AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Striatonigral degeneration (SND) is a neurodegenerative disease that represents a manifestation of multiple system atrophy (MSA). The other manifestations are Shy-Drager syndrome (autonomic failure predominates) and sporadic olivopontocerebellar degeneration (cerebellum predominates). Parkinsonism predominates in SND, although cerebellar symptoms and autonomic failure may be present. Frequently, the disease begins with 1 of these 3 forms predominating and then ultimately converges to a combination of all 3 plus additional degeneration of the corticospinal system, including both track and motor neuron degeneration and cognitive deterioration. However, sometimes 1 of the 3 forms appears to remain dominant indefinitely, or at least the patient dies before the other manifestations develop to a major extent. This has been most clearly described for the cerebellar form.

SND was first definitively delineated by Adams et al in 1961 and 1964. However, in 1933, Scherer described 2 cases that seemed to have been SND. In 1969, Graham and Oppenheimer coined the term MSA to combine the common features seen in the 3 manifestations. The "Consensus statement on the diagnosis of multiple system atrophy" by Gilman et al in 1999 recommended the terms MSA with predominantly parkinsonian features (MSA-P) to replace SND and MSA with predominantly cerebellar features (MSA-C) for sporadic olivopontocerebellar degeneration. The consensus group also concluded that the term Shy-Drager syndrome was no longer useful, so they excluded it. They described the clinical features of the disease and set the criteria for the diagnosis of possible, probable, and definite MSA (see Multiple System Atrophy).

A separate set of diagnostic criteria, the Quinn criteria, are simpler to use in clinical practice. A comparison of the 2 criteria showed that they do not always agree but they are approximately equal in efficacy. In addition, neither totally predicts the ultimate neuropathological findings in all cases.

Although use of the new nomenclature (MSA-P and MSA-C) has become common in publications subsequent to 1999, the term Shy-Drager syndrome is still used. A Medline search using Shy-Drager as a keyword or a subject heading found 84 papers published between 2000 and 2006. Thus, the term is still used in publications. Many neurologists believe that it is a good term for the autonomic presentation. The problem with the term appeared to be that it was used inconsistently and often used for SND and a purely autonomic presentation. One can usually find either parkinsonian or cerebellar findings in what might have previously been classified as Shy-Drager syndrome; thus, the terms MSA-P or MSA-C can be used. Alternatively, if both parkinsonian and cerebellar findings are present, the term MSA can be used without qualification.

Pathophysiology

MSA is a clinicopathological entity. The different phenotypes have characteristic pathological changes in common but in varying degrees. The oligodendrocytes have glial cytoplasmic inclusions (GCIs) and glial nuclear inclusions (GNIs). The neurons also have inclusions in cytoplasm, termed neuronal cytoplasmic inclusions (NCIs), and in the nucleus, termed neuronal nucleus inclusions (NNIs). The oligodendrocyte inclusions are distributed in the suprasegmental areas that include the primary motor system and other motor areas of the cerebral cortical, pyramidal, extrapyramidal, and corticocerebellar systems. Changes in the neurons include neuronal loss, NCIs, and NNIs in the striatum, substantia nigra, locus ceruleus, inferior olivae, pontine nuclei, cerebellar Purkinje cells, dorsal nucleus of the vagus, nucleus vestibularis, intermediolateral cell column of the spinal cord, and Onuf nucleus.

The inclusion bodies (particularly the GCIs) in the oligodendrocytes are a particularly prominent feature of MSA, as is the ultimate loss of oligodendrites, presumably due to apoptosis. The inclusion bodies have complex structures that are not fully understood. Most research has been on the GCIs, which are the most prominent, although the other inclusions may be similar. The GCIs are composed of microtubules that immunoreact with ubiquitin; they also contain nonphosphorylated tau protein, which resembles tau in a healthy adult brain and contrasts with the hyperphosphorylated tau present in the coiled bodies of oligodendroglia in persons with Alzheimer disease, corticobasal degeneration, and progressive supranuclear palsy. GCIs also contain alpha-beta-crystallin.

A particularly interesting protein contained in the inclusions is alpha-synuclein. This protein is also abundant in the nervous system of MSA patients, apart from the inclusions. Alpha-synuclein can be a normal component of the nervous system; however, MSA patients have a significant amount of it in an abnormal conformation because of the extent and distribution of its phosphorylation. Especially within the GCIs, GNIs, NCIs, and NNIs, it exists as a tubular, filamentous, nonsoluble protein. Interestingly, it has been found to be associated in the GCIs with what are called 14-3-3 proteins. These 14-3-3 proteins are considered to be a diagnostic marker for prion diseases when they are found in the cerebrospinal fluid. However, 14-3-3 proteins are actually normal components of the nervous system, and the precise relationships between these and other proteins present in the inclusion are not known or understood.

Because of the prominence of alpha-synuclein associated with MSA, it is considered an alpha-synucleinopathy. Other alpha-synucleinopathies are Lewy body disease, Parkinson disease, progressive supranuclear palsy (also a tauopathy), and pantothenate kinase–associated neurodegeneration (PKAN) or pantothenate kinase 2 (PANK2) deficiency (previously called Hallervorden-Spatz disease). The morphology and array of components that are immunoreactive to anti–alpha-synuclein antibodies in persons with these diseases differ from those found in persons with MSA.

Although the term alpha-synucleinopathy would appear to tie all these diseases together, it is far from clear that the alpha-synuclein abnormalities are the whole key to the diseases. For example, the ultimate cause of PKAN is a mutation in the PKAN2 gene; therefore, the alpha-synuclein abnormalities in persons with PKAN must be secondary to that mutation. MSA is sporadic and is not caused by a single gene mutation; however, regardless, thealpha-synuclein abnormalities may be an incidental epiphenomenon, one of many components of a multifactorial pathophysiological mechanism, or even a compensatory reaction of the nervous system.

Frequency

United States

The prevalence of MSA is difficult to establish because the disease is frequently misdiagnosed. In parkinsonian brain banks, MSA accounts for 5-22% of cases.

International

The prevalence of MSA is difficult to establish because the disease is frequently misdiagnosed.

Mortality/Morbidity

Mean survival is 9.3 years from the appearance of the first symptoms, with progression over 1-18 years. Mean survival in patients with pathologically confirmed MSA is 7 years.

Race

No racial predilection has been observed.

Sex

Males and females are equally affected.

Age

The mean age at diagnosis is 53 years (range, 33-76 y); it has never been reported in people younger than 30 years.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Ninety percent of patients with MSA develop parkinsonism. Autonomic failure of some degree is almost universal and may be the first symptom. Half of all patients develop cerebellar and pyramidal signs.

• Parkinsonism: Symptoms are present in most patients; they may be asymmetric.
• • Bradykinesia: Tremor is usually irregular and postural and often incorporates myoclonus; rest tremor may be present but is uncommon.
  • Rigidity
  • Postural instability
• Autonomic findings
• • Male erectile dysfunction: This manifests early in the disease course.
  • Urinary problems: Frequency, urgency, and incontinence appear early in the disease course.
  • Postural hypotension: Findings include a reduction in systolic blood pressure of 30 mm Hg or more or a reduction in diastolic blood pressure of 15 mm Hg or more within 3 min of standing from a recumbent position.
  • Postprandial hypotension
  • Loss of consciousness (syncope) due to cerebral hypoperfusion
• Cerebellar findings
• • Gait ataxia
  • Limb ataxia
  • Dysarthria
  • Ocular findings: These include saccadic pursuit movements, sometimes gaze-evoked nystagmus, and ocular dysmetria.
• Affective disorders
• • Depression
  • Emotional lability
• Corticospinal findings: Hyperreflexia and an extensor plantar response are present in 50% of patients.
• Exclusion criteria for MSA
• • Family history: MSA is a sporadic degenerative disease.
  • Prominent slowing of vertical saccades or vertical supranuclear gaze palsy: These are signs of progressive supranuclear palsy.
  • Dementia: Note, however, that dementia can occur in the late stages of the disease.
  • Prominent hallucinations: This suggests Lewey body disease.

Physical

See History for more information.

• Others findings include the following:
• • Myoclonus
  • Laryngeal stridor
  • External sphincter neuropathy (anal or urethral)
  • Peripheral axonal neuropathy
  • Subclinical denervation
  • Anterocollis
  • Raynaud phenomenon
  • Cold hand sign
  • Supranuclear ophthalmoplegia
  • Sleep disorders
  • Hypopnea or apnea

Causes

MSA is a sporadic, degenerative disorder. Recently, molecular biological research has revealed that MSA is an alpha-synucleinopathy (ie, a disease in which abnormalities of the protein alpha-synuclein are prominent). As previous noted, alpha-synuclein is abundant in the nervous systems of patients with MSA. It has been especially studied with the inclusion bodies (ie, GCIs, GNIs, NCIs, NNIs) that are characteristic of this disease. In addition, it appears to be associated with other proteins, such as tau and 14-3-3 proteins. However, whether alpha-synuclein is causing the disease remains unknown; the cause of MSA remains unknown.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Primary autonomic failure

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• No laboratory studies are indicated.

Imaging Studies

• Positron emission tomography scanning - Down-regulation of postsynaptic D2 receptor binding, especially before levodopa-carbidopa treatment
• Single-proton emission computed tomography scanning with iodine I 123 iodobenzamide - Down-regulation of postsynaptic D2 receptor binding
• MRI - Cerebellar or brainstem atrophy late in the course of the disease or changes in T2 images in these areas
• CT scanning - Cerebellar or brainstem atrophy late in the course of the disease

Other Tests

• Autonomic tests
• • Orthostatic blood pressure testing - Reduction of systolic blood pressure by 30 mm Hg or more and diastolic blood pressure by 15 mm Hg or more within 3 min of standing from a recumbent position
  • Heart rate response to respiration
  • Vasopressin testing - To differentiate from primary autonomic failure
• Electromyography - Shows denervation of external sphincter (urethral or anal); however, normal findings do not exclude the disease
• Growth hormone response to clonidine infusion testing - No increase in growth hormone levels in MSA patients; normal increase in Parkinson disease patients, with or without autonomic failure

Histologic Findings

GCIs consist of alpha-synuclein, tau, and ubiquitin.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• No effective pharmacotherapy is known; 30% of patients respond to a levodopa-carbidopa combination initially, although not as well as patients with Parkinson disease. Eventually, levodopa loses its efficacy.
• Symptomatic orthostatic hypotension that does not respond to nonpharmacological measures may be treated with fludrocortisone or midodrine.
• The dopamine agonist amantadine may have some benefits.

Surgical Care

• No surgical treatment currently exists for SND; however, deep brain stimulation is an important topic related to the treatment of this condition.
• While no systematic or controlled studies of deep brain stimulation have been performed in SND, occasionally patients are mistakenly implanted with stimulators by physicians who believe they have conventional Parkinson disease. The results are almost always poor. The bulk of the poor results of such practices likely have never been published.
• • In 2003, Tarsy et al reported a case of a woman who was responsive to levodopa therapy. Stimulator implantation was performed to reduce motor fluctuations, and the levodopa induced dyskinesia. The procedure brought about some improvement of upper limb bradykinesia but worsened speech, swallowing, and gait. Further clinical examination and MRI findings were consistent with MSA.
  • In 2004, Chou et al reported a case in which the patient was given bilateral subthalamic stimulators, with the thought that he had Parkinson disease. He had responded poorly, if at all, to levodopa therapy (and for that reason alone probably would not have been implanted at most centers). He showed no beneficial response and died shortly after surgery. Neuropathology findings were indicative of MSA.
  • Finally, however, in 2006, Talmant et al reported a 63-year-old man who was originally thought to have Parkinson disease. The patient had previously shown responsiveness to levodopa for 6 years and then developed a severe axial syndrome and nonmotor fluctuations with vegetative "off" periods (ie, time he was unresponsive to his medications). Bilateral subthalamic nucleus stimulators were implanted, and he showed some symptomatic improvement in nonmotor fluctuations and off time and was able to reduce his required levodopa dose.
• In current practice, deep brain stimulators are not considered warranted for any of the manifestations of MSA, including SND (MSA-P).

Diet

If the patient has no contraindications, salt intake can be increased in patients with symptomatic postural hypotension.

Activity

If the patient has symptomatic postural hypotension, situations and activities that produce excessive vagal stimulation or vasodilation should be avoided (eg, extreme heat, overeating, straining at stool).

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Antiparkinson agents

Although levodopa-carbidopa yields no response in most patients, it is the drug of choice because 30% of patients initially respond to it; this response rate is not as good as that in persons with Parkinson disease. Eventually, however, levodopa loses its efficacy, typically in less than 5 years. Other dopamine agonists include pramipexole, ropinirole, and bromocriptine.

Drug Category: Sympathomimetic agents

Used for orthostatic hypotension if simple measures yield no improvement.

Drug Category: Mineralocorticoids

Used for orthostatic hypotension.

Drug Category: Antidote, neuromuscular blocking agents

Anti-acetylcholinesterase may improve autonomic sympathic ganglion transmission via enhancement of the function of the preganglionic sympathetic neurons.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Symptomatic orthostatic hypotension
• • Avoid activities that produce increase in vagal activity, such as overeating and straining at stool.
  • Avoid peripheral dilatation as in exposure to extreme heat.
  • Use pressure stockings.
  • Elevate the head of the bed by 6 inches.
  • Increase sodium intake if the patient does not have contraindications such as renal disease or cardiac problems.

Complications

• Paresis of the larynx or pharynx requiring tracheostomy
• Aspiration pneumonia due to dysphagia and vocal cord paralysis
• Central chronic respiratory failure
• Sudden death

Prognosis

• Mean survival duration in pathologically confirmed cases is 7 years (range, 2-15 y).

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Advance directives regarding feeding tubes, respirators, and other respiratory care should be established.

Special Concerns

• Patients may have severe trauma after syncope episodes; the family and/or care personnel should be aware of this situation.
• Patients should be advised to sit or lie down as soon as symptoms of hypotension appear.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Berciano J, Combarros O, Polo JM, et al. An early description of striatonigral degeneration. J Neurol. Jun 1999;246(6):462-6. [Medline].
• Chou KL, Forman MS, Trojanowski JQ, et al. Subthalamic nucleus deep brain stimulation in a patient with levodopa-responsive multiple system atrophy. Case report. J Neurosurg. Mar 2004;100(3):553-6. [Medline].
• Gilman S, Low PA, Quinn N, et al. Consensus statement on the diagnosis of multiple system atrophy. J Neurol Sci. Feb 1 1999;163(1):94-8. [Medline].
• Gilman S. Multiple System Atrophy. In: Jankovic J, Tolosa E, eds. Parkinson's Disease and Movement Disorders. 3rd ed. Baltimore, Md: Williams & Wilkins; 1998:. 245-62.
• Jaros E, Burn DJ. The pathogenesis of multiple system atrophy: past, present, and future. Mov Disord. 2000;Sep;15(5):784-8. [Medline].
• Jellinger KA. Neuropathological spectrum of synucleinopathies. Mov Disord. Sep 2003;18 Suppl 6:S2-12. [Medline].
• Klein C, Brown R, Wenning G, Quinn N. The "cold hands sign" in multiple system atrophy. Mov Disord. Jul 1997;12(4):514-8. [Medline].
• Kofler M, Wenning GK, Poewe W. Cortical and brain stem hyperexcitability in striatonigral degeneration. Mov Disord. May 1998;13(3):602-7. [Medline].
• Kurisaki H. [Prognosis of multiple system atrophy--survival time with or without tracheostomy]. Rinsho Shinkeigaku. May 1999;39(5):503-7. [Medline].
• Lu X, Chen J, Wang L, et al. Correlative studies of MR findings with neuropathology in Shy-Drager syndrome and striatonigral degeneration. Chin Med J (Engl). Aug 1997;110(8):628-31. [Medline].
• Miwa H, Kondo T, Mizuno Y. [Striatonigral degeneration and sporadic olivopontocerebellar atrophy: a consideration of the clinical entity of multiple system atrophy]. No To Shinkei. Apr 1999;51(4):305-12. [Medline].
• Palace J, Chandiramani VA, Fowler CJ. Value of sphincter electromyography in the diagnosis of multiple system atrophy. Muscle Nerve. Nov 1997;20(11):1396-403. [Medline].
• Plazzi G, Cortelli P, Montagna P, et al. REM sleep behaviour disorder differentiates pure autonomic failure from multiple system atrophy with autonomic failure. J Neurol Neurosurg Psychiatry. May 1998;64(5):683-5. [Medline].
• Saper CB. "All fall down": the mechanism of orthostatic hypotension in multiple systems atrophy and Parkinson''s disease [editorial; comment]. Ann Neurol. Feb 1998;43(2):149-51. [Medline].
• Schrag A, Kingsley D, Phatouros C, et al. Clinical usefulness of magnetic resonance imaging in multiple system atrophy. J Neurol Neurosurg Psychiatry. Jul 1998;65(1):65-71. [Medline].
• Talmant V, Esposito P, Stilhart B, et al. [Subthalamic stimulation in a patient with multiple system atrophy: a clinicopathological report]. Rev Neurol (Paris). Mar 2006;162(3):363-70. [Medline].
• Tarsy D, Apetauerova D, Ryan P, Norregaard T. Adverse effects of subthalamic nucleus DBS in a patient with multiple system atrophy. Neurology. Jul 22 2003;61(2):247-9. [Medline].
• Wenning GK, Tison F, Ben Shlomo Y, et al. Multiple system atrophy: a review of 203 pathologically proven cases. Mov Disord. 1997;Mar;12(2):133-47.
• Wenning GK, Seppi K, Tison F, Jellinger K. A novel grading scale for striatonigral degeneration (multiple system atrophy). J Neural Transm. Mar 2002;109(3):307-20. [Medline].

Article Last Updated: Mar 30, 2007