Two susceptible HLA-DRB1 alleles for multiple sclerosis differentially regulate anti-JC virus antibody serostatus along with fingolimod.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) caused by JC virus (JCV) is a rare but serious complication of some disease-modifying drugs used to treat multiple sclerosis (MS). Japanese MS patients treated with fingolimod were reported to be 10 times more likely to develop PML than equivalent patients in other countries. The strongest susceptibility human leukocyte antigen (HLA) class II alleles for MS are distinct between races (DRB1*15:01 for Caucasians and DRB1*04:05 and DRB1*15:01 for Japanese); therefore, we investigated whether HLA class II alleles modulate anti-JCV antibody serostatus in Japanese MS patients with and without fingolimod. METHODS: We enrolled 128 Japanese patients with MS, in whom 64 (50%) were under fingolimod treatment at sampling, and examined the relationship between HLA class II alleles and anti-JCV antibody serostatus. Serum anti-JCV antibody positivity and index were measured using a second-generation two-step assay and HLA-DRB1 and -DPB1 alleles were genotyped. RESULTS: HLA-DRB1*15 carriers had a lower frequency of anti-JCV antibody positivity (57% vs 78%, p = 0.015), and lower antibody index (median 0.42 vs 1.97, p = 0.037) than non-carriers. Among patients without HLA-DRB1*15, DRB1*04 carriers had a higher seropositivity rate than non-carriers (84% vs 54%, p = 0.030), and DPB1*04:02 carriers had a higher anti-JCV antibody index than non-carriers (3.20 vs 1.34, p = 0.008) although anti-JCV antibody-positivity rates did not differ. Patients treated with fingolimod had a higher antibody index than other patients (1.46 vs 0.64, p = 0.039) and treatment period had a positive correlation with antibody index (p = 0.018). Multivariate logistic regression analysis revealed that age was positively associated, and HLA-DRB1*15 was negatively associated with anti-JCV antibody positivity (odds ratio [OR] = 1.06, p = 0.006, and OR = 0.37, p = 0.028, respectively). Excluding HLA-DRB1*15-carriers, DRB1*04 was an independent risk factor for the presence of anti-JCV antibody (OR = 5.50, p = 0.023). CONCLUSIONS: HLA-DRB1*15 is associated with low anti-JCV antibody positive rate and low JCV antibody index, and in the absence of DRB1*15, DRB1*04 carriers are associated with a high antibody positive rate in Japanese, suggesting the effects of two susceptible HLA-DRB1 alleles on anti-JCV antibody serostatus differ.

Recurrent aortic root pseudoaneurysm after transcatheter occlusion-A word of caution.

A 48-year-old male developed a recurrent aortic-root pseudoaneurysm after surgical repair for acute dissection. Although the initial closure of the pseudoaneurysm was successfully managed by transcatheter endovascular occlusion and coiling utilizing a hybrid transapical and transfemoral approach, the pseudoaneurysm was recanalized after 3 months and a third-time surgical repair was required. The potential risk for recurrence of pseudoaneurysms should be considered when applying endovascular occlusion devices to treat aortic root anatomy.

[Surgical Devices for Minimally Invasive Cardiac Surgery(MICS)].

Minimally invasive cardiac surgery(MICS)rapidly has become popular in recent years. To perform meticulous surgical procedures in the limited space, specially designed surgical instruments are very useful. For excellent exposure of the surgical target, thoracoscopic system with high imaging quality such as 4K or 3D HD endoscopy is often used. An articulated rib spreader and/or soft tissue retractor is also useful since those instruments do not interfere with other surgical instruments. A suture catcher is used to pull traction sutures through the chest wall. There are various types of atrial retractor designed for MICS. For fine manipulation in the limited space, long-shafted forceps, needle holders, and scissors are necessary. Those instruments reach deeply located targets and do not interfere surgeon's and endoscopic view or other instruments. A knot pusher is another essential device to tie knots through a small incision. The automatic tying device is available outside the country. For cardiopulmonary bypass, cannulas designed for peripheral access are used. Most of those cannulas have multiple side holes that work well for excellent perfusion and drainage. There are also specially designed aortic cross-clamps. To make surgeons more comfortable and improve quality of MICS, surgical devices for MICS need to be further innovated.

Outcomes of Totally Endoscopic Atrial Septal Defect Closure Using a Glutaraldehyde-Treated Autologous Pericardial Patch.

BACKGROUND: We evaluated the outcomes of totally endoscopic minimally invasive surgery for atrial septal defect (ASD) using a glutaraldehyde-treated autologous pericardial patch in the transcatheter interventional era.Methods and Results:We retrospectively reviewed 37 consecutive patients who underwent totally endoscopic ASD closure with a glutaraldehyde-treated autologous pericardial patch between June 2011 and April 2015. All patients had been deferred from catheter-based intervention for clinical or anatomical reasons. We analyzed operative outcomes and postoperative echocardiographic data. The mean age was 45.7±16.5 years, and 25 patients (67.6%) were women. The mean ratio of pulmonary to systemic flow was 2.4±0.7. Six patients (16.2%) underwent concomitant tricuspid valve repair, and 3 patients (8.1%) underwent concomitant atrial fibrillation surgery. There were no operative deaths, and the median length of hospital stay was 5 days. Postoperative echocardiography revealed trivial residual shunt in 1 patient. During the follow-up period, there were no re-interventions for ASD or readmission for heart failure. Follow-up echocardiography revealed no recurrent shunt or calcification of the autologous pericardial patch. CONCLUSIONS: Totally endoscopic ASD closure with a glutaraldehyde-treated autologous pericardial patch demonstrated excellent outcomes. It is a useful option for patients with unfavorable anatomy or other reasons excluding transcatheter intervention.

Copy number variations in multiple sclerosis and neuromyelitis optica.

OBJECTIVE: To clarify the potential association of copy number variations (CNVs) with multiple sclerosis (MS) and neuromyelitis optica (NMO) in Japanese cases. METHODS: Genome-wide association analyses of CNVs among 277 MS patients, 135 NMO/NMO spectrum disorder (NMOSD) patients, and 288 healthy individuals as a discovery cohort, and among 296 MS patients, 76 NMO/NMOSD patients, and 790 healthy individuals as a replication cohort were performed using high-density single nucleotide polymorphism microarrays. RESULTS: A series of discovery and replication studies revealed that most identified CNVs were 5 to 50kb deletions at particular T cell receptor (TCR) gamma and alpha loci regions. Among these CNVs, a TCR gamma locus deletion was found in 16.40% of MS patients (p = 2.44E-40, odds ratio [OR] = 52.6), and deletion at the TCR alpha locus was found in 17.28% of MS patients (p = 1.70E-31, OR = 13.0) and 13.27% of NMO/NMOSD patients (p = 5.79E-20, OR = 54.6). These CNVs were observed in peripheral blood T-cell subsets only, suggesting the CNVs were somatically acquired. NMO/NMOSD patients carrying the CNV tended to be seronegative for anti-aquaporin-4 antibody or had significantly lower titers than those without CNV. INTERPRETATION: Deletion-type CNVs at specific TCR loci regions contribute to MS and NMO susceptibility.

Echocardiography versus (201)Tl semi-quantitative gated single photon emission tomography for the evaluation of cardiac disease associated with late stage Duchenne muscular dystrophy.

OBJECTIVE: In Duchenne muscular dystrophy (DMD) patients cardiac abnormalities are often detected. In adult DMD patients cardiac disease (CD) is a cause of death which increases by age and is related to respiratory dysfunction. Studies have demonstrated that CD in early DMD can be detected by echocardiography (EC) or semi-quantitative gated single photon emission tomography ((201)Tl SQGS), and the accuracy of these two tests is similar. As the disease advances, evaluation of CD by EC becomes difficult due to thoracic deformity and scoliosis. We compared (201)Tl SQGS and EC in the evaluation of cardiac function in late stage DMD, based on the ejection fraction (EF) value calculated by both tests. Twenty-three males with late stage DMD, 12 to 35 years of age (22.2±7.5), were studied by (201)Tl SQGS and EC. The mean EF value by (201)Tl SQGS was 60.8%±14.1%, which differed from that obtained by EC (52.7%±9.8%, P=0.003). Eleven patients less than 20 years old did not demonstrate a significant difference between the two tests (P=0.06), however, 12 patients over 20 years of age had significantly different results between tests (P=0.002). CONCLUSION: Although our patients were few we indicated that in DMD patients, aged older than 20 years, at an advanced stage of the disease, the EF values calculated by EC were lower than those by (201)Tl SQGS possibly due to thoracic deformity.

Distinct genetic and infectious profiles in Japanese neuromyelitis optica patients according to anti-aquaporin 4 antibody status.

OBJECTIVE: To clarify whether genetic and common infectious backgrounds are distinct, according to anti-aquaporin 4 (AQP4) antibody status in Japanese patients with neuromyelitis optica (NMO). METHODS: We analysed human leucocyte antigen (HLA)-DRB1 and HLA-DPB1 alleles, and IgG antibodies against Helicobacter pylori, Chlamydia pneumoniae, varicella zoster virus and Epstein-Barr virus nuclear antigen (EBNA) in 116 patients with NMO, including 39 patients with neuromyelitis optica spectrum disorder (NMOSD), 145 multiple sclerosis (MS) patients and 367 unrelated healthy controls. 77 NMO/NMOSD patients were seropositive for AQP4 antibody while 39 were seronegative. RESULTS: Compared with healthy controls, NMO/NMOSD patients showed a significantly lower frequency of DRB1*0901 and significantly higher frequencies of DRB1*1602 and DPB1*0501, which conferred susceptibility to anti-AQP4 antibody positive NMO/NMOSD, but not antibody negative NMO/NMOSD. DRB1*0901 was a common protective allele, irrespective of the presence or absence of anti-AQP4 antibody. Anti-H pylori and anti-C pneumoniae antibodies were more commonly detected in anti-AQP4 antibody positive NMO/NMOSD patients than healthy controls. Antibody negative NMO/NMOSD patients did not differ from healthy controls regarding the presence of these antibodies. The presence or absence of antibodies against varicella zoster virus and EBNA did not vary among the groups. The frequencies of antibodies against these four pathogens were not significantly different between MS patients and healthy controls. CONCLUSIONS: Our results suggest that HLA-DRB1*1602 and DPB1*0501 alleles and H pylori and Chlamydia pneumonia infection are risk factors only for anti-AQP4 antibody positive NMO/NMOSD but not for anti-AQP4 antibody negative NMO/NMOSD.

[A case of systemic amyloidosis with cholangiectasis diagnosed by liver biopsy].

A 60-year-old man presented with fever and fatigue in a medical clinic and was given a diagnosis of cholangitis with mild cholangiectasis. The cholangiectasis remained even after treatment with an appropriate antibiotic agent. When the patient was transferred to our hospital for further examination, he was newly suffering from orthostatic hypotension and peripheral facial nerve palsy. Computed tomography (CT) scan revealed multiple low-density areas in the liver and intrahepatic bile duct dilatation. We performed percutaneous liver biopsy, and histopathological findings showed amyloid deposition around the portal vein. We diagnosed his condition as AL amyloidosis. Oral administration of melphalan and dexamethasone improved his clinical features and CT findings. We consider this case as rare in that the deposition of amyloid protein caused cholangiectasis.

Quantitative assays for anti-aquaporin-4 antibody with subclass analysis in neuromyelitis optica.

BACKGROUND: To clarify the clinical relevance of anti-aquaporin-4 (anti-AQP4) antibody titers and immunoglobulin (IgG) subclass. METHODS: Using a bridging enzyme-linked immunosorbent assay (ELISA), a flow cytometric assay (FCMA) and an immunofluorescence assay (IFA) for anti-AQP4 antibodies, sera from 142 patients with multiple sclerosis (MS) as defined by the McDonald criteria (2005), 29 with neuromyelitis optica (NMO) who fulfilled the 1999 criteria, 19 with recurrent and/or longitudinally extensive myelitis (RM/LM), 86 with other non-inflammatory neurological diseases (OND) and 28 healthy controls (HC) were studied. RESULTS: Anti-AQP4 antibody positivity rates by IFA, FCMA, and ELISA were 41.4%, 51.7% and 48.3%, respectively, in NMO (1999) patients, and 0% in the OND and HC groups. Twenty-six MS patients (18.3%) were positive for the antibody; 17 met the 2006 NMO criteria, including positivity for anti-AQP4 antibody, and five had longitudinally extensive myelitis (LM). Among the cases with anti-AQP4 antibody detected by FCMA, IgG1, 2, 3, and 4 anti-AQP4 antibodies were found in 97.8%, 37.0%, 6.5% and 6.5% respectively. There was no association of either antibody positivity or level of anti-AQP4 antibody IgG subclasses with clinical parameters after adjustment of p values for multiple comparisons. CONCLUSIONS: FCMA and bridging ELISA are useful for detecting and quantifying anti-AQP4 antibodies.

[Relapsing polychondritis presenting as encephalitis].

Relapsing polychondritis (RP) is a rare, generalized autoimmune disorder that is characterized by recurrent inflammation of various cartilaginous structures. Involvement of the central nervous system is rarely observed in RP. Here we report a case of encephalitis associated with RP. A 60-year-old man presented with headache and bilateral ear swelling. Three weeks later, he came to our hospital because of the acute onset of a speech impediment. A non-contrast computed tomography scan of the head showed slight high-density areas in his left frontal lobe, but he refused to be admitted and went home. On the next day, he developed acalculia, agraphia, right-left disorientation, and mild right hemiparesis. Brain MRI revealed hyperintensity areas in the left frontal sulcus on fluid-attenuated inversion recovery (FLAIR) images, and these hyperintensity areas were enhanced by gadolinium. Therefore, the patient's symptoms were diagnosed as focal epilepsy caused by meningoencephalitis. Other examinations, including laboratory blood tests, cerebrospinal fluid tests, and a cerebral angiography, were all negative. Therefore, a brain biopsy of the left frontal cortex was performed 5 days after the patient's admission. Pathological findings revealed chronic inflammation of the meninges, so prednisone was administered. After receiving oral prednisone, the patient's bilateral ear swelling dramatically improved and the lesions apparent on cranial MRI gradually subsided. The patient was diagnosed with RP by a neurologist after discharge from the hospital. In this study, early diagnosis and steroid treatment is recommended for patients with neurological complications due to RP.

Early outcomes of transatrial mitral valve replacement in severe mitral annular calcification.

OBJECTIVE: Mitral valve replacement (MVR) in the setting of severe mitral annular calcification is a technically challenging operation with increased morbidity and mortality. Transseptal/apical transcatheter MVR (TMVR) in mitral annular calcification has emerged as an option for these cases, although may not be feasible due to anatomical reasons. Transatrial TMVR is a potential treatment option for this subgroup of patients. METHODS: Patients who underwent transatrial TMVR between June 2018 and November 2020 at a single institution were included. Patients were selected by a structural heart team based on their surgical risk, pattern of mitral annular calcification, risk of valve migration, left ventricular outflow obstruction, and paravalvular leak. RESULTS: A total of 11 patients underwent transatrial TMVR. Mean patient age was 74.2 years and mean Society of Thoracic Surgeons predicted risk of mortality score was 9.1%. All patients had the presence of both mitral stenosis and regurgitation-dominant etiology-was mitral stenosis in 81.2%, and mitral regurgitation in 18.8%. Among patients, 54.5% had a concomitant cardiac procedure. There was no in-hospital or 30-day mortality. Technical success defined by the Mitral Valve Academic Research Consortium was achieved in 90.9% of patients. Postoperative paravalvular leak was mild or less in all patients. CONCLUSIONS: In this series, transatrial TMVR was shown to be a safe and effective treatment option for patients who are high risk for surgical MVR and should be in surgeons' armamentarium in the treatment of this high-risk patient population. Dissemination of safe technique will be critical in the successful conduct of this surgery.

HLA genotype-clinical phenotype correlations in multiple sclerosis and neuromyelitis optica spectrum disorders based on Japan MS/NMOSD Biobank data.

HLA genotype-clinical phenotype correlations are not established for multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD). We studied HLA-DRB1/DPB1 genotype-phenotype correlations in 528 MS and 165 NMOSD cases using Japan MS/NMOSD Biobank materials. HLA-DRB1*04:05, DRB1*15:01 and DPB1*03:01 correlated with MS susceptibility and DRB1*01:01, DRB1*09:01, DRB1*13:02 and DPB1*04:01 were protective against MS. HLA-DRB1*15:01 was associated with increased optic neuritis and cerebellar involvement and worsened visual and pyramidal functional scale (FS) scores, resulting in higher progression index values. HLA-DRB1*04:05 was associated with younger onset age, high visual FS scores, and a high tendency to develop optic neuritis. HLA-DPB1*03:01 increased brainstem and cerebellar FS scores. By contrast, HLA-DRB1*01:01 decreased spinal cord involvement and sensory FS scores, HLA-DRB1*09:01 decreased annualized relapse rate, brainstem involvement and bowel and bladder FS scores, and HLA-DRB1*13:02 decreased spinal cord and brainstem involvement. In NMOSD, HLA-DRB1*08:02 and DPB1*05:01 were associated with susceptibility and DRB1*09:01 was protective. Multivariable analysis revealed old onset age, long disease duration, and many relapses as independent disability risks in both MS and NMOSD, and HLA-DRB1*15:01 as an independent risk only in MS. Therefore, both susceptibility and protective alleles can influence the clinical manifestations in MS, while such genotype-phenotype correlations are unclear in NMOSD.

A CD63 mutant inhibits T-cell tropic human immunodeficiency virus type 1 entry by disrupting CXCR4 trafficking to the plasma membrane.

We have discovered that an N-terminal deletion mutant of a membrane protein, CD63, (CD63DeltaN) blocks entry of CXCR4-using, T-cell tropic human immunodeficiency virus type 1 (X4 HIV-1) by suppressing CXCR4 surface expression. This suppression was observed for CXCR4 but not for CD4, CCR5, CD25, CD71 or other tetraspanin proteins. The suppression of CXCR4 expression on the plasma membrane appeared to be caused by mislocalization of CXCR4 and exclusive transportation of CXCR4 toward intracellular organelles, mainly late endosomes/lysosomes. Our data suggest that CXCR4 trafficking can be modified in terms of its recruitment to the plasma membrane without enhancing the degradation or arresting vesicular transport of CXCR4.

[Case of Borrelia brainstem encephalitis presenting with severe dysphagia].

We report the case of a 30-year-old man who developed severe dysphagia owing to neuroborreliosis. He showed dysphagia, diplopia, hiccups, and walking difficulty Neurological examination revealed mild disturbance of consciousness, diplopia on left lateral gaze, left-side-dominant blephaloptosis, gaze-evoked horizontal nystagmus on left lateral gaze, mild bilateral muscle weakness, palatoplegia, dysphagia, dysarthria, and truncal ataxia An increased pharyngeal reflex caused dysphagia in this patient. An EEG revealed intermittent high amplitude slow wave activity. However, head MRI, blood count, serum chemistry, and cerebrospinal fluid examination showed no abnormality. Initially, brainstem encephalitis with unknown etiology was diagnosed. The hiccups, diplopia, and ptosis were improved by corticosteroid therapy, but other symptoms were refractory to corticosteroid therapy and IVIg. After these immunotherapies, anti-Borrelia IgG and IgM antibodies were found to be positive, and symptoms, including dysphagia, were improved by doxycycline and cefotaxime. Because the clinical symptoms of Borrelia infection are widely variable, neuroborreliosis should be considered in patients with brainstem encephalitis refractory to conventional immunotherapies.

[A case of myasthenia gravis with an invasive thymoma infiltrating the superior vena cava and right atrium and causing lung metastasis].

A 72-year-old woman was admitted to a local hospital with general fatigue, ptosis and dysarthria. Her anti-AchR antibody titer was high, so myasthenia gravis was diagnosed. She was given a cholinesterase inhibitor, but her symptoms did not improve. CT and MRI scans revealed a mass in the anterior mediastinum infiltrating the superior vena cava (SVC) and the right atrium (RA) . The diagnosis was an invasive thymoma extending into the SVC and the RA. Moreover, there was a mass in the right middle lobe of her lung, which was suspected to be the result of metastasis of the thymoma. She was transferred to our hospital for medication and surgery for the invasive thymoma. Urgent surgery was performed without preoperative therapy, because the tumor was nearly obstructing her tricuspid valve. An expanded thymomectomy and a right middle lobectomy were performed. As the tumor had infiltrated into the SVC, the SVC was replaced with an artificial graft. The clinicopathological diagnosis of thymoma (Masaoka Stage IVb) was given. The patient had a myasthenic crisis for several weeks after surgery, so her breathing was controlled by an artificial respirator. Her symptoms improved after treatment with steroids, tacrolimus and a cholinesterase inhibitor. Although major surgery was required to prevent tumor embolism, the patient survived. Careful observation is necessary to detect signs of relapse of invasive thymoma.

Facial onset sensory and motor neuronopathy (FOSMN) syndrome responding to immunotherapies.

We report the first non-Caucasian case of facial onset sensory and motor neuronopathy (FOSMN) syndrome partially responding to various immunotherapies. A 55-year-old man had first felt paresthesia on his right cheek at age 45. This gradually extended to the scalp. Paresthesia of bilateral fingers and dysphagia appeared 6 years later. On admission, facial sensory impairment and bulbar palsy were found. There were no sensory or motor deficits evident in any limb, except for decreased deep tendon reflex and vibratory sensation. Videofluorography (VF) revealed decreased pharyngeal clearance. The sensory nerve action potential (SNAP) amplitudes of median and ulnar nerves were decreased. Intravenous immunoglobulin therapy and plasma exchange ameliorated his dysesthesia and dysphagia after several weeks, and resulted in improvements in VF and SNAP abnormalities. These observations suggest that FOSMN syndrome maybe, in part, immune-mediated.

Intrathecal upregulation of IFN-gamma and MIP-1beta in juvenile muscular atrophy of the distal upper extremity.

Juvenile muscular atrophy of the distal upper extremity (JMADUE) is associated with airway allergy and hyperIgEaemia, suggesting the involvement of immunological processes. In this study we aimed to clarify the changes in various cytokines/chemokines in cerebrospinal fluid (CSF) from JMADUE patients. We simultaneously measured 17 cytokines/chemokines in sera and CSF from 6 patients with JMADUE before treatment and from 14 patients with cervical spondylosis (CS) as a disease control (mean age at examination 23+/-7 and. 57+/-16 years, respectively), using a fluorescent bead-based immunoassay. We also assayed CSF from a JMADUE patient before and after plasma exchanges. In sera, only an increase of MIP-1beta (CCL3) in the JMADUE patients had a marginal significance as compared with the CS patients. In the CSF, IFN-gamma and MIP-1beta (CCL3) were significantly elevated in JMADUE patients compared with controls (1.5 and 2-fold increases, respectively), while no other cytokines/chemokines showed any significant differences. Moreover, the upregulated cytokines decreased after plasma exchanges in accord with improvement of distal upper limb weakness. The intrathecal upregulation of proinflammatory Th1 cytokines/chemokines, such as IFN-gamma and MIP-1beta (CCL3), in the CSF of JMADUE patients indicates the possible involvement of intrathecal immunological processes in this condition.

Heterogeneity and continuum of multiple sclerosis in Japanese according to magnetic resonance imaging findings.

There are two distinct subtypes of multiple sclerosis (MS) in Asians: optic-spinal (OSMS) and conventional (CMS). Longitudinally extensive spinal cord lesions (LESCLs) extending over three or more vertebral segments are characteristic of patients with OSMS, yet in Asians, one-fourth of CMS patients also have LESCLs. To clarify the distinction between LESCLs in OSMS and CMS, and to characterize the relationship between the presence of LESCLs and brain magnetic resonance imaging (MRI) findings, we studied 142 patients with clinically definite MS of relapsing-remitting onset and 12 patients with primary progressive MS (PPMS) by MRI of the whole spinal cord and brain. The former was diagnosed by Poser criteria, including 57 with OSMS, 67 with CMS and 18 with brainstem-spinal form of MS, while the latter by McDonald criteria. The presence of LESCLs throughout the entire clinical course was significantly more common in OSMS patients than in CMS patients, while brain lesions fulfilling the Barkhof criteria (Barkhof brain lesions) were significantly more common in CMS patients than OSMS patients. LESCLs in OSMS patients most frequently affected the upper to middle thoracic cord, with either holocord or central gray matter involvement. By contrast, 70% of LESCLs in CMS patients predominantly affected the peripheral white matter of the mid-cervical cord. LESCLs in patients with PPMS also showed preferential involvement of the peripheral white matter of the mid-cervical cord. One-third of OSMS patients had neither LESCLs nor Barkhof brain lesions more than 10 years after disease onset, and showed significantly milder disability than OSMS patients with LESCLs. These findings suggest that LESCLs are heterogeneous between OSMS and CMS patients, and that there are distinct subtypes of MS in Japanese, according to clinical and MRI findings.

Atopic myelitis with focal amyotrophy: a possible link to Hopkins syndrome.

Among 22 consecutive patients with myelitis, of unknown etiology, and atopic diathesis (atopic myelitis) who from April 2002 to March 2006 had been studied in our clinic, 5 (23%) showed focal amyotrophy in one or two limbs. These 5 patients were subjected to combined clinical, electrophysiological, neuroimaging and immunological studies. Ages were 18 to 58-years-old (average 39). Four showed amyotrophy of unilateral or bilateral upper limbs while one showed amyotrophy in both thighs. All patients showed on-going denervation potentials in the affected muscles, while motor conduction study including F wave was normal except for in one patient who showed prolonged F wave latency in one nerve. Two had localized high signal intensity lesions involving anterior horns on spinal cord MRI and three showed abnormalities suggesting pyramidal tract involvement on motor evoked potentials. All had a present and/or past history of atopic disorders and specific IgE against common environmental allergens, such as mite antigens and cedar pollens, and four showed mild eosinophilia, all of which were compatible with atopic myelitis. When clinical and laboratory findings were compared between atopic myelitis with (n=5) or without focal amyotrophy (n=17), the former showed a significantly higher frequency of present and past history of asthma (80% vs. 24%, p=0.0393) and tended to have higher EDSS scores (3.8+/-1.6 vs. 3.1+/-1.4). Two patients showed mild to moderate improvements after immunotherapies such as methylprednisolone pulse therapy or plasma exchange, while two recovered with low dose corticosteroids and one without treatment had a gradually progressive course. Although atopic myelitis preferentially involves the posterior column of the cervical spinal cord, it is possible that anterior horn cells are affected in some cases of atopic myelitis, especially in patients with asthma. This suggests a possible link between atopic myelitis and Hopkins syndrome (asthmatic amyotrophy).

Heterogeneity of aquaporin-4 autoimmunity and spinal cord lesions in multiple sclerosis in Japanese.

Opticospinal multiple sclerosis (OSMS) in Asians has similar features to the relapsing-remitting form of neuromyelitis optica (NMO) seen in Westerners. OSMS is suggested to be NMO based on the frequent detection of specific IgG targeting aquaporin-4 (AQP4), designated NMO-IgG. The present study sought to clarify the significance of anti-AQP4 autoimmunity in the whole spectrum of MS. Sera from 113 consecutive Japanese patients with clinically definite MS, based on the Poser criteria, were assayed for anti-AQP4 antibodies by immunofluorescence using GFP-AQP4 fusion protein-transfected HEK-293T cells. Sensitivity and specificity of the anti-AQP4 antibody assay, 83.3 and 100%, respectively, were calculated using serum samples with NMO-IgG status predetermined at the Mayo Clinic. The anti-AQP4 antibody positivity rate was significantly higher in OSMS patients (13/48, 27.1%) than those with CMS (3/54, 5.6%), other neurological diseases (0/52) or healthy controls (0/35). None of the 11 patients tested with a brainstem-spinal form of MS were positive. Among OSMS patients, the antibody positivity rate was highest in OSMS patients with longitudinally extensive spinal cord lesions (LESCLs) extending over three vertebral segments and brain lesions that fulfilled the Barkhof criteria (5/9, 55.6%). Multiple logistic analyses revealed that emergence of the anti-AQP4 antibody was positively associated only with a higher relapse rate, but not with optic-spinal presentation or LESCLs. Compared with anti-AQP4 antibody-negative CMS patients, anti-AQP4 antibody-positive MS patients showed significantly higher frequencies of severe optic neuritis, acute transverse myelitis and LESCLs while most conditions were also common to anti-AQP4 antibody-negative OSMS patients. The LESCLs in anti-AQP4 antibody-positive patients were located at the upper-to-middle thoracic cord, while those in anti-AQP4 antibody-negative OSMS patients appeared throughout the cervical-to-thoracic cord. On axial planes, the former most frequently showed central grey matter involvement, while holocord involvement was predominant in the latter. In contrast, LESCLs in anti-AQP4 antibody-negative CMS patients preferentially involved the mid-cervical cord presenting a peripheral white matter-predominant pattern, as seen in the short lesions. Anti-AQP4 antibody-positive MS patients fulfilling definite NMO criteria showed female preponderance, higher relapse rate, greater frequency of brain lesions and less frequent responses to interferon beta-1b than anti-AQP4 antibody-negative OSMS patients with LESCLs. These findings suggested that LESCLs are distinct in anti-AQP4 antibody positivity and clinical phenotypes. There were cases of anti-AQP4 antibody-positive MS/NMO distinct from CMS, and anti-AQP4 antibody-negative OSMS with LESCLs in Japanese. This indicated that the mechanisms producing LESCLs are also heterogeneous in cases with optic-spinal presentation, namely AQP4 autoimmunity-related and -unrelated.