The neuroanatomical basis of slow saccades in spinocerebellar ataxia type 2 (Wadia-subtype).

In a case of spinocerebellar ataxia type 2, Wadia-subtype (SCA2), with slow horizontal saccades, we used parvalbumin immunohistochemistry to identify the omnipause (OPNs) excitatory (EBNs), and inhibitory burst neurons (IBNs) of the saccade generator. Nissl sections was used to measure neuronal diameters, and synaptophysin staining to estimate of synaptic density on the cell somata. Morphometric and synaptic density measurements of the abducens motoneurons were identical in SCA2 and the control. A significant cell loss and reduced synaptic density on somata was found only in the EBN area. We conclude that degeneration of the EBNs is the most likely cause for the slowing of horizontal saccades.

Selective, circuit-wide sparing of floccular connections in hereditary olivopontine cerebellar atrophy with slow saccades.

We present a systems-oriented histopathologic analysis of the ocular motor control circuits in the cerebellum and brainstem from a patient with a hereditary form of olivopontine cerebellar atrophy of the Wadia type, which has a characteristic ocular motor presentation of slow saccades but relative preservation of smooth pursuit and gaze-holding. This differential pattern of clinical involvement is associated with a lobule-specific pattern of cerebellar degeneration. We asked whether these patterns of sparing and degeneration were consistent throughout the associated deep cerebellar and brainstem structures. Specimens were fixed in formalin, embedded in paraffin, and stained for various markers. We found that elements of the floccular and nodular pathways, controlling smooth pursuit and vestibular reflexes, were relatively spared, particularly those structures that are interconnected with the medial regions. Conversely, the elements of the dorsal vermis pathway controlling saccade adaptation were relatively involved. This subregional specificity of degeneration further defines possible areas of investigation for elucidating pathophysiology, testing biomarkers of disease, and developing areas for therapeutic intervention.

Late-onset episodic ataxia type 2 due to an in-frame insertion in CACNA1A.

Episodic ataxia type 2 (EA2) is caused by calcium channel (CACNA1A) mutations and typically begins before age 20 years. The molecular basis of late-onset EA2 is unclear. The authors describe a case of late-onset EA2 associated with the first multiple-base pair insertion in CACNA1A. Molecular expression revealed evidence of impaired calcium channel function, suggesting that genetically induced reduction in calcium channel function may associate with cases of late-onset EA2.

Search for pi(0)-->nu(mu)nu(mu) decays in the LSND detector.

We observe a net beam excess of 8.7+/-6.3(stat)+/-2.4(syst) events, above 160 MeV, resulting from the charged-current reaction of nu(micro) and/or nu;(mu) on C and H in the LSND detector. No beam-related muon background is expected in this energy regime. Within an analysis framework of pi(0)-->nu(mu)nu;(mu), we set a direct upper limit for this branching ratio of Gamma(pi(0)-->nu(mu)nu;(mu))/Gamma(pi(0)-->all)<1.6 x 10(-6) at 90% confidence level.

A proposal to declare neurocysticercosis an international reportable disease.

Neurocysticercosis is an infection of the nervous system caused by Taenia solium. It is the most important human parasitic neurological disease and a common cause of epilepsy in Africa, Asia, and Latin America, representing enormous costs for anticonvulsants, medical resources and lost production. Neurocysticercosis is a human-to-human infection, acquired by the faecal-enteric route from carriers of intestinal T. solium, most often in areas with deficient sanitation. Intestinal tapeworms cause few symptoms, but adult taeniae carried by humans release large numbers of infective eggs and are extremely contagious. Ingestion of poorly cooked pig meat infested with T. solium larvae results in intestinal taeniosis but not neurocysticercosis. With a view to hastening the control of taeniosis and neurocysticercosis we propose that neurocysticercosis be declared an international reportable disease. New cases of neurocysticercosis should be reported by physicians or hospital administrators to their health ministries. An epidemiological intervention could then be launched to interrupt the chain of transmission by: (1) searching for, treating and reporting the sources of contagion, i.e. human carriers of tapeworms; (2) identifying and treating other exposed contacts; (3) providing health education on parasite transmission and improvement of hygiene and sanitary conditions; and (4) enforcing meat inspection policies and limiting the animal reservoir by treatment of pigs. We believe that the first step required to solve the problem of neurocysticercosis is to implement appropriate surveillance mechanisms under the responsibility of ministries of health. Compulsory notification also has the major advantage of providing accurate quantification of the incidence and prevalence of neurocysticercosis at regional level, thus permitting the rational use of resources in eradication campaigns.

Posttraumatic akinetic-rigid syndrome resembling Parkinson's disease: a report on three patients.

We describe three patients who developed a rapidly evolving posttraumatic akinetic-rigid syndrome (ARS), the clinical manifestations of which were similar to Parkinson's disease, including response to levodopa. Despite initial imaging studies showing traumatic damage to the substantia nigra, the ARS appeared after a delay of 1-5 months after the injury. We stress the importance of magnetic resonance imaging to illustrate nigral damage in all patients in whom head trauma precedes an ARS.

A common disease haplotype segregating in spinocerebellar ataxia 2 (SCA2) pedigrees of diverse ethnic origin.

The identification of a CAG trinucleotide repeat expansion, located within the coding sequence of the ataxin-2 gene, as the mutation underlying spinocerebellar ataxia 2 (SCA2) has facilitated direct investigation of pedigrees previously excluded from linkage analysis due to insufficient size or pedigree structure. We have previously described the identification of the ancestral disease haplotype segregating in the Cuban founder population used to assign the disease locus to chromosome 12q23-24.1. We now report evidence for the segregation of the identical core haplotype in pedigrees of diverse ethnic origin from India, Japan and England, established by the analysis of the loci D12S1672 and D12S1333 located 20kb proximal and 200 kb distal to the triplet repeat motif respectively. Interpretation of this data is suggestive that for these pedigrees at least, the mutation has arisen on a single ancestral or predisposing chromosome.

Acute renal failure with neurological involvement in adults associated with measles virus isolation.

BACKGROUND: Three people with clinical manifestations of acute renal failure with neurological involvement of unknown cause were admitted to a hospital in Mumbai, India. We describe clinical presentations and investigations of the cause. METHODS: We analysed case reports and laboratory findings for the patients (age 37-43 years, two men, one woman) that were provided by the clinicians in charge. Serum and cerebrospinal fluid were tested for viral cause by IgM ELISA to Japanese encephalitis, West Nile fever, dengue, and measles. Samples were inoculated in vero-cell culture for virus isolation. The virus isolates were confirmed with indirect immunofluoresence with antimeasles immune sera and mouse monoclonal antibodies to measles HA and F proteins and with neutralisation tests using antimeasles immune sera. FINDINGS: Clinical features were fever, vomiting, oliguria or anuria, bilateral facial weakness, impaired hearing, blindness, proximal and distal areflexic limb paralysis, and respiratory paralysis. No patient had a macropapular rash. Blood urea nitrogen (4.64-27.8 mmol/L) and creatinine (601.1-1105.0 micromol/L) were high, and cerebrospinal fluid contained high concentrations of proteins and pleocytosis. Kidney biopsy samples in two patients showed severe interstitial nephritis. IgM antibodies to measles were found in blood and cerebrospinal fluid. Vero-cell cultures from serum and cerebrospinal fluid of one patient and cerebrospinal fluid of two patients, showed cytopathic effects characteristic of measles. INTERPRETATION: Unusual manifestations of acute renal failure with neurological involvement associated with measles virus in adults presenting without rash was confirmed. Our findings may affect the development of measles-elimination programmes.

A clinicogenetic analysis of six Indian spinocerebellar ataxia (SCA2) pedigrees. The significance of slow saccades in diagnosis.

Clinical revaluation and genetic analysis of six Indian pedigrees, segregating autosomal dominant cerebellar ataxia, slow saccades and peripheral neuropathy, has been undertaken, and expansion at the spinocerebellar ataxia 2 (SCA2) locus was confirmed in 14 affected family members. These families became available from 31 phenotypically similar families seen over the years. In common with other neurodegenerative disorders resulting from expansion of a CAG trinucleotide repeat motif, an inverse correlation between repeat size and age at onset and severity is observed, although the size range (36-45 repeat units) for the expanded alleles is comparatively limited. Saccadic velocity was reduced in all our patients, even in the early stages of the disease. The observation of slow saccades in affected individuals has been proposed previously as an important diagnostic criterion serving to distinguish the SCA2 phenotype. This is now confirmed in a retrospective study of the clinical literature, facilitated by the cloning of the SCA2 gene and the subsequent genetic analysis of families segregating this phenotype. We therefore argue that the clinical appraisal of 'ophthalmoplegia' be subject to more precise definition, as differentiation between the various types of ocular dysfunction can be an important adjunct to diagnosis.

Proposal of diagnostic criteria for human cysticercosis and neurocysticercosis.

Taenia solium cysticercosis is a major public health problem in several areas of the world. While the disease has a recognized etiologic agent, its definitive histological diagnosis is not possible in most cases because this parasite tends to lodge in cerebral tissues where routine biopsy is not feasible. Therefore, the diagnosis of human cysticercosis (and neurocysticercosis) should rest on the proper interpretation of the patients' symptoms together with data provided by radiological studies and immunologic tests for the detection of anticysticercal antibodies. Unfortunately, the pleomorphism of this parasitic disease creates confusion when non-specific clinical, radiological, or immunologic criteria alone are used to detect cases among populations or to diagnose hospitalized patients with neurological manifestations. We propose a chart of diagnostic criteria for human cysticercosis that objectively permit clinicians and health care workers to evaluate clinical, radiological, immunologic, and epidemiologic data of patients. The chart uses four degrees of criteria: absolute, major, minor, and epidemiologic, that were selected on the basis of their individual diagnostic strength. Interpretation of such criteria will result in three categories of diagnostic certainty: definitive, probable and possible, according to the likelihood that cysticercosis is present in a given person.

Autosomal recessive hereditary sensory neuropathy with spastic paraplegia.

Five patients are described with a progressive sensory neuropathy in association with a spastic paraplegia and a mutilating lower limb acropathy. Disease onset was in childhood. Two pairs of siblings were both the offspring of normal consanguinous parents, suggesting autosomal recessive inheritance. The fifth case was sporadic; her parents were normal and non-consanguinous. Nerve biopsy in three patients showed an axonopathy with a loss of myelinated nerve fibres of all diameters and also of unmyelinated axons. In combination with the previous report by Cavanagh et al. (Brain 1979; 102: 79-94), the present patients establish the existence of an autosomal recessive form of hereditary sensory neuropathy with spastic paraplegia. There have been previous descriptions of a dominantly inherited form.

IgM deposits at nodes of Ranvier in a patient with amyotrophic lateral sclerosis, anti-GM1 antibodies, and multifocal motor conduction block.

We studied a patient with amyotrophic lateral sclerosis, multifocal motor conduction block, and IgM anti-GM1 antibodies. A sural nerve biopsy demonstrated deposits of IgM at nodes of Ranvier by direct immunofluorescence. The deposits were granular and located in the nodal gap between adjacent myelin internodes, and in some instances, they extended along the surface of the paranodal myelin sheath. When injected into rat sciatic nerve, the serum IgM bound to the nodes of Ranvier, and the binding activity was removed by preincubation with GM1. These observations suggest that anti-GM1 antibodies may have caused motor dysfunction by binding to the nodal and paranodal regions of peripheral nerve.

Multiple sclerosis is prevalent in the Zoroastrians (Parsis) of India.

Using Schumacher's classification, we determined the prevalence rate of clinically definite multiple sclerosis (MS) in the distinct but tiny Zoroastrian (largely Parsi) community in the adjacent cities of Bombay (latitude, 18.55 degrees) and Poona (Pune). On prevalence day, 16 clinically definite cases of MS were counted, 14 in Bombay and 2 in Poona, from a total Zoroastrian population of 50,053 and 3,399, respectively. The crude prevalence ratio was 26 per 100,000 for Bombay and 58 per 100,000 for Poona. The age-adjusted prevalence ratio for Bombay was 24 per 100,000, with 95% confidence limits of 13.1 to 40.3. These are much higher than the low rates believed to be prevalent in India, and are comparable with those found in parts of Europe and the United States.

Disseminated cysticercosis. New observations, including CT scan findings and experience with treatment by praziquantel.

Although the symptom complex of disseminated cysticercosis has been well recognized for over half a century, it is not clearly included in recent disease classifications. Three such patients are described whose main features were uncontrolled seizures, progressive dementia, behaviour disorder, muscular pseudohypertrophy, and a relative paucity of localizing neurological signs or signs of raised intracranial pressure. Radiographic calcification in muscles was not seen. A CT scan of the brain showed numerous small discrete lesions. Their attenuation density values were appreciably less than that of calcium and they enhanced slightly with contrast. Magnification revealed that these were scolices within cysticerci. There was no enhancement of the cyst wall and no pericystic oedema. CT scan of muscles showed similar cysticerci producing a 'honeycomb' appearance. This is the first CT demonstration of widely disseminated living cysticerci in brain and muscles. It was confirmed histologically. In the absence of palpable cysticerci, the clinical diagnosis can be missed, although no other disease in its full form presents in this manner. The symptoms are mainly caused by the space-occupying effect of the large number of cysticerci rather than by adjacent tissue swelling such as is seen in the presence of dying parasites. Praziquantel was ineffective and hazardous, causing some known and some previously unreported responses and reactions. All 3 patients died.