Overview^[1]

Multiple system atrophy (MSA) is a rare neurodegenerative disorder, caused by cell loss in certain 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. There may also be some corticospinal disorders. It is sporadic, of adult onset and progressive. The aetiology is not fully understood although recently, α-synuclein has been found to have an important role.^[2] It is not contagious.^[3] Novel treatment options are being investigated but currently management options are very limited. There is no cure.

MSA is referred to as MSA-P type if Parkinsonian features predominate. The terms striatonigral degeneration or Parkinsonian variant are sometimes used in these cases. MSA-P accounts for about two-thirds of cases.^[2] MSA-C type describes disease where cerebellar symptoms predominate. This may also be described as sporadic olivopontocerebellar atrophy. MSA-C accounts for about one third of cases.^[2] The term Shy-Drager syndrome, which was used to describe MSA with predominant autonomic dysfunction, is not now used, as almost every patient is affected by autonomic or urinary dysfunction.

Aetiology^[2]

Little was known about the pathogenesis of MSA until the past 5 years or so. It is now known to be 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. 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.

Epidemiology

• The prevalence rate is 0.9-8.4/100,000.^[1]
• The incidence is 0.6/100,000 per year, rising to 3/100,000 per year in the population aged over 50 years.^[2]
• Some say that there is no gender difference^[2] but others report a higher diagnosis rate in males, with a ratio of male:female of between 1:3 and 1:93.^[1]
• Most patients with MSA develop the disease when older than 40 years and the mean age at onset is between 50 and 70 years.^[4]

Presentation

• The most common presentations are urinary dysfunction (83%), postural hypotension (75%) and cerebellar ataxia (64%).^[2]
• Patients may also present with Parkinsonian symptoms, often with a poor or temporary response to levodopa therapy, or cerebellar dysfunction.
• 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.
• There may possibly be mild intellectual impairment,^[3] particularly in older patients with greater physical disability.^[5]
• Other neuropsychiatric problems may include depression, insomnia, daytime sleepiness, restless legs, hallucinations and dementia.^[2]

Diagnosis^[1]

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.^[6] Definite diagnosis can only be made postmortem.^[1] However, major and additional features have been identified which support a possible diagnosis. Additionally, there are some aspects of the history and examination that go against the diagnosis.

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

Major features supporting diagnosis of probable MSA^[1]

Additional features supporting diagnosis of possible MSA^[1][2]

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 table below:

Features suggesting alternative diagnosis

Differential diagnosis^[1]

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 MSA over Parkinson's disease include:

• Rapid progression of symptoms.
• Poor response to levodopa.
• Autonomic features are more pronounced.
• Rigidity and bradykinesia are out of proportion to the tremor.
• Speech may be severely affected.
• Aspiration, inspiratory gasps and stridor 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.

Investigations

• Autonomic function testing:^[2] 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 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.
• Iodine-123 (I-123) metaiodobenzylguanidine (MIBG) scintigraphy:
  • Thought to be useful for differentiation between Parkinson's disease and MSA early after onset of autonomic dysfunction.
  • Patients with Parkinson's disease have significantly lower cardiac uptake of I-123 MIBG than patients with MSA and controls.
• MRI and proton magnetic resonance:
  • Brain imaging may be normal in MSA. Localised brain degeneration may be detected by MRI techniques.
  • The slit hyperintensity of the lateral margin of the putamen in T2-weighted MRI is a characteristic finding in patients with MSA, involving the extrapyramidal system.
• Fluoride 2-(F18)fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) imaging:
  • Can be used for differentiation between MSA and Parkinson's disease.
  • The caudate-putamen index (difference in the uptakes in the caudate and putamen divided by the caudate uptake) is lower in patients with MSA than in patients with Parkinson's disease.
• Histology:
  • Neuropathologic changes consist of a high density of glial cytoplasmic inclusions in association with degenerative changes in certain brain structures, eg putamen, caudate nucleus, globus pallidus, thalamus, pontine nuclei, cerebellar Purkinje's cells and autonomic nuclei of the brainstem.
  • Glial cytoplasmic inclusions: can be stained by the Gallyas silver technique and are a hallmark of MSAs.

Management

Currently, no therapy can reverse or halt progression of the disease. Management is symptomatic and targets Parkinsonism and autonomic failure.^[2] The extrapyramidal and cerebellar aspects of the disease are debilitating and difficult to treat. Orthostatic hypotension is often the problem that brings the patient to the doctor and 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.

Nondrug

• Orthostatic hypotension:
  • Mechanical manoeuvres such as leg-crossing, squatting, abdominal compression, bending forward, and placing one foot on a chair can be effective to prevent episodes of orthostatic hypotension.
  • Wearing an external support garment that comes to the waist improves venous return and preload to the heart during standing (but loses effectiveness if the patient also wears it while supine).^[1]
  • Tilted sleeping with the head elevated can help.
• Postprandial hypotension:
  • Small and more frequent meals prevent a blood pressure drop after eating.
  • Intake of water half an hour before meals, or drinking coffee, can counteract postprandial hypotension.
• Supine hypertension:
  • Patients should not lie down during the day.
  • Tilted sleeping with the head elevated is helpful to lower supine hypertension during the night, decrease nocturia and prevent orthostatic hypotension in the morning.
• Exercise of muscles of the lower extremities and abdomen (aqua-aerobics is particularly useful but not swimming, which causes polyuria) and postural training.
• Speech and language therapy may help with the swallowing and communication difficulties associated with stridor.^[1]
• A high-fibre diet ± laxatives for constipation.
• Occupational therapy can be of significant help.

Water^[1]

Water has a particular role in addressing the orthostatic hypotension in MSA: it has marked pressor effects in patients with autonomic dysfunction, by increasing sympathetic activity, that other fluids do not. On average, a pint (a little under half a litre) of water will raise the blood pressure by about 30 mm Hg. This can be used prophylactically as patients will be able to do much more in the hour following this. Suggest a pint on waking and again mid-morning or at lunchtime and again mid-afternoon. Large amounts should be avoided 2 hours before bedtime to avoid exacerbating supine hypertension. You may encounter scepticism that such an 'un-medical' intervention may be so effective, so patient education is important. The drawbacks are increased urination (difficult when there is a coexisting urinary dysfunction) and the fact that the beneficial effects only last about an hour.

Drugs

• Orthostatic hypotension:
  • Fludrocortisone:
    • Traditionally, this has been the mainstay of therapy.
    • Disadvantages include possible hypokalaemia, hypomagnesaemia and excessive fluid accumulation.
    • Most patients have supine hypertension, even when receiving no therapy. This limits the degree to which upright blood pressure can be increased with fludrocortisone.
  • Midodrine and short-acting sympathomimetics:
    • Midodrine avoids the electrolyte abnormalities associated with fludrocortisone.
    • Supine hypertension often limits the dose and therefore effectiveness of treatment.
  • Recombinant erythropoietin:
    • Increases the functional capacity of patients, particularly if there is associated mild anaemia, which is common.
    • Recombinant erythropoietin has been shown to correct anaemia and improve standing blood pressure.
  • Other agents that are much less often used include non-steroidal anti-inflammatory drugs, antihistamines, somatostatin analogues, caffeine, and yohimbine.
• Movement disorder:
  • Usually treated with levodopa, dopaminergic agonists, anticholinergic agents, or amantadine, but effectiveness may be very limited.
  • However levodopa is effective in 40-60% of patients with predominant Parkinsonian features.^[3]

Future therapeutic options^[2]

Drug therapy

At the moment, no neuroprotective treatment is available. But 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.

Neurotransplantation

Striatal grafting has been discussed as a therapeutic option to 'turn MSA into Parkinson's disease' by recovering dopaminergic response in experimental models. However, early trials on mice models have given rise to a number of problems and much more work has yet to be done in this area.

Prognosis

Most patients have a poor prognosis with an average survival rate of 9 years following disease onset^[7] although there can be substantial variation. Poor prognostic factors include:^[2]

• Older age at onset.
• Female gender.
• Early autonomic failure.
• Shorter intervals between clinical milestones (eg frequent falling, cognitive disability, unintelligible speech, dysphagia. etc.).

Bronchopneumonia and sudden death are common terminal events.