Temporal changes and geographical differences in multiple sclerosis phenotypes in Japanese: nationwide survey results over 30 years.

BACKGROUND: There are two distinct phenotypes of multiple sclerosis (MS) in Asians, manifesting as optic-spinal (OSMS) and conventional (CMS) forms. In Japan, four nationwide surveys of MS have been conducted. The first three were in 1972, 1982, and 1989, and we performed the fourth in 2004. RESULTS: The recent survey showed six main findings as follows: (1) a four-fold increase in the estimated number of clinically definite patients with MS in 2003 (9900; crude MS prevalence, 7.7/100,000) compared with 1972; (2) a shift in the peak age at onset from early 30s in 1989 to early 20s in 2003; (3) a successive proportional decrease in optic-spinal involvement in clinically definite patients with MS; (4) a significant north-south gradient for the CMS/OSMS ratio; (5) after subdivision of the mainland (30-45 degrees North) into northern and southern parts at 37 degrees N, northern-born northern residents (northern patients) showed a significantly higher CMS/OSMS ratio and higher frequency of brain lesions fulfilling the Barkhof criteria (Barkhof brain lesions) than southern-born southern residents (southern patients); (6) among northern patients, the absolute numbers of patients with CMS and those with Barkhof brain lesions rapidly increased with advancing birth year. CONCLUSIONS: These findings suggest that MS phenotypes are drastically altered by environmental factors, such as latitude and "Westernization."

Association of the HLA-DRB1 alleles with characteristic MRI features of Asian multiple sclerosis.

BACKGROUND: In Asian patients with multiple sclerosis (MS), a paucity of brain lesions and longitudinally extensive spinal cord lesions (LESCLs) extending three or more vertebral segments are characteristic findings on magnetic resonance imaging (MRI). We aimed to disclose possible factors contributing to the development of such MRI features. METHOD: Genotyping of HLA-DRB1 and -DPB1 alleles was performed in 121 consecutive Japanese patients with clinically definite MS based on the Poser criteria and 125 healthy controls. Possible factors associated with MRI features were determined by multiple logistic analysis. Patients with MS were classified based on the presence or absence of brain lesions fulfilling the Barkhof criteria (Barkhof brain lesions) and LESCLs. Barkhof brain lesion-negative (-) patients had a markedly lower frequency of HLA-DRB1*0901 than controls (P(corr) < 0.05), whereas the frequency of DRB1*1501 was increased in the Barkhof brain lesion-positive (+) group, although this increase was not significant after correction. No Barkhof(-)LESCL(+) patients carried DRB1*0901 (P(corr) < 0.05), despite this being the most common allele in Japanese. The Barkhof(-)LESCL(-) group showed a significant increase in the frequency of DRB1*0405 compared with controls (P(corr) < 0.05). None of the DPB1 alleles were significantly different among the groups. Using multiple logistic analysis, the absence of oligoclonal bands was positively associated with an absence of Barkhof brain lesions, whereas a higher EDSS score was positively associated with the presence of LESCLs; however, the presence of anti-aquaporin-4 antibodies was not associated with either feature. CONCLUSION: The characteristic MRI features in Asians are partly related to distinct HLA-DRB1 gene alleles and an absence of oligoclonal bands.

Reduction of angiotensin II in the cerebrospinal fluid of patients with multiple sclerosis.

We previously demonstrated that angiotensin II acts as a crucial neuroprotective factor after neural injury through angiotensin II type-2 (AT2) receptor signaling. Although the pathway is known to play an important role in the development of experimental autoimmune encephalomyelitis, cerebrospinal fluid (CSF) angiotensin II levels in patients with multiple sclerosis (MS) have never been studied. To clarify the significance of angiotensin II in MS, we assayed angiotensin II concentrations using an established enzyme-linked immunoabsorbent assay in CSF samples from patients with MS (n = 21), patients with inflammatory neuropathies (IN) (n = 23) and control individuals who did not have either of the neurological diseases or any other disease that might affect the angiotensin II levels in the CSF (control) (n = 24). Angiotensin II levels in the CSF were 3.79 +/- 1.54 pg/ml in the MS group, 5.13 +/- 2.27 pg/ml in the IN group and 6.71 +/- 2.65 pg/ml in the control group. The angiotensin II levels in the CSF of the MS group were significantly lower than in the control group (p = 0.00057). Angiotensin II concentration in the CSF tended to have a negative correlation with the Kurtzke's Expanded Disability Status Scale scores during MS relapse (p = 0.0847). These findings suggest that reduced levels of intrathecal angiotensin II may be related to the abnormal neural damage and repair processes in MS.

The contactin 4 gene locus at 3p26 is a candidate gene of SCA16.

OBJECTIVE: To identify of the gene responsible for the onset of spinocerebellar ataxia type 16 (SCA16). METHODS: We reanalyzed the linkage of the original Japanese pedigree using updated information, including three additional subjects. We then screened all exons located in the critical region. RESULTS: We reassigned the locus of SCA16 to 3p26.2-pter (maximum logarithm-of-odds score = 5.177) and identified only one point mutation (4,256C-->T) in the 3' untranslated region of the contactin 4 gene (CNTN4) on chromosome 3p26.2-26.3, which cosegregated with the disease. This mutation was not detected in 520 control subjects; moreover, we revised the phenotype of SCA16 from pure to complicated SCA. CONCLUSION: The contactin 4 gene (CNTN4) is associated with cerebellar degeneration in spinocerebellar ataxia type 16. Additional studies are necessary to prove 4,256C-->T to be a causative mutation.

Expression of granulysin in polymyositis and inclusion-body myositis.

BACKGROUND: Granulysin, a recently defined cytolytic molecule, is expressed in cytotoxic T cells and natural killer cells in a similar way to perforin, which is reported to have a major role in the pathogenesis of polymyositis and inclusion-body myositis (IBM). OBJECTIVE: To clarify the role of granulysin in polymyositis and IBM. METHODS: The expression of granulysin and perforin was examined by double staining with CD8, CD4 and CD56 in endomysial infiltrating cells and autoinvasive cells in muscle biopsy specimens of 17 patients with polymyositis (6 steroid resistant and 11 steroid responsive) and of 7 patients with IBM. RESULTS: Similar to perforin, granulysin was expressed in CD8, CD4 or CD56 cells in patients with polymyositis and IBM. The ratio of cells double positive for granulysin and CD8 to all CD8 cells at endomysial sites was notably higher in steroid-resistant polymyositis than in steroid-responsive polymyositis and IBM. CONCLUSION: Granulysin expression in CD8 cells seems to be correlated with steroid resistance in polymyositis.

History of allergic disorders in common neurologic diseases in Japanese patients.

OBJECTIVE: To clarify the association between past and present history of allergic disorders and neurologic diseases. METHODS: The past and present history of common allergic disorders together with family history was prospectively studied in all out-patients at the Department of Neurology at Kyushu University Hospital from March 1998 to February 2000. RESULTS: Among 3113 out-patients, 2152 (69.1%) completed a questionnaire. Myelitis showed a statistically significant increase of concomitant atopic dermatitis (P=0.006) and concomitant and past atopic dermatitis (P=0.014), as compared with neurologically healthy controls. Moreover, patients with lower motoneuron disease (LMND) had a statistically significant increase of past and concomitant asthma (P=0.007). None of the other common neurologic diseases showed any increase of allergic disorders when compared with controls. CONCLUSIONS: The present study supports the significant association between allergic disorders and such spinal cord diseases as myelitis and LMND in Japanese patients.

Th2 shift in mononeuritis multiplex and increase of Th2 cells in chronic inflammatory demyelinating polyneuropathy: an intracellular cytokine analysis.

To elucidate the T helper 1 (Th1)/T helper 2 (Th2) balance in various inflammatory neuropathies, we measured the ratio of intracellular interferon-gamma (IFN-gamma)-positive to IL-4-positive cells (intracellular IFN-gamma/IL-4 ratio) by flow cytometry in peripheral blood CD4(+) T cells of 14 patients with mononeuritis multiplex (MNM), 12 patients with chronic inflammatory demyelinating polyneuropathy (CIDP), 10 patients with Guillain-Barré syndrome (GBS), 23 patients with neurodegenerative disorders and 36 healthy controls by intracellular labeling. The patients with MNM showed a significantly lower intracellular IFN-gamma/IL-4 ratio (P<0.05) and higher IL-4(+)/IFN-gamma(-) cell percentages (P<0.05) than the controls. The increase of IL-4(+)/IFN-gamma(-) cell percentages was especially prominent in MNM of unknown etiology (P<0.005). The patients with CIDP also showed significantly higher IL-4(+)/IFN-gamma(-) cell percentages (P<0.05) than the controls. The IL-4(+)/IFN-gamma(-) cell percentages were increased in some patients with GBS, but the difference was not significant compared with the controls. Thus, our results suggest that a Th2 shift is a characteristic of MNM and may play an important role in the development of the disease.

Tc1/Tc2 and Th1/Th2 balance in Asian and Western types of multiple sclerosis, HTLV-I-associated myelopathy/tropical spastic paraparesis and hyperIgEaemic myelitis.

CD8+ T cells, like CD4+ T cells, can differentiate into at least two subsets with distinct cytokine patterns: Tc1 cells produce Th1-like cytokines and Tc2 cells produce Th2-like cytokines. To clarify the immunopathological roles of Tc1 and Tc2 cells in central nervous system (CNS) inflammation, we examined intracellular cytokines in CD8+ and CD4+ T cells by flow cytometry and analyzed the Tc1/Tc2 balance as well as the Th1/Th2 balance in 80 patients with various CNS inflammatory diseases, including 20 with optico-spinal multiple sclerosis (OS-MS), 21 with conventional MS (C-MS), 22 with human T-lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and 17 with hyperIgEaemic myelitis. Twenty-two healthy subjects were also examined as controls. Patients with OS-MS showed a significantly higher percentage of INF-gamma+IL-4- CD8+ T cells as well as CD4+ T cells and a significantly higher intracellular interferon-gamma (IFN-gamma)/interleukin-4 (IL-4) ratio both in CD8+ and CD4+ T cells throughout the relapse and remission phases than the healthy controls. Furthermore, the patients with OS-MS showed a significantly lower percentage of INF-gamma-IL-4+ CD4+ T cells as well as CD8+ T cells during the relapse phase than the healthy controls. On the other hand, the patients with C-MS showed a significantly higher percentage of IFN-gamma-IL-4+ CD8+ T cells in addition to more IFN-gamma+IL-4- CD4+ T cells during the relapse phase than the healthy controls. The HAM/TSP patients showed a significantly higher percentage of INF-gamma+IL-4- CD8+ T cells and a significantly higher intracellular IFN-gamma/IL-4 ratio in CD8+ T cells than the healthy controls. In contrast, in hyperIgEaemic myelitis, in addition to a significantly lower intracellular IFN-gamma/IL-4 ratio in CD4+ T cells, a tendency toward a lower intracellular IFN-gamma/IL-4 ratio in CD8+ T cells in comparison to the healthy controls was observed. These results clarified for the first time the distinct Tc1/Tc2 balance in each disease condition as follows: Tc1 cell response is predominant in OS-MS and HAM/TSP, while Tc2 cell response is predominant in hyperIgEaemic myelitis and at relapse phase of C-MS. Furthermore, our results suggest that CD8+ T cells play an adjunctive role in disease induction and the clinical course of MS.

Myelitis associated with atopic disorders in Japan: a retrospective clinical study of the past 20 years.

OBJECTIVE: To clarify the clinical features of myelitis associated with atopic disorders in Japanese patients. SUBJECTS AND METHODS: We retrospectively studied the clinical, immunological and electrophysiological features of 68 consecutive patients with myelitis of acute or subacute onset diagnosed at Kyushu University Hospital during the past 20 years. RESULTS: While only 2 of 28 (7%) patients with myelitis diagnosed between 1979 and 1993 had either atopic dermatitis (AD) or bronchial asthma (BA), 19 of 40 (48%) patients with myelitis diagnosed between 1994 and 1998 did. Among the 40 patients with myelitis diagnosed between 1994 and 1998, 19 patients with either AD or BA as well as 21 patients without either disease showed a significantly higher level of serum total IgE, higher frequency of hyperIgEaemia and higher frequency of mite antigen-specific IgE than 82 healthy controls. Myelitis patients with AD presenting as persistent paresthesia/dysesthesia in all four limbs showed cervical cord lesions on MRI and abnormalities in upper limb motor evoked potentials but no abnormalities in the cerebrospinal fluid (CSF), while myelitis patients with BA showed preferential involvement of the lower motor neurons clinically and electromyographically. In addition, 12 patients with myelitis who had hyperIgEaemia and mite antigen-specific IgE but neither AD nor BA showed incomplete transverse myelitis with mild motor disability and few CSF abnormalities. CONCLUSION: The clinical features of myelitis associated with atopic disorders were in part distinguished by the type of preceding atopic disorder, and also were different from those of hyperIgEaemic myelitis with no preceding atopic disorders.

Hepatic epithelioid hemangioendothelioma.

Epithelioid hemangioendothelioma (EHE) is a rare neoplasm of vascular origin with unpredictable malignant potential. We describe two patients with primary EHE of the liver and review 34 cases previously published in Japan and compare them with those in Western countries. The clinical aspects of EHE and relevant treatment results in Japanese patients were similar to those found in Western countries, the exception being the matter of difference in incidence between genders. Although this tumor type has been reported to be more frequent among women, there was no significant difference in incidence between men and women. Hepatic EHE generally behaves as a low-grade malignant tumor with a slow progression phenotype; however, this disease seems to be resistant to chemotherapy and to be lethal in some cases. Surgical resection or liver transplantation is recommended after rapid diagnosis by radiologic examination and histologic findings, including positive staining of tumor cells for factor VIII-related antigen.

Spinal cord lesions of myelitis with hyperIgEemia and mite antigen specific IgE (atopic myelitis) manifest eosinophilic inflammation.

We report the neuropathological findings of spinal cord specimens obtained from two patients who had localized myelitis with hyperIgEemia and mite antigen specific IgE (atopic myelitis). Both cases showed mild spinal cord dysfunction, and the gadolinium-enhanced area of the isolated spinal cord lesion observed on MRI was biopsied, respectively. Neuropathologically, both cases showed many perivascular lymphocyte cuffings associated with disrupted vessels, and the infiltration of eosinophils in the spinal cord lesions. Both myelin and axons were lost in the lesions, which were associated with astrogliosis. These findings suggest that an allergic mechanism may play a role in this condition.

[An autopsy case of dementia with motor neuron disease accompanying Alzheimer's disease lesion].

We report the case of a 60-year-old man with autopsy-proven dementia with motor neuron disease (D-MND) and Alzheimer's disease lesion. The patient presented with clumsiness of his right hand at the age of 55 years old and subsequently developed dysarthria, weakness and atrophy of his upper limbs. He was unaffectionate towards his family, repeated the same phrase, and showed severe disorientation of time and place. Neurological examination on admission showed not only diffuse lower motor neuron signs, such as weakness, atrophy, fasciculation and areflexia in both upper limbs, but also dementia (HDS-R 9/30). He died of respiratory insufficiency. Neuropathological examination showed mild atrophy of the frontal and temporal lobes and anterior spinal roots. Microscopic examination of cortical sections revealed degenerative changes with simple atrophy and gliosis, and these changes were predominant in layers 1 and 2 of the frontal and temporal cortices. Using immunohistochemical staining, ubiquitin-positive but tau-negative inclusions were frequently found in neurons of the hippocampal granular cell layers and temporal lobes. Many senile plaques and neurofibrillary tangles were present in all sections of the brain. Our final diagnosis was dementia with motor neuron disease accompanying Alzheimer's disease lesion, because of hypoperfusion in the parietal lobe as well as the frontal lobe demonstrated by SPECT, and the presence of many senile plaques and neurofibrillary tangles in the cerebral cortex. Overlapping of pathologically-proven D-MND and Alzheimer's disease lesion is extremely rare, and this case may improve our understanding of the process of neurodegeneration.

[A patient with vitamin E deficient, myopathy presenting with amyotrophy].

We report a 61-year-old man with vitamin E deficiency, presenting with, myopathy as an only clinical symptom. In 1997, at 59 years of age, he noted mild proxymal-muscle weakness and atrophy in the four extremities, nine years after he received a Billroth II partial gastrectomy for a gastric ulcer. His muscle weakness slowly exacerbated, and he was admitted to our hospital in 1999. On admission, neurological examination confirmed mild proximal-muscle weakness and atrophy in the four extremities. Intelligence, cranial nerves, coordination, sensation and tendon reflexes were all normal. Laboratory examination showed normochromic anemia (Hb 9.9 g/dl, Ht 30.9%, MCV 97.5 fl, MCHC 31.2 pg), hypoproteinemia (5.0 g/dl), and hypocholesterolemia (107 mg/dl). The levels of serum CK, lactate and pyruvate were normal. The serum vitamin E level was markedly reduced (0.17 mg/dl; normal 0.75-1.41). Cerebrospinal fluid was normal. Nerve conduction, sensory evoked potentials (SEP), electromyography (EMG), head CT and electroencephalography (EEG) were all normal. Muscle biopsy from the right deltoid muscle showed both mild myogenic and neurogenic changes. Remarkably, type 1 muscle fiber predominance and granular accumulation of autofluorescent lipofuscin granules in the muscle fibers were found. These pathological findings were compatible with those of vitamin E-deficient myopathy. Thus, he was diagnosed as having vitamin E-deficient myopathy, which was confirmed by apparent effective supplementation of vitamin E. Interestingly, our present case did not show any other neurological manifestations such as deep sensory disturbance, sensory ataxia or polyneuropathy. A long-term workload due to hard physical labor and smoking in our patient may have accelerated oxidative muscle damage, resulting in amyotrophy mainly due to vitamin E deficient myopathy.

[A case of myelitis caused by visceral larva migrans due to Ascaris suum presenting only with Lhermitte's sign].

A 27-year-old woman was admitted because of pain radiating through her back on neck flexion that had begun a month ago. She frequently ate raw beef liver. General physical examination revealed no abnormal findings, but she showed Lhermitte's sign neurologically. Fecal examination revealed no worm eggs. Blood cell counts showed mild eosinophilia (8.2%). The IgE level was mildly increased to 397 IU/ml (normal < 250). Cerebrospinal fluid examination showed 7 cells/microliter with 50% eosinophils. A test for anti-Ascaris suum IgG antibody was strongly positive in serum as well as in cerebrospinal fluid. Cervical MRI showed high-intensity areas in the spinal cord extending from the lower medulla to the C4 spine level on the T2-weighted images, and part of the lesion at the C3 spine level was enhanced by gadolinium. Treatment with albendazole 500 mg/day for six weeks ameliorated the Lhermitte's sign and MRI lesions, and reduced the anti-Ascaris suum antibody titers in the serum and cerebrospinal fluid. Larva migrans of Ascaris suum involving the central nervous system is considered to be extremely rare, but such cases showing mild neurologic impairment without systemic symptoms may have been overlooked.

Flow cytometric differentiation of Asian and Western types of multiple sclerosis, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and hyperIgEaemic myelitis by analyses of memory CD4 positive T cell subsets and NK cell subsets.

We examined the alterations of memory CD4(+) T cell subsets bearing surface receptors linked to either Th1 or Th2 cytokine production as well as natural killer (NK) cell subsets by three color flow cytometry in the peripheral blood from 36 patients with clinically definite multiple sclerosis (MS), 27 patients with HAM/TSP, 13 patients with hyperIgEaemic myelitis who had mite antigen-specific IgE and 25 healthy controls (HC). The patients with MS were clinically classified into an optico-spinal form of MS (Asian type, MS-A) and the conventional form of MS (Western type, MS-W). MS-A showed a significant increase of CD4(+)CD45RA(-)CCR5(+) cells (Th1 cells) through the relapse and remission phases in comparison to HC, while MS-W showed a significant increase of CD4(+)CD45RO(+)CD62L(-) cells (Th1 cells) only at the relapse phase. HAM/TSP showed a significant increase of CCR5(+) and CD62L(-) memory CD4(+) T cells as well as CD30(+) memory CD4(+) T cells (Th2 cells) in comparison to HC. On the other hand, a selective increase of CD4(+)CD45RO(+)CD30(+) cells was found in hyperIgEaemic myelitis. The percentage of mature NK cells (CD3(-)CD16(+)CD56(+) cells) as well as double negative T cells (CD3(+)CD4(-)CD8(-) cells) decreased significantly in HAM/TSP in comparison to HC. Our findings therefore suggest a flow cytometric analysis of Th1/Th2-associated markers on memory CD4(+) T cells as well as NK cell subsets to be useful for differentiating various inflammatory neurologic conditions.

Hyperprolactinemia in optico-spinal multiple sclerosis.

OBJECTIVE: To clarify the clinical features of MS patients with hyperprolactinemia. SUBJECTS AND METHODS: The serum prolactin level was measured in 67 Japanese patients (19 men and 48 women) with multiple sclerosis (MS) and in 16 patients (4 men and 12 women) with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) using a two-site immunoradiometric assay. RESULTS: In the MS patients, 32 were classified as having Asian type MS showing a selective involvement of the optic nerves and spinal cord, while the other 35 were classified as having Western type MS which displayed disseminated central nervous system involvement. In women, the serum prolactin level was found to be significantly higher only in Asian type MS (mean=23.1 ng/ml, n=25) than in HAM/TSP (mean=6.9 ng/ml, n=12) (p=0.0297), while it did not differ significantly in men among the three groups. Hyperprolactinemia was significantly associated with acute relapse involving the optic nerves. All MS patients with hyperprolactinemia (7 women with Asian type MS and 2 women with Western type MS) showed recurrent opticomyelitis either throughout or in the early course of the disease, and also had a higher age of onset, a higher Expanded Disability Status Scale score, a greater visual impairment, and higher cell counts and protein contents in the cerebrospinal fluid than did the normoprolactinemic patients. CONCLUSION: Hyperprolactinemia may be one of the characteristic features of Asian patients with MS who preferentially show the optic nerve involvement.

Acute myelitis after asthma attacks with onset after puberty.

A poliomyelitis-like illness after asthma attacks has been found and is called asthmatic amyotrophy (Hopkins' syndrome). All of the previously reported cases were under 13 years of age. Three patients are described who developed acute myelitis after asthma attacks at 15, 22, and 73 years of age. All of them showed acute flaccid monoparesis, and needle EMG disclosed denervation potentials in the relevant muscles. In addition, in the two adult patients the sensory or pyramidal tracts were involved, and evoked potential studies confirmed an involvement of the pyramidal tracts in one of them. This 22 year old patient showed a second episode of monoparesis in the other limb after another asthma attack. All three patients had no significant changes in their antiviral antibody titres, whereas every patient had hyperIgEaemia and allergen specific IgE. These findings suggest that asthmatic amyotrophy can develop after puberty and that patients who develop this disease in adulthood seem to show both a widespread involvement of the spinal cord and a more varied course.

[A case of mortor neuron syndrome with onset 9 months after electrical injury].

A 72-year-old man noticed progressive weakness of both upper limbs, more severe on the left side, 9 months after an electric shock of a 20,000 V alternating current. He had diffuse scars of superficial burns with skin graft in four limbs, more on the right side. A neurological examination revealed diffuse muscle atrophy, weakness and fasciculation in both upper limbs, predominantly on the left side, hyper-reflexia in four limbs with mildly exaggerated jaw jerk, left Babinski sign, and mild decrease of touch and pain sensation in the right C6 and C7 segments. Painful dysesthesia was present in the left hand and right lower limb. The search for serum antibodies against GM1, GM2, GM3, GD1a, Gd1b, GQ1b, GA1, and GT1b was negative. No abnormality except mild cervical spondylotic changes was evident in the magnetic resonance imaging of the brain and spinal cord. The upper limb motor evoked potentials (MEPs) were not elicited by the left cortical stimulation and the central motor conduction time by the right cortical stimulation was remarkably prolonged in the upper limb MEPs. Nerve conduction study showed a delay of motor conduction velocity and distal latency in the right median and bilateral ulnar nerves with low amplitude and delayed velocity of sensory nerves of those nerves. Needle EMG revealed diffuse ongoing denervation potentials in bilateral upper limbs and giant motor unit potentials in the right triceps and first dorsal interossei muscles. These findings indicate that the delayed motor neuron syndrome induced by electrical shock is characteristic for having demyelination as well as axonal changes in both central and peripheral nervous systems.