Central Nervous Disorders Research Articles

Non-invasive Ventilation and CPAP Failure in Children and Indications for Invasive Ventilation.

Non-invasive ventilation (NIV) and continuous positive airway pressure (CPAP) are effective treatments for children with severe sleep disordered breathing (SBD). However, some patients may present too severe SDB that do not respond to NIV/CPAP or insufficient compliance to treatment. A careful revaluation of the interface and of ventilator settings should be performed before considering alternative treatments. In patients with obstructive sleep apnea (OSA), alternatives to CPAP/NIV rely on the underlying disease. Ear-nose-throat (ENT) surgery such as adeno-tonsillectomy (AT), turbinectomy or supraglottoplasty represent an effective treatment in selected patients before starting CPAP/NIV and should be reconsidered in case of CPAP failure. Rapid maxillary expansion (RME) is restricted to children with OSA and a narrow palate who have little adenotonsillar tissue, or for those with residual OSA after AT. Weight loss is the first line therapy for obese children with OSA before starting CPAP and should remain a priority in the long-term. Selected patients may benefit from maxillo-facial surgery such as mandibular distraction osteogenesis (MDO) or from neurosurgery procedures like fronto-facial monobloc advancement. Nasopharyngeal airway (NPA) or high flow nasal cannula (HFNC) may constitute efficient alternatives to CPAP in selected patients. Hypoglossal nerve stimulation has been proposed in children with Down syndrome not tolerant to CPAP. Ultimately, tracheostomy represents the unique alternative in case of failure of all the above-mentioned treatments. All these treatments require a multidisciplinary approach with a personalized treatment tailored on the different diseases and sites of obstruction. In patients with neuromuscular, neurological or lung disorders, non-invasive management in case of NIV failure is more challenging. Diaphragmatic pacing has been proposed for some patients with central congenital hypoventilation syndrome (CCHS) or neurological disorders, however its experience in children is limited. Finally, invasive ventilation via tracheotomy represents again the ultimate alternative for children with severe disease and little or no ventilatory autonomy. However, ethical considerations weighting the efficacy against the burden of this treatment should be discussed before choosing this last option.

Biallelic loss-of-function variants in NEMF cause central nervous system impairment and axonal polyneuropathy.

We aimed to detect the causative gene in five unrelated families with recessive inheritance pattern neurological disorders involving the central nervous system, and the potential function of the NEMF gene in the central nervous system. Exome sequencing (ES) was applied to all families and linkage analysis was performed on family 1. A minigene assay was used to validate the splicing effect of the relevant discovered variants. Immunofluorescence (IF) experiment was performed to investigate the role of the causative gene in neuron development. The large consanguineous family confirms the phenotype-causative relationship with homozygous frameshift variant (NM_004713.6:c.2618del) as revealed by ES. Linkage analysis of the family showed a significant single-point LOD of 4.5 locus. Through collaboration in GeneMatcher, four additional unrelated families' likely pathogenic NEMF variants for a spectrum of central neurological disorders, two homozygous splice-site variants (NM_004713.6:c.574+1G>T and NM_004713.6:c.807-2A>C) and a homozygous frameshift variant (NM_004713.6: c.1234_1235insC) were subsequently identified and segregated with all affected individuals. We further revealed that knockdown (KD) of Nemf leads to impairment of axonal outgrowth and synapse development in cultured mouse primary cortical neurons. Our study demonstrates that disease-causing biallelic NEMF variants result in central nervous system impairment and other variable features. NEMF is an important player in mammalian neuron development.

Preparation of a Unique Bioavailable Bacoside Formulation (Cognique®) Using Polar-Nonpolar-Sandwich (PNS) Technology and Its Characterization, In Vitro Release Study, and Proposed Mechanism of Action

Bacopa monnieri Linn. (B. monnieri) is a medicinal herb that has been utilized as a traditional medicine to improve memory and learning. Bacosides, the important components of B. monnieri, are used in Ayurvedic herbal formulation to improve cognitive and neuroprotective action and as therapeutics for the management of many central nervous disorders. A novel bioavailable bacoside formulation, Cognique®, was prepared through the preservation of bacosides with complete multiple natural matrix including gingerols and rosemary extracts containing rosemary essential oil, rosmarinic acid, and carnosic acid using Polar-Nonpolar-Sandwich (PNS) technology. The successful PNS formulation of Cognique® was confirmed by different instrumental methods. The SEM images clearly indicated that Cognique® was almost well dispersed and has hollow core nest-like spherical structure with porous nature and rough surface due to the interaction between the polar-bacosides-nonpolar matrixes. IR, XRD, and DSC studies also confirmed the existence of bacosides in Cognique® with high stability due to the PNS formulation. The stability and in vitro drug release studies revealed that the PNS technology is an advanced technology to preserve the bioactive components, particularly bacosides, and they are capable of maintaining the sustained release of bacosides at target sites. The existence of synergistic effects of bacosides, extracts of rosemary, and gingerols in Cognique® can be utilized as a natural nutritional supplement for supporting neuroprotective effect and cognition improvement through maintenance of gut-brain axis. This study demonstrated a novel bioavailable bacoside formulation—Cognique®—through the preservation of bacosides with multiple natural matrix. Future study will investigate the efficacy, safety, and improvement of normal cognitive function in human volunteers.

Management of Idiopathic CNS inflammatory diseases during the COVID-19 pandemic: Perspectives and strategies for continuity of care from a South East Asian Center with limited resources.

The Covid-19 pandemic poses a grave health management challenge globally of unprecedented nature. Management of idiopathic Central Nervous system inflammatory disorders (iCNSID) such as Multiple sclerosis, Neuromyelitis optica and its spectrum disorders and related conditions during this pandemic needs to be addressed with affirmative and sustainable strategies in order to prevent disease related risks, medication related complications and possible COVID-19 disease associated effects.Global international iCNSIDs agencies and recent publications are attempting to address this but such guidance is not available in South East Asia. Here we outline prospectively qualitatively and quantitatively novel strategies at a tertiary center in Malaysia catering for neuroimmunological disorders despite modest resources during this pandemic.In this retrospective study with longitudinal follow-up, we describe stratification of patients for face to face versus virtual visits in the absence of formal teleneurology, stratification of patients for treatment according to disease activity, rescheduling, deferring initiation or extending treatment intervals of certain disease modifying therapies(DMT's) or immunosuppressants(IS), especially those producing lymphocyte depletion in MS and the continuation of IS in patients with NMO/NMOSD.Furthermore, we highlight the use off-label treatments such as Intravenous immunoglobulins/rituximab,bridging interferons/Teriflunomide temporarily replacing more potent DMT choices,supply challenges of IS/DMT's and tailoring blood watches and neuroimaging surveillance based on the current health needs to stave off the pandemic and prevent at risk patients with iCNSID/health care workers from possibly being exposed to the COVID-19.

Livedo racemosa in neurological diseases: an update on the differential diagnoses.

Livedo is a net-like violaceous skin pattern. It can be classified as physiological or pathological. The physiological livedo reticularis usually appears in cold conditions, whereas the pathological and irregular livedo, which persists in warm temperatures, is often labeled as 'livedo racemosa'. Some neurological pathologies are associated with livedo, most commonly those with an inflammatory component or those derived from systemic disorders. The present review summarizes the most important central and peripheral neurological diseases in pediatric and adult age groups associated with livedo, providing physicians with an overview of the clinical presentation, etiology, diagnosis and management of these conditions.

The Incidence of Central Neurological Disorders Among Patients With Isolated Dizziness and the Diagnostic Yield of Neuroimaging Studies.

Dizziness is a common symptom among emergency department (ED) patients and is often associated with benign processes. The aim of this study was to investigate the incidence of severe central neurological pathologies in isolated dizziness cases and the diagnostic efficiency of neuroimaging studies. All applications for isolated dizziness to an academic ED between January 1, 2011, and December 31, 2017 were retrospectively reviewed. The frequency of these admissions, the demographic data of the patients, the results of cranial computed tomography (CT) and diffusion-weighted magnetic resonance imaging (DW-MRI) studies, and the central neurological causes of isolated dizziness were recorded. The percentage of patients with isolated dizziness among all ED admissions was 2.5% (29,510/1,190,857). The median age of these patients was 52 years (interquartile range: 38 to 66) and 58% were female. During the study period, the rate of neuroimaging studies for isolated dizziness increased year by year, and a total of 6406 (21.7%) cranial CTs and 2896 (9.8%) DW-MRIs were performed. The diagnostic yield of neuroimaging studies was 0.6% for cranial CT and 3.9% for DW-MRI. Central neurological disorders were detected in 143 (0.48%) patients with isolated dizziness. The most common causes were posterior circulation ischemic strokes (47.5%), other ischemic strokes (18.9%), vertebrobasilar insufficiency (10.5%), and transient ischemic attack (8.4%). Isolated dizziness is rarely associated with central neurological pathologies. Neuroimaging studies, especially cranial CT, have low diagnostic yield in isolated dizziness and should therefore not be routine in the evaluation process.

Epidermal growth factor-immobilized surfaces for the selective expansion of neural progenitor cells derived from induced pluripotent stem cells.

Neural progenitor cells (NPCs) are considered to be a promising source for stem cell-based regenerative therapy for central nervous disorders. However, the widespread clinical application of NPCs requires another technology that permits the efficient production of pure NPCs in large quantities. In this study, culture substrates were designed by immobilizing epidermal growth factor (EGF) onto the substrate and evaluated for their feasibility of expanding NPCs obtained through the neurosphere culture of induced pluripotent stem (iPS) cells. After three passages we obtained neurospheres that contained cells abundantly expressing an EGF receptor. The neurospheres were dissociated into single cells and seeded onto the EGF-immobilized substrates. It was observed that neurosphere-forming cells seeded and cultured on the EGF-immobilized surface formed a two-dimensional cellular network characteristic of NPCs. These cells were found to be capable of being subcultured, while remaining their proliferation potential. Furthermore, a majority of cells (~99% of total cells) on the substrate was shown to express an NPC marker, nestin, whereas a limited number of cells (~1% of total cells) expressed neuronal marker, β-tubulin III. These results as a whole demonstrate that the EGF-immobilized substrate allows for iPS cell-derived NPCs to efficiently proliferate while maintaining the undifferentiated state.

0912 Central Sleep Apnea Patterns On Pediatric Polysomnograms

Abstract Introduction Central sleep apneas (CA) are frequently seen on pediatric polysomnograms (PPSG) independently or in conjunction with obstructive sleep apnea (OSA). In the pediatric population, the AASM defines CA as the absence of chest and/or abdominal movement associated with a cessation of airflow of more than 20s or longer than 2 baseline respiratory cycles if associated with an arousal, an awakening or oxygen desaturation ≥ 3%. Scoring CAs on PPSG based on AASM definition can cause confusion among providers as CAs are generally associated with central nervous disorders causing reduced or absent respiratory drive. Methods Retrospective review of 71 consecutive diagnostic PPSGs to analyze patterns of CAs scored per AASM definition was performed. None of the children had a disorder causing reduced respiratory drive. Data on age, obstructive AHI (Apnea Hypopnea Index), CO2, Oxygen saturation, Central AHI and diagnosis were collected. Results 68 of 71 children had varying degree of OSA and CAs. Three main patterns of CAs were observed: occurring in NREM, following sigh breaths or arousals and CAs seen in REM sleep. CO2 and oxygen saturation were in the normal range. Conclusion In our study, CAs were more often seen in young children related to reduced functional residual capacity and immaturity of chest wall. CAs in REM sleep was seen more often in children with lung disorders and gastroesophageal reflux. CAs associated with arousals/awakenings were seen in conjunction with OSA or periodic limb movement disorder (PLMD). Though a finding of CAs >5/hour is considered significant, the minimum number of events required to cause a specific disorder or syndrome remains elusive and may be different in different patient populations. As such, there is no threshold of the number of central apneas associated with disease. CAs associated with disorders causing reduced or absent respiratory drive are mostly seen in NREM sleep and associated with abnormal gas exchange. The context in which the CAs are seen on PPSGs should be clearly described to avoid confusion among ordering providers. In CAs associated with arousals/awakenings, it is important to target the cause of arousals such as OSA or PLMD. Support None

Assessment of Autonomic Nervous System in Children with Celiac Disease: A Heart Rate Variability Study

We evaluated the activity of autonomic nervous system in children with celiac disease by using heart rate variability (HRV) analysis. HRV parameters of 37 children with celiac disease were compared to 36 age- and sex-matched healthy controls. None of the participants had a systemic, central or peripheral neurological disease. Statistically significant differences were present in two parameters; standard deviation of all RR intervals (SDNN) and standard deviation of 5-minute RR interval means (SDANN). Age was negatively correlated with mean, minimum and maximum heart rate. Duration of disease was positively correlated with low frequency power-high frequency power ratio. No correlation was found between anti-tissue transglutaminase IgA level and HRV parameters. Celiac disease may affect autonomic nervous function in children even if there are no symptoms of dysautonomia.

Intracranial peripherally enhancing lesions in cardiac transplant recipients: A rare case series and literature review

Intracranial peripherally enhancing lesions in immunosuppressed solid organ transplant recipients represent a unique diagnostic and management dilemma due to the vast array of differentials that demand consideration. Diagnosis of the underlying pathology is often guided by the use of magnetic resonance imaging (MRI). We present the first published case series of three cardiac transplant recipients with significantly atypical neuroradiological findings contrary to the tenets of contemporary literature. Our rare case series consists of: (1) A sterile Mycobacterium pyogenic abscess mimicking glioblastoma multiforme due to an immunosuppressed state (2) Epstein Barr Virus encephalitis masquerading as Central Nervous System Post-Transplant Lymphoproliferative Disorder (3) An unusual case of partially treated disseminated Nocardiosis warning of the need to consider the immunosuppressed state and partial treatment response obfuscating classical MRI appearances. We utilise these unprecedented cases as the basis of a literature review to understand the pathophysiology behind the peculiar imaging findings in this rarefied cohort of transplant recipients, and rationalise why the MRI findings in each instance contradicts the accepted imaging patterns. In the setting of potential unreliability of neuroradiology in this immunosuppressed unique subgroup, we hope to impart to clinicians that definitive diagnosis obtained by emergent neurosurgical intervention may be necessary to accurately and expediently guide further medical management.

Encephalitis related to immunotherapy for lung cancer: Analysis of a multicenter cohort

IntroductionUsing immune-checkpoint inhibitors (ICIs) to manage cancer is associated with various immune-related adverse events. Central and/or peripheral neurological disorders are rare and potentially serious. We analyzed the characteristics of non-small–cell lung cancer (NSCLC) patients who developed immune-related encephalitis under anti–programmed-death protein-1 or its ligand (PD-1/PD-L1). MethodsClinical, biological and radiological characteristics of ICI-treated NSCLC patients with immune-related encephalitis, from 6 centers, were evaluated retrospectively. ResultsThe 6 centers included 9 patients: all men, all smokers, median (range) age 67 (48–77) years, 78% adenocarcinomas, first- or second-line ICI for 5 and 4 patients, respectively. Two patients had non-active cerebral metastases at ICI onset. A median of 5 (1–22) ICI infusions preceded neurological symptoms, the most frequent being confusion (78%), fever (45%) and cerebellar ataxia (33%). CSF analyses revealed a median white blood cell count of 22/mm3 (1–210/mm3), with hyperlymphocytosis in 8 patients and high protein levels in all. All bacteriological and virological analyses were negative. Cerebral MRI was considered normal for 5 patients; 4 patients had FLAIR hypersignals consistent with brain parenchyma inflammation. Three patients required intensive care. All patients received corticosteroids (different doses), a median of 8.5 (6–18) days post-onset. Corticosteroids achieved rapid symptom regression without sequelae in 8 patients. The last patient, with the longest time until corticosteroid introduction, died. ICIs were never restarted in any patient. ConclusionImmune encephalitis, a rare but serious complication of anti–PD-1/PD-L1 therapy, carries a good prognosis when managed with early corticosteroids.

Production and evaluation of biosynthesized cellulose tubes as promising nerve guides for spinal cord injury treatment.

Spinal cord injury (SCI) is a central nervous disorder that can result in permanent motor and sensory damage due to a severed communication pathway. Although there is currently no effective treatment, nerve guide tubes have been used to bridge the injured stumps and act as drug delivery systems. In this study, biosynthesized cellulose (BC) nerve guides were prepared, and nerve growth factor (NGF)-a model growth factor-was incorporated into the tubular nerve guide in order to obtain a nerve guide/drug delivery system to assist the regeneration. To achieve this, Gluconacetobacter hansenii was cultivated in a special bioreactor to produce biosynthesized cellulose tubes (BCTs) in situ, and the physical and mechanical properties of the BCTs obtained from different cultivation time points were evaluated. Our results showed that the properties of the BCTs were comparable to those of the native human neural tissues, and that the NGF released from the BCTs was bioactive for at least 7 days as evaluated by PC12 cell cultures in vitro. In summary, this study evaluated the use of BCT as a drug releasing nerve guide, and our results showed that the BCT is an attractive strategy to enhance nerve regeneration after the SCI.

Neurofilament Proteins as Prognostic Biomarkers in Neurological Disorders.

Neurofilaments: light, medium, and heavy (abbreviated as NF-L, NF-M, and NF-H, respectively), which belong to Type IV intermediate filament family (IF), are neuron-specific cytoskeletal components. Neurofilaments are axonal structural components and integral components of synapses, which are important for neuronal electric signal transmissions along the axons and post-translational modification. Abnormal assembly of neurofilaments is found in several human neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), infantile spinal muscular atrophy (SMA), and hereditary sensory-motor neuropathy (HSMN). In addition, those pathological neurofilament accumulations are known in α-synuclein in Parkinson's disease (PD), Aβ and tau in Alzheimer's disease (AD), polyglutamine in CAG trinucleotide repeat disorders, superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP43), neuronal FUS proteins, optineurin (OPTN), ubiquilin 2 (UBQLN2), and dipeptide repeat protein (DRP) in amyotrophic lateral sclerosis (ALS). When axon damage occurs in central nervous disorders, neurofilament proteins are released and delivered into cerebrospinal fluid (CSF), which are then circulated into blood. New quantitative analyses and assay techniques are well-developed for the detection of neurofilament proteins, particularly NF-L and the phosphorylated NF-H (pNF-H) in CSF and serum. This review discusses the potential of using peripheral blood NF quantities and evaluating the severity of damage in the nervous system. Intermediate filaments could be promising biomarkers for evaluating disease progression in different nervous system disorders.

Anti-lysoganglioside and other anti-neuronal autoantibodies in post-treatment Lyme Disease and Erythema Migrans after repeat infection

BackgroundMolecular mimicry targeting neural tissue has been reported after Borrelia burgdorferi(Bb) infection. Herein, we investigate whether antineuronal autoantibodies are increased and whether antibody-mediated signaling of neuronal cells is elevated in a cohort of symptomatic adults with a history of Lyme Disease (LD). MethodsParticipants (n ​= ​179) included 24 with recent Erythema Migrans (EM) without prior LD, 8 with recent EM and prior LD (EM ​+ ​prior LD), 119 with persistent post-treatment LD symptoms (PTLS), and 28 seronegative endemic controls with no prior LD history. Antineuronal immunoglobulin G (IgG) titers were measured by standard ELISA and compared with mean titers of normal age-matched sera against lysoganglioside, tubulin, and dopamine receptors (D1R and D2R). Antibody-mediated signaling of calcium calmodulin dependent protein kinase II (CaMKII) activity in a human neuronal cell line (SK-N-SH) was identified in serum. ResultsEM ​+ ​prior LD cases had higher antibody titers than controls for anti-lysoganglioside GM1 (p ​= ​0.002), anti-tubulin (p ​= ​0.03), and anti-D1R (p ​= ​0.02), as well as higher expression in the functional antibody-mediated CaMKII Assay (p ​= ​0.03). The EM cases with no prior history showed no significant differences on any measures. The PTLS cases demonstrated significantly higher titers (p ​= ​0.01) than controls on anti-lysoganglioside GM1, but not for the other measures. ConclusionThe finding of elevated anti-neuronal autoantibodies in our small sample of those with a prior history of Lyme disease but not in those without prior Lyme disease, if replicated in a larger sample, suggests an immune priming effect of repeated infection; the CaMKII activation suggests that antineuronal antibodies have functional significance. The elevation of anti-lysoganglioside antibodies among those with PTLS is of particular interest given the established role of anti-ganglioside antibodies in peripheral and central neurologic diseases. Future prospective studies can determine whether these autoantibodies emerge after Bb infection and whether their emergence coincides with persistent neurologic or neuropsychiatric symptoms.

Interdisciplinary management for chronic pain in central neurological disorders: a retrospective study

Background/aims Chronic pain in central neurological disorders is common and the current management of chronic pain is through an interdisciplinary approach. The aim of this study was to compare outpatient interdisciplinary-based treatment for chronic pain in patients with central neurological disorders to those without central neurological disorders. Methods This was a retrospective study and pain-related outcome measures were collected from a clinical outcomes registry (electronic Persistent Pain Outcomes Collaboration). This registry contained data on people who attended a pain management service who, for the purpose of this study, were categorised into those with a central neurological disorder and those without a central neurological disorder. The two sample t-test was used to determine the significance of the difference between the groups and statistical significance was defined as P<0.05. Outcome measures compared included the Brief Pain Inventory, Depression, Anxiety and Stress Scale 21, Patient Self-efficacy Questionnaire and Patient Catastrophisation Scale. Results There was a total of 1924 participants with a central neurological disorder. The electronic Persistent Pain Outcomes Collaboration registry shows that after engagement with an interdisciplinary pain management service, there was a reduction in pain severity scores, interference, mean depression, anxiety and stress in both groups at end of an episode of care compared to referral. There was a significant difference in mean changes for pain catastrophising between those with a central neurological disorder (−10.3) and those without (−7.8). Conclusions This study shows that people with central neurological disorders can also benefit from interdisciplinary management and have similar results to those without these conditions.

Cell therapy against central nervous disorders – Current and future perspectives –

Cell therapy against central nervous disorders – Current and future perspectives –

Hyperhomocysteinemia: Clinical Insights.

Homocysteine (Hcy) is a sulfhydryl-containing amino acid, and intermediate metabolite formed in metabolising methionine (Met) to cysteine (Cys); defective Met metabolism can increase Hcy. The effect of hyperhomocysteinemia (HHcy) on human health, is well described and associated with multiple clinical conditions. HHcy is considered to be an independent risk factor for common cardiovascular and central nervous disorders, where its role in folate metabolism and choline catabolism is fundamental in many metabolic pathways. HHcy induces inflammatory responses via increasing the pro-inflammatory cytokines and downregulation of anti-inflammatory cytokines which lead to Hcy-induced cell apoptosis. Conflicting evidence indicates that the development of the homocysteine-associated cerebrovascular disease may be prevented by the maintenance of normal Hcy levels. In this review, we discuss common conditions associated with HHcy and biochemical diagnostic workup that may help in reaching diagnosis at early stages. Furthermore, future systematic studies need to prove the exact pathophysiological mechanism of HHcy at the cellular level and the effect of Hcy lowering agents on disease courses.

Isolated B cell central nervous system posttransplant lymphoproliferative disorder: Role of magnetic resonance imaging in the diagnosis and management in the absence of neurological signs - a case report

A 29-year-old female who received a kidney from her mother 9 months ago, on minimal triple immunosuppression presented with short duration vertigo. There were no focal neurological deficits. Magnetic resonance imaging of the brain revealed peripherally enhancing periventricular lesions, predominantly in the bilateral frontal lobes. Positron-emission tomography showed increased uptake in the brain lesions. A stereotactic biopsy revealed CD20+ monomorphic B cell posttransplant lymphoproliferative disorder. The donor mother and daughter were Epstein–Barr virus (EBV) immunoglobulin G (IgG+)/IgG−. The cerebrospinal fluid and brain biopsy were positive for EBV. Treatment consisted of discontinuing prednisolone and MMF and reducing tacrolimus to 0.5 mg od. Rituximab, zidovudine, ganciclovir, and dexamethasone are being used. She has stable renal function.

Clinical Course, Imaging Characteristics, and Therapeutic Response in Myelin Oligodendrocyte Glycoprotein Antibody Disease: A Case Series.

Myelin oligodendrocyte glycoprotein (MOG) antibody disease is a novel central nervous system autoimmune disorder which forms part of aquaporin 4 (AQP-4) negative, neuromyelitis optica (NMO) spectrum disorder. It has a distinct clinical profile, neuroimaging features and courses from AQP-4 positive NMO and multiple sclerosis. This article is a case series of six patients with MOG antibody disease with longitudinal follow-up for up to 8 months.

Primary Central Nervous System Methotrexate-associated Lymphoproliferative Disorder in a Patient with Rheumatoid Arthritis: Case Report and Review of Literature

Methotrexate (MTX) is an immunosuppressor that is widely used to treat autoimmune diseases, including rheumatoid arthritis (RA). However, it can have serious adverse effects including a lymphoma: MTX-associated lymphoproliferative disorder (MTX-LPD). Extranodal lesions are common in MTX-LPD patients. However, MTX-LPD in the central nervous system (CNS) is extremely rare with few reported cases. Here, we describe a case of primary CNS MTX-LPD in a patient with RA, with a review of the literature. A 68-year-old woman who had received MTX for her RA for more than 10 years was referred to our hospital. Head magnetic resonance imaging (MRI) showed multiple lesions with heterogeneous contrast enhancement scattered throughout both hemispheres. As immunosuppression caused by MTX was suspected, MTX was discontinued, based on a working diagnosis of MTX-LPD. We performed an open biopsy of her right temporal lesion. Histopathologic examination showed atypical CD20+ lymphoid cells, leading to a definitive diagnosis of diffuse large B-cell lymphoma (DLBCL). In situ hybridization of an Epstein-Barr virus-encoded small RNA (EBER) was positive. Sanger sequencing confirmed that both MYD88 L265 and CD79B Y196 mutations were absent. The LPD regressed after stopping MTX. Follow-up head MRI at 8 months after surgery showed no evidence of recurrence. Although primary CNS MTX-LPD is extremely rare, it should be included in the differential diagnosis when a patient receiving MTX develops CNS lesions. Diagnosis by biopsy and MTX discontinuation are required as soon as possible.