MSA usually manifests in middle age (the median age of onset is 53), affects both sexes, and progresses relentlessly with a mean survival of 6-9 yr (13,19,20). MSA patients may present with akinetic-rigid parkinsonism that usually responds poorly to levodopa. This has been identified as the most important early clinical discriminator of MSA and PD (11,21-23), although a subgroup of MSA patients may show a good or, rarely, excellent, but usually short-lived, response to levodopa (24-26). Progressive ataxia, mainly involving gait, may also be the presenting feature of MSA (27,28). A cerebellar presentation of MSA appears to be more common than the parkinsonian variant in Japan compared to Western countries (29). Autonomic failure with symptomatic orthostatic hypotension and/or urogenital and gastrointestinal disturbance may accompany the motor disorder in up to 50% of patients at disease onset (20). Besides the poor response to levodopa, and the additional presence of pyramidal or cerebellar signs or autonomic failure as major diagnostic clues, certain other features ("red flags") such as orofacial dystonia, stridor, or disproportionate antecollis (Fig. 1) may raise suspicion of MSA (11) (Table 2). Red flags often are early warning signs of MSA (30).
MSA is a progressive disease characterized by the gradual accumulation of disability reflecting involvement of the systems initially unaffected. Thus, patients who present initially with extrapyramidal features commonly progress to develop autonomic disturbances, cerebellar disorders, or both (see video of an advanced MSA-P patient showing marked akinesia and rigidity as well as cerebellar incoordination, particularly of lower limbs). Conversely, patients who begin with symptoms of cerebellar dysfunction often progress to develop extrapyramidal or autonomic disorders, or both. Patients whose
A. Nomenclature of clinical domains, features (disease characteristics) and criteria (defining features or composite of features) used in the diagnosis of MSA Domain Criterion Feature
Autonomic and urinary dysfunction Orthostatic fall in blood pressure Orthostatic hypotension (by 20 mmHg systolic or 10 mmHg diastolic)
(by 30 mmHg systolic or 15 mmHg diastolic)
Bradykinesia plus rigidity or postural instability or tremor
Gait ataxia plus ataxic dysarthria or limb ataxia or sustained gaze-evoked nystagmus No defining features
Urinary incontinence or incomplete bladder emptying
Bradykinesia (progressive reduction in speed and amplitude of voluntary movements during repetitive actions)
Postural instability (loss of primary postural reflexes)
Tremor (postural, resting, or both)
Gait ataxia (wide-based stance with irregular steps)
Ataxic dysarthria Limb ataxia
Sustained gaze-evoked nystagmus Extensor plantar responses with hyperreflexia
Possible MSA-P Criterion for parkinsonism plus two features from separate other domains. A poor levodopa response qualifies already as one feature, hence only one additional feature is required. Possible MSA-C Criterion for cerebellar dysfunction plus two features from separate other domains.
Probable MSA-P Criterion for autonomic failure/urinary dysfunction plus poorly levodopa-responsive parkinsonism.
Probable MSA-C Criterion for autonomic failure/urinary dysfunction plus cerebellar dysfunction.
Definite MSA Pathological confirmation: high density of a-synuclein-positive GCIs associated with degenerative changes in the nigrostriatal (SND and olivopontocerebellar pathways (OPCA).
Reproduced with kind permission from Whitehouse Publishing: Wenning and Geser, Diagnosis and treatment of multiple system atrophy: an update. ACNR 2004;3(6):5-10.
symptoms initially are autonomic may later develop cerebellar, extrapyramidal, or both types of disorders. In a recent large study on 230 cases carried out in Japan, MSA-P patients had more rapid functional deterioration than MSA-C patients, but showed similar survival (29).
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