Tumefactive demyelinating lesions: a retrospective cohort study in Thailand.

Tumefactive demyelinating lesions (TDL), characterized by large (≥ 2 cm) demyelinating lesions mimicking tumors, are a rare manifestation of the central nervous system inflammatory demyelinating diseases (CNS-IDD). Distinguishing TDL from other brain lesions can be challenging, often necessitating biopsy or advanced diagnostics. The natural history of TDL varies among races. This study aimed to assess demographics, clinical and radiological features, laboratory findings, management, and outcomes of Thai patients with TDL. We retrospectively reviewed records of twenty-six patients with TDL from the Multiple Sclerosis and Related Disorders registry from two tertiary medical centers. Among 1102 CNS-IDD patients, 26 (2.4%) had TDL. The median age at TDLs onset was 34.5 years (range 17-75); 69.2% were female. Over 70% manifested TDL as their initial CNS-IDD presentation. Common presenting symptoms included motor deficits, sensory disturbances, and cognitive problems. About two-fifths exhibited multiple lesions, most frequently in the frontoparietal region (46.2%). Half of the patients showed an incomplete ring on post-contrast T1-weighted imaging, with peripheral diffusion-weighted imaging restriction in twenty-one patients. T2-hypointense rims were present in thirteen (56.5%) patients. Brain biopsy was performed in 12 cases (46.1%). Serum aquaporin-4 immunoglobulin was positive in 16.7% of tested (4/24) cases. Serum myelin oligodendrocyte glycoprotein immunoglobulin was negative in all thirteen patients tested. Twenty patients (76.9%) received intravenous corticosteroids for TDL attacks. After the median follow-up period of 48 months (range 6-300), 23.1% experienced CNS-IDD relapses. Median Expanded Disability Status Scale at TDL diagnosis was 4.3 (range 0.0-9.5), and improved to 3.0 (range 0.0-10.0) at the last follow-up. This study suggested that TDL were rare among Thai CNS-IDD patients, frequently presenting as a monophasic condition with a favorable outcome.

Cognitive Impairment and Risk Factors in Post-COVID-19 Hospitalized Patients.

Introduction: Numerous reports regarding cognitive deficits after the coronavirus disease 2019 (COVID-19), described as "brain fog," have been published. However, the clinical presentations and risk factors of post-COVID-19 cognitive impairment are controversial. This study aimed to assess (a) the prevalence of cognitive impairment after COVID-19 hospitalization, (b) characteristics of the cognitive deficits, (c) risk factors of post-COVID-19 cognitive impairment, and (d) comparison of cognitive function between post-COVID-19 patients and healthy people. Methods: The study comprised 34 SARS-CoV-2-infected patients, admitted to the Neurological Institute of Thailand during the peak of COVID-19 pandemic in 2021-2022. These patients came for neuropsychological and clinical evaluations at 2-week follow-up visit. The cognitive impairment and characteristics were measured by TMSE and MoCA. Clinical risk factors and post-COVID-19 cognitive impairment were assessed. The comparison of cognitive function in post-acute COVID-19 patients and 22 healthy controls was also performed. Results: The prevalence of post-COVID-19 cognitive impairment defined by a total MoCA score below 25 points was 61.76%. Years of education were the only predictive factors related to cognitive impairment. Our multivariate analysis revealed no statistical difference in cognitive outcomes between post-acute COVID-19 patients and healthy controls. Conclusion: This study showed a moderate prevalence of cognitive dysfunction after COVID-19 hospitalization similar to previous reports. However, there was no significant difference in cognitive measurements between these patients and healthy people. Whether SARS-CoV-2 infection causes cognitive dysfunction is a myth or fact that still has a long way to prove via further longitudinal study.

Rituximab for the treatment of relapsing-remitting multiple sclerosis in Thailand: an economic evaluation and budget impact analysis.

BACKGROUND: Multiple sclerosis is an inflammatory demyelination process in the central nervous system (CNS) causing neurological disability and poor quality of life. Currently, Thai Food and Drug Administration (FDA)-approved disease-modifying therapy is costly, and most patients with multiple sclerosis are ineligible for treatment in Thailand as previous studies have challenged its cost-effectiveness. Off-label use of rituximab is inexpensive and highly effective in treating multiple sclerosis, but evidence of its cost-effectiveness in Thailand is yet to be collected. METHODS: This study aimed to evaluate the cost-utility and budget impact of rituximab for multiple sclerosis treatment compared with best supportive care, the standard practice in Thailand to treat the disease. A Markov model with a one-month cycle length and lifetime horizon was applied to compare the costs and outcomes of rituximab and best supportive care based on a societal perspective. Accordingly, incremental cost-effectiveness ratios were estimated. Probabilistic and one-way sensitivity analyses were conducted to investigate parameter uncertainty. In addition, the Markov model was used to assess the 5-year budget impact from the government perspective. RESULTS: A rituximab biosimilar demonstrated higher effectiveness and lower associated costs, compared to best supportive care, with the highest probability of being cost-effective (96%). The probability of relapse was the most sensitive parameter according to the one-way sensitivity analysis. The calculated budget impact of treating patients with multiple sclerosis in Thailand was 26,360,000 Thai baht (THB) or 844,255 United States dollars (USD) in the first fiscal year, and approximately 20,810,000-23,080,000 THB (666,608-739,388 USD) in the next four fiscal years. CONCLUSION: In Thailand, a rituximab biosimilar would reduce the overall costs of multiple sclerosis treatment and should, therefore, be included in the National List of Essential Medicines.

Efficacy and safety of monoclonal antibody therapy in patients with neuromyelitis optica spectrum disorder: A systematic review and network meta-analysis.

Introduction: Neuromyelitis optica spectrum disorder (NMOSD) is a devastating inflammatory CNS demyelinating disease. Two groups of monoclonal antibodies (mAbs) are used to prevent disease relapse, i.e., Food and Drug Administration (FDA)-approved mAbs (e.g., eculizumab satralizumab, inebilizumab), and off-label mAb drugs (e.g., rituximab and tocilizumab). The FDA-approved mAbs have high efficacy but more expensive compared to the off-labels, and thus are less accessible. This systematic review and network meta-analysis (NMA) was to assess the efficacy and safety of both classes of mAbs compared to the current standard treatments. Methods: Systematically searches were conducted in MEDLINE and SCOPUS from inception until July 2021. Randomized-controlled trials (RCTs) were eligible if they compared any pair of treatments (mAbs, immunosuppressive drugs, or placebo) in adult patients with NMOSD. Studies with AQP4-IgG positive or negative were used in the analysis. Probability of relapse and time to event were extracted from the Kaplan-Meier curves using Digitizer. These data were then converted into individual patient time-to-event data. A one-stage mixed-effect survival model was applied to estimate the median time to relapse and relative treatment effects using hazard ratios (HR). Two-stage NMA was used to determine post-treatment annualized relapse rate (ARR), expanded disability status score (EDSS) change, and serious adverse events (SAE). Risk of bias was assessed using the revised cochrane risk of bias tool. Results: A total of 7 RCTs with 776 patients were eligible in the NMA. Five of the seven studies were rated low risk of bias. Both FDA-approved and off-label mAbs showed significantly lower risk of relapse than standard treatments, with HR (95% CI) of 0.13 (0.07, 0.24) and 0.16 (0.07, 0.37) respectively. In addition, the FDA-approved mAbs had 20% lower risk of relapse than the off-label mAbs, but this did not reach statistical significance. The ARRs were also lower in FDA-approved and off-label mAbs than the standard treatments with the mean-difference of-0.27 (-0.37,-0.16) and-0.31(-0.46,-0.16), respectively. Conclusion: The off-label mAbs may be used as the first-line treatment for improving clinical outcomes including disease relapse, ARR, and SAEs for NMOSD in countries where resources and accessibility of the FDA-approved mAbs are limited. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=283424, identifier: CRD42021283424.

Clinical and fringe benefits of rituximab in multiple sclerosis treatment in a poor resource setting: Case series and cost analysis.

BACKGROUND: Multiple sclerosis (MS) is an inflammatory demyelinating condition of the central nervous system that leads to neurological disability and a poor quality of life (QoL). Rituximab has been used off-label in many countries to treat MS because of its high efficacy and affordability. However, there is no evidence of its effectiveness in Thailand. Therefore, the objective of this study was to evaluate the efficacy and additional benefits of rituximab in Thai patients with MS. METHODS: This was a prospective cohort study of patients diagnosed with MS who started treatment with rituximab between November 1, 2020, and October 31, 2022. Patients with MS eligible for the study received intravenous rituximab with a starting dose of 1000 mg at the first visit and another 1000 mg dose 2 weeks later. Thereafter, 1000 mg rituximab was administered every 6 months until the end of the study. The primary outcome was the annualized relapse rate (ARR). In addition, magnetic resonance imaging (MRI) activity of the gadolinium-enhancing lesion, QoL, number of hospital visits, and treatment costs were considered secondary outcomes. RESULTS: Ten patients diagnosed with relapsing-remitting multiple sclerosis were included in the study. The median ARR markedly decreased from 2.14 (0-4) to 0 (0-0.5) (p=0.005). The median Expanded Disability Status Scale score improved from 3.25 (1.5-6.0) to 1 (1-4) (p=0.005). The median number of enhancing lesions decreased from 1 (0-7) to 0 (0-3) (p=0.017). In addition, the median EuroQoL 5 Dimension 5 Level score, indicating QoL, improved from 0.7 (0.41-0.85) to 0.88 (0.68-1.00) (p=0.005). The median number of outpatient department visits significantly decreased from 6 (4-12) to 3 (2-5) (p=0.009). Hospitalization or inpatient department visits diminished from 1 (0-2) to 0 (0-1) (p=0.007). The total direct medical cost of rituximab treatment was not significantly different from that of the pre-treatment condition: 70,891 THB (65,391-116,358) VS 66,961 THB (33,927-109,248) or 1,904 USD (1,756-3,125 USD) VS 1,798 USD (911-2,934) (p=0.173). CONCLUSION: Rituximab was effective in the treatment of MS in Thailand. The use of rituximab reduced the number of relapses, reduced disability, decreased the number of active MRI lesions, and improved QoL. Moreover, the benefit of rituximab in treating MS in Thailand surpasses the current cost of treatment.

Cost effectiveness of rituximab and mycophenolate mofetil for neuromyelitis optica spectrum disorder in Thailand: Economic evaluation and budget impact analysis.

Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory condition of the central nervous system. The extent of disability depends on the severity of the disease and the number of relapses. Although azathioprine is currently the main treatment for patients with NMOSD in Thailand, patients often relapse during its use. Hence, it is argued that there are other drugs that would be more effective. The purpose of this study is to evaluate, from a societal perspective and from the economic impact on Thailand's healthcare system, the cost utility of treatment with mycophenolate mofetil (MMF) and rituximab in patients resistant to azathioprine. The Markov model with a one-year cycle length was applied to predict the health and cost outcomes in patients with NMOSD over a lifetime. The results showed that rituximab exhibited the highest quality-adjusted life year (QALY) gains among all the options. Among the rituximab-based treatments, the administration of a rituximab biosimilar with CD27+ memory B cell monitoring proved to be the most cost-effective option. At the willingness-to-pay threshold of 160,000 Thai baht (THB), or 5,289 US dollar (USD), per QALY gained, the treatment exhibited the highest probability of being cost effective (48%). A sensitivity analysis based on the adjusted price of a generic MMF determined that the treatment was cost effective, exhibiting an incremental cost-effectiveness ratio of -164,653 THB (-5,443 USD) and a 32% probability of being cost effective. The calculated budget impact of treating patients resistant to conventional therapy was 1-6 million THB (33,000-198,000 USD) for the first three years, while after the third year, the budget impact stabilized at 3-4 million THB (99,000-132,000 USD). These data indicate that, in Thailand, treatment of drug resistant NMOSD with a rituximab biosimilar with CD27+ memory B cell monitoring or treatment with a generic MMF would be cost effective and would result in a low budget impact. Therefore, the inclusion of both the rituximab biosimilar and a generic MMF in the National Drug List of Essential Medicine for the treatment of NMOSD may be appropriate.

Abnormal level of consciousness predicts outcomes of patients with anti-NMDA encephalitis.

Anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis is an acute form of encephalitis with an autoimmune etiology. We aimed to study clinical characteristics and treatment outcomes and assess the predictive factors associated with patient outcome. In this retrospective study, patients who presented with cardinal symptoms of anti-NMDA encephalitis and positive anti-NMDA receptor antibody results in their cerebrospinal fluid were included in the study. Thirty-one patients were identified. The median age of onset was 19 years (IQR 15.0-31.0). Females were predominant (61.8%). The main clinical symptoms were neuropsychiatric symptoms (87.1%) followed by abnormal movement (71%), seizures (51.1%), and autonomic instability (41.9%). Eleven patients (35.5%) exhibited decreased levels of consciousness. Abnormal MRI results were found in only 35.5% of the patients. CSF abnormalities usually involved mild pleocytosis. Only 67.7% of serum samples were positive against the anti-NMDAR antibody, whereas 100% of CSF samples were positive. Tumor-related information was only available for 20 patients. Only one case involved an ovarian teratoma. All patients received first-line therapy (intravenous pulse methylprednisolone and plasmapheresis). Three patients were treated with second-line therapy (IV cyclophosphamide). Twenty patients (64.5%) had favorable outcomes in our cohort (mRS 0-2) after a 1-year follow-up. An abnormal level of consciousness was a factor associated with a nonfavorable outcome (OR 15.65, 95% CI 2.30-106.29, p value <0.01).

Clinical outcomes and predictive factors related to good outcomes in plasma exchange in severe attack of NMOSD and long extensive transverse myelitis: Case series and review of the literature.

OBJECTIVE: To investigate the predictive factors associated with good outcomes of plasma exchange in severe attacks through neuromyelitis optica spectrum disorder (NMOSD) and long extensive transverse myelitis (LETM). In addition, to review the literature of predictive factors associated with the good outcomes of plasma exchange in central nervous system inflammatory demyelinating diseases (CNS IDDs). METHODS: Retrospective study in 27 episodes of severe acute attacks myelitis and optic neuritis in 24 patients, including 20 patients with NMOSD seropositive, 1 patient with NMOSD seronegative and 3 patients with LETM. Plasma exchange was performed, reflecting poor responses to high-dose intravenous methylprednisolone (IVMP) therapy. The outcomes of the present study were the functional outcome improvements at 6 months after plasma exchange. The predictive factors of good outcomes after plasma exchange were determined in this cohort, and additional factors reported in the literature were reviewed. RESULTS: Plasma exchange was performed in 16 spinal cord attacks and 11 attacks of optic neuritis. Twenty patients were female (83%). The median age of the patients at the time of plasma exchange was 41 years old. The median disease duration was 0.6 years. The AQP4-IgG status was positive in 20 patients (83%). Plasma exchange following IVMP therapy led to a significant improvement in 81% of the cases after 6 months of follow up. A baseline Expanded Disability Status Scale (EDSS) score ≤6 before the attack was associated with significant improvement at 6 months (p=0.02, OR 58.33, 95%CI 1.92-1770). In addition, we reviewed the evidence for factors associated with good outcomes of plasma exchange in CNS IDDs, classified according to pre-plasma exchange, post-plasma exchange, and radiological features. CONCLUSION: Plasma exchange following IVMP therapy is effective as a treatment for patients experiencing a severe attack of NMOSD or LETM. The factors associated with good outcomes after plasma exchange in CNS IDDs are reviewed in the literature. We classified 3 different aspects, including pre-plasma exchange factors, based on minimal disability at baseline, preserved reflexes, early initiation, and short disease duration; post plasma exchange factors, including early improvement or lower disability at last follow up; and radiographic factors, for which the presence of active gadolinium lesions and the absence of spinal cord atrophy seem to be good outcomes for plasmapheresis.

Importance of calcium-binding site 2 in simian virus 40 infection.

The exposure of molecular signals for simian virus 40 (SV40) cell entry and nuclear entry has been postulated to involve calcium coordination at two sites on the capsid made of Vp1. The role of calcium-binding site 2 in SV40 infection was examined by analyzing four single mutants of site 2, the Glu160Lys, Glu160Arg, Glu157Lys (E157K), and Glu157Arg mutants, and an E157K-E330K combination mutant. The last three mutants were nonviable. All mutants replicated viral DNA normally, and all except the last two produced particles containing all three capsid proteins and viral DNA. The defect of the site 1-site 2 E157K-E330K double mutant implies that at least one of the sites is required for particle assembly in vivo. The nonviable E157K particles, about 10% larger in diameter than the wild type, were able to enter cells but did not lead to T-antigen expression. Cell-internalized E157K DNA effectively coimmunoprecipitated with anti-Vp1 antibody, but little of the DNA did so with anti-Vp3 antibody, and none was detected in anti-importin immunoprecipitate. Yet, a substantial amount of Vp3 was present in anti-Vp1 immune complexes, suggesting that internalized E157K particles are ineffective at exposing Vp3. Our data show that E157K mutant infection is blocked at a stage prior to the interaction of the Vp3 nuclear localization signal with importins, consistent with a role for calcium-binding site 2 in postentry steps leading to the nuclear import of the infecting SV40.