Nationwide Laboratory Surveillance of Progressive Multifocal Leukoencephalopathy in Japan: Fiscal Years 2011-2020.

Progressive multifocal leukoencephalopathy (PML) is a devastating demyelinating disease caused by JC virus (JCV), predominantly affecting patients with impaired cellular immunity. PML is a non-reportable disease with a few exceptions, making national surveillance difficult. In Japan, polymerase chain reaction (PCR) testing for JCV in the cerebrospinal fluid (CSF) is performed at the National Institute of Infectious Diseases to support PML diagnosis. To clarify the overall profile of PML in Japan, patient data provided at the time of CSF-JCV testing over 10 years (FY2011-2020) were analyzed. PCR testing for 1537 new suspected PML cases was conducted, and 288 (18.7%) patients tested positive for CSF-JCV. An analysis of the clinical information on all individuals tested revealed characteristics of PML cases, including the geographic distribution, age and sex patterns, and CSF-JCV-positivity rates among the study subjects for each type of underlying condition. During the last five years of the study period, a surveillance system utilizing ultrasensitive PCR testing and widespread clinical attention to PML led to the detection of CSF-JCV in the earlier stages of the disease. The results of this study will provide valuable information not only for PML diagnosis, but also for the treatment of PML-predisposing conditions.

AJM300 (carotegrast methyl), an oral antagonist of α4-integrin, as induction therapy for patients with moderately active ulcerative colitis: a multicentre, randomised, double-blind, placebo-controlled, phase 3 study.

BACKGROUND: AJM300 is an oral, small-molecule α4-integrin antagonist. We assessed the efficacy and safety of AJM300 in patients with moderately active ulcerative colitis. METHODS: This multicentre, randomised, double-blind, placebo-controlled, phase 3 study consisted of two phases: a treatment phase and an open-label re-treatment phase. The study was done at 82 hospitals and clinics in Japan. Patients with a Mayo Clinic score of 6-10, endoscopic subscore of 2 or more, rectal bleeding subscore of 1 or more, and an inadequate response or intolerance to mesalazine were enrolled. Patients were randomly allocated (1:1) via a website to either AJM300 (960 mg) or placebo by the minimisation method, which was adjusted centrally by dynamic assignment against the Mayo Clinic score (≥6 to ≤7, ≥8 to ≤10 points), any use of corticosteroid, anti-TNFα antibody, or immunosuppressants during the disease-active period (yes vs no), duration of induction therapy until randomisation (<4 weeks vs ≥4 weeks) as the minimisation factors. Patients, investigators, site staff, assessors, and the sponsor were masked to treatment assignments. The study drug was administered orally, three times daily, for 8 weeks, and continued for up to 24 weeks if endoscopic remission was not achieved or rectal bleeding did not stop. The primary endpoint was the proportion of patients with a clinical response at week 8, and was analysed in the full analysis set. Clinical response was defined as a reduction in Mayo Clinic score of 30% or more and 3 or more, a reduction in rectal bleeding score of 1 or more or rectal bleeding subscore of 1 or less, and an endoscopic subscore of 1 or less at week 8. The study is registered with ClinicalTrials.gov, NCT03531892, and is closed to recruitment. FINDINGS: Between June 6, 2018, and July 22, 2020, 203 patients were randomly assigned to AJM300 (n=102) or placebo (n=101). At week 8, 46 (45%) patients in the AJM300 group and 21 (21%) patients in the placebo group had a clinical response (odds ratio 3·30, 95% CI 1·73-6·29; p=0·00028). During the 8-week treatment and 16-week extension treatment periods, adverse events occurred in 39 (39%) of 101 patients in the placebo group and 39 (38%) of 102 patients in the AJM300 group. We found no difference in the incidence of adverse events between groups or after repeated administration of AJM300. The most common adverse event was nasopharyngitis (11 [11%] of 101 patients in the placebo group and ten [10%] of 102 patients in the AJM300 group). The most common treatment-related adverse event was also nasopharyngitis (four [4%] of 101 patients in the placebo group and three [3%] of 102 patients in the AJM300 group). Most adverse events were mild-to-moderate in severity. No deaths were reported. A serious adverse event was reported in the AJM300 group (one patient with anal abscess), but this was judged to be unrelated to study drug. INTERPRETATION: AJM300 was well tolerated and induced a clinical response in patients with moderately active ulcerative colitis who had an inadequate response or intolerance to mesalazine. AJM300 could be a novel induction therapy for the treatment of patients with moderately active ulcerative colitis. FUNDING: EA Pharma and Kissei Pharmaceutical. TRANSLATION: For the Japanese translation of the abstract see Supplementary Materials section.

Natalizumab for Achieving Relapse-Free, T1 Gadolinium-Enhancing-Lesion-Free, and T2 Lesion-Free Status in Japanese Multiple Sclerosis Patients: A Phase 2 Trial Subanalysis.

INTRODUCTION: In a phase 2 trial of natalizumab in Japanese patients with relapsing-remitting multiple sclerosis (RRMS), treatment-related changes in relapses, brain lesions, and disability worsening were found to be comparable with those observed in the phase 3 studies of natalizumab in primarily non-Asian RRMS patients. METHODS: This subanalysis of the placebo-controlled phase 2 trial of natalizumab in Japanese RRMS patients (n = 94) evaluated the effects of natalizumab versus placebo on the proportion of patients who achieved relapse-free, T1 gadolinium-enhancing (Gd+) lesion-free, and new/newly enlarged T2 lesion-free status, defined as "no evidence of inflammatory disease activity" (NEDA)-like status, after 24 weeks of treatment. RESULTS: In this subanalysis, significantly more natalizumab-treated than placebo-treated patients achieved NEDA-like status (76.6% vs. 31.9%; P < 0.0001). In addition, the odds ratio (95% confidence interval) for patients on natalizumab to reach NEDA-like status was 6.98 (2.80-17.38) compared with placebo patients. CONCLUSION: These results confirm previous findings indicating that natalizumab is efficacious in Japanese patients with RRMS. FUNDING: Biogen. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01440101.

Efficacy, safety, and pharmacokinetics of natalizumab in Japanese multiple sclerosis patients: A double-blind, randomized controlled trial and open-label pharmacokinetic study.

BACKGROUND: Natalizumab, an anti-α4 integrin monoclonal antibody, has demonstrated efficacy in phase 2 and 3 studies of predominantly Caucasian patients with relapsing-remitting multiple sclerosis (RRMS). OBJECTIVE: To evaluate the efficacy, safety, pharmacokinetics (PK), and pharmacodynamics (PD) of natalizumab in Japanese RRMS patients. METHODS: This multicenter, phase 2 study included an open-label PK/PD study in 12 patients (part A) and a double-blind, placebo-controlled, randomized (computer-generated sequence) study in 94 patients (part B). For part B, patients received intravenous natalizumab 300mg (n=47) or placebo (n=47) every 4 weeks. The primary efficacy endpoint was the rate of development of new active lesions (gadolinium-enhancing or new/enlarging T2 lesions) over 24 weeks. Clinical relapses and safety were also assessed. RESULTS: New active lesions developed at a significantly lower mean rate in natalizumab-treated patients (0.06 lesions/24 weeks) than in placebo-treated patients (0.35 lesions/24 weeks) (p<0.001). The annualized relapse rate was 0.53 for natalizumab and 1.73 for placebo (p<0.001). Twice as many natalizumab-treated patients (79%) as placebo-treated patients (38%) were relapse-free (p<0.001). The safety, PK, and PD profiles of natalizumab in this study were consistent with data in Caucasian RRMS patients. CONCLUSIONS: In Japanese RRMS patients, natalizumab treatment every 4 weeks for 24 weeks was well tolerated and reduced the development of new brain lesions and relapses (Funded by Biogen; ClinicalTrials.gov identifier: NCT01440101).

Safety and Efficacy of Natalizumab in Japanese Patients with Relapsing-Remitting Multiple Sclerosis: Open-Label Extension Study of a Phase 2 Trial.

INTRODUCTION: The efficacy of natalizumab was evaluated in Japanese patients with relapsing-remitting multiple sclerosis (RRMS) in a 24-week, phase 2 bridging study. An open-label, 2-year extension study from this trial was conducted to assess the safety and efficacy of natalizumab treatment in Japanese patients. METHODS: A total of 97 patients (43 previously on placebo; 54 previously on natalizumab) who had completed the bridging study were treated with 300 mg natalizumab every 4 weeks. Multiple sclerosis relapses, changes in Expanded Disability Status Scale (EDSS) scores, and adverse events were assessed at regular intervals. Anti-natalizumab and anti-JC virus (JCV) antibodies were measured. RESULTS: After 2 years of natalizumab treatment, the mean adjusted annualized relapse rate was 0.30 (95% confidence interval [CI]: 0.18-0.52) among previously-on-placebo patients and 0.13 (95% CI: 0.05-0.29) among previously-on-natalizumab patients. The mean change in EDSS score from baseline to week 120 was -0.03 among previously-on-placebo patients and -0.18 among previously-on-natalizumab patients. In both groups, >90% of patients experienced ≥1 adverse event. Two previously-on-placebo patients developed persistently positive anti-natalizumab antibodies. Approximately 65% of all patients tested positive for anti-JCV antibodies at open-label treatment initiation. No deaths or progressive multifocal leukoencephalopathy cases were reported. CONCLUSIONS: The efficacy and safety findings from this 2-year open-label extension study are comparable to and confirm the results of other clinical trials of natalizumab conducted in non-Asian patient populations, and provide longer-term evidence of efficacy and safety in Japanese patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01416155. FUNDING: Biogen.

CD8 Encephalitis Caused by Persistently Detectable Drug-resistant HIV.

We herein report a 52-year-old man infected with human immunodeficiency virus (HIV) who was referred to our hospital due to the development of severe neurocognitive disorders and bilateral leukoencephalopathy. He has been treated with antiretroviral agents for 17 years, but low-level viremia has been detected consistently prior to admission. Drug resistant testing of the serum and the cerebrospinal fluid (CSF) both demonstrated a M184V mutation. A brain biopsy revealed perivascular CD8(+) T-lymphocyte infiltration, leading to the diagnosis of CD8 encephalitis. The clinical symptoms improved drastically after changing to a nucleoside reverse transcriptase inhibitor sparing regimen, which subsequently decreased the HIV viral load to an undetectable level in both the serum and CSF.

[Evaluation of HIV-infected patients suspected as having HIV-associated neurocognitive disorders].

BACKGROUND: HIV-associated neurocognitive disorders (HAND) have emerged as a problem among HIV-infected individuals in the era of antiretroviral therapy. However, there are insufficient data on HAND regarding its prevalence and clinical features in Japan. METHODS: A test battery composed of eight neuropsycological tests proposed by the Ministry of Health, Labour and Welfare (MHLW test battery) was applied to assess 30 subjects at Tokyo Metropolitan Komagome Hospital. Among them, 5 subjects were excluded due to central nervous system complications. The background of each patient along with the results of head magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) analysis and neuropsychological tests were compared to each HAND category. In addition, the clinical utility of a combination of neuropsychological tests as an abbreviated test battery of HAND was evaluated. RESULTS: A total of 19 (76%) subjects were diagnosed as having a HAND. Among them, HIV-associated dementia, mild neurocognitive disorders and asymptomatic neurocognitive disorders were diagnosed in 7, 8, and 4 subjects, respectively. Neither the patient's background nor the results of the head MRI and CSF analysis showed relevance to disease severity. The conventional International HIV Dementia Scale with the Digit Symbol Substitute Test was capable of detecting 94.7% cases of HAND. CONCLUSIONS: Most HIV-infected subjects clinically suspected as having neurocognitive disorders were diagnosed as having a HAND. Neuropsychological tests of the MHLW test battery were in some part useful to diagnose HAND. However, more precise neuropsychological tests are warranted to screen and diagnose HAND, based on the current criteria.

[Neurological complications with HIV infection].

Human immunodeficiency virus (HIV) induces acquired immunodeficiency syndrome (AIDS) in humans. Neurological complications occur frequently in patients with AIDS. About 20 to 40% of all these patients develop neurological symptoms, and in about 10% of AIDS patients, the onset of the disease is characterized by neurological symptoms. These may be related to primary HIV infection or to any of a large number of opportunistic viral and non-viral infections. HIV itself induces acute HIV aseptic meningitis, HIV-1-associated neurocognitive disorder (HAND), HIV distal sensory polyneuropathy, and HIV vacuolar myelopathy. The opportunistic neurological infections are cytomegalovirus encephalitis and polyradiculomyelitis, toxoplasmosis encephalitis, cryptococcal meningitis, and progressive multifocal leukoencephalopathy. Other neurological complications are primary central nervous system lymphoma, cerebral vascular disease (CVD), and nucleoside neuropathy (NN). Among these complications, HAND, CVD, and NN are expected to have an increased incidence in the future, they may be more important complications in HIV infection.

Sequential changes in the non-coding control region sequences of JC polyomaviruses from the cerebrospinal fluid of patients with progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) is caused by JC polyomavirus (JCV) infection in the brain. JCV isolates from PML patients have variable mutations in the non-coding control region (NCCR) of the genome. This study was conducted to examine sequential changes in NCCR patterns of JCV isolates obtained from the cerebrospinal fluid (CSF) of PML patients. CSF specimens were collected from PML patients at different time points, the NCCR sequences were determined, and their compositions were assessed by computer-based analysis. In patients showing a marked increase in JCV load, the most frequent NCCR sequences in the follow-up specimens were different from those in the initial samples. In contrast, the dominant NCCRs in the CSF remained unaltered during the follow-up of individuals in whom the viral load decreased after therapeutic intervention. These data demonstrate that the majority of JCV variants emerge with the progression of PML and that these changes are suppressed when the viral load is decreased.

Characteristics of progressive multifocal leukoencephalopathy clarified through internet-assisted laboratory surveillance in Japan.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML), a rare but fatal demyelinating disease caused by JC virus (JCV), occurs mainly in immunocompromised patients. As PML develops in individuals with various underlying disorders sporadically and infrequently, a nationwide survey of PML is difficult. This study was conducted to elucidate the characteristics of PML in Japan through an internet-assisted laboratory surveillance program. METHODS: A diagnostic support system for PML was established using a real-time PCR assay of JCV DNA in cerebrospinal fluid (CSF), and requests for testing were received from clinicians via specialized websites. Medical histories of patients were collected through standardized questionnaires, and a database of CSF JCV loads and clinical information was created and analyzed. RESULTS: For 4 years from April 2007 to March 2011, CSF specimens from 419 patients were tested. Forty-eight individuals were found positive for JCV DNA in their CSF and were diagnosed with PML. PML primarily occurred not only in HIV-positive patients (33.3%) but also in patients with hematologic disorders after receiving stem cell transplantation, chemotherapy, and/or immunosuppressive treatment (39.6%). The frequencies of PML cases among the subjects in these two categories were 20.3% and 23.5%, respectively. Although no significant features were observed with respect to CSF JCV loads in PML patients with an HIV infection or hematologic disorder, males were predominant in both groups (100% and 89.5%, respectively). The proportion of PML cases with autoimmune disorders (6.3%) or solid-organ transplants (2.1%) was smaller than those with HIV infection or hematologic disorders, probably due to the limited availability of therapeutic monoclonal antibodies and transplantation from brain dead donors. CONCLUSIONS: The results suggest that the internet-assisted laboratory surveillance program might be a useful strategy for collecting precise real-time information on PML on a national level. The current database provides important background information for the diagnosis and treatment of patients with risk factors for PML.

Isolated shoulder palsy due to infarction of the cortical branch of the middle cerebral artery.

A 71-year-old man with hyperlipidemia abruptly developed left-sided isolated shoulder palsy. Cranial magnetic resonance imaging demonstrated infarction of the cortical branch of the right middle cerebral artery (MCA). In the primary motor cortex, there is broad somatotopic representation of various body parts in a particular arrangement, and the area corresponding to the shoulder is very small. Consequently, there have been only 3 reported cases of isolated shoulder palsy due to cerebral infarction, and its vascular supply remains uncertain. The present case indicates that the corresponding area to the shoulder receives its blood from the cortical branch of the MCA.

Isolated trochlear nerve palsy in Tolosa-Hunt syndrome.

A 67-year-old Japanese woman without contributory medical history developed acute onset of left-sided trochlear nerve palsy (TNP) with persistent and severe periorbital pain. There were no other neurological abnormalities. Funduscopic findings were normal. Cranial and orbital magnetic resonance (MR) imaging, and cranial MR angiography demonstrated no abnormalities. By administration of prednisolone 40 mg/day from the day after onset, periorbital pain was resolved within 24 hours, and TNP within 5 days. Thereafter, prednisolone was gradually tapered off. She remained asymptomatic under no medication. In the English language literature, this is the first reported case of Tolosa-Hunt syndrome presenting with isolated TNP.

Pure Motor Monoparesis in the Leg due to a Lateral Medullary Infarction.

A 76-year-old man with essential hypertension abruptly presented with slight left-sided leg weakness, despite normal strength in the other extremities. Left-sided Babinski's reflex was detected. There were no other neurologic abnormalities. Cranial magnetic resonance imaging demonstrated a small infarction in the lower lateral medulla oblongata on the left side. Cranial magnetic resonance angiography demonstrated an absence of flow of the left vertebral artery. He became asymptomatic within 10 days under intravenous antiplatelet agent. The corticospinal tract fibers innervating the lower extremity caudal to the pyramidal decussation might be involved. We emphasize that this is a first reported case of pure motor monoparesis in the leg due to lateral medullary infarction.

Anterior uveitis as an initial manifestation of polymyalgia rheumatica.

A 74-year-old woman without contributory medical history presented with acute iridocyclitis in the right eye. Although the iridocyclitis disappeared within two weeks under topical steroid, she complained of acute progressing bilateral shoulder pain and morning stiffness of upper extremities. She was diagnosed as having polymyalgia rheumatica (PMR), and iridocyclitis was considered as its related manifestation. PMR and giant cell arteritis (GCA) are closely related conditions and frequently occur together. GCA with uveitis has been rarely noted. However, ocular symptoms in PMR have not been previously mentioned. This is a first reported case of PMR presented with uveitis, without a complication of GCA. This anterior uveitis might be caused by ischemia of the posterior ciliary arteries and their branches.