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Walking With Ataxia
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Cerebellar Degeneration

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Multiple System Atrophy
A Clinical Review

Description

Multiple system atrophy (MSA) is a sporadic, progressive, adult-onset neurodegenerative disease characterized clinically by autonomic dysfunction, parkinsonism, and cerebellar ataxia in any combination. Symptoms of MSA vary in distribution, onset and severity from person to person. Because of this, MSA was originally thought to be three different diseases: Shy-Drager syndrome, striatonigral degeneration, and sporadic olivopontocerebellar atrophy. These terms are no longer in use, and these diseases are now considered forms of MSA.

Symptoms

MSA can cause a wide range of symptoms, including:

  • Stiffness or rigidity
  • Freezing or slowed movements
  • Postural instability; loss of balance; incoordination
  • Tremor
  • Orthostatic hypotension
  • Male impotence
  • Urinary incontinence
  • Constipation
  • Speech and swallowing difficulties
  • Sleep disorder
  • Hyperreflexia

There are 2 forms of motor presentation in MSA:

  • MSA-P. Parkinsonism is seen in the majority of patients at onset. Akinesia, rigidity, and tremor are often asymmetrical, and postural tremor is more common than rest tremor. Dystonia of the head and neck is common. Falls are not as common in the first year of the disease (about 25%) as in progressive supranuclear palsy (PSP - 50%).
     
  • MSA-C. Cerebellar symptoms are seen in about 20% of patients at onset, presenting as limb ataxia, gait ataxia, scanning dysarthria, and oculomotor dysfunction. MSA-C is difficult to distinguish from late-onset pure cerebellar ataxia until the disease progresses to include other MSA signs and symptoms.

In addition, autonomic disturbance is seen in both MSA-P and MSA-C. It is present at diagnosis in about 40% of patients, and develops shortly after diagnosis in virtually all other patients. In males, impotence is the most frequent initial symptom, while in females, urinary incontinence is seen most often. Orthostatic hypotension is present in about two-thirds of patients. Fecal incontinence affects about one-third of patients. Other autonomic symptoms may include cold hands, obstructive sleep apnea, and vocal cord abductor paralysis.

Dysphagia is common early in the disease. Sleep disorders, particularly REM sleep behavior disorder (RBD) occur in about two-thirds of patients. Confusion and hallucinations are uncommon, and much less frequent than in Parkinson's disease (PD).

MSA progresses over the course of several years to cause more widespread and severe symptoms. While patients with Parkinson's disease decline by approximately 1% to 2% per year in motor function, MSA patients decline by 25% to 30% per year. Orthostatic hypotension can cause fainting and falls. Loss of coordination, slowed movements, and rigidity can interfere with activities of daily living. Some patients with MSA have mild cognitive impairment.

Diagnosis

The diagnosis of MSA is a clinical one. Consensus criteria originally formulated in 1998 were refined and updated by a group of experts in the field, and published in late 2008.[1] Diagnosis is described as "definite," "probable," or "possible."

Definite MSA. Requires neuropathologic finding of widespread and abundant central nervous system glial cytoplasmic inclusions that are positive for alpha-synuclein, in association with neurodegeneration in striatonigral or olivopontocerebellar structures.

Probable MSA. A sporadic, progressive adult-onset (after age 30) disease characterized by:

  • Autonomic failure involving urinary incontinence plus erectile dysfunction in males, or an orthostatic decrease of blood pressure within 3 minutes of standing by at least 30 mm Hg systolic or 15 mm Hg diastolic, and
  • Poorly levodopa-responsive parkinsonism or
  • A cerebellar syndrome (gait ataxia with cerebellar dysarthria, limb ataxia, or cerebellar oculomotor dysfunction).

Possible MSA. A sporadic, progressive adult-onset (after age 30) disease characterized by:

  • Parkinsonism (bradykinesia with rigidity, tremor, or postural instability) or
  • A cerebellar syndrome (gait ataxia with cerebellar dysarthria, limb ataxia, or cerebellar oculomotor dysfunction, and
  • At least one feature suggesting autonomic dysfunction (otherwise unexplained urinary urgency, frequency, or incomplete bladder emptying, erectile dysfunction in males, or significant orthostatic hypotension decline that does not meet the level requires in probable MSA, and
  • At least 1 additional feature from Table 1.

"Red flags" supporting a diagnosis of MSA include orofacial dystonia, dysphonia, dysarthria, hand or foot contractures, camptocormia, inspiratory sighs, worsened snoring, cold hands and feet, myoclonic tremor, and pathologic laughter or crying. REM sleep behavior disorder. External anal sphincter electromyography may be used to detect sphincter dysfunction, which typically occurs much earlier in MSA than in Parkinson's disease. Misdiagnosis, especially as Parkinson's disease, is common. Early gait impairment, early and severe autonomic failure, early cerebellar symptoms, and absence of cognitive impairment all suggest MSA versus PD. Definitive diagnosis occurs only at autopsy.[1]

Features suggesting another diagnosis include onset after age 75, family history of ataxia or parkinsonism, classic pill-rolling rest tremor, and dementia.

Epidemiology and Etiology

MSA occurs more commonly in men than women (approximately 1.3:1). Onset is typically in the 6th decade.

A study of incidence MSA indicated there are 3 new cases per 100,000 person-years in those between ages 50 and 99. There were no cases with onset younger than age 50 in this study. Prevalence studies suggest there are 2 to 5 cases per 100,000 people.

There are no known genetic causes of MSA, and no familial pattern suggesting a strong genetic contribution to the disease. Inherited cerebellar degenerations are sometimes mistaken for MSA, but genetic investigations can often differentiate the two. Environmental factors have been implicated in MSA. Specifically, risk might be increased from occupational history of farming, and decreased with smoking.

Pathology

Neurodegeneration in MSA-P is most prominent in the striatonigral system, while in MSA-C it is more marked in the olivopontocerebellar system. Autonomic system involvement is accompanied by cell loss in the dorsomotor nucleus of the vagus nerve, the locus coeruleus, and the ventrolateral medulla, as well as parasympathetic preganglionic nuclei in the spinal cord. Other cell populations may also be affected.

The pathologic hallmark of MSA is the presence of cytoplasmic inclusion bodies in glial cells of the basal ganglia, supplementary and primary motor cortices, reticular formation, and pontocerebellar system. These inclusions contain ubiquitin, tau, and alpha-synuclein proteins. Glial cytoplasmic inclusions are definitive for the diagnosis of MSA. The discovery of alpha-synuclein in MSA inclusions linked the disease with Parkinson's disease and Lewy body dementia, together known as "synucleinopathies." The pathogenic significance of the inclusions, and how an excess of protein is involved in the disease process, is unknown.


Treatment
There are no treatments that halt or slow the neurodegenerative process. There are also no symptomatic treatments for cerebellar symptoms. Treatments are available for parkinsonism and autonomic symptoms, although they become less effective as the disease progresses.

Ataxia
A cane, walker, or wheel chair may be needed for mobility.

Parkinsonism
Levodopa
: Between 30% and 70% of MSA patients experience benefit from levodopa. Responsiveness may be tested with increasing doses over 3 months up to 1000 mg/day (Wenning, 2004). Levodopa-induced dyskinesias emerge in about half of MSA patients, without corresponding improvement in motor function. These uncontrolled movements manifest primarily as dystonia, especially of the head and neck region. Dopaminergic drugs may worsen orthostatic hypotension, limiting their use in affected patients.

Dopamine agonists: These should be used as second-line agents in patients for whom levodopa is ineffective or poorly tolerated.

Autonomic Dysfunction
Treatments for autonomic dysfunction are multifactorial and involve addressing the following adverse effects.

Symptomatic orthostatic hypotension.

  • Fludrocortisone
  • Midodrine
  • Liberal salt intake
  • Postural changes, such as leg crossing or squatting
  • Compressive stockings
  • Head-up tilt of the bed at night
  • Avoid large meals, alcohol, straining during elimination

Male impotence.

  • Penile implants
  • Sildenafil (but may worsen hypotension)
  • Intracavernosal papaverine
  • Prostaglandin E1

Incontinence.

  • Anticholinergics (but may induce retention)
  • Catheterization (intermittent, indwelling or suprapubic)

Constipation.

  • Increased dietary fiber
  • Laxatives

Treatments for Other MSA Symptoms

Treatments for inspiratory stridor include continuous positive airway pressure, botulinum toxin injection into the vocal cords, and tracheostomy. Swallowing and speaking difficulty may be managed with speech-language pathologist referral, softer foods, and gastrostomy tube. Psychological support for the patient and family are valuable throughout the course of the disease.[2]

Prognosis

Early striatonigral involvement predicts a poorer prognosis, while cerebellar features are associated with a slightly better prognosis. The interval from symptom onset to combined motor and autonomic dysfunction is predictive of functional deterioration and survival in MSA. In a Japanese study of 230 (mostly MSA-C) patients, the median time from symptom onset to multi-system involvement was 2 years. Median survival time was 9 (range 2-17) years. Time to assisted walking, wheelchair requirement, bed confinement, and death were proportional to time between symptom onset and multisystem involvement. Patients in whom multisystem involvement occurred within one year of symptom onset proceeded to each of these milestones 2 to 3 times as fast as those for whom multisystem involvement occurred after 3 years or more. In the London brain bank series of 100 (mostly MSA-P) cases average survival was 7 (range 2-16) years.[3] The most common causes of death are aspiration, sleep apnea, and cardiac arrhythmia.


Authors

Horacio Kaufmann, MD

Professor of Neurology, Pediatrics, and Medicine, New York University School of Medicine, New York, New York; Director, Dysautonomia Center and Research Lab and Attending Physician, Neurology, NYU Langone Medical Center, New York, New York

Disclosure: Horacio C. Kaufmann, MD, has disclosed that he has received grants for clinical research from Chelsea Therapeutics and the National Institutes of Health. Dr. Kaufmann has also disclosed that he is employed by a commercial interest, Dysautonomia Foundation.
 

Niall Quinn, MA, MD, FACP, FAAN

Professor of Clinical Neurology, Institute of Neurology UCC, London, United Kingdom

Disclosure: Niall Quinn, MA, MD, FACP, FAAN, has disclosed no relevant financial relationships.