic velocity (EDV) is calculated in all the patients. PSV greater than 200 cm/s, EDV greater than 55 cm/s are suggestive of celiac artery stenosis associated with MALS. Results: Out of 93 patients, 95% patients are Females (n = 88, age 28.88 ± 9.36), 5% patients are Males (n = 5, age 25.83 ± 6.19). PSV (cm/sec) 223.84 ± 109.52, EDV (cm/sec) 71.07 ± 54.46, PSV (neutral) 179.77 ± 83.01, PSV Expiration 218.58 ± 109.79. PSV (cm/sec) N 200 in 51 patients (55%), EDV (cm/sec) N55 in 50 patients (54%), PSV Expiration (cm/sec) N 200 in 52 patients (56%). PSV (Cm/sec) N300 in 18 Patients. Conclusion: Our research study demonstrated that higher percentages of POTS patients (N50%) are found to have MALS. MALS was found to be more common in females POTS Patients. There appears to be tremendous improvement in symptoms of two POTS patients after surgery for MALS.