MULTIPLE SYSTEM ATROPHY

Multiple system atrophy is a group of disorders that share common clinical features, which include Parkinsonism, problems with balance (ataxia), and dysfunction of the autonomic nervous system. It is a sporadic neurodegenerative disease of adult onset. Its cause remains unknown.

Parkinsonism is a part of the constellation of symptoms, hence multiple system atrophy also falls within the rubric of disorders called Parkinson-plus syndromes. In addition to multiple system atrophy, Parkinson-plus syndromes include progressive supranuclear palsy and corticobasal ganglionic degeneration. Some also consider Lewy-body disease to be one these syndromes. The Parkinson-plus syndromes are distinct from idiopathic Parkinson's disease because of certain aspects of clinical presentations, but more importantly, are differentiated by clinical response to treatment with L-dopa and related drugs, and neuropathology. In early stages, Parkinson-plus syndromes can be difficult to distinguish from idiopathic Parkinson's disease. However, patients with idiopathic Parkinson's disease have significant improvement of symptoms with dopaminergic drugs, while patients with Parkinson-plus syndrome have, at best, a modest response, so that a diagnosis of Parkinson-plus syndrome is often first considered only when patients show an atypically modest response to treatment. Within the context of Parkinson-plus syndromes, multiple system atrophy is a distinct entity because of its clinical features and neuropathological expression.

In 1900, Déjérine and Thomas coined the term olivopontocerebellar atrophy to describe a disorder in which the predominant clinical feature was ataxia, but also included parkinsonism and autonomic dysfunction. In 1960, Shy and Drager described patients in whom there was predominant autonomic dysfunction manifested primarily by a sudden fall in the blood pressure on standing (orthostatic hypotension). These patients also had parkinsonism, and to a lesser degree, ataxia. The disorder has been called Shy-Drager Syndrome. In the 1960s, Adams and his colleagues described a group of patients with predominant parkinsonism who also had autonomic failure and, to a lesser degree, ataxia. They termed this disorder striatonigral degeneration.

The neuropathological description of these disorders shows changes in various structures, predominantly the basal ganglia, cerebellum, and certain brainstem nuclei. Because of the common features, both clinically and neuropathologically, Graham and Oppenheimer suggested that these three sporadic, adult-onset, neurodegenerative disorders be considered as one diagnostic entity, namely multiple system atrophy. This grouping of patients with sporadic olivopontocerebellar atrophy, striatonigral degeneration, and Shy-Drager Syndrome as one entity was further strengthened by the observation that all these disorders had a common neuropathological feature, namely intracytoplasmic inclusion bodies (a collection of abnormal molecules) in the oligodendrocytes, which are cells that provide structural and functional support for the brain cells (neurons).

Clinical features

Four features are present in idiopathic Parkinson's disease: slowing of movement (bradykinesia), tremor, muscle rigidity, and a tendency to fall. The four together mean that Parkinson's disease can be diagnosed. When three or fewer are present, the combination is referred to as parkinsonism.

Parkinsonism occurs, to some degree, in the majority of patients with multiple system atrophy. This is more prominent in striatonigral degeneration type of multiple system atrophy. Slowing of movement (bradykinesia) and rigidity are more common, while tremor, which is more common in idiopathic Parkinson's disease, is less prominent in multiple system atrophy. Furthermore, like idiopathic Parkinson's disease, these patients also display gait disturbance, which is independent of ataxia. In contrast to idiopathic Parkinson's disease, the parkinsonian symptoms in these patients respond poorly to dopaminergic agents.

Ataxia

Ataxia of the limbs generally occurs first, predominantly in patients with olivopontocerebellar-type of multiple system atrophy. This leads to gait disturbance. Ataxia in these patients is of cerebellar origin and this can progress to other cerebellar signs, which include dysarthria (speech impairment), and myoclonus (jerking movement of muscles). Abnormalities of eye movements of the cerebellar origin also occur, such as nystagmus (involuntary movements of the eyeball). Examination of the eye movements is important in terms of diagnosis because supranuclear vertical gaze abnormalities, that is, inability to move eyes voluntarily, particularly downward, would be consistent with a diagnosis of progressive supranuclear palsy rather than multiple system atrophy.

Autonomic dysfunction

Autonomic dysfunction occurs in a significant number of patients with multiple system atrophy and is more prominent in patients with Shy-Drager Syndrome. Clinical manifestations of autonomic dysfunction include orthostatic hypotension, gastrointestinal disturbance (i.e., constipation or fecal incontinence), urinary disturbance including urinary retention, urinary incontinence, and impotence. In addition to this, there is impairment in sweating. Postural hypotension in which there is a drop in the systolic blood pressure of 20 mm or more upon standing can cause significant disability in these patients. Some of the symptoms include lightheadedness, although loss of consciousness can also occur leading to morbidity in these patients. In terms of gastrointestinal symptoms, constipation is more common, however, dysphagia (inability to swallow) may become prominent as the disease progresses. While urinary incontinence and retention may occur, impotence is another significant autonomic dysfunction, particularly in men, which occurs in approximately 95 percent of patients at some point of the disease process.

Other general neurological findings in these patients may include upper motor neuron findings, including brisk deep tendon reflexes (such as knee jerk reflex) and extensor plantar responses (that is, up-going toe on stroking the sole of the foot. Normal response is for the toe to go down or remain in neutral position). These findings may occur in up to two-thirds of patients with multiple system atrophy, but are not a common feature of idiopathic Parkinson's disease.

Cognitive function

The majority of patients with multiple system atrophy displays a mild form of cognitive impairment reflecting frontal-subcortical system dysfunction. This is predominantly manifested by disturbances in attention, mild problems with memory, visuospatial dysfunction, and executive dysfunction.

Natural history

The age range for onset of multiple system atrophy is between 33.3 years to 75.6 years with a mean age of onset of this disease at 52.5 years. The male to female ratio ranges from 1.1:1 to 1.9:1. Mean survival time ranges from 5.5 to 9.5 years.

Treatment

The parkinsonian features in multiple system atrophy respond poorly or, at best, have modest response to dopaminergic agents. Anti-cholinergic agents and amantadine sometimes give mild benefit. The cerebellar signs in multiple system atrophy do not respond to any medical treatment. For postural hypotension, a high salt diet, head up-tilt of the bed at night, and elastic support stockings or tights could be used. Other agents that help postural hypotension include ephedrine fludrocortisone and octreotide. Urinary bladder dysfunction can be helped with oxybutynin, as well as intermittent catheterization. Some patients have respiratory failure such as respiratory stridor, which may require tracheostomy (a tube inserted in the wind-pipe to help a person breath) if indicated. Some patients have dysphagia, which may require gastrostomy (a tube inserted in the stomach through which nutrition is given). In general, the medical treatment of multiple system atrophy is disappointing. Physical therapy, occupational therapy, speech therapy, and other measures for safety are of paramount importance.

Sultan Darvesh

See also Brain; Dementia; Demetia with Lewy Bodies; Fainting; Parkinsonism.

BIBLIOGRAPHY

Adams, R. D., Van Bogaert, L.; and Vander Eecken, H. "Striato-nigral Degeneration." Journal of Neuropathology and Experimental Neurology 23 (1964): 584–608.

DÉjÉine, J., and Thomas, A. A. "L'atrophie olivo-ponto-cérébelleuse." Nouveau Inconog. Salpetriere 13 (1900): 330–370.

Graham, J. G., and Oppenheimer, D. R. "Orthostatic Hypotension and Nicotine Sensitivity in a Case of Multiple System Atrophy." Journal of Neurology, Neurosurgery and Psychiatry 32 (1969): 28–34.

Nakazato, Y.; Yamazaki, H.; Hirato, J.; Ishida, Y.; and YAMAGUCHI, H. "Oligodendroglial Microtubular Tangles in Olivopontocerebellar Atrophy." Journal of Neuropathology and Experimental Neurology 49 (1990): 521–530.

Quinn, N. P., and Wenning, G. K. "Multiple System Atrophy." Advances in Neurology 69 (1996): 413–419.

Shy, G. M., and Drager, G. A. "A Neurologic Syndrome Associated with Orthostatic Hypotension." Archives of Neurology 2 (1960): 511–527.

Wenning, G. K.; Ben Shiomo, Y.; Magalhaes, M.; Daniel, S. E.; and Quinn, N. P. "Clinical Features and Natural History of Multiple System Atrophy: An Analysis of 100 Cases." Brain 117 (1994): 835–845.