Multiple system atrophy syndrome

A degenerative neurological disorder.

An adult onset fatal neurodegenerative disease with progressive autonomic failure, Parkinson features, cerebellar and pyramidal features in varying combination.

Classified as parkinsonian subtype if parkinsonism is the predominant feature or as cerebellar type if cerebellarfeatures are predominant.

A major diagnostic challenge in neurology, gastroenterology, urology, cardiology, otolaryngology, and sleep medicine.

Associated with autonomic failure that manifests as orthostatic hypotension or urodynamic dysregulation.

Clinically difficult to distinguish from Parkinson’s disease or idiopathic late-onset cerebellar ataxia.

Associated with the degeneration of nerve cells in specific areas of the brain.

Neuron degeneration causes problems with movement, balance, and other autonomic functions of the body such as bladder control or blood-pressure regulation.

Prior terminology for this disorder include:olivopontocerebellar atrophy (OPCA), Shy–Drager syndrome (SDS), and striatonigral degeneration (SND)

Describes three neurologic entities: olivopontocerebellar atrophy, the Shy-Drager syndrome, and striatonigral degeneration, with predominately cerebella, autonomic, or parkinsonian features, respectively.

Estimated mean incidence 0.6-0.7 cases per 100,000 person years with the range of 0.1-2.4 cases per 100,000 person-years.

Estimated prevalence 3.4-4.9 cases for 100,000 population that increases to 7.8 per 100,000 among individuals older than 40 years of age.

Parkinsonian subtype outnumbers the cerebeller subtype in most countries by 2:1 to 4:1.

The cerebeller subtype is more frequent in Japan.

Cause is unknown.

Loss of function mutation in COQ2 encoding the coenzyme Q10 synthesizing enzyme has reported in Japanese.

Abnornmalities SNCA, encoding alpha-synuclein, reported in familial Parkinson’s with features similar to multiple system atrophy.

A G51D SNCA mutation recently described.

A possible link has been identified with the chromosome 19 (19p13.

Around 55% of cases occur in men.

Onset in the late 50s to early 60s.

Disease onset do usually occurs in the six decade of life. 

The mean survival from onset of symptoms is 6-10 years, with few individuals surviving more than 15 years.

The use of alcohol and nicotine less common among patients with multiple-system atrophy.

Considered a sporadic disease, although genetic factors have a role in some families.

Rarely reported as an autosomal dominant or recessive inheritance disease.

Varying amounts olivopontocerebeller atrophy and striatonigral degeneration seen at autopsy, reflecting ataxia and Parkinsonism.

Neurodegenerative changes affect central autonomic nervous system, hypothalamus, brain stem nuclei, vagus nerve, nucleus ambiguus, and spinal cord columns.

Atrophy of the frontal lobe may be seen.

Often presents with the same symptoms as Parkinson’s disease, but has minimal if any response to the dopamine medications used for Parkinsons.

Prevalence of MSA is estimated at 4.6 cases per 100,000 people.

Patients often suffer from akinetic-rigid syndrome with slowness of initiation of movement resembling Parkinson’s disease.

Slowness of initiation of movement seen in 62% as first presentation.

Associated was autonomic dysfunction, parkinsonism, and ataxia.

When autonomic dysfunction predominates clinically the term Shy–Drager syndrome is sometimes used.

May coexist with Lewy body dementia may also exist.

The most common first sign is the appearance of an akinetic-rigid syndrome with slowness of movement resembling Parkinson’s disease and is found in 62% at first presentation.

Other common signs at onset include.: cerebellar ataxia found in 22% at first presentation, followed by genito-urinary problems (9%).

For men, the first sign can be erectile dysfunction.

Patients often experience urgency, frequency, incomplete bladder emptying, or urinary retention.

About 1 in 5 patients will suffer a fall in their first year of disease.

Symptoms include: Parkinsonism with slow, stiff movement, writing becomes small and spidery, Cerebellar dysfunction with poor coordinating movement and balance, impaired automatic body functions including: postural or orthostatic hypotension, urinary incontinence or urinary retention, impotence, constipation, vocal cord paralysis, dry mouth and skin, trouble regulating body temperature due to sweating deficiency in all parts of the body, snoring, abnormal breathing or inspiratory stridor during sleep, sleep apnea, REM behavior disorder, and double vision can occur.

Not all patients experience all of these symptoms.

20% of patients may experience cognitive impairment.

Usually progresses more quickly than Parkinson’s disease.

No remissions occur and the average remaining lifespan after the onset of symptoms is 7.9 years.

Almost 80% of patients are disabled within five years of onset of the motor symptoms.

Only 20% survive past 12 years.

Rate of progression differs in every case and speed of decline may vary widely in individual patients.

Early autonomic dysfunction is the most important early clinical prognostic feature regarding survival.

Patients with concomitant motor and autonomic dysfunction have a shorter survival and become wheelchair dependent and bed-ridden at an earlier stage.

Patients with autonomic dysfunction have frequent falling, wheelchair dependence, more severe dysphagia, and higher likelihood to require residential care.

Patients with autonomic dysfunction have a shorter interval to death.

No test that can definitively make or confirm the diagnosis.

Signs and symptoms of MSA also occur with other disorders, such as Parkinson’s disease.

Definitive diagnosis can only be made pathologically on finding abundant glial cytoplasmic inclusions in the central nervous system, and alpha synuclein immunohistochemistry shows many glial inclusions.

There is degeneration of the catecholaminergic neurons to the rostral ventral lateral medulla and partial degeneration of  sympathetic Preganglionic neurons in the thoracic spinal cord, with preservation of neurons in the sympathetic ganglia.

This pattern of neuronal degeneration disrupts regulation of blood pressure and heart rate in response to an upright posture.

No cure exists, so treatment involves controlling the symptoms.

Postural hypotension often responds to fludrocortisone, a synthetic mineralocorticoid and midodrine (an alpha-agonist).

Non-drug treatments include head-up tilt, elevating the head of the whole bed, salt tablets , increasing salt in the diet, generous intake of fluids, and pressure stockings.

Avoiding triggers of low blood pressure are crucial.

Levodopa used in the treatment of Parkinson’s disease, fails to improve the parkinsonian symptoms of most MSA patients.

Only 1.5% of MSA patients experienced a less than 50% improvement when taking levodopa, and even this was a transient effect lasting less than one year.

Mesenchymal stem cell therapy could delay the progression of neurological deficits in patients with MSA-cerebellar type.

Management by rehabilitation is required to maintain the patient’s mobility and will help to prevent contractures.

Speech therapists are key in assessing, treating and supporting dysarthria) and dysphagia difficulties.

The orthostatic hypotension has been treated by stimulating the dorsal root entry zones of the thoracic spinal cord with an implantable neural prosthesis.

Multiple-system atrophy associated with cell loss and proliferation of astrocytes in damaged areas of the central nervous system, forming a scar which is then termed a glial scar.

A confirmed diagnosis can only be made post-mortem as glial cytoplasmic inclusion bodies are visible.

When brain tissue of a person with MSA is examined under a microscope, these glial structures are visible, confirming the diagnosis.

The presence of these inclusions, known as Papp-Lantos bodies, are the defining histopathologic hallmark of the disease.

These histopathologic changes in the motor, balance and automatic control centers of the brain are pathognomonic.

The major filamentous component of glial and neuronal cytoplasmic inclusions is alpha-synuclein, and mutations in this substance may play a role in the disease..

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