Mika Komori

Interferon-β1b Treatment in Neuromyelitis Optica

Background: The effects of interferon-β1b (IFN-β1b) administration in multiple sclerosis (MS) patients have been confirmed, however, those in neuromyelitis optica (NMO) patients have not been shown. In this study, we assessed the effects of IFN-β1b treatment on disease exacerbation and disability progression in MS or NMO patients. Methods: We reviewed a series of 104 consecutive patients with relapsing-remitting MS (RRMS) (69) or NMO (35) treated with IFN-β1b in the MS clinical center of a national hospital in Japan. Results: The relapse number in the RRMS patients significantly decreased within 1 year after IFN-β1b treatment (p < 0.00001); however, that in the NMO patients did not show a significant decrease (p = 0.5601). The decrease in annualized relapse rates in each RRMS patient after treatment was significant (p < 0.01), but that in each NMO patient was not (p > 0.05). The change in Kurtzke’s Expanded Disability Status Scale score 1 year after treatment was higher in the NMO patients than in the RRMS patients (p = 0.0225). Conclusion: In NMO patients, IFN-β1b treatment was not effective in reducing the relapse number and the disability progression.

Anti-aquaporin 4 antibody in Japanese multiple sclerosis: the presence of optic–spinal multiple sclerosis without long spinal cord lesions and anti-aquaporin 4 antibody

Background: Anti-aquaporin 4 (AQP4) antibodies were found in patients with neuromyelitis optica (NMO) and Japanese optic–spinal multiple sclerosis (OSMS). Objective: To review the clinical features and investigate anti-AQP4 antibodies of Japanese patients with multiple sclerosis (MS), with or without long spinal cord lesions (LCL). Methods: Anti-AQP4 antibodies were examined in the sera of 128 consecutive Japanese patients by the immunofluorescence method using AQP4 transfected cells. Results: The 45 LCL-MS patients included 28 with a long spinal cord lesion extending contiguously over three vertebral segments on sagittal T2 weighted images (long T2 lesion) and 17 with segmental cord atrophy extending more than three vertebral segments. We identified 25 patients with anti-AQP4 antibody with LCL and anti-AQP4 antibody. Anti-AQP4 antibody was found in 12/17 (70.6%) LCL-MS patients with segmental cord atrophy, and in 13/28 (46.4%) LCL-MS patients without segmental long cord atrophy (p = 0.135, Fisher’s exact test). Seropositive MS patients with LCL had more relapses than seronegative patients (p = 0.0004, Mann–Whitney U test). 9 patients with OSMS were negative for anti-AQP4 antibody who did not show LCL. Conclusion: These results suggest that an anti-AQP4 antibody is found not only in MS patients with long T2 lesions but also in patients with segmental cord atrophy extending more than three vertebral segments. It is a marker of LCL-MS showing frequent exacerbations. Japanese OSMS cases comprised those that were identical to NMO cases and those that were more closely related to classic MS.

Increased T-cell immunity against aquaporin-4 and proteolipid protein in neuromyelitis optica

In neuromyelitis optica (NMO), B-cell autoimmunity to aquaporin-4 (AQP4) has been shown to be essential. However, the role of T cells remains ambiguous. Here, we first showed an increase in CD69+ activated T cells in PBMCs during NMO relapses. Next, T-cell responses to AQP4 and myelin peptides were studied in 12 NM0 patients, 10 multiple sclerosis (MS) patients and 10 healthy subjects (HS). Four hours after adding 1 of 28 overlapping AQP4 peptides, a mixture of AQP4 peptides (AQP4-M) or one of six distinct myelin peptides to 2-day cultured PBMC, CD69 expression on CD4+ T cells was examined. Data were analyzed by paired t-test, frequency of samples with 3-fold increase of CD69 on CD4+ cells (fSI3) and mean stimulation index (mSI). The T-cell response to AQP4-M was significantly increased in NMO (fSI3 = 10/12, mSI = 5.50), with AQP4 (11-30) and AQP4 (91-110) representing the two major epitopes (AQP4 (11-30), fSI3 = 11/12, mSI = 16.0 and AQP4 (91-110), fSI3 = 11/12, mSI = 13.0). Significant but less extensive responses to these two epitopes were also observed in MS and HS. Significant reactivities against AQP4 (21-40), AQP4 (61-80), AQP4 (101-120), AQP4 (171-190) and AQP4 (211-230) were exclusively found in NMO. In addition, responses to AQP4 (81-100) were higher and more frequently detected in NMO, without reaching statistical significance. Interestingly, among the six myelin peptides studied, proteolipid protein (95-116) induced a significant T-cell response in NMO (fSI3 = 7/12, mSI = 4.60). Our study suggests that cellular as well as humoral responses to AQP4 are necessary for NMO development and that the immune response to myelin protein may contribute to disease pathogenesis.

Insufficient disease inhibition by intrathecal rituximab in progressive multiple sclerosis

Inaccessibility of the inflammation compartmentalized to the central nervous system (CNS) may underlie the lack of efficacy of immunomodulatory treatments in progressive multiple sclerosis (MS). The double blind combination of Rituximab by IntraVenous and IntraThecAl injection versus placebo in patients with Low‐Inflammatory SEcondary progressive MS (RIVITALISE; NCT01212094) trial was designed to answer: (1) Whether an induction dose of intravenous and intrathecal rituximab efficiently depletes CNS B cells? and (2) If so, whether this leads to global inhibition of CNS inflammation and slowing of CNS tissue destruction?

Cerebrospinal fluid proteomic patterns discriminate Parkinson's disease and multiple system atrophy

The differential diagnosis of Parkinsons disease and multiple system atrophy can be challenging, especially in the early stages of the diseases. We developed a proteomic profiling strategy for parkinsonian diseases using mass spectrometry analysis for magnetic‐bead‐based enrichment of cerebrospinal fluid peptides/proteins and subsequent multivariate statistical analysis. Cerebrospinal fluid was obtained from 37 patients diagnosed with Parkinsons disease, 32 patients diagnosed with multiple system atrophy, and 26 patients diagnosed with other neurological diseases as controls. The samples were from the first cohort and the second cohort. Cerebrospinal fluid peptides/proteins were purified with C8 magnetic beads, and spectra were obtained by matrix‐assisted laser desorption ionization time‐of‐flight mass spectrometry. Principal component analysis and support vector machine methods are used to reduce dimension of the data and select features to classify diseases. Cerebrospinal fluid proteomic profiles of Parkinsons disease, multiple system atrophy, and control were differentiated from each other by principal component analysis. By building a support vector machine classifier, 3 groups were classified effectively with good cross‐validation accuracy. The model accuracy was well preserved for both cases, training by the first cohort and validated by the second cohort and vice versa. Receiver operating characteristics proved that the peak of m/z 6250 was the most important to differentiate multiple system atrophy from Parkinsons disease, especially in the early stages of the disease. A proteomic pattern classification method can increase the accuracy of clinical diagnosis of Parkinsons disease and multiple system atrophy, especially in the early stages.

Proteomic pattern analysis discriminates among multiple sclerosis-related disorders

To use a new, unbiased biomarker discovery strategy to obtain and assess proteomic data from cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS)‐related disorders.

Spinal Arachnoiditis as a Complication of Cryptococcal Meningoencephalitis in Non-HIV Previously Healthy Adults.

Background. Cryptococcus can cause meningoencephalitis (CM) among previously healthy non-HIV adults. Spinal arachnoiditis is under-recognized, since diagnosis is difficult with concomitant central nervous system (CNS) pathology. Methods. We describe 6 cases of spinal arachnoiditis among 26 consecutively recruited CM patients with normal CD4 counts who achieved microbiologic control. We performed detailed neurological exams, cerebrospinal fluid (CSF) immunophenotyping and biomarker analysis before and after adjunctive immunomodulatory intervention with high dose pulse corticosteroids, affording causal inference into pathophysiology. Results. All 6 exhibited severe lower motor neuron involvement in addition to cognitive changes and gait disturbances from meningoencephalitis. Spinal involvement was associated with asymmetric weakness and urinary retention. Diagnostic specificity was improved by MRI imaging which demonstrated lumbar spinal nerve root enhancement and clumping or lesions. Despite negative fungal cultures, CSF inflammatory biomarkers, sCD27 and sCD21, as well as the neuronal damage biomarker, neurofilament light chain (NFL), were elevated compared to healthy donor (HD) controls. Elevations in these biomarkers were associated with clinical symptoms and showed improvement with adjunctive high dose pulse corticosteroids. Conclusions. These data suggest that a post-infectious spinal arachnoiditis is an important complication of CM in previously healthy individuals, requiring heightened clinician awareness. Despite microbiological control, this syndrome causes significant pathology likely due to increased inflammation and may be amenable to suppressive therapeutics.

Pharmacodynamic effects of daclizumab in the intrathecal compartment

It was previously demonstrated that daclizumab therapy normalizes cellular cerebrospinal fluid (CSF) abnormalities typical of multiple sclerosis (MS) in the majority of treated patients. However, CSF cells represent only the mobile portion of intrathecal immune responses. Therefore, we asked whether daclizumab also reverses compartmentalized inflammation and if not, whether residual inflammation correlates with clinical response to the drug.