Multiple System Atrophy

Multiple System Atrophy (MSA) is a rare, progressive neurodegenerative disorder, caused by cell loss in certain areas of the brain leading to a variety of symptoms affecting especially the functions of the autonomic nervous system and the motor system, causing various combinations of parkinsonism, ataxia, corticospinal motor signs, and postural hypotension or urinary incontinence.

MSA is referred to as MSA-P type if parkinsonian features predominate or MSA-C type if cerebellar symptoms predominate. The term Shy-Drager syndrome, which was used to describe multiple system atrophy with predominant autonomic dysfunction, is not now used as almost every patient is affected by autonomic or urinary dysfunction. The pathological hallmark of the disease is the presence of glial and neuronal cytoplasmic inclusions.

• The prevalence rate is about 4/100,000.¹
• 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.²
• The disease is more often diagnosed in males than in females, with a ratio of between 1:3 and 1:93.

• Most patients with MSA develop the disease when older than 40 years and the mean age at onset is between 50 and 70 years.³
• The most common presentation is postural hypotension and urinary dysfunction.
• Patients may also present with parkinsonian symptoms, with often poor or only temporary response to levodopa therapy, or cerebellar dysfunction.
• Corticospinal tract dysfunction may occur but is not usually a major feature.
• When the disorder presents with non-autonomic features, imbalance caused by cerebellar or extrapyramidal abnormalities is the most common feature.
• Genitourinary dysfunction is the most frequent initial complaint in women and erectile dysfunction in men.
• Postural hypotension:
  • Defined as a reduction of systolic blood pressure of at least 20 mm Hg or of diastolic BP of at least 10 mm Hg within 3 minutes of standing.
  • Is common and associated symptoms include light-headedness, dizziness, weakness of legs, fatigue and syncope. Postprandial hypotension may be a major feature.
  • Associated supine hypertension is common, and is aggravated by medication used to reduce orthostatic hypotension.
• Parkinsonism:
  • Akinesia and rigidity predominate, but tremor may also be present. The classic pill-rolling parkinsonian resting tremor is uncommon.
  • There is usually a poor or only temporary response to levodopa.
• Cerebellar dysfunction:
  • Cerebellar symptoms are rarely the only presenting feature.
  • Most commonly presents with gait and limb ataxia.
  • Tremor, pyramidal signs, and myoclonus are less common.
• Other possible features include:
  • Vocal cord paralysis with hoarseness and stridor.
  • Sleep apnoea.

• Parkinson's disease
• Pure autonomic failure
• Progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome)
• Multi-infarct dementia
• Multiple sclerosis
• Neuroacanthocytosis
• Neurosarcoidosis
• Neurosyphilis

• The diagnosis of multiple system atrophies is based mainly on clinical features. Definite diagnosis can be only be established at postmortem examination.⁴
• Response to levodopa: poor or no response.
• Iodine I₁₂₃ metaiodobenzylguanidine (MIBG) scintigraphy:
  • Thought to be useful for differentiation between Parkinson's disease and multiple system atrophies early after onset of autonomic dysfunction.
  • Patients with Parkinson's disease have significantly lower cardiac uptake of I₁₂₃ MIBG than patients with Multiple-system atrophy and controls.
• MRI and proton magnetic resonance:
  • Brain imaging may be normal in multiple system atrophies. Localised brain degeneration may be detected by MR techniques.
  • The slit hyperintensity of the lateral margin of the putamen in T2-weighted MRI is a characteristic finding in patients with multiple system atrophies involving the extrapyramidal system.
• Fluoride F 18 fluordeoxyglucose dopa positron emission tomography (PET) imaging:
  • Can be used for differentiation between multiple system atrophies 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 multiple system atrophies than in patients with Parkinson's disease.
• Autonomic function testing:
  • Diminished respiratory sinus arrhythmia
  • Abnormal response to valsalva maneuver (no BP 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
  • Sphincter electromyography (EMG) - hyperreflexia of detrusor
• Histology:
  • Neuropathologic changes consist of a high density of Glial cytoplasmic inclusions in association with degenerative changes in certain brain structures, e.g. putamen, caudate nucleus, globus pallidus, thalamus, pontine nuclei, cerebellar Purkinje cells and autonomic nuclei of the brain stem.
  • Glial cytoplasmic inclusions: can be stained by Gallyas silver technique and are a hallmark of multiple system atrophies.

• No current therapy can reverse or halt progression of the disease.
• The extrapyramidal and cerebellar aspects of the disease are debilitating and difficult to treat.

Non-Drug

• 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.
  • Increased salt and fluid intake and tilted sleeping with the head elevated increase the circulatory plasma volume.
• Postprandial hypotension:
  • Small and more frequent meals prevent 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) and postural training.

Drugs

• 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.⁵
• Orthostatic hypotension:
  • Fludrocortisone:
    • Traditionally 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.

• Most patients have a poor prognosis with an average survival rate of 9 years following disease onset.⁶
• Bronchopneumonia and sudden death are common causes of death.