akayanagi T

International Cooperative Ataxia Rating Scale for pharmacological assessment of the cerebellar syndrome

Despite the involvement of cerebellar ataxia in a large variety of conditions and its frequent association with other neurological symptoms, the quantification of the specific core of the cerebellar syndrome is possible and useful in Neurology. Recent studies have shown that cerebellar ataxia might be sensitive to various types of pharmacological agents, but the scales used for assessment were all different. With the long-term goal of double-blind controlled trials-multicentric and international-an ad hoc Committee of the World Federation of Neurology has worked to propose a one-hundred-point semi-quantitative International Cooperative Ataxia Rating Scale (ICARS). The scale proposed involves a compartimentalized quantification of postural and stance disorders, limb ataxia, dysarthria and oculomotor disorders, in order that a subscore concerning these symptoms may be separately studied. The weight of each symptomatologic compartment has been carefully designed. The members of the Committee agreed upon precise definitions of the tests, to minimize interobserver variations. The validation of this scale is in progress.

Spinocerebellar ataxia type 6 Molecular and clinical features of 35 Japanese patients including one homozygous for the CAG repeat expansion

Spinocerebellar ataxia type 6 (SCA6) is a newly classified autosomal-dominant cerebellar ataxia (ADCA) associated with CAG repeat expansion. We screened 111 patients with cerebellar ataxia for the SCA6 mutation. Of these, 35 patients were found to have expanded CAG repeats in the SCA6 gene, indicating that second to SCA3, SCA6 is the most common ADCA in Japan. Expanded alleles ranged from 21 to 29 repeats, whereas normal alleles had seven to 17 repeats. There was no change in the CAG repeat length during meiosis. The age at onset was inversely correlated with the repeat length. The main clinical feature of the 35 patients with SCA6 was slowly progressive cerebellar ataxia; multisystem involvement was not common. The 35 patients included nine cases without apparent family history of cerebellar ataxia. The sporadic cases had smaller CAG repeats (21 or 22 repeats) and a later age at onset (64.9 ± 4.9 years) than the other cases with established family history. We also identified one patient who was homozygous for the SCA6 repeat expansion. The homozygote showed an earlier age of onset and more severe clinical manifestations than her sister, a heterozygote carrying an expanded allele with the same repeat length as the homozygote. This finding suggests that the dosage of the CAG repeat expansion plays an important role in phenotypic expression in SCA6.

Spinocerebellar degenerations in Japan: a nationwide epidemiological and clinical study

A nationwide survey of patients in Japan with spinocerebellar degenerations (SCD), including SDS and SND, was conducted from 1988 to 1989. The survey consisted of two parts. The first revealed that the estimated total number of patients with SCD in Japan was 5,050 (range: 4,100–6,000) with an estimated prevalence of 4.53 per 100,000 in 1987. The second part investigated the neurological and functional status of patients with SCD. The percentages of those belonging to each subtype of SCD were: OPCA; 34.4%, LCCA; 15.2%, MHCA; 12.6%, HHCA; 7.5%, SDS; 7.0%, HSP; 3.9%, DRPLA; 2.5%, FA; 2.4%, MJD; 2.0% and SND; 1.5%. Compared with European epidemiological studies Japan had a higher proportion of non‐hereditary types of SCD. Various clinical features of SCD subtypes were compared grouped by pathological lesion and heredity. HHCA and LCCA: cerebellar ataxia predominated in all stages, and neurological signs other than cerebellar ataxia were rare. MHCA, DRPLA and MJD: inthe early phase ataxia was the most common symptom in MHCA, the AC form of DRPLA and MJD, but ataxia was less common and chorea or epilepsy were often observed in ME and PH forms of DRPLA. Other frequently observed clinical features were parkinsonian rigidty in MHCA, abnormal movements and posture in DRPLA and MJD, and disturbances of eye movements in MHCA, the AC form of DRPLA and MJD. OPCA, SDS and SND: dominant clinical features were cerebellar ataxia in OPCA, autonomic disturbance in SDS, and parkinsonian rigidity in SND. FA and HSP: both were rare in Japan. Clinical features related to supra‐supinal lesions were frequently observed in FA. Functional status of SCD: the severity of illness was significantly associated with the level of independence in each item of ADL. Activities not requiring dynamic balance were performed independently for a longer period than those requiring dynamic balance. Among SCD subtypes, functional prognosis was poorest in non‐hereditary, multi‐systemic types (OPCA, SDS and SND) followed by hereditary multi‐systemic types (MHCA, DRPLA and MJD), and better in spinal types (FA and HSP) and cerebellar types (HHCA and LCCA).

Effects of phosphodiesterase inhibitors on cytokine production by microglia

Type III and IV phosphodiesterase inhibitors (PDEIs) have recently been shown to suppress the production of TNF-α in several types of cells. In the present study, we have shown that all the types of PDEIs, from type 1- to V-specific and non-specific, suppress the production of TNF-α by mouse microglia stimulated with lipopolysaccharide (LPS) in a dose-dependent manner. Certain combinations of three different types of PDEIs synergistically suppressed TNF-α production by microglia at a very low concentration (1 μM). Since some PDEIs reportedly pass through the blood-brain barrier (BBB), the combination of three PDEIs may be worth trying in neurological diseases, such as multiple sclerosis and HIV-related neurological diseases in which TNF-α may play a critical role. Some PDEIs also suppressed interleukin-1 (IL-1) and IL-6 production by mouse microglia stimulated with LPS. In contrast, the production of IL-10, which is known to be an inhibitory cytokine, was upregulated by certain PDEIs. The suppression of TNF-α and induction of IL-10 were confirmed at the mRNA level by RT - PCR. PDEIs may be useful anti-inflammatory agents by downregulating inflammatory cytokines and upregulating inhibitory cytokines in the central nervous system. (CNS).

Sweat function in Parkinson's disease

Sweat function was studied in patients with Parkinsons disease and in normal adults by sympathetic skin response, the bromphenol blue printing method and the silicone mould method. In patients with Parkinsons disease, dysfunction of sweating was classified into two types: one type involved the postganglionic fibres and the other involved the preganglionic fibres or the central nervous system. The latter was observed in patients with milder disease and the former was observed in patients with severe disease. The progressive involvement of sweat function in Parkinsons disease may reflect spread from the central nervous system or preganglionic fibres to postganglionic fibres. In a few patients the results of sweat tests were normal. Ceruletide increased sweating in Parkinsons disease patients, and decreased the prolonged latency of the sympathetic skin response. It is hypothesized that ceruletide facilitates the preserved somatosympathetic reflex of sweating.

Production of interleukin-12 and expression of its receptors by murine microglia

Production of interleukin-12 (IL-12) by cultured murine microglia and astrocytes was examined, by means of ELISA to detect heterodimeric p70 and RT-PCR to analyze the expression of mRNA encoding p35 and p40. Microglia, but not astrocytes, produced IL-12 p70 in response to lipopolysaccharide and interferon-gamma. The microglial cell line, Ra2, produced only p40, but not p35, upon above stimulation. Thus, it is possible that some population of microglia induce helper 1 type T cell response via producing IL-12 in the CNS. Microglia were induced to express mRNA encoding IL-12 receptors which were exclusively expressed in activated T and NK cells.

Myeloneuropathy with abdominal disorders in Japan: A clinical study of 752 cases

A XZYELONEUROPATHY WITH ABDOMINAL DISORDERS has occurred in Japan since about 1956. The incidence of this illness has markedly increased from 1963 or 1964 to the present, and it is currently prevalent in Japan. This condition has clinicopathologic features and its true causes remain to be defined. Many papers dealing with various aspects of this disorder have been reported in Japan. A review of the main literature on clinical symptomatology, pathology, epidemiology, and etiology up to 1969 has been attempted by the authors1,* This disorder has been studied at the Nagoya University Hospital by the authors over the past decade. This report is based on an analysis of 752 cases studied from 1956 to 1969.

CAG repeat expansions in patients with sporadic cerebellar ataxia

CAG repeat expansions cause spinocerebellar ataxia type 1 (SCA1), SCA2, SCA3, SCA6 and dentatorubral‐pallidoluysian atrophy (DRPLA). So far these expansions have been examined mainly in ataxia patients with a family history. However, some sporadic cases with SCA have recently been reported. To elucidate the frequency and characteristics of sporadic SCAs, we screened 85 Japanese ataxia patients without a family history for the SCA1, SCA2, SCA3, SCA6 and DRPLA mutations. As a result, 19 patients (22%) were found to have expanded CAG repeats. Among sporadic SCAs, the SCA6 mutation was most frequently observed. The sporadic SCA6 patients had smaller CAG repeats and a later age of onset than SCA6 patients with an established family history. We also identified one father‐child pair in which intermediate sized CAG repeats expanded into the SCA2 disease range during transmission. These findings suggest that patients with ataxia even without a family history should be examined for a CAG repeat expansion.

Glutamate dehydrogenase and its isozyme activity in olivopontocerebellar atrophy

Evaluation of glutamate dehydrogenase (GDH) in 12 patients with olivopontocerebellar atrophy showed deficiency of the enzyme in the group as well as in each patient. The activity of total GDH was 77.7% of that in controls. We also demonstrated two components of this enzyme differentiated by their thermostabilities. The activity of the heat-labile component was remarkably reduced in patients although that of the heat-stable component showed the same magnitude as in controls. These data suggest that GDH deficiency is mainly caused by its heat-labile component deficiency, which might be related to the pathogenesis of this disease.

Drop in relapse rate of MS by combination therapy of three different phosphodiesterase inhibitors.

Phosphodiesterase inhibitors (PDEIs), when used in combination, synergistically suppress TNFa production by various cells and also suppress experimental demyelination at very low concentrations. We conducted a pilot study to determine whether the combination of three PDEIs suppresses the relapse of MS at the usual therapeutic doses. Of the 12 relapsing remitting MS, the mean relapse rate/year dropped remarkably (from 3.08+3.32 to 0.92+1.86) after PDEI treatment. Seven out of 12 (58.3%) were relapse-free in the follow up period (499+142 days). The combination of three PDEIs can be safe and useful strategy for the future treatment of MS.