Spanish family with Machado-Joseph disease: neurophysiological features and neuropathy study.

OBJECTIVES: We have carried out electrophysiological studies and sural nerve biopsy evaluation in a Spanish family with genetically proven Machado-Joseph disease (SCA3/MJD) phenotype III. PATIENTS AND METHODS: Two symptomatic and other two asymptomatic members of the family were clinically examined. Electrophysiological evaluation included multimodal evoked potentials, quantitative electromyography and nerve conduction studies, and central motor conduction time. We also report neuropathological findings in the sural nerve biopsy in the proband. RESULTS: Analysis of the SCA3/MJD CAG trinucleotide repeat at the ataxin 3 gene in the DNA of the proband and one of his daughters demonstrated an expanded allele of 63 CAG repeat units. Ataxic pursuit was primary disturbed in MJD, followed by gaze evoked nystagmus, hypermetric saccades and glissades. Limitation of vertical and horizontal gaze, impaired sinusoidal vestibulo-ocular reflex and vestibulo-ocular reflex-fixation-suppression, and active and passive optokinetic nistagmus loss appeared at later stages. Evoked potential studies showed multimodal abnormalities. Electrophysiological and sural nerve biopsy findings correspond well to a pattern of both anterior horn and root ganglion cell distal dominant degeneration. Central motor conduction time was normal in our patients up to advanced stages of the disease. CONCLUSIONS: Electrophysiological and neuropathological studies suggested widespread peripheral and central affection in MJD. Repeated application of electrophysiological techniques may prove useful for monitoring disease progress.

Enfermedad de machado-joseph en una familia española: datos neurofisiológicos y estudio de la neuropatía / Spanish family with Machado-Joseph disease: neurophysiological features and neuropathy study

Objetivos: Se han realizado estudios neurofisiológicos y biopsia del nervio sural en una familia española con diagnóstico genético de enfermedad de Machado-Joseph (SCA3/MJD) y fenotipo clínico III. Pacientes y métodos: Se examinaron dos miembros de la familia clínicamente afectados y dos asintomáticos. El estudio neurofisiológico incluyó los siguientes estudios: potenciales evocados multimodales, electromiografía y conducción de nervio, tiempo de conducción motora central y otoneurología. Se realizó biopsia del nervio sural en el caso índice. Resultados: El análisis de la expansión del triplete CAG en el gen de la ataxina 3 de la SCA3/MJD demostró en el ADN del caso índice y de una de sus hijas una expansión alélica de 63 repeticiones. La presencia de un seguimiento ocular atáxico parece ser el primer signo oculomotor de la SCA3/MJD, seguido del nistagmo espontáneo, las sacadas hipermétricas y glissades. La limitación de los movimientos oculares conjugados verticales y horizontales, y las alteraciones del reflejo vestíbulo-ocular en la prueba pendular, de la supresión visual del reflejo vestíbulo-ocular y del nistagmo optocinético (activo y pasivo) se presentan en los estadios posteriores. Los estudios electromiográficos y de conducciones de nervios y los resultados de la biopsia del nervio sural concuerdan con un patrón de afectación degenerativa de las neuronas del asta anterior y del ganglio raquídeo. El tiempo de conducción motora central se mantuvo normal hasta estadios avanzados de la enfermedad. Conclusiones: El resultado de los estudios neurofisiológicos y los hallazgos de la biopsia del nervio sural sugieren una participación extensa del sistema nervioso central y del periférico en la SCA3/MJD. La valoración periódica mediante técnicas neurofisiológicas resulta útil para la monitorización del progreso de esta enfermedad. (AU)

Disability in multiple sclerosis. The role of transcranial magnetic stimulation.

Transcranial magnetic stimulation (TMS) was used to measure intensity threshold, conduction of the central motor pathways (CMCT) and amplitude of the motor evoked potentials (MEPs) in 50 patients with definite form of multiple sclerosis (MS), 31 females and 19 males, aged 15 to 58 years (mean 31.9 +/- 9.8). Abnormalities in at least one parameter after TMS have been found in 76% of the cases. Interside CMCT asymmetries increased the diagnostic yield to 86% of the patients. Three MS individuals with normal clinical examination have prolonged CMCT (silent lesions). There was significant correlation between CMCT and evolution of the disease, and with the degree of pyramidal signs. CMCT correlated with cerebral motor pathway, pons, and cervical cord lesions in MRI study. TMS is an easy and reliable method to quantify pyramidal and cerebellar dysfunction in MS and monitoring the evolution of the disease.

Gene dosage effect in one family with myoclonic epilepsy and ragged-red fibers (MERRF).

OBJECTIVES: We analyzed the percentage of mitochondrial DNA (mtDNA) heteroplasmy in blood samples of 13 individuals belonging to a three family generation of myoclonic epilepsy with ragged-red fibers (MERRF) and compared the 5 affected patients and the 8 unaffected relatives. MATERIAL AND METHODS: DNA was extracted from blood and muscle of the proband and from blood of 12 maternal relatives. A PCR restriction analysis method was used to detect the mutation. RESULTS: The proband had the complete MERRF phenotype. The phenotype in three other individuals in the maternal lineage was consistent with the MERRF syndrome. The remaining were asymptomatic. The np 8344 mutation was observed in muscle and blood of the proband, and in blood from every one of 12 maternal relatives, ranging from 44% to 83% of mutated genomes. Symptomatic individuals had higher levels (P < 0.001) of mutated mtDNA than asymptomatic maternal relatives. However, high proportions of mutant genomes (up to 63%) were found in asymptomatic relatives. CONCLUSIONS: Although there seems to be a gene dosage effect in MERRF, we found no absolute relationship between the relative proportion of mutant genomes in blood and clinical severity. Factors other than gene dosage in blood may account for the differences in clinical phenotype.

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.

Multimodal evoked potentials in multiple system and late onset cerebellar atrophies.

Forty subjects were clinically examined using scales for cerebellar, pyramidal, parkinsonian, and mental status and by quantitative evaluation of neuroimages. The patients were classified into two groups: cerebellar-plus and "pure" cerebellar syndromes. Patients with "pure" cerebellar syndrome were diagnosed as autosomal dominant cerebellar ataxia III (ADCA III) or "pure idiopathic" late-onset cerebellar ataxia (ILOCA) in this series. Patients with cerebellar-plus syndrome were diagnosed as multiple system atrophy (MSA), subclassified as either ILOCA-plus, ADCA I, ADCA II or autosomal recessive LOCA. We have used visual (VEP), brainstem auditory (BAEP) and somatosensory (SEP) evoked potentials in order to establish their diagnostic validity. Cerebellar-plus syndrome and "pure" cerebellar syndrome showed overlapping VEP, BAEP and SEP abnormalities. VEP P100 latency, however, shows a certain ability to differentiate between the two groups (p = 0.08) and appears useful in distinguishing between sporadic cerebellar-plus syndromes (MSA or ILOCA-plus) and "pure" cerebellar syndromes (p < 0.02). The incidence of prolonged N9-N13 latency was significantly higher in the latter subgroup (p < 0.04) as well. Within cerebellar-plus syndromes, VEP, BAEP and SEP abnormalities were more frequent in inherited cases (ADCA I and II, along with autosomal recessive LOCA) than in sporadic ones. The most apparent differences were a higher incidence of abnormal BAEPs at brainstem level (p < 0.002), and of both peripheral and possible central SEP impairment in hereditary cerebellar-plus syndrome than in sporadic cerebellar-plus syndrome (p < 0.03). EP investigation is useful to a certain extent in differentiating between some variants of LOCA.

Cerebrotendinous xanthomatosis diagnosed after traumatic subdural haematoma.

We report the case of a 34-year old man, who, after presenting with subacute traumatic subdural haematoma, was diagnosed as CTX. He presented a ten year history of progressive deterioration of cognitive functions, unsteadiness of gait and surgery for bilateral cataracts at age 21. Cholestanol level in serum was 120.7 mmol/liter, and cholestanol/cholesterol ratio 2.52%. Bile alcohols in urine were 23, 25-pentol: 2.2665 mg/mmol creatinine, 24, 25-pentol: 1.3226 mg/mmol creatinine, and 27-nor-24, 25-pentol: 0.7363 mg/mmol creatinine. Electrophysiological study was consistent with a mixed demyelinating and axonal neuropathy. The assessment of autonomic nervous system (ANS) showed a postganglionic cholinergic failure accompanying somatic peripheral neuropathy. Brain-stem auditory evoked potentials (BAEPs) demonstrated markedly low amplitude and poorly defined waves, and almost symmetrical peak V and I to V interpeak latency (IPL) slight delays. Two nodular, bilateral, symmetrical lesions, strongly suggestive of calcifications, in the cerebellar white matter on CT and MRI were noted. On T2-weighted images diffuse high signal lesions were found in the cerebellar white matter, and multiple, hyperintense cerebral foci of demyelination or gliosis. MRI study of the Achilles tendon showed neither enlargement of the tendon, nor areas of lipid deposits. After ten months of treatment with chenodeoxycholic acid (CDCA) (750 mg/d) the clinical course was unaffected and the neurophysiological measures, CT and MRI remained unchanged.

Can nimodipine prevent ischaemic reperfusion injury in the rat brain?

Reperfusion injury is a pathophysiological entity distinct from the primary ischaemic injury; the oxygen arriving with blood recirculation, although necessary for alleviating the ischaemic status, may be harmful and provoke additional injury in the already damaged tissue. This study aims to analyse whether nimodipine reduces cerebral dysfunction after transient global cerebral ischaemia, using our previously described experimental model, which permits the impregnation of cerebral tissue during the periods of ischaemia and reperfusion. Some aspects of this study contribute to our understanding of the reperfusion injury concept. Three groups of rats were used. Animals in Group 1 (n = 13) served as normal controls for neurophysiological recordings. Rats in Groups 2 (n = 7) and 3 (n = 7) were subjected to global cerebral ischaemia and either isotonic saline (Group 2) or nimodipine solution (Group 3; 40 micrograms/kg) was intra-arterially injected through the external carotid artery during ischaemia and reperfusion and distributed to the circle of Willis. Seventy-two hours after global cerebral ischaemia somatosensory evoked potentials were evaluated and P1 wave latency was used to compare the three groups of animals. The peak onset of this wave was 8.13 +/- 1.5 msec, 18.63 +/- 3.1 msec and 13.17 +/- 2 msec for Groups 1, 2 and 3 respectively. P1 latency was significantly higher in Group 2 than in Groups 1 and 3 (p < 0.01). Histopathological findings showed that the level of injury in the hippocampus and striatum in Group 3 was more limited than in Group 2, although no statistical significance could be found.(ABSTRACT TRUNCATED AT 250 WORDS)