Multiple system atrophy: clinical presentation and diagnosis

Multiple system atrophy (MSA) describes a relatively uncommon, debilitating disorder that is frequently misdiagnosed as Parkinson's disease. Patients with MSA show various combinations of parkinsonism, cerebellar ataxia, pyramidal signs and progressive autonomic failure, especially cardiovascular and urologic autonomic dysfunction. Few treatment options exist. Although some patients initially respond well to dopaminergic treatment for their parkinsonian symptoms, striatal degeneration occurs, and levodopa often becomes ineffective. Thus, physicians may provide only symptomatic treatment and support for patients with MSA. In this paper, we present a case study of a 68-year-old woman who came to the Vanderbilt Movement Disorders Clinic with severe autonomic dysfunction and parkinsonism, previously diagnosed as Parkinson's disease. Following autonomic function tests as well as clinical evaluation, she was diagnosed with MSA and began treatment for orthostatic hypotension and micturition dysfunction.     

Recurrent torticollis due to cervical osteochondroma. Case report and review of the literature]

A patient is presented who had bilateral abductor vocal fold paralysis pathologically proven to be due to multiple system atrophy (MSA) in the absence of other neurological features. MSA is a degenerative neurological condition that includes olivopontocerebellar atrophy, Shy-Drager syndrome and striatonigral degeneration. The usual predominant features of MSA are cerebellar ataxia, autonomic dysfunction and Parkinsonism. Stridor is present in over one third of patients and has been reported previously as a presenting symptom in MSA: however previously reported patients have always gone on to develop other neurological symptoms. The usual investigations of bilateral abductor vocal fold paralysis caused by MSA will not reveal the pathological process and we believe that magnetic resonance imaging (MRI) of the medulla and brain stem and autonomic function tests are probably the investigations of choice. It is a worthwhile exercise attempting to identify MSA as the cause of stridor as the prognosis is good in the medium term if appropriate support is offered.     

The diagnosis and follow-up evaluation of acute cerebellar ataxia supported by a cerebellar stimulation study]

A 70-year-old woman who has been suffering from diabetes mellitus since 67 years of age rapidly developed severe truncal ataxia. Neurological examination showed severe truncal ataxia, incoordination and decreased deep sensations in the bilateral lower extremities. A CSF study revealed a moderately elevated total protein (125 mg/dl) without any elevation of the cell count. A nerve conduction study supported the diagnosis of polyneuropathy. Lumbar MRI revealed spinal canal stenosis at the L3/L4-L5/S1 intervertebral levels due to disk herniations and ossification of the yellow ligaments. We examined cerebellar stimulation in order to determine whether the ataxia was due to dysfunction of the cerebellum or peripheral nervous system. Conditioning electrical stimulation over the cerebellum did not change the size of motor potentials evoked by magnetic cortical stimulation in the right first dorsal interosseous muscle. Her clinical course was good, and the limb and truncal ataxia became very mild about 4 months after the onset, although there was little change in the decreased deep sensations. The cerebellar stimulation in the second study was normal. We diagnosed her as having acute cerebellar ataxia and thought that the decreased deep sensations were due to diabetic polyneuropathy and lumbosacral radiculopathies. A cerebellar stimulation study was useful for the diagnosis and follow-up evaluation of acute cerebellar ataxia in this patient.     

Atypical parkinsonism in a family of Portuguese ancestry: absence of CAG repeat expansion in the MJD1 gene

We studied the clinical features and molecular genetics of a family, afflicted with a form of atypical parkinsonism, originating from the Madeira Islands of Portugal. We examined four affected individuals and reviewed clinical information on one other affected family member. Mean age at onset was 31 years. Parkinsonism (akinesia, rigidity, gait disturbance) was the most prominent feature in advanced disease. Levodopa responsiveness with peak-dose dyskinesia was present in one individual. Initial symptoms and other clinical features were variable and included other extrapyramidal signs (dystonia, action tremor of the limbs and bulbar muscles, synkinesis), ophthalmologic abnormalities (ptosis, slow saccades, progressive external ophthalmoplegia, hypometric saccades, saccadic pursuit movements), speech abnormalities (dysarthria, hypernasality), cortical impairment (dementia, frontal lobe dysfunction, palilalia, perseveration), minor cerebellar signs (dysmetria, gait ataxia), pyramidal abnormalities (spasticity, hyperreflexia), and peripheral nervous system abnormalities (propioceptive loss, areflexia, distal weakness, atrophy). The length of trinucleotide repeats in the MJD1 gene was in the normal range for all affected individuals.     

Autoantibodies to glutamic acid decarboxylase in three patients with cerebellar ataxia, late-onset insulin-dependent diabetes mellitus, and polyendocrine autoimmunity

BACKGROUND: Glutamic acid decarboxylase (GAD) is the main target of humoral autoimmunity in stiff-man syndrome (SMS) and insulin-dependent diabetes mellitus (IDDM). GAD autoantibodies (GAD-Abs) are reported in a few patients with cerebellar ataxia, but their relevance is unclear. We describe three patients with cerebellar ataxia and GAD-Abs. METHODS: GAD-Abs were assayed by radioimmunoassay (RIA) and immunohistochemistry and confirmed by immunoblot of recombinant human GAD65. The GAD-Ab levels of the three patients with cerebellar ataxia were compared with those of five with SMS, 49 with IDDM, 64 with cerebellar ataxia of probable degenerative origin without associated autoimmune features, 14 non-IDDM islet cell antibody-positive first-degree relatives of IDDM patients, and 91 normal subjects. RESULTS: The three patients with ataxia and GAD-Abs were women (mean age, 63 years) with an isolated progressive cerebellar disorder, family history of IDDM, late-onset IDDM, and several positive serum organ-specific autoantibodies. Two patients had autoimmune thyroiditis, and one had pernicious anemia. CSF analysis demonstrated oligoclonal IgG bands and intrathecal synthesis of GAD-Abs. By RIA, GAD-Ab titers from the three patients were similar to those of SMS and significantly higher, without overlap, than the titers of IDDM patients. GAD-Abs were absent in the 64 patients with cerebellar ataxia and no evidence of autoimmune disorders. CONCLUSIONS: These findings suggest a link of GAD autoimmunity not only with SMS but also with cerebellar dysfunction. GAD-Abs should be sought in patients with cerebellar ataxia who have late-onset IDDM and other organ-specific autoimmune manifestations.     

Multiple-system atrophy is genetically distinct from identified inherited causes of spinocerebellar degeneration

Multiple system atrophy (MSA) is a neurodegenerative disorder of unknown cause. The only case-control study conducted in MSA patients to date suggested a possible contributory genetic component in the pathogenesis of this disorder. The aim of this study was to evaluate a possible overlap between clinically or pathologically well-defined MSA and other conditions with an identified genetic defect causing spinocerebellar degeneration in humans or mutant mice strains. The spinocerebellar ataxia type 1 and 3 genes (SCA1 and SCA3) were analyzed for a pathologic expansion in 80 patients with MSA to evaluate a possible overlap between MSA and SCA1 or SCA3. Weaver mice and lurcher mice are animal models for spinocerebellar degeneration; both share pathologic features with MSA. We sequenced the H5 pore region of the human homologue of the weaver mouse gene, hiGIRK2, in all our patients. In lurcher mice, previous biochemical studies have shown a decreased intracellular response to insulin-like growth factor 1 (IGF-1) in the cerebellar cortex, and we thus investigated the possibility of an allelic association between MSA and the receptor for IGF-1. In addition, we evaluated a possible involvement of the ciliary neurotrophic factor gene (CNTF) and examined the role of HLA-A32 to clarify the conflicting data from previous studies. No changes were detected in any of the analyzed genes. Our studies strongly suggest that MSA is an autonomous syndrome distinct from identified genetic causes for spinocerebellar degeneration.     

Atypical Parkinson syndrome

Various clinico-pathological studies have shown that appr. 20% of patients with a clinical diagnosis of idiopathic Parkinson's disease (IPD) may have neuropathological evidence of alternative causes of parkinsonism. Most of these misdiagnosed "IPD" patients meet clinical criteria for either multiple system atrophy (MSA), or progressive supranuclear palsy (PSP), or corticobasal degeneration (CBD). A careful history and physical examination, as well as follow-ups and selected investigations are essential for an accurate clinical diagnosis of these atypical parkinsonian syndromes. The following paper therefore provides a review of clinical features and diagnostic findings in MSA, PSP and CBD, in order to facilitate recognition of these patients.     

Incidence of progressive supranuclear palsy and multiple system atrophy in Olmsted County, Minnesota, 1976 to 1990

Information on the incidence of progressive supranuclear palsy (PSP) is limited; incidence rates for multiple system atrophy (MSA) are not available. We studied the incidence of PSP and MSA in Olmsted County, Minnesota, for the years 1976 to 1990. This study was part of a larger investigation of all forms of parkinsonism. We used the medical records-linkage system of the Rochester Epidemiology Project to identify all subjects whose records contained documentation of any from of parkinsonism, related neurodegenerative diseases, or tremor of any type. A nurse abstractor screened the records and, when applicable, a neurologist reviewed them to determine the presence or absence of parkinsonism. Cases of parkinsonism were classified using specified diagnostic criteria. Population denominators were derived from census data and were corrected by removing prevalent cases of parkinsonism. Over the 15 years of the study, we found 16 incident cases of PSP and nine incident cases of MSA. No cases of PSP or MSA had onset before age 50 years. The average annual incidence rate (new cases per 100,000 person-years) for ages 50 to 99 years was 5.3 for PSP and 3.0 for MSA. The incidence of PSP increased steeply with age from 1.7 at 50 to 59 years to 14.7 at 80 to 99 years, and was consistently higher in men. Median survival time from symptom onset was 5.3 years for PSP and 8.5 years for MSA. The incidence of PSP increases with age and is consistently higher in men at all ages. PSP and MSA are more common than previously recognized.     

Simultaneous protection of G156A methylguanine DNA methyltransferase gene-transduced hematopoietic progenitors and sensitization of tumor cells using O6-benzylguanine and temozolomide

OBJECTIVE: To describe the clinical and radiologic features of superficial siderosis of the CNS after treatment of a cerebellar tumor. METHODS: Clinical assessment and MRI in four patients with superficial siderosis were performed. RESULTS: Four patients with superficial siderosis had been treated for a primary cerebellar tumor (astrocytoma in three patients, medulloblastoma in one patient) during childhood. All patients were treated with surgery and three received radiotherapy. Slowly progressive bilateral sensorineural hearing loss, gait ataxia, and limb ataxia appeared 8 to 22 years after diagnosis of the cerebellar tumor. Other clinical features were mild cognitive impairment, dysarthria, nystagmus, optic neuropathy, anosmia, and upper motor neuron signs. The CSF contained erythrocytes and increased protein. MRI with fast spin-echo T2-weighted and gradient-echo T2* sequences showed a hypointense rim of iron coating the surface of the cerebellum and brainstem. Twenty-one other patients who had survived more than 5 years after treatment of a primary cerebellar tumor did not have symptoms or signs suggestive of superficial siderosis. CONCLUSIONS: Superficial siderosis is an uncommon late complication of the treatment of a childhood cerebellar tumor, but it is probably underrecognized. The diagnosis should be suspected in patients who present with slowly progressive sensorineural hearing loss and ataxia many years after eradication of a childhood cerebellar tumor.     

Neurological complications of chlamydial infections: case report and review

We describe a patient with Chlamydia pneumoniae infection who presented with cerebellar dysfunction, followed by respiratory failure requiring mechanical ventilation. C. pneumoniae is an important respiratory pathogen, and other clinical manifestations, including neurological syndromes, are being increasingly recognized. Meningoencephalitis and other neurological complications have also been described in patients with infections due to Chlamydia psittaci and Chlamydia trachomatis. Chlamydial infections should be included in the differential diagnosis of neurological syndromes, including cerebellar dysfunction.     

Mapping of a new autosomal dominant spinocerebellar ataxia to chromosome 22

The autosomal dominant cerebellar ataxias (ADCAs) are a clinically and genetically heterogeneous group of disorders. The clinical symptoms include cerebellar dysfunction and associated signs from dysfunction in other parts of the nervous system. So far, five spinocerebellar ataxia (SCA) genes have been identified: SCA1, SCA2, SCA3, SCA6, and SCA7. Loci for SCA4 and SCA5 have been mapped. However, approximately one-third of SCAs have remained unassigned. We have identified a Mexican American pedigree that segregates a new form of ataxia clinically characterized by gait and limb ataxia, dysarthria, and nystagmus. Two individuals have seizures. After excluding all known genetic loci for linkage, we performed a genomewide search and identified linkage to a 15-cM region on chromosome 22q13. A maximum LOD score of 4.3 (recombination fraction 0) was obtained for D22S928 and D22S1161. This distinct form of ataxia has been designated "SCA10." Anticipation was observed in the available parent-child pairs, suggesting that trinucleotide-repeat expansion may be the mutagenic mechanism.     

The differential involvement of adrenoceptors in challenges of different intensities

We investigated a family with optic atrophy which occurred in childhood or early adulthood plus late-onset cerebellar ataxia. The magnetic resonance imaging in the proband revealed cerebellar atrophy. The proband and her brother were homoplasmic for the most common mitochondrial DNA (mtDNA) 11778 mutation associated with Leber's hereditary optic neuropathy (LHON). This study showed further evidence that central nervous system lesions can occur in cases of LHON mtDNA mutation.     

Magnetic resonance spectroscopy in Parkinson's disease and multiple system atrophy

Recent advances in magnetic resonance spectroscopy(MRS) allow to assay noninvasively key molecules of brain metabolism in living patients. There are several reports of MRS in Parkinson's disease(PD) and multiple system atrophy(MSA). 1H-MRS of the striatum revealed the reduced NAA/Cr and Cho/Cr ratio in MSA patients and the preserved NAA/Cr and Cho/Cr ratio in PD patients. The reduced NAA/Cr ratio probably reflects striatal neuronal loss. 1H-MRS of the striatum showed increased Cho/Cr ratio in the "on" state compared with that in the "off" state in the PD patients. The increased Cho/Cr ratio may reflect some membrane alteration or change of choline metabolism in PD with the "wearing-off" phenomena. Although studies are still preliminary, MRS shows great possibility for aiding in the differential diagnosis of parkinsonism and it will contribute to a better understanding of the pathogenesis of PD and MSA.     

Reversible neurological complications in chronic alcohol abuse with hypophosphatemia

Severe hypophosphatemia is rare, usually affecting chronic alcoholics and patients under total parenteral nutrition. The most important clinical features are rhabdomyolysis and neurological deficits. The latter may take various forms and can affect the peripheral as well as the central nervous system. Symptoms of polyradiculitis with progressive paresis or cerebellar symptoms such as dysarthria, dysphagia and ataxia are frequent manifestations. Rarely, hypophosphatemia can cause confusional states, epileptic seizure or coma. The differential diagnosis includes Guillain-Barré polyradiculitis, diffuse encephalopathy, Wernicke encephalopathy and central pontine myelinolysis. We describe the neurological signs in a female chronic alcoholic who developed severe ataxia and tetraparesis after a week's course of parenteral, phosphate-free nutrition. Complete recovery occurred after adequate substitution of phosphate.     

Primary localized amyloidosis of the ureter

The slit hyperintensity of the lateral margin of the putamen in T2 weighted MRI is a characteristic finding in those patients with multiple system atrophy (MSA) involving extrapyramidal system. In spite of some speculations such as demyelination, gliosis, iron deposition or increased extracellular fluid, the nature of the abnormal signal intensity has still been remained uncertain. In this paper, we report the coincidental findings of pathology and magnetic resonance imaging of the putaminal margin in a case of MSA. The patient was sixty three years old woman with nine years history of intreatable parkinsonism, mild ataxia and dysautonomia. At six months prior to her death, 0.5T MRI showed the pontocerebellar system atrophy, slit hyperintensity in the bilateral outer margin and left inner margin of the putamen in T2 weighted image as well as linear hypointensity in T1 weighted image. The neuropathological examinations showed severe degeneration in the olivopontocerebellar and striatonigral systems, and glial cytoplasmic inclusion in widespread regions in the brain. The putamen showed severe degeneration with rarefaction. The intertissue space was observed at the outer putaminal margin in both sides and inner margin in left side, which seemed to be caused by severe shrinkage and rarefaction of the putamen. Thus, slit hyperintensity in the putaminal margin in MSA was disclosed to represent widened intertissue space.     

Effect of buspirone, a serotonergic 5-HT-1A agonist in cerebellar ataxia: a pilot study. Preliminary communication

We propose a serotonergic hypothesis for cerebellar ataxia. The levorotatory form of 5 hydroxytryptophan has been shown to be partially active in subtypes of cerebellar ataxia, including cerebellar cortical atrophy (CCA). Buspirone, a 5-HT1A agonist usable in human medicine, has been studied in a group of 14 patients with cerebellar cortical atrophy. Patients were given Buspirone for 2 months. The evaluation of cerebellar ataxia was made by a semi-quantitative scale, 10 fully quantitative measures and measurements of the sway path and sway area of the center of gravity at posturography. The primary endpoints were the modifications of the ataxia scores. At 2 months, the decrease of the ataxia scores was significant, both in the intention-to-treat (14 cases) and target (11 cases) populations. In the target population, secondary endpoints like the time measurements for pronouncing a standard sentence, the time for drawing a ladder and posturographic parameters were significantly improved; the mean global ataxia score was improved by 37.4%. These preliminary data might confirm a link between cerebellar ataxia and the metabolism of serotonin.     

Adult polyglucosan body disease associated with an extrapyramidal syndrome

A 50 year old patient is described who presented with parkinsonism, frontal dementia, peripheral neuropathy, neurogenic bladder, and upper motor neuron signs. No improvement in objective measurements of extrapyramidal dysfunction were seen with an incremental apomorphine test or more prolonged oral dopamine challenge. Neurophysiology disclosed changes compatible with a diffuse axonal neuropathy and pathological examination of a length of sural nerve taken at biopsy showed multiple polyglucosan bodies characteristic of adult polyglucosan body disease (APGBD). This case underlines the diverse clinical presentation of this rare neurological disease and the importance of recognising the unusual association of clinical features in making the diagnosis. APGBD should be included in the differential diagnosis of parkinsonism unresponsive to dopaminergic therapy.     

Electro-oculogram in multiple system and late onset cerebellar atrophies

The present investigation uses electrooculogram to evaluate multiple system atrophy (MSA) and late onset cerebellar atrophies (LOCAs), both idiopathic (ILOCA) and late onset autosomal dominant cerebellar ataxia (ADCA). Forty cases were clinically examined using scales for cerebellar, pyramidal, parkinsonian, mental status and neuroimaging quantitative evaluations. The patients were classified into three groups: olivopontocerebellar atrophy (OPCA), striatonigral degeneration (SND), Shy-Drager syndrome (SDS), and LOCA. We have used direct current electro-oculography in order to establish their validity in making the diagnosis. Cerebellar signs were significantly correlated with impaired VOR-fix gain and OKN, abnormalities of saccades, and reduced smooth pursuit gain (p < 0.05). Pons atrophy was significantly correlated with impaired VOR-fix gain (p < 0.01), abnormalities of saccades (p < 0.01), and reduced smooth pursuit gain (p < 0.05). Cerebellar hemisphere atrophy was significantly correlated only with impaired VOR-fix gain (p < 0.05), and medulla oblongata atrophy only with abnormalities of saccades (p < 0.05). Gaze-evoked nystagmus was found in 42.8% of patients with OPCA, and only in 14.2% with SND, but was not found in LOCA patients (t test, p < 0.05). In patients with OPCA, the combination of gaze-evoked nystagmus, abnormalities of sinusoidal VOR and reduced OKN gain measurements was very frequent, while infrequent in both LOCA (Fisher's exact test, p < 0.05) and SND subjects (p < 0.01). SDS also showed abnormalities of the oculomotor system.     

Molecular and clinical studies in SCA-7 define a broad clinical spectrum and the infantile phenotype

OBJECTIVE: To screen for the SCA-7 mutation in autosomal dominant cerebellar ataxia (ADCA) families and study genotype/phenotype correlations. BACKGROUND: The association of cerebellar ataxia and progressive pigmentary macular dystrophy clinically defines a distinct form of ADCA classified as SCA-7. SCA-7 is caused by expansion of a highly unstable CAG repeat that lies in the coding region of a novel gene on chromosome 3p12-13. METHODS: We screened 51 ADCA kindreds, in which SCA-1, SCA-2, SCA-3, and SCA6 mutations had been excluded, for the SCA-7 mutation using primers that specifically amplify the SCA-7 CAG repeat. RESULTS: The SCA-7 mutation was identified in 10 independent families. Normal alleles ranged from 7 to 16 repeats; expanded alleles ranged from 41 to 306 repeats. One allele with 36 repeats was found in an asymptomatic individual carrying an at-risk haplotype. SCA-7 presents a wide spectrum of clinical features including visual loss, dementia, hypoacusia, severe hypotonia, and auditory hallucinations. Juvenile SCA-7 occurs on maternal and paternal transmission of the mutation, whereas the infantile form occurs only on paternal transmission. An infant of African American descent carried the largest SCA-7 expansion (306 CAG repeats) and had severe hypotonia, congestive heart failure, patent ductus arteriosus, cerebral and cerebellar atrophy, and visual loss. CONCLUSION: These data show a wide spectrum of phenotypic abnormalities in SCA-7 and define an infantile phenotype caused by the largest CAG repeat expansion described to date.