[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.

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.

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.

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.

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.

[A case of colon cancer with reversible posterior leukoencephalopathy syndrome following 5-FU and oxaliplatin (FOLFOX regime)].

We report a rare case of reversible posterior leukoencephalopathy syndrome (RPLS) induced by 5-FU and oxaliplatin (FOLFOX regime). A 35-year-old woman with ileus was diagnosed with sigmoid cancer Stage IV (T4N4M0P2H0), and excision of the sigmoid colon, and left ureteroureteral anastomosis was performed. Postoperative chemotherapy with FOLFOX4 was performed. Complications of hypertension were seen on day 6, and convulsions on day 11 after chemotherapy. Headache and visual disturbance were also complications. MRI of the brain revealed bilateral high signal intensities of posterior lobes on T2 weighted and FLAIR images without enhancement. The patient was treated with antihypertensive therapy and anticonvulsive therapy. Her symptoms entirely disappeared, including the bilateral posterior lesions on MRI after two weeks. This report would suggest that medical oncologists should be aware that multidrug chemotherapies may increase the risk of fatal neurological complications like RPLS.

[Molecular target therapy-associated CNS complications].

Advances in cancer chemotherapy, particularly development of molecular target therapies based on cancer biology, have significantly improved survival for cancer patients. Targeted therapies display generally favorable toxicity profiles, but reports of severe toxicities as seen with previous chemotherapeutic drugs have been increasing recently. Antineoplastic drug-induced central nervous system injuries sometimes progress to life-threatening complications. In this article, progressive multifocal leukoencephalopathy and reversible posterior leukoencephalopathy syndrome, which have been reported in association with targeted therapies, are reviewed clinically, etiologically based on reports in the literature. Treating physicians should be aware of the importance of early recognition and institution of appropriate management for these complications to reduce the risk of permanent neurological sequelae.

[Prevalence of neurological complications in Japanese patients with AIDS after the introduction of HAART].

We investigated trends in neurological complications of infection with human immunodeficiency virus (HIV) in Japan after the introduction of highly active antiretroviral therapy (HAART). Two questionnaire surveys were performed in hospitals treating acquired immunodeficiency syndrome (AIDS) to compare two periods: immediately after the introduction of HAART (1999-2001); and a few years later (2002-3). Neurological complications accompanied 15.9% in 1999-2001 and 9.8% in 2002-3. Neurological complications developed without HAART in about 80% of cases. Neurological complications developed as the first AIDS-defining disease for 8.3% of AIDS patients in 1999-2001 and for 5.4% in 2002-3. Prevalences of HIV encephalopathy and myelopathy decreased markedly over the study period, as reported in other developed nations. However, prevalences of cytomegalovirus encephalitis, PML and primary brain lymphoma did not decrease. PML and primary brain lymphoma occurred in patients who received HAART and whose CD4 counts were relatively high during the study period. This is probably related to the extended survival of HIV-infected individuals after the introduction of HAART as a worldwide therapy, and the reactivation of viremia or latent infection persisting within the central nervous system.

[Progressive multifocal leukoencephalopathy--epidemiology, clinical pictures, diagnosis and therapy].

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by the reactivation of a ubiquitous polyomavirus JC (JCV). PML was for many years a rare disease occurring only in patients with underlying severe impaired immunity. Over the past three decades, the incidence of PML has significantly increased related to the AIDS (acquired immunodeficiency syndrome) pandemic and, more recently, to the growing use of immunosuppressive drugs. The clinical presentation of PML is variable with neurological symptoms corresponding to affected cerebral areas. Usually, the clinical outcome of patients with PML is poor with an inexorable progression to death within 6 months of symptom onset. Although PML usually requires a brain biopsy or autopsy for confirmation, radiological imaging and a demonstration of JCV-DNA in the CSF (cerebrospinal fluid) provide supportive evidence for the diagnosis. Although there is no proven effective therapy for PML, patients with HIV (human immunodeficeincy virus)-related PML may benefit significantly from HAART (highly active antiretroviral therapy). In this article the author reviews the epidemiology, especially in Japan, current challenges in the diagnosis and the treatment guidelines of patients with PML based on recent advances in the understanding of the JC virus biology.

[Review of progressive multifocal leukoencephalopathy].

Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease of the central nervous system caused by a reactivation of the JC virus (JCV). PML occurs almost exclusively in the setting of cellular immune deficiency and its prevalence has recently increased greatly, in line with the AIDS (acquired immunodeficiency syndrome) epidemic in Western countries. A Japanese epidemiological survey showed an increasing trend in the number of AIDS-PML cases. To date, there are no effective and specific therapies for PML. As patients with AIDS-PML may benefit from combined antiretroviral therapy, efforts to improve the immune status of such patients is therefore considered to be a key factor in achieving a successful outcome for PML cases. However, PML deficits are nevertheless expected to be permanent and most cases of PML result in death within a few months. It is therefore hoped that improvements in diagnostic modalities can be made which can eventually allow for the earlier detection of PML while, at the same time, improved curative therapies for PML can also be developed in the near future.

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.

Successful steroid treatment of acquired idiopathic partial hypohidrosis.

The pathogenesis of idiopathic-acquired hypohidrosis remains unknown, and no specific causes have yet been established. We report a 34-year-old man with acquired idiopathic hypohidrosis successfully treated with prednisolone. The patient noticed heat intolerance and hypohidrosis of the pectoral and back during the summer. No systemic disease or neurological findings were identified. Eccrine sweat glands displayed infiltration by inflammatory cells, with immunoglobulin G and C3 deposition in the basement membrane. Steroid therapy improved the hypohidrosis. An immunological pathogenesis could be a major factor in idiopathic-acquired hypohidrosis.

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.

Delayed ischemic stroke associated with methamphetamine use.

A 19-year-old woman had right occipital infarction 3 months after she had injected methamphetamine. No other possible causes of stroke could be found in this case. Magnetic resonance angiography revealed beading of the right posterior cerebral artery, which suggested vasculitis. Her symptoms were right-sided headache, left superior quadrant hemianopia, and left hypesthesia, which gradually improved without any treatment. Methamphetamine has been known to cause hemorrhagic and ischemic stroke relatively soon after administration. We report here that methamphetamine may also cause chronic cerebral vasculitis and delayed ischemic stroke.

[Clinical investigation of the 8 cases with AIDS (acquired immunodeficiency syndrome)-associated progressive multifocal leukoencephalopathy (PML)].

We experienced 8 cases of progressive multifocal leukoencephalopathy (PML) complicated by human immunodeficiency virus (HIV) type-1 infection from 1985 to 1999. These cases showed dementia, bradykinesia, dysarthria, hemiparesis, and so on. All of the cases were severely immunocompromised hosts, because none had more than 150/mm3 CD4 + lymphocytes; indeed, 5 of the cases were below 20/mm3. Other neurological complications except PML were primary CNS lymphoma, HIV encephalitis, and CMV encephalitis. The mean life durations was 7.6 months after the first symptom appeared, for all but one of the patients; the exceptional patient lived for 24 months after. Autopsy studies of the central nervous systems were performed for 7 cases, all of which showed extensive demyelinating lesions of the white matter, and in some cases these extended into the spinal cord. In contrast to Western countries, in Japan there have been few reports of AIDS-associated PML. Thus, this report was thought to be important here.

Incapacitating lower limb pain syndrome in cord blood stem cell transplant recipients with calcineurin inhibitor.

Calcineurin-inhibitor induced pain syndrome (CIPS) is a newly described entity with a characteristic feature of sudden onset of severe lower limb pain, and high levels of cyclosporine or tacrolimus may be involved in the pathogenesis. This syndrome is rarely seen in recipients of hematopoietic stem cell transplantation (HSCT) compared with other organ transplant recipients, however, heightened awareness of this complication after HSCT may be needed for hematologists, as misdiagnosis can result in catastrophic consequences. We report herein two cases of lower limb pain syndrome, with some clinical features resembling CIPS, occurring during the early phase of cord blood stem cell transplantation for hematological malignancy.