[Diagnostic criteria for Parkinson's disease].

Diagnostic criteria for Parkinson's disease is used in all clinical studies concerning this disease. For supplying meaningful data to the evidence-based medicine, the diagnostic criteria must be clearly defined in such studies. In the setting and usage of diagnostic criteria, it is indispensable to clarify the aim and the population for which the criteria is used. Then, as for the contents of the criteria, 1) additional criteria, 2) exclusion criteria, and 3) levels of confidence must be considered. For the future re-evaluation, diagnostic criteria must be logic. Final references are also necessary for judging the accuracy of the criteria.

Effect of 1,25-dihydroxyvitamin D(3) on cultured mesencephalic dopaminergic neurons to the combined toxicity caused by L-buthionine sulfoximine and 1-methyl-4-phenylpyridine.

A decrease in intracellular glutathione content may be related to the primary event in Parkinson's disease, so increasing the glutathione level may have a therapeutic benefit. The biologically active form of vitamin D, 1,25-dihydroxyvitamin D(3) [1, 25-(OH)(2)D(3)] has been recently reported to enhance the intracellular glutathione concentration in the central nervous system. Exposing rat cultured mesencephalic neurons for 24 hr to a mixture of L-buthionine sulfoximine (BSO) and 1-methyl-4-phenylpyridium ions (MPP(+)) resulted in a relatively selective damage to dopaminergic neurons. This damage has been accompanied by a reduction of intracellular glutathione levels. Low doses, i.e., 1-100 nM, of 1,25-(OH)(2)D(3) protect cultured dopaminergic neurons against this toxicity, although higher concentrations of this active form of vitamin D have been found to enhance the toxic effect. Generation of reactive oxygen species (ROS) by this toxicity has been attenuated in cultures being pretreated with low concentrations of 1,25-(OH)(2)D(3). Because the hormone increases the intracellular glutathione content in cultures, determining how this hormone suppresses ROS generation may involve the enhancement of the antioxidative system. These data suggest that low doses of 1,25-(OH)(2)D(3) are able to protect mesencephalic dopaminergic neurons against BSO/MPP(+)-induced toxicity that causes a depletion in glutathione content.

Selective vulnerability of spinal motor neurons to reactive dicarbonyl compounds, intermediate products of glycation, in vitro: implication of inefficient glutathione system in spinal motor neurons.

We investigated the effects of two reactive dicarbonyl compounds, methylglyoxal (MG) and 3-deoxyglucosone (3-DG), on cultured spinal cord neurons. Incubation of cortical and spinal neurons with MG and 3-DG for 24 h induced neuronal death in a dose-dependent manner. Spinal motor neurons were more vulnerable than spinal non-motor neurons and cortical neurons. Treatments with glutathione (GSH)-augmenting agents showed protective effects against MG and 3-DG neurotoxicity. Motor neurons were better protected than non-motor neurons. Cotreatment, but not pretreatment, of aminoguanidine (AG), a known inhibitor of advanced glycation end-products (AGEs) from crosslinking, showed a protective effect on spinal neurons with no difference in protective rates between motor and non-motor spinal neurons. Treatments with GSH depleting agents enhanced the neurotoxicity of MG and 3-DG on spinal neurons. Motor neurons were more vulnerable than non-motor neurons with GSH-depleting treatments prior to MG and 3-DG exposures. These data demonstrate that spinal motor neurons are more vulnerable to dicarbonyl compounds, and this selectivity might be related to the relatively inefficient GSH system in spinal motor neurons.

Detection of an Amadori product, 1-hexitol-lysine, in the anterior horn of the amyotrophic lateral sclerosis and spinobulbar muscular atrophy spinal cord: evidence for early involvement of glycation in motoneuron diseases.

Glycation is a series of non-enzymatic reactions initiated by addition of reducing sugars to epsilon-amino group of lysine residues and alpha-amino group of the N terminus of proteins, leading to the formation of advanced glycation end products (AGE). It is thought to be involved in aging and various neurodegenerative conditions. In the present study using anti-1-hexitol-lysine (1-HL) antibody, Amadori product, an early glycation product, was detected in axonal spheroids in the anterior horn of amyotrophic lateral sclerosis and in atrophic neurons of spinobulbar muscular atrophy (SBMA, Kennedy disease with abnormally expanded triplet repeats in androgen receptor gene) but not in other regions of the central nervous system. Furthermore, Amadori product was undetectable in the tissues from age-matched controls. Thus, 1-HL formation could not reflect physiological aging.

[The advance in the research and therapeutic trials of amyotrophic lateral sclerosis].

The research concerning with the pathogenesis of amyotrophic lateral sclerosis (ALS) has been in steady progress in the last 10 years, including discovery of SOD mutation in familial ALS. Riluzole, by its inhibiting excitatory amino acid release, is the only drug, which has been demonstrated the neuroprotective activity in the randomised double-blind placebo-controlled clinical trials in patients with ALS, although many other clinical therapeutic trials for ALS patients has been carried out. We discussed the clinical trials being the under way, especially SR57746A, (1-[2-(naphth-2-yl)ethy]-4-(3-trifluoromethyl phenyl)-1, 2, 5, 6-tetrahydro-pyridine, hydrochloride), a non-peptide compound which has been shown to exhibit a wide range of neurotrophic effects both in vitro and in vivo, and its phase II study in Japan and two kinds of phase III studies ongoing in the United States, Canada and Europe. We also introduced the clinical guideline for practice and care of ALS patients proposed by American Academy of Neurology, expecting to establish clinical guideline to be applicable to Japanese cases.

Neurotoxicity of methylglyoxal and 3-deoxyglucosone on cultured cortical neurons: synergism between glycation and oxidative stress, possibly involved in neurodegenerative diseases.

In this study, we investigate the neurotoxicity of glycation, particularly early-stage glycation, and its mechanisms, which are possibly synergized with oxidative stress. Methylglyoxal (MG) and 3-deoxyglucosone (3DG), intermediate products of glycation, are known to further accelerate glycation and advanced glycation endproducts (AGEs) formation. Both compounds showed neurotoxicity on cultured cortical neurons and these effects were associated with reactive oxygen species production followed by neuronal apoptosis. Pretreatment with N-acetylcysteine induced neuroprotection against MG and 3DG. Cotreatment, but not pretreatment, with aminoguanidine protected neurons against the neurotoxicities of both compounds. The present study provides the first evidence that MG and 3DG are neurotoxic to cortical neurons in culture. Interference with the process by which glycation and AGEs formation occur may provide new therapeutic opportunities to reduce the pathophysiological changes associated with neurodegeneration, if, as indicated here, the participation of glycoxidation in the pathogenesis of neurodegenerative diseases is essential.

Focal (segmental) dyshidrosis in syringomyelia.

The features or mechanisms of dyshidrosis have not been sufficiently clarified. Neither has the difference between hyperhidrosis and hypohidrosis. To clarify the features and mechanisms of dyshidrosis (hyperhidrosis and hypohidrosis) in syringomyelia, the clinical features focusing on hidrosis of 30 patients with syringomyelia and Chiari malformation located from a syringomyelia database were prospectively analysed. The patients were classified into three groups: eight patients (26.7%) had segmental hypohidrosis, 10 (33. 3%) had segmental hyperhidrosis, and 12 (40.0%) had normohidrosis. We found that the Karnofsky functional status for the hyperhydrosis and normohidrosis groups were significantly higher than for the hypohidrosis group (p=0.0012), with no significant differences between the hyperhidrosis and normohidrosis groups. The duration from the onset of syringomyelia to the current dyshidrosis was significantly longer in the hypohidrosis group than in the hyperhidrosis group (p=0.0027). A significant correlation was identified between the duration from the onset of syringomyelia to the time at study and the performance score (r=-0.599, p=0.0003). The results substantiate previous hypotheses that in its early stage syringomyelia causes segmental hyperactivity of the sympathetic preganglionic neurons, and hyperactivity of these gradually subsides as tissue damage progresses. Focal hyperhidrosis may be regarded as a hallmark of a relatively intact spinal cord, as well as normohidrosis.

[The spinal somatosensory evoked potentials in amyotrophic lateral sclerosis in relation to the spinal cord conduction velocities].

The lumbar-to-cervical conduction velocity (spinal cord conduction velocity, SCCV) was electrophysiologically studied in 14 patients with amyotrophic lateral sclerosis (ALS). The age of these patients ranged from 37 to 63, averaging 51.0 years old. We recorded the spinal somatosensory evoked potentials (SSEPs) from the surface electrodes at the level of the C2 spine and the T12 spine by the simultaneous stimulation of bilateral posterior tibial nerves. SCCV from the lumbar to cervical was measured from the latency difference between both SSEPs elicited at the each position. As the results, SCCVs were in the range of 50.6-66.6 (58.6 +/- 4.7: mean +/- SD) m/sec in normal age matched controls (18 adult volunteers, 46-63 years old, averaging, 52.7). On the other hand, in ALS patients, SCCVs were in the range of 42.1-67.1 (53.5 +/- 7.8: mean +/- SD) m/sec, values of which were lowered compared to those in normal subjects. These examination documented 4 out of 14 patients with ALS (28.6%) showing abnormalities beyond standard deviation. The vibration sense was checked by using 128 Hz tuning fork at the ankles, and for the quantitative measurement, a newly designed vibriometer being attached the piezoelectric accelerometer to the end of 128 Hz tuning fork was applied in 14 ALS patients. The vibration sense at the ankles was diminished in 6 patients, and 3 patients showed the abnormalities beyond 2 standard deviations. The degree of lowering in SCCVs among ALS patients were correlated with the degree of diminution of impaired vibration sense and the duration of illness, but were not correlated with the H/M ratio and the latency difference between T wave and H wave. Since SSEP impulses are transmitted in dorsal columns and dorsolateral fasciculus predominantly by large diameter and fast-conduction fibers, our results may suggest that, in ALS patients, spinal cord conduction velocities of ascending fibers mediating the dorsal columns and dorsolateral fasciculus are disturbed compared to those in normal subjects, and that the functional disturbance of ascending fibers mediating the dorsal columns and dorsolateral fasciculus plays the important role in the high rates of impaired vibration sense among ALS patients.

Protective effects of the TNF-ceramide pathway against glutamate neurotoxicity on cultured mesencephalic neurons.

Pretreatments with TNF-alpha and lower concentrations of C2-ceramide protected cultured mesencephalic neurons from excitotoxicity in a dose-dependent manner. These protective effects are reduced by cotreatment with N,N-dimethylsphingosine (DMS), an inhibitor of sphingosine kinase. Since the pretreatment with sphingosine-1-phosphate (SPP) showed a neuroprotective effect, our data suggest that protective effects of TNF and C2-ceramide could be attributable to their further metabolism to SPP.

Facial palsy in multiple sclerosis.

Facial palsy occurred in 21 (19.6%) of 107 Japanese patients with multiple sclerosis (MS) during a mean follow-up period of 4.3 years. We observed residual signs of facial palsy in five other patients in whom acute onset was confirmed from medical records. Facial palsy began on average 7.6 years after the onset of MS but in five patients (4.7%) was the first symptom of MS, preceding the next MS symptom by 0.5-3 years. Facial palsy was usually associated with other brainstem signs, while two patients showed only facial palsy 1 and 3 years after the onset of MS. Twenty-one (84.0%) of the 25 patients who underwent brain magnetic resonance imaging (MRI) showed brainstem lesions in the pontine tegmentum ipsilateral to the facial palsy. However, the two patients without other symptoms or signs had no apparent causal lesion on MRI, which suggests difficulty in differentiating idiopathic Bell's palsy from MS- associated facial palsy by MRI, although it has an excellent capacity to detect causal lesions of facial palsy associated with MS.

Autosomal dominant spastic paraplegia linked to chromosome 2p: clinical and genetic studies of a large Japanese pedigree.

Autosomal dominant spastic paraplegia (ADSP) is a genetically heterogenous disorder. To date, 3 loci of ADSP have been identified on chromosome 2p, 14q, and 15q, but specific gene mutations remain unknown. To determine the genetic background of ADSP in the Japanese, we studied a large 3-generation pedigree, clinically and genetically. Of the 36 individuals clinically examined, 15 were affected. The main feature in the affected individuals was a slowly progressive spastic paraplegia, associated with upper limb hyperreflexia (58%), reduction of vibration sense (27%) and bladder disturbance (13%). Age at onset ranged from 13 to 50 years with a mean of 30.3 +/- 14.2 (SD). There were 6 parent-child pairs with anticipation and at least 3 others with 'anti-anticipation'. Linkage with 14q and 15q ADSP loci was excluded, and a highly significant lod score was obtained only in the case of the 2p locus (Zmax = 3.53 for D2S400/D2S352, at theta = 0.00). Our study is the first to confirm the existence of 2p-linked ADSP in the Japanese. There is a significant variety in age at onset and disease severity in these 2p-linked families, but the implication for underlying ADSP mutation is not clear.

[Amyotrophic lateral sclerosis].

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal illness characterized by upper and lower motor neuron degeneration of adults. Recently, many advances are being made in our understanding of the pathogenesis of ALS, which are the role of autoimmunity, the glutamate excitotoxicity, the neurotrophic factor and the defined mutation of superoxide dismutase in familial ALS cases. The therapeutic trials have been carried out more commonly based on the putative pathogenesis described. Among them, riluzole, antiglutamate agent, is proved to have the survival advantage in a controlled double-blind randomized study. These current putative pathogenesis and therapeutic trials of ALS are discussed.

Trochlear nerve palsy associated with superficial siderosis of the central nervous system.

A 56-year-old man with superficial siderosis of the central nervous system (SSCN) presented with complaints of trochlear palsy, visual field defects, gait ataxia, and hearing loss. He had no history of trauma and there were no signs of tumors or aneurysms. T2-weighted magnetic resonance imaging demonstrated characteristic hypointensity in the meninges. We believe that SSCN should be added to the differential diagnosis of trochlear nerve palsy.

Infiltrating cell profiles of sarcoid lesions in the muscles and peripheral nerves: an immunohistological study.

In order to study the pathological mechanisms of neuromuscular sarcoidosis, we carried out an immunohistochemical investigation in five cases (five muscle specimens and two sural nerve specimens). We evaluated the distribution of inflammatory mononuclear cells and major histocompatibility complex (MHC) antigen expressions. Our data showed a dominant infiltration of helper/inducer T cells (CD4-T cells), suggesting the importance of cell-mediated immune responses in neuromuscular sarcoidosis. However, we could not identify the distinct distributional patterns of T cells as reported in sarcoid lymphadenitis. This result may be attributed to the difference of the affected organs. Moreover, failure to detect class II antigens in the muscle fibers may imply the difference in pathogenic mechanism between neuromuscular sarcoidosis and other inflammatory myopathies.

A case of bilateral optic neuropathy and recurrent transverse myelopathy associated with perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA).

A case involving a 52-year-old man having bilateral optic neuropathy and recurrent transverse myelopathy is reported. His clinical features resembled multiple sclerosis, but neuroimaging failed to show evidence of demyelination or inflammation in the brain or the optic nerves. The patient experienced sudden visual loss despite massive steroid therapy. Positive perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA) is suggestive that optic neuropathy and recurrent transverse myelopathy may have been caused by some common inflammatory processes associated with p-ANCA, however, having a different etiology from multiple sclerosis.