Characteristics of the dysarthria of multiple system atrophy.

OBJECTIVE: To characterize the dysarthria in patients with multiple system atrophy (MSA). DESIGN: Motor speech examinations, consisting of oral motor, oral agility, and perceptual speech analysis, were performed on 46 patients with MSA. SETTING: University department of neurology referral center. RESULTS: All patients had dysarthria with combinations of hypokinesia, ataxia, or spasticity. Thirty-two patients had all 3 components, 13 had 2 components, and 1 had only 1 component. In most patients the hypokinetic components were the most severe. Hypokinetic components predominated in 22 patients (48%), whereas ataxic components predominated in 16 (35%), and spastic components in 5 (11%). In 1 patient (2%) the hypokinetic and spastic components were equal and greater than the ataxic components, and in 1 patient (2%) the hypokinetic and ataxic components were equal and greater than the spastic components. One patient (2%) had only ataxic dysarthria. The predominant type of dysarthria corresponded well to the subtype of MSA. CONCLUSIONS: The finding of a mixed dysarthria with combinations of hypokinetic, ataxic, and spastic components is consistent with both the overall clinical and the neuropathologic changes in MSA. Motor speech examination can provide helpful information in evaluating patients who might have MSA.

Structural and functional brain imaging in Friedreich's ataxia.

BACKGROUND: Although the major neuropathologic changes in Friedreich's ataxia (FA) affect the spinal cord and peripheral nerves, we previously found abnormally increased glucose metabolism in the cerebral hemispheres in ambulatory patients and a return toward normal metabolism in nonambulatory patients. OBJECTIVE: To determine whether brain atrophy accompanies the decline in cerebral glucose metabolism in FA and whether the degree of atrophy and the extent of decline in cerebral glucose metabolism are related to clinical severity. DESIGN: Prospective series. SETTING: University referral center. PATIENTS: Twenty-two patients with FA and 26 patients with dizziness, headache, or minor acute head trauma, serving as control subjects, who underwent computed tomographic scans that were interpreted as normal. MEASURES: In patients with FA and control subjects, regional atrophy was assessed using subjective and objective measures on computed tomographic scans. In patients with FA, local cerebral glucose metabolism was measured with positron emission tomography, and clinical severity was assessed with a clinical rating scale. RESULTS: Atrophy in the cerebral hemispheres, cerebellum, and brain stem was significantly greater in patients with FA than in control subjects, and the degree of atrophy correlated with the clinical severity. Local cerebral metabolic rate for glucose declined significantly from the initially elevated levels in the thalamus, cerebellum, and brain stem in correlation with increasing clinical severity. CONCLUSIONS: The structure and function of wide-spread brain regions including the cerebral hemispheres are abnormal in FA, and these abnormalities correlate with the clinical severity.

Initial therapy of patients with Wilson's disease with tetrathiomolybdate.

Patients with Wilson's disease who present with acute neurological symptoms often become clinically worse when initially treated with penicillamine. Other available anticopper drug therapies do not appear to offer a solution to this treatment problem. We are developing and evaluating a new drug, ammonium tetrathiomolybdate for this purpose. Theoretically, tetrathiomolybdate has optimal properties, including an immediate blockade of copper absorption and the property of forming complexes with copper in the blood, rendering the copper nontoxic. In this article, we present results from six patients treated with tetrathiomolybdate for up to 8 weeks as initial therapy. None of the five patients who had presented with acute neurological symptoms worsened. Also presented are methods of assay, preliminary stability studies, and methods of evaluating therapeutic end points with respect to copper metabolism.

Impaired upper limb coordination in alcoholic cerebellar degeneration.

BACKGROUND: Alcoholic cerebellar degeneration (ACD) is a disorder resulting from severe chronic alcoholism and malnutrition and is characterized by cognitive disturbances, ataxia of gait, and truncal instability, with generally preserved coordination of the upper extremities. OBJECTIVES: To determine whether cognitive deficits in patients with ACD are the same as those seen in patients with severe chronic alcoholism without ACD and to determine whether upper limb motor coordination is different in the 2 groups. DESIGN: We examined cognitive function and upper limb coordination in 56 patients with severe chronic alcoholism, 13 with ACD and 43 without ACD, who had comparable levels of total alcohol intake. Neuropsychological and motor function was measured using an expanded Halstead-Reitan Neuropsychological Test Battery, including the Tactual Performance Test and Grooved Pegboard Test. RESULTS: Neither group had impaired coordination of upper limb function on clinical neurological examination. Both groups had impaired performance on neuropsychological tests involving executive function, but the patients with ACD had greater impairment of upper limb coordination than the patients without ACD as measured by the Tactual Performance Test and Grooved Pegboard Test. CONCLUSIONS: The findings suggest that these 2 groups have similar cognitive deficits but that upper extremity motor functions are more significantly impaired in the ACD group and that quantitative tasks of motor function reveal these impairments.

Treatment of Wilson disease with ammonium tetrathiomolybdate. II. Initial therapy in 33 neurologically affected patients and follow-up with zinc therapy.

OBJECTIVE: To test the efficacy and toxic effects of ammonium tetrathiomolybdate in the initial treatment of a relatively large series of patients with neurologic symptoms and signs caused by Wilson disease. Two key aspects of efficacy are to preserve the neurologic function present at the onset of therapy and to maximize the opportunity for long-term recovery. DESIGN: An open study of 33 patients treated for 8 weeks each, including further follow-up data on the original 17 patients. Neurologic function was evaluated by frequent quantitative neurologic and speech pathology examinations. Several copper-related variables were studied to evaluate the effect of the drug on copper, and several biochemical and clinical variables were studied to evaluate potential toxic effects. Patients were then followed up at yearly intervals, with follow-up periods of 1 to 8 years reported. SETTING: A university hospital referral setting. INTERVENTION: Patients were generally treated for 8 weeks with tetrathiomolybdate, followed by zinc maintenance therapy. MAIN OUTCOME MEASURES: Neurologic function was evaluated by quantitative neurologic and motor speech examinations and magnetic resonance imaging scans of the brain. RESULTS: During the 8 weeks of tetrathiomolybdate administration, only 1 of the 33 patients showed deterioration in neurologic function. Copper status and potential further toxic effects were generally well controlled quickly. Evaluation of data from individual patients revealed evidence of a toxic side effect in only 1 patient, who exhibited reversible anemia. During the ensuing period of follow-up of 1 to 6 years, neurologic recovery in most patients was good to excellent. CONCLUSIONS: Tetrathiomolybdate appears to be an excellent form of initial treatment in patients with Wilson disease who present with neurologic symptoms and signs. In contrast to penicillamine therapy, initial treatment with tetrathiomolybdate rarely allows further, often irreversible, neurologic deterioration.

Neuropsychological changes in olivopontocerebellar atrophy.

We used standardized neuropsychological measures of intellectual, cognitive, psychomotor, and emotional functioning to compare 39 patients with olivopontocerebellar atrophy and 25 normal controls of similar age. The patients reflected greater depression, anxiety, and subjective emotional discomfort than did the control subjects. While 4 of the patients had below-normal IQ scores (Wechsler Adult Intelligence Scale [WAIS-R] Full-Scale IQ [FSIQ] less than 80), their clinical histories suggested lifelong functioning at such levels. As a group, the patients were not abnormal in general intellectual functioning and related cognitive abilities (WAIS-R FSIQ, mean [+/- SD], 93.46 +/- 13.19; Wechsler Memory Scale mental quotient, 108.95 +/- 17.43). These scores were lower than those of the normal controls (WAIS-R FSIQ, 113.72 +/- 12.68; mental quotient, 127.80 +/- 12.40); however, the controls were a highly educated group with intelligence levels that were higher than those of the average population. Moreover, when education and motor dysfunction were statistically covaried, no significant differences between the patients and the normal controls were apparent on the cognitive and intellectual tasks. Further analysis of specific memory performance in a subgroup of patients and controls matched for age, sex, and education yielded findings that were comparable with the overall group analysis. We conclude that motor dysfunction and depressed mood could leave patients with olivopontocerebellar atrophy appearing to be impaired in memory, even demented, when they are not.

Perceptual analysis of speech disorders in progressive supranuclear palsy.

We used oral motor examinations and quantitative perceptual speech analysis to study deviant speech dimensions in 44 patients with progressive supranuclear palsy (PSP). All patients had dysarthria with variable degrees of spasticity, hypokinesia, and ataxia; 28 patients had all three of these components, and 16 patients had only two components. Twenty-two patients (50%) had predominantly spastic components, 15 (34%) had predominantly hypokinetic components, six (14%) had predominantly ataxic components, and in one (2%) the spastic, hypokinetic, and ataxic components were equal. Stuttering occurred in nine patients (20%) and palilalia in five (11%). The finding of a mixed dysarthria with a combination of spastic, hypokinetic, and ataxic components might assist in diagnosis and is consistent with the widespread neuropathologic changes found in PSP.

A comparison of cerebral blood flow and glucose metabolism in olivopontocerebellar atrophy using PET.

OBJECTIVE: In sporadic cases of olivopontocerebellar atrophy (OPCA), to determine whether local cerebral blood flow (lCBF) is reduced, whether lCBF is coupled to local cerebral metabolic rate for glucose (lCMRglc), and whether lCBF measurements are potentially useful in diagnosing OPCA. DESIGN: Positron emission tomography was used with [15O]H2O to measure lCBF and with [18F]fluorodeoxyglucose to measure lCMRglc in 17 patients with OPCA and 21 normal control subjects. RESULTS: In OPCA patients, lCBF was significantly decreased in the cerebellum, but not in the cerebral cortex, basal ganglia, thalamus, or brainstem. In the same patients, lCMRglc was significantly decreased in the cerebellum and brainstem, where the largest changes were observed, and also in the cerebral cortex, basal ganglia, and thalamus. The ratio of lCBF to lCMRglc, an indicator of the coupling of blood flow to metabolism, was similar in OPCA patients and normal subjects for all regions except the brainstem, where the ratio was marginally decreased in OPCA patients. Using logistic discriminant analysis to assess the ability of lCBF and lCMRglc to differentiate OPCA patients from normal subjects, we found the cross-validated sensitivity of absolute lCMRglc as a predictor of OPCA was 82% with a corresponding specificity of 71%; the sensitivity of absolute lCBF was 71% and the specificity 76%. CONCLUSIONS: In sporadic cases of OPCA, lCBF is reduced in the cerebellum, CBF remains coupled to lCMRglc, and the lCBF pattern is a useful predictor of the diagnosis.

Evolution of sporadic olivopontocerebellar atrophy into multiple system atrophy.

OBJECTIVE: To determine the percentage of sporadic olivopontocerebellar atrophy (sOPCA) patients who later develop multiple system atrophy (MSA). METHODS: Observations of the course of 51 sOPCA patients 20 years of age or older initially evaluated in an ataxia clinic over 14 years and followed at 3- to 6-month intervals for 3 months to 10 years (median 2.5 years, interquartile range 5 months to 4 years). RESULTS: Seventeen patients evolved to develop MSA, whereas the remaining 34 manifested only progressively worsening cerebellar ataxia. The features of the MSA cases included autonomic failure and parkinsonism in 10 patients, autonomic failure without parkinsonism in six, and parkinsonism without autonomic failure in one. Using survival analysis methods, the authors estimated that 24% of subjects in this population will evolve to MSA within 5 years of the onset of sOPCA symptoms (95% CI 10% to 36%). An older age at onset of symptoms and a shorter time from onset of symptoms to first presentation in a neurology specialty clinic were both highly predictive of evolution to MSA. Six of the 17 patients who evolved to MSA died 4 months to 5 years after they had met diagnostic criteria for MSA. The estimated median survival time from time of transition was 3.5 years. In contrast, death occurred in only one of the 34 patients with sOPCA who did not evolve to MSA. Autopsy examination of all six patients with MSA who died confirmed the diagnosis. CONCLUSIONS: Approximately one-fourth of sporadic olivopontocerebellar atrophy patients will evolve to multiple system atrophy within 5 years, and this transition carries a poor prognosis for survival. Older age at onset of ataxia and earlier presentation in a neurologic specialty clinic predicted transition to MSA.

Absence of normal activation of the left anterior fusiform gyrus during naming in left temporal lobe epilepsy.

Patients with left temporal lobe epilepsy (TLE) often have impaired naming. We studied 13 patients with left TLE and 10 healthy control subjects with [(15)O]H2O PET during visual confrontation naming. Statistical mapping detected multiple regions of significant cerebral blood flow increases within individuals. The left fusiform gyrus was activated in nine healthy subjects, but only in two patients with TLE (a significant difference, p < 0.001). Other activation sites were more variable in healthy subjects and those with TLE. Impaired naming ability may be associated with a lack of increased cerebral blood flow in the left fusiform gyrus in TLE.

Dysphagia in elderly men with myasthenia gravis.

Eight elderly men whose primary symptoms of myasthenia gravis were decreased speech and swallowing ability were seen for speech pathology evaluations and videofluoroscopic swallow studies. All patients had fatigable flaccid dysarthria and greater than expected pharyngeal phase dysphagia on videofluoroscopy; eight had decreased pharyngeal motility as demonstrated by residual material in the valleculae and pyriform sinuses bilaterally; seven had episodes of laryngeal penetration secondary to overflow of residual material; and five experienced silent aspiration despite gag reflexes and the ability to cough to command. Five patients required feeding tubes because their dysphagia responded poorly to treatment. Videofluoroscopic swallow studies revealed a common swallowing profile with pharyngeal phase dysphagia greater than expected from patient symptoms. Dysphagia did not improve at the same rate as other manifestations of myasthenia gravis.

The patient requiring mechanical ventilatory support: use of the cuffed tracheostomy "talk" tube to establish phonation.

Many patients requiring mechanical ventilatory support via a cuffed tracheostomy tube possess a normal larynx and intact linguistic and cognitive abilities yet are unable to communicate normally because of the interruption of airflow through the intact larynx. The usual alternative means of communication such as writing, gesturing, or the use of an electrolarynx have obvious limitations and are often impossible when there is neurologic motor impairment. Frustration, depression, and compromised medical care are frequent side effects of the patient's inability to communicate. An adapted speaking-aid tracheostomy tube has been available since 1975 for the patient requiring mechanical ventilatory support. However, acceptance and satisfaction with this aid to phonation have not been uniform and there have been few claims of consistent acquisition of phonation. Reasons for success or failure have been unclear. We wish to report experience with the single-cuffed tracheostomy "talk" tube in 19 patients, 14 of whom acquired satisfactory functional laryngeal phonation. Indications for its use, technical aspects of the tube, solutions of common problems, and potential reasons for failure are discussed.

Cerebral glucose hypermetabolism in Friedreich's ataxia detected with positron emission tomography.

Local cerebral metabolic rate for glucose was studied with 18F-2-fluoro-2-deoxy-D-glucose and positron emission tomography (PET) in 22 patients with Friedreich's ataxia and 23 age-matched normal control subjects. The diagnosis of Friedreich's ataxia was established by the history and physical findings and by excluding other diseases through laboratory investigations. PET studies revealed a statistically significant widespread increase of local cerebral metabolic rate for glucose in the brains of patients with Friedreich's ataxia who were still ambulatory, in comparison with normal control subjects. Nonambulatory patients with Friedreich's ataxia, in comparison with normal control subjects, had significantly increased local cerebral metabolic rates for glucose in the caudate and lenticular nuclei, but not in the other structures studied. The rate was significantly greater in ambulatory patients with Friedreich's ataxia than in nonambulatory patients in all structures studied except the caudate and lenticular nuclei. The data suggest that early in the course of Friedreich's ataxia, the local cerebral metabolic rate for glucose is increased extensively in the central nervous system, and as the disease progresses, it decreases in a regionally specific manner.

Patterns of cerebral glucose metabolism detected with positron emission tomography differ in multiple system atrophy and olivopontocerebellar atrophy.

We used positron emission tomography with [18F]fluorodeoxyglucose to study local cerebral metabolic rates for glucose (ICMRglc) in patients with multiple system atrophy (MSA), sporadic olivopontocerebellar atrophy (sOPCA), and dominantly inherited olivopontocerebellar atrophy (dOPCA) in comparison with normal control subjects. IN MSA, absolute lCMRglc was significantly decreased in the brainstem, cerebellum, putamen, thalamus, and cerebral cortex. In sOPCA, absolute lCMRglc was significantly decreased in the brainstem, cerebellum, putamen, thalamus, and cerebral cortex. In dOPCA, absolute lCMRglc was significantly decreased in the brainstem and cerebellum but not in the other structures. Examination of lCMRglc normalized to the cerebral cortex in comparison with normal controls revealed in MSA significant decreases in the brainstem, cerebellum, and putamen but, in both sOPCA and dOPCA, significant decreases only in the brainstem and cerebellum. The findings indicate that these three disorders all show a marked decrease of lCMRglc in the brainstem and cerebellum but differ in the degree of hypometabolism in forebrain and cerebral cortical structures. The results are consistent with the possibility that, in many cases, sOPCA will evolve into MSA. Moreover, positron emission tomography may provide helpful diagnostic information in these neurodegenerative diseases.

Speech disorders in olivopontocerebellar atrophy correlate with positron emission tomography findings.

We compared the severity of ataxic and spastic dysarthria with local cerebral metabolic rates for glucose (lCMRGlc) in 30 patients with olivopontocerebellar atrophy (OPCA). Perceptual analysis was used to examine the speech disorders, and rating scales were devised to quantitate the degree of ataxia and spasticity in the speech of each patient. lCMRGlc was measured with 18F-2-fluoro-2-deoxy-D-glucose and positron emission tomography (PET). PET studies revealed marked hypometabolism in the cerebellar hemispheres, cerebellar vermis, and brainstem of OPCA patients compared with 30 control subjects. With data normalized to the cerebral cortex, a significant inverse correlation was found between the severity of ataxia in speech and the lCMRGlc within the cerebellar vermis, cerebellar hemispheres, and brainstem, but not within the thalamus. No significant correlation was found between the severity of spasticity in speech and lCMRGlc in any of these structures. The findings support the view that the severity of ataxia in speech in OPCA is related to the functional activity of the cerebellum and its connections in the brainstem.

Motor dysfunction in olivopontocerebellar atrophy is related to cerebral metabolic rate studied with positron emission tomography.

We compared the severity of motor dysfunction with local cerebral metabolic rates for glucose (lCMRGlc) and the degree of tissue atrophy in 30 patients with olivopontocerebellar atrophy (OPCA). We devised a scale to quantitate the degree of ataxia in the neurological examinations. lCMRGlc was measured with 18F-2-fluoro-2-deoxy-D-glucose and positron emission tomography (PET). Tissue atrophy was assessed by visual rating of computed tomographic scans. PET studies revealed marked hypometabolism in the cerebellar vermis, cerebellar hemispheres, and brainstem of OPCA patients compared with 30 control subjects. A significant correlation was found between severity of motor impairment and lCMRGlc within the cerebellar vermis, both cerebellar hemispheres, and the brainstem. A significant but weaker relationship was noted between the degree of tissue atrophy in these regions and clinical severity. Partial correlation analysis revealed that motor dysfunction in OPCA correlated more strongly with lCMRGlc than with the amount of tissue atrophy. These results suggest that the clinical manifestations of OPCA are more closely related to the metabolic state of the tissue than to the structural changes in the cerebellum.

Benzodiazepine receptor binding in cerebellar degenerations studied with positron emission tomography.

We used positron emission tomography with [11C]flumazenil to study gamma-aminobutyric acid type A/benzodiazepine receptor binding quantitatively in the cerebral hemispheres, basal ganglia, thalamus, cerebellum, and brainstem of 72 subjects, including 14 with multiple system atrophy of the ataxic (olivopontocerebellar atrophy) type, 5 with multiple system atrophy of the extrapyramidal/autonomic (Shy-Drager syndrome) type, 18 with sporadic olivopontocerebellar atrophy, 15 with dominantly inherited olivopontocerebellar atrophy, and 20 normal control subjects with similar age and sex distributions. In comparison with data obtained from the normal control subjects, we found significantly decreased ligand influx in the cerebellum and brainstem of multiple system atrophy patients of the olivopontocerebellar atrophy type and in patients with sporadic olivopontocerebellar atrophy, but not in patients with multiple system atrophy of the Shy-Drager syndrome type. Despite these differences in ligand influx, benzodiazepine binding was largely preserved in the cerebral hemispheres, basal ganglia, thalamus, cerebellum, and brainstem in patients with multiple system atrophy of both types as well as those with sporadic or dominantly inherited olivopontocerebellar atrophy as compared with normal control subjects. The finding of relative preservation of benzodiazepine receptors indicates that these sites are available for pharmacological therapy in these disorders.

Spinocerebellar ataxia type 1 with multiple system degeneration and glial cytoplasmic inclusions.

Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited progressive neurological disorder characterized by neuronal degeneration and reactive gliosis in the cerebellum, brainstem, spinocerebellar tracts, and dorsal columns. Multiple system atrophy is a sporadic progressive neurological disorder with degeneration and gliosis in the basal ganglia, cerebellum, brainstem, and spinal autonomic nuclei, and with argyrophilic glial cytoplasmic inclusions. We describe 4 members of a family with the SCA1 mutation and a dominantly inherited progressive ataxia in which autopsy examination of 1 member showed neuropathological changes typical of multiple system atrophy, including glial cytoplasmic inclusions. In this patient, magnetic resonance imaging revealed marked brainstem and cerebellar volume loss and mild supratentorial generalized volume loss. Positron emission tomography with [18F]fluorodeoxyglucose revealed widespread hypometabolism in a pattern found in sporadic multiple system atrophy and not in dominantly inherited olivopontocerebellar atrophy. Positron emission tomography with [11C]flumazenil revealed normal benzodiazepine receptor distribution volumes, similar to those seen in sporadic multiple system atrophy. Two other family members still living had similar changes in the imaging studies. The findings in this family suggest that the SCA1 gene mutation can result in a disorder similar to multiple system atrophy, both clinically and neuropathologically.

Treatment of Wilson's disease with zinc. XVII: treatment during pregnancy.

Therapy of Wilson's disease continues to evolve. In 1997, zinc acetate was added to the list of drugs approved by the Food and Drug Administration, which includes penicillamine and trientine. The mechanism of zinc's anticopper action is unique. It induces intestinal cell metallothionein, which binds copper and prevents its transfer into blood. As intestinal cells die and slough, the contained copper is eliminated in the stool. Thus, zinc prevents the intestinal absorption of copper. It is universally agreed that pregnant Wilson's disease patients should remain on anticopper therapy during pregnancy. There are numerous reports of such patients stopping penicillamine therapy to protect their fetus from teratogenicity, only to undergo serious deterioration and even death from renewed copper toxicity. Penicillamine and trientine have teratogenic effects in animals, and penicillamine has known teratogenic effects in humans. In this report we discuss the results of 26 pregnancies in 19 women who were on zinc therapy throughout their pregnancy. The evidence is good that zinc protects the health of the mother during pregnancy. Fetal outcomes were generally quite good, although one baby had a surgically correctable heart defect and one had microcephaly.