[Acute necrotizing encephalopathy: patient with a relapsing and lethal evolution]. / Encefalopatia necrotizante aguda: paciente com evolução recidivante e letal.

Acute necrotizing encephalopathy was initially reported in Japanese children. The rapid evolution and symmetrical brain lesions seen in the brainstem, cerebellum and specially in the thalamus characterize the disease. We studied a 7-month-old-girl, who presented with two episodes of rapid loss of consciousness and paresis without metabolic disturbances. At the first time she had a rapid improvement, but at the second episode the course was fulminant and in two days she lapsed into a clinical state of brain death. The magnetic resonance studies showed symmetrical lesions in the thalamus and additional lesions involving the brainstem and the cerebellum.

Limits of clinical assessment in the accurate diagnosis of Machado-Joseph disease.

BACKGROUND: Machado-Joseph disease (MJD) is a type of autosomal dominant spinocerebellar ataxia for which molecular diagnosis is available. We identified 4 families segregating the MJD mutation in which no unequivocal clinical diagnosis could be established prior to molecular testing. Ethnic background, clinical, and molecular characteristics of 19 individuals carrying the MJD mutation in these 4 families were compared with a group of 32 Portuguese families who were clinically diagnosed as having MJD and were found to carry the MJD mutation. RESULTS: Several factors seemed to have an impact in the accuracy of the clinical diagnosis, such as ethnic origin; the number of affected individuals available for examination in each family; the absence of patients showing specific clinical features, such as extrapyramidal signs; and the size of the expanded CAG repeat in the MJD gene. CONCLUSION: Since the recognition of MJD based solely on clinical grounds might sometimes be misleading, a search for the MJD mutation should be performed in patients with a clinical diagnosis of spinocerebellar degeneration.

Selective electroencephalograph-guided microsurgical callosotomy for refractory generalized epilepsy.

Between 1978 and 1985, 35 patients with medically refractory multiform seizures were submitted for sections of variable portions of the corpus callosum. Guided by intraoperative electroencephalographic and electrocorticographic monitoring, the section was carried out only in the portion of callosum that was involved in the maintenance of the bilaterally synchronous slow spike and wave discharge (as documented by intraoperative electrocorticography). In our patients, only part of the frontal corpus callosum needed to be sectioned to interrupt the bilateral synchrony of epileptic discharge. Of the 35 patients, operated on, 28 have had an adequate long-term follow up and are presented herein. All had significant improvement in seizure frequency and psychosocial functioning.

Machado-Joseph disease of Azorean ancestry in Brazil: the Catarina kindred. Neurological, neuroimaging, psychiatric and neuropsychological findings in the largest known family, the "Catarina" kindred.

At the moment 9 seemingly independent families with the clinical diagnosis of MJD are known in Brazil. The largest family tree of Azorean ancestry contains 622 individuals in 9 generations. 236 were examined, 39 found to be affected by two examiners. Phenotypes I, II and III were expressed by 12, 23 and 4 patients with age of onset by phenotypes being 10-48, 14-54 and 30-55 respectively. Although clinically more severe, juvenile onset type I disease did not show as severe a ponto-mesencephalic atrophy on MRI as the father with type II disease of similar symptomatic duration. None of the 8 patients examined with MRI showed olivary atrophy or pallidal abnormalities. 12 affected and 23 at risk were evaluated with neuropsychological tests. Attention was normal in both groups. Verbal memory scores were below normal in the affected and there was greater decay with time than in the risk group. Both scored below normal in identifying silluettes and constructional praxis. Visual memory scores were well below normal for both, with many rotations but no omissions or confabulations. A peculiar pattern of multiplying internal details called "the fly-eye effect" was observed in 6 affected and 8 at risk. Defective color distinction when multiple colors presented close to each other, in face of proper naming of individual colors ("color simulatanagnosia"), was looked for in 29 people. 4/10 affected and 4/19 at risk showed this phenomenon. Cognitive dysfunctions in this MJD family are prominent in the sphere of vision. Whether they constitute an early manifestation in those at risk and thus serve as a clinical identifier of the illness is yet to be established. Depression was looked for in the history of the family with DSM III-R criteria and an attempt at quantification with the Montgomery-Asberg Rating Scale. There was no significant quantitative difference between affected and at risk. Once undeniably symptomatic however, the patients had no, or less depression than themselves before or at the early stages of the illness. Covert depression was appropriately excluded. Fully established MJD in this family seemed to exert a protective effect from depression.

Frequency of the different mutations causing spinocerebellar ataxia (SCA1, SCA2, MJD/SCA3 and DRPLA) in a large group of Brazilian patients.

Spinocerebellar ataxia type 1 (SCA1), spinocerebellar ataxia type 2 (SCA2) and Machado-Joseph disease or spinocerebellar ataxia type 3 (MJD/SCA3) are three distinctive forms of autosomal dominant spinocerebellar ataxia (SCA) caused by expansions of an unstable CAG repeat localized in the coding region of the causative genes. Another related disease, dentatorubropallidoluysian atrophy (DRPLA) is also caused by an unstable triplet repeat and can present as SCA in late onset patients. We investigated the frequency of the SCA1, SCA2, MJD/SCA3 and DRPLA mutations in 328 Brazilian patients with SCA, belonging to 90 unrelated families with various patterns of inheritance and originating in different geographic regions of Brazil. We found mutations in 35 families (39%), 32 of them with a clear autosomal dominant inheritance. The frequency of the SCA1 mutation was 3% of all patients; and 6% in the dominantly inherited SCAs. We identified the SCA2 mutation in 6% of all families and in 9% of the families with autosomal dominant inheritance. The MJD/SCA3 mutation was detected in 30% of all patients; and in the 44% of the dominantly inherited cases. We found no DRPLA mutation. In addition, we observed variability in the frequency of the different mutations according to geographic origin of the patients, which is probably related to the distinct colonization of different parts of Brazil. These results suggest that SCA may be occasionally caused by the SCA1 and SCA2 mutations in the Brazilian population, and that the MJD/SCA3 mutation is the most common cause of dominantly inherited SCA in Brazil.

Case report: computed tomography in the diagnosis of primary lymphoma of the central nervous system.

A case of primary central nervous system lymphoma is presented with characteristics shown by computed tomography (CT) closely resembling those of the only other case reported in the literature. The combination of the arteriographic and CT appearances suggests the diagnosis of this radiosensitive group of tumors.

Whipple's disease confined to the brain: a case studied clinically and pathologically.

A 40 year old man developed seizures, intermittent fever, and progressive dementia ending in coma and death after four years. The cerebrospinal fluid showed variable pleocytosis and occasional elevation of protein. The necropsy revealed many lesions characteristic of Whipple's disease confined to the grey matter of the brain. The pathological changes were studied with the light and electron microscope. The findings permitted an understanding of the temporal sequence of changes in the lesions. Involvement of the brain in this condition is rare, but the disease is treatable and the diagnosis can be made by brain biopsy.

Azorean disease of the nervous system.

We studied a family of Portuguese ancestry from the Azores who suffered a progressive neurologic disease characterized by gait ataxia, features similar to Parkinson's disease in some patients, limitation of eye movements, widespread fasciculations of muscles, loss of reflexes in the lower limbs, followed by nystagmus, mild cerebellar tremor and extensor plantar responses. Two post-mortem examinations revealed loss of neurons and gliosis in the substantia nigra, nuclei pontis (and in the putamen in one case) as well as in the nuclei of the vestibular and other cranial nerves, columns of Clarke and anterior horns, in the spinal cord there were also loss of fibers in the fasciculi gracilis and mild changes in the pyramidal tracts. Comparison of the disease in this family with the findings reported in three families of similar ancestry, previously thought to have different disorders, suggests that they may all represent a single genetic entity with variable expression.

Prevalence of multiple sclerosis in the city of São Paulo, Brazil, in 1990.

A case register of multiple sclerosis (MS) was set up in the city of São Paulo, Brazil, situated at a latitude of 23-24 degrees south. Cases were notified by neurologists, neuroradiologists and by an association of patients with MS. Prevalence rate was 4.27 x 10(-5) (men: 2.89 x 10(-5); women: 5.59 x 10(-5)), with a preponderance of young adults. We discuss here whether these rates are artifact due to poor health care facilities, to poor notification and deficiencies in diagnosis, or whether these rates are really low.

A familial factor independent of CAG repeat length influences age at onset of Machado-Joseph disease.

Machado-Joseph disease (MJD) is a late-onset, progressive, neurodegenerative disorder caused by the expansion of an unstable trinucleotide (CAG) repeat sequence in a novel gene (MJD1) on chromosome 14. Previous studies showed that age at onset is negatively correlated with the number of CAG repeat units, but only part of the variation in onset age is explained by CAG repeat length. Ages at onset and CAG repeat lengths of 136 MJD patients from 23 kindreds of Portuguese descent were analyzed, to determine whether familial factors independent of CAG repeat length modulate age at onset of MJD. Correlation among sibs for onset age adjusted for CAG repeat length was .43, which indicates that an environmental or genetic factor common to sibs influences onset age. Positive correlations were also observed for avuncular (r = .22) and first-cousin pairs (r = .28), which supports the hypothesis that a genetic factor is influencing age at onset. Commingling analysis of onset ages adjusted for CAG repeat length identified three distributions in this population of affected individuals. Further studies of a much larger sample are needed to determine whether these distributions represent the influence of a genetic or environmental factor.

Correlation between CAG repeat length and clinical features in Machado-Joseph disease.

Machado-Joseph disease (MJD) is associated with the expansion of a CAG trinucleotide repeat in a novel gene on 14q32.1. We confirmed the presence of this expansion in 156 MJD patients from 33 families of different geographic origins: 15 Portuguese Azorean, 2 Brazilian, and 16 North American of Portuguese Azorean descent. Normal chromosomes contain between 12 and 37 CAG repeats in the MJD gene, whereas MJD gene carriers have alleles within the expanded range of 62-84 CAG units. The distribution of expanded alleles and the gap between normal and expanded allele sizes is either inconsistent with a premutation hypothesis or most (if not all) of the alleles we studied descend from a common ancestor. There is a strong correlation between the expanded repeat size and the age at onset of the disease as well as the clinical presentation. There is mild instability of the CAG tract length with transmission of the expanded alleles; both increase and decrease in size between parents and progeny occur, with larger variations in male than in female transmissions. Together, these effects can partly explain the variability of age at onset and of phenotypic features in MJD; however, other modifying factors must exist.

Machado Joseph disease is not an allele of the spinocerebellar ataxia 2 locus.

Machado Joseph disease (MJD) is a progressive, spinocerebellar ataxia (SCA) with an autosomal dominant mode of inheritance and almost complete penetrance. Clinically, it is difficult to distinguish it from other autosomal dominantly inherited ataxias, and it has been suggested that MJD may be caused by an allelic variant of SCA. Exclusion of MJD from the SCA1 locus on chromosome 6p has previously been demonstrated. However, following the recent assignment of a second locus for spinocerebellar ataxia (SCA2) to chromosome 12q in a large Cuban kindred of Spanish origin, we have investigated linkage in MJD families using the two markers, D12S58 and PLA2, that flank this disease gene. The MJD locus was definitively excluded from an interval spanning approximately 70 cM, which includes these loci. These studies demonstrate that MJD and SCA2 are genetically distinct despite similarities in disease phenotype and ancestral origins of the patients. Thus, the as yet unmapped MJD locus represents a third SCA locus, providing further evidence for genetic heterogeneity within these disorders.

Anterior callosotomy in epileptics with multiform seizures and bilateral synchronous spike and wave EEG pattern.

Cerebral commissurotomy is a well established procedure in the treatment of epileptics refractory to drug therapy. Breeching of the ventricles in complete commissurotomy carries a certain morbidity. This has led others to perform operations in which the entire corpus callosum or only its anterior portion with or without the anterior commissure were sectioned. Sectioning of the anterior corpus callosum alone is justified by: a) frequent appearance in patients of seizures attributable to a frontal focus, b) clinical and experimental evidence that frontal discharges spread across the corpus callosum leading to subsequent generalized its, c) the attempt to understand the mechanisms involved in generalized seizures, d) even further reduced surgical morbidity and neuropsychological disability. Five epileptics were submitted to anterior callosotomy. The seizures in all of them suggested a frontal focus and consisted of absences, adversive, tonic, atonic, and tonic-clonic attacks. All patients were incapacitated by the frequency of seizures. Their EEGs showed paroxysms of bilateral synchronous slow spike and wave with uni-, or multiple (including bilateral symmetrical) focal accentuation. In two patients there were additional independent temporal lobe discharges. Neuropsychological evaluation showed cognitive deficits caused by inattention paroxysms and absences. After anterior callosotomy there was marked reduction in frequency of all types of seizures, the greatest improvement being in the reduction of frequency of absences. There was a marked decrease in physical, social and neuropsychological disabilities.

Anterior callosotomy as a substitute for hemispherectomy.

Two patients with epilepsy and large hemispheric lesions underwent section of the frontal fibres of the corpus callosum for the treatment of seizures refractory to medical treatment. A severely retarded girl of 18 had encephalotrigeminal angiomatosis (Sturge-Weber syndrome) with multiple daily absences, tonic-clonic, myoclonic, atonic and adversive seizures since infancy. All types of fits--with the exception of adversive seizures and rare tonic-clonic fits--disappeared after anterior callosotomy. Another moderately retarded girl of 18 had an old cystic lesion over the entire territory of the left middle cerebral artery. She had had right hemiplegia since infancy and frequent brief absences and massive myoclonus triggered by unexpected sensory stimuli since the age of six years. Following anterior callosotomy there was an almost complete disappearance of the absences and a marked reduction of her startle myoclonus. Frontal callosotomy is a useful procedure in epileptics with large hemispheric lesions and carries less risk than hemispherectomy or total commissurotomy.

The Machado-Joseph disease locus is different from the spinocerebellar ataxia locus (SCA1).

Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative spinocerebellar ataxia that has been described primarily in families of Azorean or Portuguese descent. MJD and chromosome 6p-linked spinocerebellar ataxia (SCA1) are difficult to differentiate clinically, and it has been suggested that they may be allelic variants of the same disorder. We have tested MJD families for linkage to six DNA sequence polymorphisms located on chromosome 6p, including the highly informative dinucleotide repeat, D6S89. Seventeen centimorgans telomeric to and 41 cM centromeric to D6S89, a region that includes the SCA1 locus reported to be within 3 cM of D6S89, have been excluded. These data provide conclusive evidence that MJD and SCA1 are nonallelic.

Machado Joseph disease maps to the same region of chromosome 14 as the spinocerebellar ataxia type 3 locus.

Machado Joseph disease (MJD) is an autosomal dominantly inherited neuro-degenerative disorder primarily affecting the motor system. It can be divided into three phenotypes based on the variable combination of a range of clinical symptoms including pyramidal and extra-pyramidal features, cerebellar deficits, and distal muscle atrophy. MJD is thought to be caused by mutation of a single gene which has recently been mapped, using genetic linkage analysis, to a 29 cM region on chromosome 14q24.3-q32 in five Japanese families. A second disorder, spinocerebellar ataxia type 3 (SCA3), which has clinical symptoms similar to MJD, has also been linked to the same region of chromosome 14q in two French families. In order to narrow down the region of chromosome 14 which contains the MJD locus and to determine if this region overlaps with the predisposing locus for SCA3, we have performed genetic linkage analysis in seven MJD families, six of Portuguese/Azorean origin and one of Brazilian origin, using nine microsatellite markers mapped to 14q24.3-q32. Our results localise the MJD locus in these families to an 11 cM interval flanked by the markers D14S68 and AFM343vf1. In addition we show that this 11 cM interval maps within the 15 cM interval containing the SCA3 locus, suggesting that these diseases are allelic.