Multiple system atrophy

What is multiple system atrophy?

Multiple system atrophy (MSA) is a rare progressive neurodegenerative disorder, caused by cell loss in areas of the brain and the spinal cord, leading to a variety of symptoms affecting especially the functions of the autonomic nervous system and the motor system. These are characterised by Parkinsonian features of varying severity, cerebellar ataxia and autonomic (particularly urogenital) dysfunction.¹ There may also be some corticospinal features.

The aetiology is not fully understood.² It is thought likely that a combination of genetic and environmental factors plays a part in the development of MSA though neither genetic nor environmental causes have yet been found. ³ There seems to an accumulation of intracellular alpha-synuclein, particularly in oligodendrocytes which may cause MSA.⁴

Whilst novel treatment options are being investigated, current management options are very limited. There is no cure.

MSA is referred to as MSA-P type if Parkinsonian features predominate.³ The terms striatonigral degeneration or Parkinsonian variant are sometimes used in these cases.

MSA-C type describes disease where cerebellar symptoms predominate.³ This may also be described as sporadic olivopontocerebellar atrophy.

The term Shy-Drager syndrome, which was used to describe MSA with predominant autonomic dysfunction, is now less commonly used.

Causes of multiple system atrophy (aetiology)

MSA is characterised by widespread glial cytoplasmic inclusions (GCIs) which are the hallmark of the disease. More recently, misfolded, hyperphosphorylated fibrillar α-synuclein has been identified as the main component of GCIs.⁵ The build-up of GCIs in glial cells rather than nerve cells may be one of the differentiating factors between MSA and Parkinson's disease.³

The density of GCI containing α-synuclein correlates significantly with neuronal deterioration and disease duration. Another important protein, p25α has been found to stimulate α-synuclein in vitro. It is thought that there may be both genetic and environmental processes that contribute to these pathological processes.

The presence of GCIs is associated with neuronal loss in the basal ganglia, cerebellum, pons, inferior olivary nuclei and the spinal cord, hence giving rise to the spectrum of symptoms and clinical findings. Disease is often defined at the time of initial manifestation of any motor or autonomic features, although subclinical neuropathology is likely to start several years before overt disease.

Ongoing studies suggest that this excess alpha-synuclein is either a result of genetic overexpression in oligodendrocytes of affected patients or a result of increased uptake from the surrounding extracellular environment. ⁴Some patients with MSA have been shown to have COQ2 gene which codes for Coenzyme Q10, although this has only been shown in the cerebellar form of MSA.⁴

How commons is multiple system atrophy? (Epidemiology)

• MSA is a progressive neurodegenerative disorder with an estimated annual worldwide incidence of about 0·6 to 0.7 per 100,000.⁴

• MSA-C appears to be more common in Japan whilst MSA-P is more common in the West.⁴

• Most patients with MSA develop the disease when older than 40 years and the average age of onset is approximately 55 years.⁶

Symptoms of multiple system atrophy (presentation)

• The first symptoms are often autonomic and may predate recognition of motor manifestations. Orthostatic hypotension and, in men, erectile failure are among the first symptoms.⁶

• Patients may also present with Parkinsonian symptoms, often with a poor or temporary response to levodopa therapy, or cerebellar dysfunction.¹

• Corticospinal tract dysfunction may occur but is not usually a major presentation.

• When the disorder presents with non-autonomic features, imbalance caused by cerebellar or extrapyramidal abnormalities is the most common feature.

• Constipation may also occur.

• Up to 49% of patients with MSA have been shown to have executive dysfunction.¹ Cognitive impairment is more prominent in older patients with greater physical disability.⁷

• Other neuropsychiatric problems may include depression, insomnia, daytime sleepiness, restless legs, hallucinations and dementia.⁸ Emotional lability, similar to that in progressive supranuclear palsy, has also been described.¹

Diagnosis

The diagnosis of MSA is based mainly on clinical features. Most patients do not receive the correct diagnosis during their lifetime because of the difficulty in differentiation from other disorders, particularly Parkinson's disease and pure autonomic failure.

Definite diagnosis can only be made post-mortem and post-mortem studies suggest an accuracy of diagnosis in only 62-79%.⁹

Diagnosis is often delayed with an average of 3.8 years from onset of symptoms to diagnosis.⁹

Thus levels of certainty of diagnosis are described, depending on the clinical findings and investigations. Categories include definitive MSA, probable MSA and possible MSA.²

MRI scanning is useful for diagnosis of MSA with significant atrophy being seen in specific brain regions such as the putamen, middle cerebellar peduncle, pons, and cerebellum. The appearance is pathognomonic.¹⁰However, these findings tend to occur in later disease and MRI scans in the early stages are indistinguishable from those in Parkinson's disease.

Use of imaging with fluorodeoxyglucose 18F-FDG-PET has shown some promise in distinguishing early MSA. Use of DAT-SPECT, and 123I-MIBG-SPECT in imaging may prove useful in the future but are still theoretical at this stage.¹⁰

Major features supporting diagnosis of probable MSA

Additional features supporting diagnosis of possible MSA⁸

Sporadic, progressive disease of onset after 30 years of age, characterised by:

• Parkinsonism.

• Cerebellar signs.

• At least one feature suggesting autonomic dysfunction (eg, urinary symptoms, erectile dysfunction, orthostatic hypotension that doesn't meet the level required in 'probable MSA' - see table above).

• At least one of the features in the table below:

Features suggesting alternative diagnosis

Differential diagnosis

Parkinson's disease is the main differential; about 10% of patients diagnosed with Parkinson's disease are actually found to have MSA on autopsy. Features that suggest MSA¹³ over Parkinson's disease include:

• Rapid progression of symptoms.

• Poor response to levodopa.

• More pronounced autonomic features.

• Rigidity and bradykinesia being out of proportion to the tremor.

• Speech which may be severely affected.

• Aspiration, inspiratory gasps and stridor which may be present.

Other diagnoses to consider include:

• Pure autonomic failure.

• Progressive supranuclear palsy (Steele-Richardson-Olszewski disease).

• Multi-infarct dementia.

• Multiple sclerosis.

• Neuroacanthocytosis.

• Neurosarcoidosis.

• Neurosyphilis.

Diagnosing multiple system atrophy (investigations)

Diagnostic techniques include structural and functional brain imaging, cardiac sympathetic imaging, cardiovascular autonomic testing, olfactory testing, sleep study, urological evaluation, and dysphagia and cognitive assessments.¹⁹

Autonomic function testing⁴

Bladder function assessment often detects early abnormalities consistent with neurogenic disturbance. Initially, detrusor hyperreflexia and abnormal urethral sphincter function predominate; these are later followed by increased residual urinal volume (as detected by bladder ultrasound). Other autonomic abnormalities include:

• Diminished respiratory sinus arrhythmia.

• Abnormal response to the Valsalva manoeuvre (no blood pressure recovery in late phase II and/or no overshoot in phase IV).

• Diminished response to isometric exercise (hand grip).

• Diminished response to cold pressor stimuli.

Management of multiple system atrophy

Currently, no therapy can reverse or halt progression of the disease. Management is symptomatic and targets Parkinsonism and autonomic failure.¹

The extrapyramidal and cerebellar aspects of the disease are debilitating and difficult to treat. Orthostatic hypotension is associated with reduced physical activity (and the consequent deconditioning and problems associated with this) so management of this is a particularly important aspect of patient care. Management of patients with MSA will include:

• Management of postural hypotension: see the separate Hypotension article. Midodrine has been shown to have been of benefit in MSA.⁹

• Management of constipation, urinary incontinence and falls. Desmopressin may help as nocturnal polyuria is common in MSA.⁹

• Physical activity, especially in water, to prevent physical deconditioning.

• Speech therapy which may be required to help with speech and swallowing.

• Movement disorder: usually treated with levodopa, dopaminergic agonists, anticholinergic agents, or amantadine, but effectiveness may be limited.

Future therapeutic options⁸

At the moment, no neuroprotective treatment is available.¹¹ However, there are potential drug candidates that have been considered:

• Growth hormone therapy: experimentally, growth hormone therapy appears to slow progression of the disease but not significantly.

• Minocycline: this is a tetracycline with neuroprotective efficacy in transgenic MSA mice which has shown some promise in the early stages of the disease in laboratory studies.

• Rasagiline: this is a monoamine-oxidase-B inhibitor which appears to have disease-modifying effects and is soon expected to enter phase 3 trials.

• Rifampicin: this has been shown to have the property of preventing α-synuclein aggregation and so is also being considered as a therapeutic candidate.

Prognosis

The clinical symptoms are rapidly progressing with a mean life expectancy following diagnosis of 7-9 years.⁶⁹

One review found prognostic indicators of shorter survival were older age at onset, early bladder catheterisation, and early generalised autonomic failure.¹²

Bronchopneumonia and sudden death are common terminal events.