Striatonigral Degeneration

Striatonigral degeneration is a sporadic, progressive neurodegenerative disorder that represents one manifestation of multiple system atrophy (MSA). Other manifestations of multiple system atrophy are Shy-Drager syndrome, in which autonomic failure predominates, and sporadic olivopontocerebellar degeneration, which is characterized primarily by cerebellar signs. While symptoms of autonomic failure and cerebellar degeneration may be present in striatonigral degeneration, the predominant finding is parkinsonism. (See Presentation and Workup.)

The group of disorders classified under multiple system atrophy belong to a broader class called the Parkinson-plus syndromes, which have in common features such as bradykinesia and rigidity seen in Parkinson disease, combined with additional components such as autonomic dysfunction, ataxia, or dementia.

In many cases, the disease process begins with 1 of the 3 presentations predominating (ie, parkinsonism, autonomic failure, cerebellar signs) and then later converges to include a combination of all 3 plus additional degeneration of the corticospinal system, including tract and motor neuron degeneration, as well as cognitive deterioration. However, in some cases, one presentation remains dominant throughout the course of the disease, or it may be that the patient dies before additional symptoms can manifest. This has been most clearly described for the cerebellar form of multiple system atrophy. (See Etiology and Pathophysiology.)

In 1933, Sherer described 2 cases that likely represented striatonigral degeneration. However, this condition was first definitively outlined in 1961 and 1964 by Adams et al. In 1969, Graham and Oppenheimer coined the term multiple system atrophy in an effort to emphasize the common features found in all the 3 manifestations.

Thirty years later, the first consensus statement on the diagnosis of multiple system atrophy, by Gilman et al, recommended that the term striatonigral degeneration be replaced with multiple system atrophy with predominantly parkinsonian features (MSA-P) and that the term sporadic olivopontocerebellar degeneration be replaced with multiple system atrophy with predominantly cerebellar features (MSA-C).[1] The term Shy-Drager syndrome was deemed unnecessary and was excluded. The consensus group described the clinical features of the disease and set the criteria for diagnosis of possible, probable, and definite multiple system atrophy. (See Presentation and Workup.)

In 2008, the second consensus statement on the diagnosis of multiple system atrophy was published. The purpose of revisiting this topic was to incorporate advances in research, such as the identification of alpha-synuclein as a key pathologic finding, and to simplify the original diagnostic criteria.[2]

Use of the new nomenclature (MSA-P and MSA-C) became common in publications subsequent to 1999; however, the term Shy-Drager syndrome is still frequently used. Many neurologists find this a useful term for the autonomic presentation, but consideration must be given to whether subtle parkinsonian or cerebellar findings are present, in which case the MSA-P or MSA-C classifications, respectively, would be more appropriate. In the event that both parkinsonian and cerebellar signs are present, the term multiple system atrophy can be used without qualification.

MSA-P is characterized by the presence of glial cytoplasmic inclusions (GCIs) in oligodendroglial cells. These inclusions are widely distributed throughout the brains of affected individuals. Neuronal cytoplasmic inclusions and neuronal nuclear inclusions can also be found but are far less prominent relative to GCIs. It has been suggested that the involvement of both neurons and oligodendrocytes synergistically affect the neurodegenerative process in MSA.[3] The identification of these inclusion bodies was a unifying factor in the pathologic classification of the 3 entities that now fall under the category of multiple system atrophy: MSA-P, MSA-C, and, less formally, Shy-Drager syndrome.[4, 5]

Immunostaining of inclusion bodies has revealed the presence of alpha-synuclein fibrils, which further classifies this group of disorders as synucleinopathies. (However, the significance of this finding remains unclear.) Other neurodegenerative conditions that fall under this category include Parkinson disease and diffuse Lewy body disease.[6] Alpha-synuclein, in its soluble form, is found in normal brain tissue. It is the insoluble aggregate that forms the fibrils associated with synucleinopathies that appears to be pathologic.[7] A recent theory suggests that alpha-synuclein is spread from neuron to oligodendrocyte via a prion-like process. In association with neuroinflammation, this leads to a specific pattern of neurodegeneration.[8]

In addition to inclusion bodies, microscopic evaluation of tissue reveals neuronal loss and gliosis. This is manifested at a macroscopic level as atrophy, primarily of the pons and midbrain. The substantia nigra shows loss of pigmentation, while the putamen, also atrophic, may become grayish-green in color. This pattern of degeneration is consistent with clinical findings.

The prevalence of multiple system atrophy (including all 3 subtypes) in the United States is difficult to establish because the disease is frequently misdiagnosed; however, the prevalence has been estimated to be 3-5 cases per 100,000 people in the general population. International data show a prevalence of 1.86-4.9 cases per 100,000 people.[9, 10]

In one Japanese study, review of the pathologic features of 102 multiple system atrophy cases revealed that MSA-C (olivopontocerebellar type MSA) was relatively more frequent in Japan than MSA-P (striatonigral degeneration type MSA), while the converse is found in western countries.[11]

Formerly, no gender predominance was observed, but information now suggests a male predominance of approximately 2:1. Some reports show a much greater disparity, with the suggestion that males who seek treatment for autonomic symptoms, such as erectile dysfunction, may be more likely to be diagnosed.

Onset occurs most often in the sixth decade. The mean age at diagnosis is 53 years, with an age range of 33-76 years.

Multiple system atrophy is a progressive neurodegenerative disorder without remission. The prognosis is poor, and all 3 subtypes of multiple system atrophy have a mean survival period of less than a decade from diagnosis. In a study by Schrag et al, median survival time was 8.6 years for men and 7.3 years for women.[12]

Gender, phenotype, and gait instability do not appear to be prognostic indicators of shorter survival, as has previously been proposed. However, autonomic failure continues to be a negative prognostic factor. Data from one study suggest that early development of severe generalized autonomic failure more than triples the risk of shorter survival in patients with MSA.[13]

The most marked clinical deterioration is seen in MSA-P, although the time frame for survival in this disease is similar to that of the other 2 subtypes.

Morbidity and mortality

Complications of multiple system atrophy include the following:

• Vocal fold paresis and glottic airway compromise requiring continuous positive airway pressure support or tracheostomy[14]

• Aspiration pneumonia secondary to dysphagia and vocal fold paresis

• Sudden death, often occurring at night and associated with sleep-disordered breathing

Patients with symptomatic postural hypotension should be educated with regard to the following:

• Activities or environments that produce excessive vagal stimulation or vasodilation (eg, extreme heat, overeating, alcohol, straining at stool) should be avoided

• Always rise slowly and carefully from seated or recumbent positions

• Sit or lie down as soon as symptoms appear

• Consider using pressure stockings, elevating the head of the bed, and increasing sodium intake

• Be aware that there is a risk of fall with associated trauma; always seek medical attention for any but the most minor of falls

Parkinsonism

The vast majority of patients with multiple system atrophy develop parkinsonism at some point, and the condition is often rapidly progressive.

Bradykinesia with rigidity, tremor, or postural instability is seen. Although the presentation can be asymmetrical (as is usually the case in Parkinson disease), symmetry of onset is particularly suggestive of multiple system atrophy with predominantly parkinsonian features (MSA-P). Absence of tremor is also suggestive of MSA-P (vs Parkinson disease). When present, tremor is usually irregular, postural, and may be associated with myoclonus. While resting tremor can be observed, it is uncommon.

Multiple system atrophy patients with parkinsonism may have a limited response to a trial of levodopa. However, a clear-cut response that is sustained beyond 2 years is unusual.

Dysautonomia

Some degree of autonomic failure is almost universal and may be the presenting symptom. Genitourinary complaints are common early in the disease. Symptoms include the following:

• Male erectile dysfunction

• Urinary symptoms - Frequency, urgency, incomplete bladder emptying, and incontinence

• Postural or postprandial hypotension - Syncopal events may occur secondary to cerebral hypoperfusion

Sleep disturbances

When possible, obtain information on the patient’s history from the patient’s sleeping partner. Sleep-related symptoms include the following:

• Rapid eye movement (REM) sleep behavior disorder

• Obstructive symptoms - Snoring, stridor, obstructive apneas

• Central symptoms - Central apneas, dysrhythmic breathing patterns

• Insomnia and/or excessive daytime sleepiness

• Restless legs syndrome

Additional findings

Additional findings in MSA-P include the following:

• Cerebellar findings - Gait or limb ataxia, cerebellar dysarthria

• Affective disorders - Depression, emotional lability

• Cognitive impairment - difficulty with visuospatial tasks, decreased verbal fluency, diminished executive function skills

• Dysphagia and/or dysphonia

Other etiologies

Features that suggest an etiology other than multiple system atrophy include the following:

• Family history - Multiple system atrophy is a sporadic neurodegenerative disease; however, Machado-Joseph disease (SCA-3) can present with similar clinical features and has a genetic basis

• Dementia - Cognitive deficits are sometimes present in multiple system atrophy, but dementia is not a predominant feature, unlike with diffuse Lewy body disease

• Presence of visual hallucinations (not secondary to medication) - This suggests Lewy body disease[15]

Parkinsonism

Bradykinesia with rigidity, tremor, or postural instability occurs. Symmetrical onset is suggestive of multiple system atrophy (vs Parkinson disease). Absence of tremor is suggestive of MSA-P (vs Parkinson disease). When present, tremor is usually irregular, postural, and is associated with myoclonus. While resting tremor can be observed, it is uncommon.

Dysautonomia

Symptoms of dysautonomia include the following:

• Urinary retention, elevated postvoid residual

• Orthostatic hypotension - Systolic blood pressure reduction of more than 30 mm Hg or diastolic blood pressure reduction of more than 15 mm Hg within 3 minutes of standing from a previous period of recumbency of greater than 3 minutes

Cerebellar findings

Cerebellar findings include the following:

• Gait or limb ataxia

• Cerebellar dysarthria

• Cerebellar oculomotor dysfunction - This may include saccadic pursuit movements, gaze-evoked nystagmus, and ocular dysmetria

Cognitive impairment

Although dementia (as a predominant feature) is a criterion for exclusion of multiple system atrophy, studies suggest that some degree of cognitive impairment is common in multiple system atrophy, and particularly so in MSA-P.[16] The extent of impairment varies significantly. When present, deficits include the following:

• Visuospatial and constructional dysfunction

• Impaired verbal fluency

• Dysexecutive syndrome

Additional findings

Additional findings in MSA-P include the following:

• Dysphagia and/or dysphonia

• Stridor - Initially, stridor occurs during sleep, but later in the course of the disease it may occur during wakefulness

• Corticospinal findings - Hyperreflexia or extensor plantar response is often present

• Raynaud phenomenon, or "cold hands sign" - Cold, dusky, violaceous hands with poor circulatory return after blanching pressure[17]

• Affective disorders - Depression, emotional lability

Other etiologies

Features that suggest an etiology other than multiple system atrophy include the following:

• Classic pill-rolling tremor - Suggests Parkinson disease

• Significant slowing of vertical saccades or vertical supranuclear gaze palsy - A sign of progressive supranuclear palsy

• Dementia - Cognitive deficits are sometimes present in multiple system atrophy, but dementia is not a predominant feature

• Presence of visual hallucinations (not secondary to medication) - Suggests Lewy body disease[15]

No laboratory studies are diagnostic for multiple system atrophy with predominantly parkinsonian features (MSA-P). If a family history is noted, then testing for the SCA-3 mutation can identify Machado-Joseph disease.

Electromyography

Electromyography shows denervation of the external sphincter (urethral or anal); however, normal findings do not exclude the disease.

Clonidine growth hormone test

Studies show that after infusion of clonidine, serum growth hormone concentration does not subsequently rise in patients with multiple system atrophy. In contrast, the normal response, an increase in secretion, is found in Parkinson disease, pure autonomic failure, and control subjects.[18, 19]

Neuropsychiatric evaluation

Studies suggest that cognitive impairment is more common than previously thought in multiple system atrophy. Due to the nature of the deficits associated with this disease, the standard mental status examination has been found to be a poor tool for assessment. Neuropsychiatric testing is more sensitive and may be more a more helpful resource in multiple system atrophy.[16]

Sleep studies

Sleep disorders, particularly nocturnal stridor and REM sleep behavior disorder, are common in multiple system atrophy. Formal sleep studies should be considered, as research suggests that treatment can improve survival and quality of life.[20]

REM sleep behavior disorder is common in Parkinson disease and atypical parkinsonian disorders including striatonigral degeneration (MSA-P). Clonazepam is an effective treatment for many patients. Nocturnal stridor is specific to MSA and is produced by vocal cord dysfunction during sleep. CPAP is appropriate for long term treatment.[21]

Histologic findings

Findings in MSA-P include widespread glial cytoplasmic inclusions (primarily in oligodendrocytes) and, to a lesser degree, neuronal cytoplasmic inclusions and neuronal nuclear inclusions. Immunostaining of inclusion bodies reveals the presence of alpha-synuclein fibrils.[22]

Other tests

Autonomic tests for orthostatic vital signs such as the tilt-table test and urodynamic studies can be conducted. Scintigraphy with iodine-123-metaiodobenzylguanidine (MIBG) has recently shown utility in the differential diagnosis between Parkinson disease and multiple system atrophy; this method shows high sensitivity and adequate specificity in this field.[23]

A study measuring the clinical utility of skin biopsy for differentiating between Parkinson disease and multiple system atrophy concluded that detection of alpha-synuclein aggregates on cutaneous nerves in distal body sites is insufficiently sensitive; however, intraepidermal nerve fiber density (IEND) may be useful for this purpose. Further study is needed.[24]

Computed tomography (CT) scans may show cerebellar or brainstem atrophy late in the course of the disease.

A study using single-photon emission CT (SPECT) scanning revealed significantly decreased cerebellar and dorsolateral prefrontal perfusion in patients with multiple system atrophy, relative to that of control subjects.[16]

Magnetic resonance imaging (MRI) may show 1 or more of the following[25] :

• Atrophy of the putamen is best seen on inversion-recovery coronal sequences and/or putaminal hypointense signal on T2-weighted sequences. In rare instances, hyperintense bands lateral to the putamen may be seen.

• There may be narrowing and hypointensity of the pars compacta of the substantia nigra, which can give the appearance of fusion between the pars reticularis and the red nucleus.

• In a retrospective review, identification of the pontine "hot-cross bun" sign on T-2 weighted MRI sequences supported the diagnosis of MSA.[26]

Positron emission tomography (PET) scans demonstrate decreased postsynaptic D2-receptor density and impaired uptake of fluoro-L-dopa.[27] The recently approved DaTscan single-photon emission computed tomography (SPECT) imaging can help confirm the diagnosis of parkinsonism but does not distinguish idiopathic Parkinson disease from multiple system atrophy.[28]

In patients with multiple system atrophy, response to antiparkinsonian medications is suboptimal at best. However, these drugs remain the treatment of choice in the absence of better options.[29] Other medical therapies used in multiple system atrophy target associated symptoms (eg, orthostatic hypotension).[30] Surgical treatment

Currently, no surgical treatment is appropriate for multiple system atrophy. Because it can be difficult to clinically distinguish multiple system atrophy from Parkinson disease, there are cases of multiple system atrophy patients undergoing placement of deep brain stimulators. The outcomes have generally been poor, even in patients who responded well to levodopa therapy.[31, 32]

Inpatient care

Multiple system atrophy with predominantly parkinsonian features (MSA-P) is unlikely to be the primary cause of a patient’s hospitalization. Thus, the focus of care would be treatment of the diagnoses that required admission.

Outpatient care

Outpatient care includes the following:

• Management of antiparkinsonian drug regimen (if used)

• Patient education regarding orthostatic hypotension

• Assessment for history or physical signs of falls at each office visit

• Assistive devices as needed - Cane, walker, wheelchair, and household implements

• Patient education regarding self-catheterization if urinary retention develops

• Referrals as needed

Consultations

Consultations in multiple system atrophy can include professionals in the following specialties:

• Neurology

• Sleep medicine

• Otolaryngology

• Physical and occupational therapy

• Speech-language pathology

• Psychiatry or counseling

Diet

Unless there are contraindications, patients with symptomatic postural hypotension may benefit from increased salt intake.

Activity

Patients with symptomatic postural hypotension should be advised to avoid activities or environments that produce excessive vagal stimulation or vasodilation (eg, extreme heat, overeating, straining at stool) and to rise slowly and carefully from seated or recumbent positions.

The drugs in the tables below are specific to the treatment of parkinsonism and postural hypotension associated with multiple system atrophy with predominantly parkinsonian features (MSA-P). As previously mentioned, in patients with multiple system atrophy, the response to antiparkinsonian medications is suboptimal at best. Because better options are not available, however, these agents remain the treatment of choice for the disease.

Adjunct medications

Anticholinergic medications, such as oxybutynin, are sometimes used for incontinence but often lead to subsequent retention. Although sildenafil has been used for treatment of erectile dysfunction, it is generally not recommended, due to its high potential to provoke or exacerbate hypotension. The use of a fiber supplement or another bowel regimen may be necessary for constipation.

A selective serotonin reuptake inhibitor (SSRI) or similar drug may be required for the treatment of depression often associated with all subtypes of multiple system atrophy. For patients who suffer from REM sleep behavioral disorder, clonazepam may be beneficial. Botulinum toxin (BOTOX®) injection to the vocal cords has been used for the treatment of stridor.

Class Summary

Dopaminergic drugs can exacerbate orthostatic hypotension. They must be initiated at low doses and cautiously titrated up.

Levodopa-carbidopa (Sinemet, Parcopa)

Levodopa is a dopamine precursor used to increase central nervous system (CNS) dopamine concentration, as it is not possible for dopamine to cross the blood-brain barrier. Carbidopa is a peripheral dopa decarboxylase inhibitor that prevents premature conversion of levodopa to dopamine in the tissues prior to entering the CNS. It increases the efficiency of levodopa therapy, allows for lower dosages, and also decreases the side effects associated with peripheral conversion.

Standard release forms of levodopa-carbidopa are available in 25/100-, 10/100-, and 25/250-mg tablets. Controlled-release preparations are available in 50/200 mg and 25/100 mg.

Pramipexole (Mirapex)

Pramipexole is a nonergot dopamine agonist that is used with or without concomitant levodopa therapy. It binds D2 and D3 dopamine receptors. Due to pramipexole's high specificity for D3 receptors (relative to other dopamine agonists), it may cause less orthostatic hypotension. It has no significant effect on other adrenergic or serotonergic receptors. The drug's absolute bioavailability is greater than 90%. Its peak serum concentration is reached in approximately 2 hours and its half-life is approximately 8 hours.

There are no known metabolites; roughly 90% of this drug is renally excreted in its unchanged form. Tablets are available in 0.125-, 0.25-, 0.5-, 0.75-, 1-, and 1.5-mg forms.

Ropinirole (Requip)

Ropinirole is a nonergot dopamine agonist that is used with or without concomitant levodopa therapy. It binds to D2 and D3 receptors but has a greater affinity for D3. Ropinirole's bioavailability is 55%, its peak plasma concentration is reached in 1-2 hours, and its half-life is approximately 6 hours. Ropinirole is extensively metabolized by the liver via P450 CYP1A2. Less than 10% of the drug is renally excreted; no dosage change is required in mild to moderate renal insufficiency. If ropinirole is used as adjunct therapy, it may be possible to titrate levodopa dosage slowly downward.

Class Summary

These are used to treat orthostatic hypotension that is refractory to nonpharmacologic recommendations.

Fludrocortisone

Fludrocortisone is a synthetic steroid with predominantly mineralocorticoid activity. It acts on renal distal tubules to enhance the reabsorption of sodium and increase the urinary excretion of potassium. The net effect is an increase in plasma volume and an elevation of blood pressure. The drug's metabolism is primarily hepatic.

Class Summary

These drugs are used to treat orthostatic hypotension that is refractory to nonpharmacologic recommendations.

Midodrine

Midodrine is a selective alpha1-adrenergic agonist used for the treatment of hypotension.

Class Summary

These drugs are used for REM sleep behavior disorder (RBD).

Clonazepam (Klonopin)

Clonazepam is a benzodiazepine which binds to gamma aminobutyric acid (GABA)-A receptors in the CNS. It may help regulate sleep disorders.