Tatsuo Kohriyama

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° North) into northern and southern parts at 37°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.”

Clinical diagnosis of MM2-type sporadic Creutzfeldt-Jakob disease

Background: No method for the clinical diagnosis of MM2-type sporadic Creutzfeldt-Jakob disease (sCJD) has been established except for pathologic examination. Objective: To identify a reliable marker for the clinical diagnosis of MM2-type sCJD. Methods: CSF, EEG, and neuroimaging studies were performed in eight patients with MM2-type sCJD confirmed by neuropathologic, genetic, and western blot analyses. Results: The eight cases were pathologically classified into the cortical (n = 2), thalamic (n = 5), and combined (corticothalamic) (n = 1) forms. The cortical form was characterized by late-onset, slowly progressive dementia, cortical hyperintensity signals on diffusion-weighted imaging (DWI) of brain, and elevated levels of CSF 14-3-3 protein. The thalamic form showed various neurologic manifestations including dementia, ataxia, and pyramidal and extrapyramidal signs with onset at various ages and relatively long disease duration. Characteristic EEG and MRI abnormalities were almost absent. However, all four patients examined with cerebral blood flow (CBF) study using SPECT showed reduction of the CBF in the thalamus as well as the cerebral cortex. The combined form had features of both the cortical and the thalamic forms, showing cortical hyperintensity signals on DWI and hypometabolism of the thalamus on [18F]2-fluoro-2-deoxy-d-glucose PET. Conclusion: For the clinical diagnosis of MM2-type sporadic Creutzfeldt-Jakob disease, cortical hyperintensity signals on diffusion-weighted MRI are useful for the cortical form and thalamic hypoperfusion or hypometabolism on cerebral blood flow SPECT or [18F]2-fluoro-2-deoxy-d-glucose PET for the thalamic form.

Detection of cervical nerve root hypertrophy by ultrasonography in chronic inflammatory demyelinating polyradiculoneuropathy

Several studies have demonstrated abnormal MRI findings in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), especially hypertrophy and abnormal enhancement of spinal nerve roots, but there have been few reports on ultrasonographic findings of spinal nerve roots in CIDP. To determine whether ultrasonography (US) enables detection of hypertrophy of the cervical nerve roots, how frequently hypertrophy occurs in CIDP, and whether US findings correlate with any clinical and laboratory features, US of cervical nerve roots was performed using a 7.5-MHz linear-array transducer in 13 CIDP patients and 35 control subjects. A coronal oblique plane with a transducer placed on the lateral side of the neck was used to visualize the cervical nerve roots just after their point of exit from the cervical foramina, and their diameters were measured. US demonstrated hypertrophy of the cervical nerve roots in 9 (69%) of the 13 CIDP patients as compared with findings in control subjects. The degree of hypertrophy was significantly associated with the level of CSF protein (chi2=5.8, p<0.05, logistic simple regression analysis) but not with other clinical features. US is considered to be a useful method for evaluating cervical nerve root hypertrophy, which is frequently seen in patients with CIDP, particularly in patients with elevated level of CSF protein.

Association between central systolic blood pressure, white matter lesions in cerebral MRI and carotid atherosclerosis.

White matter hyperintensities (WMHs) observed on cerebral magnetic resonance images (MRIs) are associated with age and hypertension, suggesting a vascular mechanism of pathogenesis. Central systolic blood pressure (cSBP) correlates more closely with measures of cardiovascular disease risk than brachial pressure. We sought to determine whether cSBP correlates with WMHs and if cSBP is predictive of cerebrovascular disease. Radial applanation tonometric measurements for cSBP and augmentation index (AI) were carried out in unselected individuals undergoing carotid ultrasound. WMHs were assessed retrospectively using fluid-attenuated inversion recovery (FLAIR)-MRIs as periventricular (PVH) and deep white matter hyperintensities (DWMH), and they were rated using the Fazekas scale. A total of 179 patients, 94 (53%) men and 85 (47%) women, with a mean age of 66±13 years were included in the study. On MRI, 17, 74, 67 and 21 patients had PVH grades 0, 1, 2 and 3, respectively. Forty-eight, 69, 49 and 13 had DWMH grades 0, 1, 2 and 3, respectively. In our study population, PVH correlated with age, brachial SBP, cSBP and AI (r=0.49, 0.28, 0.23; P<0.002 and r=0.13; P<0.05, respectively). DWMH also correlated with age, brachial SBP and cSBP (r=0.41, 0.30, 0.22; P<0.003, respectively), but not with AI. cSBP values were associated with PVH/DWMH grades 2 and 3, but brachial SBP correlated only with grade 3. Mean carotid intima–media thickness (common carotid arteries (CCA)-IMT) was 0.68±0.13 mm. CCA-IMT and plaque score (PS) correlated with PVH/DWMH. Multivariate regression analysis showed cSBP, age and PS to be independently associated with PVH and DWMH. Correlation of cSBP with PVH and DWMH was independent of PS. Central SBP correlated with PVH and DWMH in FLAIR-MRIs and can better predict WMHs than brachial SBP in earlier stages.

Endothelial markers and adhesion molecules in acute ischemic stroke—sequential change and differences in stroke subtype

The progress of a stroke concerns the activation of endothelial cells and platelets. We measured the plasma activities of von Willebrand factor (vWf) and the serum levels of soluble thrombomodulin (sTM) as endothelial markers, and the plasma concentrations of soluble P-selectin (sP-selectin) and soluble E-selectin (sE-selectin) as adhesion molecules during the acute (within 48 h from onset) and subacute (after 1 month from the onset) phases of 52 consecutive patients with acute ischemic stroke and 86 age-matched control subjects. The plasma vWf activities and levels of sP-and sE-selectins in stroke patients were significantly elevated compared with those in controls during both the acute and subacute phases. The serum levels of sTM in stroke patients were significantly higher than those in controls only during the subacute phase. In atherothrombotic infarction, the vWf activities and the levels of sP-selectin, markers for endothelial and platelet activation, remained higher until the subacute phase compared with controls, and the concentrations of sTM, a marker for endothelial injury, were increased during the subacute phase compared with during the acute phase. In lacunar infarction, the levels of sTM and sE-selectin of patients were higher only during the acute phase than controls. These findings suggest that the endothelial cell damage might be maintained until the subacute phase in atherothrombotic infarction, whereas it is remarkable only during the acute phase in lacunar infarction. The evaluation of endothelial markers and adhesion molecules would represent the pathophysiological states of stroke and may provide useful information for the treatment of the ischemic infarction.

Subcellular Localization of Sulfated Glucuronic Acid-Containing Glycolipids Reacting with Anti-Myelin-Associated Glycoprotein Antibody

Abstract: Peripheral nerve glycolipids, with which anti‐myelin‐associated glycoprotein (MAG) antibodies from patients with demyelinating neuropathy and plasma cell dyscrasia cross‐react, proved to be novel glycosphingolipids containing a sulfated glucuronyl residue. Consequently, there has been much interest in the immunological role that these sulfated glucuronyl‐glycosphingolipids (SGGLs) may play in the pathogenesis of this disorder. For the determination of the distribution of these glycolipids in various nervous tissues and, thereby, the elucidation of their pathoge‐nicity, a quantitative immunostaining‐TLC method for their detection has been devised. Using this method, we demonstrated that these glycolipids were distributed in greatly different amounts in the peripheral nerves from human, bovine, chicken, rat, and rabbit. Subcellular localization studies of bovine peripheral nerve also demonstrated that they were enriched in the axolemma‐enriched fraction and present in glial‐related membranes in lower concentrations. In addition, these glycolipids were present in bovine dura mater and transformed rat Schwann cells. These biochemical results suggest that not only myelin but also axons could be involved as targets of the anti‐MAG antibody in macroglobulinemia neuropathy, and it may also be necessary to examine anti‐SGGL activity in patients with axonal neuropathy associated with plasma cell dyscrasia.

Antibodies to sulfated glucuronic acid containing glycosphingolipids in neuropathy associated with anti-MAG antibodies and in normal subjects

Serum of patients with neuropathy and IgM monoclonal antibodies (M-proteins) that bind to the myelin-associated glycoprotein (MAG) were tested for binding to the major cross-reactive sulfated glucuronic acid containing glycosphingolipid, sulfated glucuronic acid paragloboside (SGPG). IgM binding to the glycolipid was detectable at serum dilutions of 1:10,000 and reactivity was greatest at 4 degrees C. Low titers of IgM binding to the glycolipid were also detected in sera from normal subjects and from patients with neurologic or rheumatologic diseases without serum M-proteins. Binding activity was present in 25% of the sera tested, and titers ranged between 1:25 and 1:400. One patient with peripheral neuropathy, however, had a measurable titer of 1:12,800 in the absence of monoclonal gammopathy. The study indicates that cold reacting anti-SGPG IgM antibodies are frequent constituents of the normal human antibody repertoire, and that monoclonal or polyclonal expansion of B cells that secrete these antibodies, is associated with peripheral neuropathy.

Preparation and characterization of antibodies against a sulfated glucuronic acid-containing glycosphingolipid

Abstract: In some patients with demyelinating neuropathy there are immunoglobulin M paraproteins that react with carbohydrate determinants shared by myelin‐associated glycoprotein (MAG) and two peripheral nerve acidic glycolipids, termed sulfoglucuronosylglycosphingolipids (SGGLs). To study the antigenicity of these glycolipids, we immunized three New Zealand white rabbits with sulfoglucuronosylparagloboside (SGPG), a major SGGL in peripheral nerve, emulsified in Freunds complete adjuvant and keyhole limpet hemocyanin. All three rabbits inoculated with SGPG showed weight loss and mild weakness, predominantly in their hind feet, 2–5 weeks postinoculation (PI). Two of the three rabbits again showed moderate weakness 3 and 8 months PI, respectively. Electrophysiological studies demonstrated a slowed nerve conduction velocity in the sciatic nerve. Anti‐SGPG antibody titers in sera were detected at dilutions of 1:1,000 to 1:2,500 by an enzyme‐linked immunosorbent assay. Although all three rabbit sera reacted with SGGLs, two reacted with a desulfated form of SGPG and the other did not, suggesting a fine heterogeneity in antigenic specificity. As with sera from patients with demyelinative paraproteinemia, all rabbit sera reacted with MAG in human CNS and PNS myelin. They also reacted with MAG from bovine CNS myelin as well as several low‐molecular‐weight glycoproteins in bovine peripheral nerve myelin. Thus, we demonstrated that the rabbit antisera generated against SGPG have the same or similar antigenic specificity as those of the anti‐MAG M‐proteins from patients with neuropathy. The results suggest that an autoimmune response against the sulfoglucuronosyl residue may participate in the immunopathogenesis of this type of neuropathy.

Neuropathy and IgM paraproteinemia Differential binding of IgM M‐proteins to peripheral nerve glycolipids

Two patients with neuropathy and IgM paraproteinemia displayed different immunoreactivity to acidic peripheral nerve glycolipids: In one patient, immunostaining on thin-layer chromatographic plate revealed binding of the IgM to sulfated glucuronosyl paragloboside (SGPG) and sulfated glucuronosyl lactosaminyl paragloboside (SGLPG). The other IgM bound SGPG, SGLPG, and a new third glycolipid. Immunoreactivity of the IgM varies in this syndrome.

Diffusion tensor imaging of peripheral nerve in patients with chronic inflammatory demyelinating polyradiculoneuropathy: a feasibility study

IntroductionThe purpose of this study was to assess the clinical feasibility of diffusion tensor imaging (DTI) for the evaluation of peripheral nerves in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).MethodsUsing a 3-T magnetic resonance imaging scanner, we obtained DTI scans of the tibial nerves of 10 CIDP patients and 10 sex- and age-matched healthy volunteers. We prepared fractional anisotropy (FA) maps, measured the FA values of tibial nerves, and compared these values in the two study groups. In nine patients, we also performed tibial nerve conduction studies and analyzed the correlation between the FA values and parameters of the nerve conduction study.ResultsThe tibial nerve FA values in CIDP patients (median 0.401, range 0.312–0.510) were significantly lower than those in healthy volunteers (median 0.530, range 0.469–0.647) (Mann–Whitney test, p < 0.01). They were significantly correlated with the amplitude of action potential (Spearman correlation coefficient, p = 0.04, r = 0.86) but not with nerve conduction velocity (p = 0.79, r = 0.11).ConclusionOur preliminary data suggest that the noninvasive DTI assessment of peripheral nerves may provide useful information in patients with CIDP.