Parkinson plus syndrome ch. 2. nd

Parkinson plus syndrome ch. 2. nd


Neuroimaging findings in patients with MSA correlate partially with the neuronal subsystems involved. All clinical subtypes tend to cause atrophy of the cerebellum, brainstem, putamen, and caudate nucleus. The globus pallidus tends to be spared in MSA. The cerebellum and brainstem tend to be atrophied in patients who present with predominantly cerebellar features, whereas the putamen and caudate nucleus tend to be involved in patients who present with parkinsonian features. Slitlike hyperintensities are noted on T2- and proton density–weighted MRIs of the pons, middle cerebellar peduncle, and cerebellum. An autopsy-proven case of MSA had hyperintensities in the pyramidal system on T2-weighted fluid-attenuated inversion recovery (FLAIR) MRI.

Correlations between MRI and histopathologic findings support the theory that iron deposition, microgliosis, astrocytosis, and severe neuronal loss may contribute to the abnormal hyperintensities. The most reliable findings specific to MSA are putaminal atrophy, hyperintensity in the rim of the putamen, and infratentorial changes. However, these findings are not observed in all patients with MSA. Altered size of the inferior olivary nuclei and putaminal isointensity or hypointensity relative to the globus pallidus are not useful findings.

While the sensitive detection of putaminal iron deposition by T2*-weighted imaging (T2*-WI) is of dianostic value for MSA, the diagnostic significance of the pontine hot-cross bun (HCB) sign remained unknown. Deguchi et al found that T2*-WI is of value for detecting the HCB sign, which might improve the diagnosis of MSA.

Reduced metabolic activity in the putamen and decreased dopaminergic function in the striatonigral system have been demonstrated on positron emission tomography (PET) in patients with the parkinsonian subtype of MSA. However, these findings also are observed in idiopathic PD. Decreased metabolic activity in the cerebellum has been noted in the cerebellar subtype of MSA. PET studies may be useful in the differential diagnosis of MSA, PSP, and CBD.

Routine MRI can be somewhat helpful in distinguishing MSA, PSP, and CBD. Putaminal involvement and vermian cerebellar atrophy are significantly most common in MSA, but cortical atrophy, midbrain atrophy, and third ventricle enlargement are most common in PSP and CBGD. The role of transcranial sonography in the investigation of these disorders is described below.


Although the exact cause of MSA evades understanding, many pathophysiologic mechanisms have been uncovered.

Iron and ferritin levels appear to be increased in the substantia nigra and striatum. Oligodendroglial and microglial cells are predominantly involved, with neurons and astrocytes relatively spared. Iron levels in the putamen are 5 times higher than normal and are associated with coarse electron-dense granules and fine granular and fibrillary material in lamellated structures. This excessive iron accumulation correlates with the signal voids noted in these structures on MRI. Excessive iron may produce neurotoxicity because of its role in oxidation and reduction reactions. This type of oxidative stress is postulated to be involved in various neurodegenerative disorders. Iron also promotes fibril formation from alpha-synuclein that may be responsible for the formation of GCIs (see Glial cytoplasmic inclusions, below).

Genetic susceptibility involving various genetic markers has been examined without confirmation. Genetic markers for previously identified spinocerebellar disorders are not found in patients with MSA. Mitochondrial chain function in the substantia nigra and platelets of patients with MSA are similar to those of age-matched controls.

Pathologic findings

MSA syndromes have common pathologic findings such as cell loss and gliosis in the striatum, substantia nigra, locus ceruleus, inferior olive, pontine nuclei, dorsal vagal nuclei, cerebellar Purkinje cells, and intermedio-lateral cell columns of the spinal cord. The specific histologic hallmark is glial cytoplasmic inclusions (GCI), which are found mainly in oligodendrocytes.

Macroscopic findings in patients with MSA correlate with neuroimaging and clinical findings. Each MSA subtype demonstrates various degrees of atrophy in the extrapyramidal, spinocerebellar, pyramidal, and autonomic nervous systems. Some depigmentation of the substantia nigra and locus ceruleus is noted in all MSA subtypes. Atrophy of the motor and premotor cortices has also been noted. The intermediolateral cell column of the spinal cord is preferentially involved.

Patients with MSA-P primarily develop extrapyramidal system atrophy such that the posterolateral putamen and ventrolateral substantia nigra appear atrophic and discolored. Patients with MSA-C primarily have shrinkage of the cerebellum, middle cerebellar peduncles, inferior olives, and basis pontis.

Histopathologic findings include neuronal loss, gliosis, and microvacuolation in the involved neuronal systems. These findings are present in varying degrees proportional to the volume loss on gross inspection. Even in regions where atrophy is not noted, these changes are present to some extent.

Demyelination eventually ensues in the white matter in the involved regions. An epitope of myelin basic protein was discovered only in degenerating myelin. Monoclonal antibody probes for this aberrant myelin demonstrate that these white matter lesions are more widespread than previously demonstrated with routine myelin stains.

Autonomic and endocrine manifestations of MSA may be related to neuronal loss in the hypothalamus, spinal cord, and medulla. Cell loss has been found in histaminergic neurons in the tuberomammillary nucleus, arginine-vasopressin neurons in the suprachiasmatic nucleus, and tyrosine hydrolase neurons in the medulla, arcuate nucleus, and spinal cord lateral horns and intermediate zone of the anterior horns. Abnormalities in peripheral nerves and muscles that are absent in patients with idiopathic PD have been found in patients with MSA. Sural nerve biopsy demonstrates a 23% reduction in unmyelinated nerve fibers. Nerve conduction studies are abnormal in 40% of patients with MSA. Abnormal electromyography findings suggesting partial denervation have been found in 22.5% of patients with MSA.

Neurodegeneration affecting axons may be a distinctive characteristic that can differentiate patients with MSA or PSP patients from patients with idiopathic PD. Neurofilament proteins reflecting axonal degeneration are increased in the CSF of patients with MSA or PSP.

Glial cytoplasmic inclusions

Microscopic findings in patients with MSA are distinctive for the cytoplasmic inclusions in the oligodendroglial cells, as well as for neuronal loss, astrocytosis, and loss of myelin. These lesions are predominantly located in the substantia nigra, locus ceruleus, putamen, inferior olives, pontine nuclei, Purkinje cells, and intermediolateral columns of the spinal cord. The globus pallidus, caudate nucleus, corticospinal tracts, anterior horn cells of the cord, dentate nucleus, and vestibular nuclei are relatively spared.

Many neurodegenerative disorders have been associated with a distinctive pathognomonic histopathologic lesion that can assist in diagnosis. Until 1989, no such distinctive lesion was associated with MSA, and the histopathologic diagnosis was based on nonspecific and variable neuronal-system atrophy, cell loss, myelin pallor, and astrocytosis. In 1989, GCIs were described in patients with MSA.

GCIs are argyrophilic and have various shapes (eg, triangular, sickle, half-moon, oval, conical). They are occasionally flame shaped and may superficially resemble neurofibrillary tangles. However, cytoplasmic location, size, ultrastructure, immunocytochemical profile, and regional distribution of GCIs are distinctive. GCIs vary in size; they may fill the cytoplasm completely and push the nucleus to the side. The distribution of GCIs follows the suprasegmental motor system, supraspinal autonomic system, and their targets. This distribution includes the primary and secondary motor cortices, the pyramidal and extrapyramidal tracts, and the corticocerebellar systems.

The density of GCIs correlates with the severity of symptoms of patients with MSA. The distribution of GCIs correlates with the subtypes of MSA: putaminal lesions are prevalent in patients with the MSA-P subtype, and corticopontine lesions are prevalent in patients with the MSA-C subtype. Pyramidal lesions correlate with the severity of symptoms in both subtypes.

Ultrastructural studies of GCIs with electron microscopy and monoclonal antibody probes have confirmed their location in oligodendroglial cells and revealed them to be composed of ubiquitin, tau, microtubule-associated protein-5, cyclin-dependent kinase 5 (cdk5), mitogen-activated protein kinase (MAPK), and alpha synuclein. The tau component in GCIs appears to be immunologically distinct from the tau protein found in patients with Alzheimer disease, PSP, or corticobasal degeneration (CBD). MAPK and cdk5 are usually found in neurons and not oligodendroglial cells. Phosphorylation of these microtubular proteins of the cytoskeleton by these aberrantly located or expressed protein kinases may lead to the formation of GCIs.

Other neuronal inclusions have been observed in both the cytoplasm and nucleus of both oligodendroglial cells and neurons in patients with MSA. However, these findings are seen less commonly than GCIs, which remain the hallmark lesion of MSA. The density of GCIs appears to correlate with the severity of oligodendroglial degeneration and not with the potential degeneration of axons or neurons.

The finding of GCIs within oligodendroglial cells of patients with MSA has led to a shift in research interest from neurons to glial cells in patients with various neurodegenerative disorders. A variety of cellular alterations in glial cells of patients with various neurodegenerative disorders has been described. However, none have resembled GCIs, and the clinical significance of these markers remains unclear. Further research in glial pathology may help uncover the pathophysiology in patients with neurodegenerative disorders.

Treatment and prognosis

Patients who develop MSA are routinely faced with a progressive disorder that eventually culminates in disability and death. Median survival in a study of 100 patients was 6.2 years, with a range of 0.5-24 years. Patients with the cerebellar subtype of MSA survived longer. Response to drug therapy is poor. The ataxia is particularly resistant to therapy. Levodopa replacement is the mainstay of therapy for the parkinsonian features (see carbidopa/levodopa). Responses tend to be less clear-cut and may be transient. Dopamine agonists are not effective and are more likely to cause hallucinations and psychosis. Blepharospasm and limb dystonia can be reduced with botulinum toxin injections.

Autonomic dysfunction, especially orthostatic hypotension, is a prominent feature of the disease. Initial treatment includes reduction of antihypertensive agents, increased salt and water intake, abdominal binders, and use of elastic stockings. Fludrocortisone and midodrine can be helpful when other measures fail. Other medications for treatment of orthostatic hypotension include droxidopa and pyridostigmine.

More in next chapter….

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