Iatrogenic immunodeficiency-associated lymphoproliferative disorders of the central nervous system: a treatment paradox.

Background: Primary central nervous system lymphomas (PCNSLs) have historically had dismal survival rates until the advent of high-dose methotrexate (HD-MTX) based chemotherapy regimens. With increasing prevalence of autoimmune disease and development of new immunosuppressants, a genetically distinct entity known as iatrogenic immunodeficiency-associated lymphoproliferative disorder (LPD) has emerged. Many of these cases arise following methotrexate use, challenging feasibility of standard HD-MTX regimens. The aim of this study was to further characterize this disorder and determine the optimal management strategy. Methods: We describe a case of a 76-year-old female with iatrogenic immunodeficiency-associated PCNSL successfully treated with surgical resection followed by an antiviral and rituximab based regimen. We then performed a systematic literature review and identified 58 cases of non-transplant iatrogenic immunodeficiency-associated LPD involving the CNS. We used a linear probability statistical model to determine correlations with outcome. Results: Natalizumab was associated with EBV negative tumors (P = .023), and EBV positive tumors were associated with improved outcomes (P = .016). Surgical resection was associated with improved outcomes (P = .032), although limited by potential confounding effect. Antiviral treatment (P = .095), rituximab (P = .111), and stem cell transplant (SCT) (P = .198) showed a trend toward improved outcomes. The remaining treatments including methotrexate showed no improvement. Conclusion: We propose that surgical resection, rituximab, and antiviral treatment may be considered as an alternative to standard HD-MTX based regimens when managing iatrogenic immunodeficiency-associated LPD of the CNS. Further study through prospective cohort studies or randomized clinical trials is warranted.

Assessment of cervical spinal cord volume in pediatric-onset multiple sclerosis.

PURPOSE: Several studies of adult-onset multiple sclerosis (AOMS) patients have demonstrated that spinal cord volume loss is associated with disease progression and clinical disability. However, complementary studies of young patients with pediatric-onset multiple sclerosis (POMS) are lacking. Our retrospective study aimed to assess spinal cord volume in POMS patients compared with that in healthy controls. METHODS: Cervical spinal cord magnetic resonance images were evaluated for 20 POMS patients and 20 age- and sex-matched controls. Cross-sectional areas (CSAs) were measured at C2 and C7, along with the spinal cord average segmental area (CASA). The POMS group was further subdivided based on the presence or absence of spinal cord lesions, specifically C2 lesions. Pairwise area and volume comparisons were made across the different groups. RESULTS: No significant difference was found in CASA and CSA at C2 and C7 between POMS patients and comparative controls. However, CASA, CSA at C7, and estimated spinal cord volume were significantly lower in a small subset of POMS patients with C2 lesions (3 patients) than in controls (P = 0.001, 0.02, and 0.001, respectively). CONCLUSION: No significant difference was found in spinal cord areas and volumes between POMS patients and controls. This finding contrasts with spinal cord volume measurements in AOMS patients.

Refractory Anti-NMDA Receptor Encephalitis in Early Pregnancy: A Case Report of Treatment Course and Pregnancy Outcomes.

BACKGROUND AND OBJECTIVES: Anti-N-methyl d-aspartate receptor (NMDAR) encephalitis classically affects women of childbearing age, producing a disproportionate number of pregnant women with anti-NMDAR encephalitis. The typical presentation includes progressive neuropsychiatric symptoms, seizures, and alterations in consciousness, all of which present potential risks to the fetus. First-line and second-line treatments similarly pose teratogenic potential; therefore, randomized studies with supportive data on pregnancy and fetal outcomes are lacking. METHODS: We present a case of refractory anti-NMDAR encephalitis during the first and second trimesters of pregnancy with the successful use of rituximab and cyclophosphamide and resultant healthy pregnancy. RESULTS: The patient was treated with an escalating immunotherapy regimen from 11 to 15 weeks of gestation, including steroids, plasma exchange, IV immunoglobulins, and rituximab, with no clinical response. At 16 weeks of gestation, she received cyclophosphamide with clinical improvement after 4 weeks. She subsequently gave birth to a healthy, term baby boy, who continued to do well at the follow-up. DISCUSSION: This case illustrates the effective use of cyclophosphamide in the second trimester of pregnancy for anti-NMDAR encephalitis. The use of second-line therapies remains an individualized decision because the relative risk-to-benefit ratio in pregnant women is incompletely understood.

Anti-NMDA receptor encephalitis and brain atrophy in children and adults: A quantitative study.

PURPOSE: To determine whether brain atrophy was present in patients with anti-N-methyl-d-aspartate receptor encephalitis (anti-NMDARE) using qualitative and quantitative analyses of brain magnetic resonance imaging (MRI) and to explore clinical differences in patients with anti-NMDARE with or without brain atrophy. METHODS: A retrospective observational study encompassing the serologic, cerebrospinal fluid, and brain MRI data of 23 patients with anti-NMDARE was conducted. Median patient age was 14 years (interquartile range [IQR], 12 years). The cohort included 15 children (<18 years old) and 8 adults (≥18 years old). There were 6 male and 17 female patients. Imaging analysis involved 2 expert readers' observations of MRIs and automated volumetric quantification using NeuroQuant (CorTechs Labs, Inc.) software. RESULTS: Of 23 pediatric and adult patients, 11 patients had 14 brain MRIs that were quantitatively analyzed. Quantitative NeuroQuant volumetric analysis showed atrophy in 9 of 14 MRIs for 7 of 11 patients compared to age-controlled normative data. In these 9 MRIs, atrophy was present in the temporal lobes (n = 9), cerebral cortex (n = 3), and cerebellum (n = 3). Qualitative analysis of 59 MRIs (23 patients) revealed volume loss in 6 patients: 5 with global cerebral and temporal lobe volume loss and 1 with temporal lobe volume loss. No patient showed cerebellar volume loss on qualitative analysis. Mean length of stay in the intensive care unit was not significantly different for patients with or without quantitative volume loss (3.5 [5.2] vs 27.4 [23.4] days; p = 0.08). CONCLUSIONS: In this cohort of patients with anti-NMDARE, quantitative volumetric analysis showed brain atrophy, particularly affecting the temporal lobes, in 64% (7/11) of the patients. Qualitative analysis showed brain atrophy in 26% (6/23). These findings highlight the increased sensitivity of quantitative methods for volume loss detection. Larger studies are needed.

Enhancing early detection of neurological and developmental disorders and provision of intervention in low-resource settings in Uttar Pradesh, India: study protocol of the G.A.N.E.S.H. programme.

INTRODUCTION: Around 9% of India's children under six are diagnosed with neurodevelopmental disorders. Low-resource, rural communities often lack programmes for early identification and intervention. The Prechtl General Movement Assessment (GMA) is regarded as the best clinical tool to predict cerebral palsy in infants <5 months. In addition, children with developmental delay, intellectual disabilities, late detected genetic disorders or autism spectrum disorder show abnormal general movements (GMs) during infancy. General Movement Assessment in Neonates for Early Identification and Intervention, Social Support and Health Awareness (G.A.N.E.S.H.) aims to (1) provide evidence as to whether community health workers can support the identification of infants at high-risk for neurological and developmental disorders and disabilities, (2) monitor further development in those infants and (3) initiate early and targeted intervention procedures. METHODS: This 3-year observational cohort study will comprise at least 2000 infants born across four districts of Uttar Pradesh, India. Community health workers, certified for GMA, video record and assess the infants' GMs twice, that is, within 2 months after birth and at 3-5 months. In case of abnormal GMs and/or reduced MOSs, infants are further examined by a paediatrician and a neurologist. If necessary, early intervention strategies (treatment as usual) are introduced. After paediatric and neurodevelopmental assessments at 12-24 months, outcomes are categorised as normal or neurological/developmental disorders. Research objective (1): to relate the GMA to the outcome at 12-24 months. Research objective (2): to investigate the impact of predefined exposures. Research objective (3): to evaluate the interscorer agreement of GMA. ETHICS AND DISSEMINATION: G.A.N.E.S.H. received ethics approval from the Indian Government Chief Medical Officers of Varanasi and Mirzapur and from the Ramakrishna Mission Home of Service in Varanasi. GMA is a worldwide used diagnostic tool, approved by the Ethics Committee of the Medical University of Graz, Austria (27-388 ex 14/15). Apart from peer-reviewed publications, we are planning to deploy G.A.N.E.S.H. in other vulnerable settings.

Autoimmune Vestibulocerebellar Syndromes.

Autoimmune disorders affecting the vestibular end organs, vestibular pathways, vestibular nuclei, and vestibulocerebellum are often underrecognized as a cause of chronic dizziness and ataxia. Autoantibodies specific for cell-surface, synaptic, and intracellular neural antigens serve as biomarkers of these disorders. This article describes the epidemiology, clinical presentation, diagnostic considerations, imaging findings, treatment, and prognosis of autoimmune disorders, in which the vestibulocerebellar syndrome is the main or presenting clinical presentation. Antibodies specific for intracellular antigenic targets described in the article are PCA-1 (Purkinje cell cytoplasmic antibody type 1, also known as anti-Yo), ANNA-1 (antinuclear neuronal antibody type 1, also known as anti-Hu), ANNA-2 (antinuclear neuronal antibody type 2, also known as anti-Ri), Ma1/2 (anti-Kelch-like 11/12 antibody), Kelch-like 11, amphiphysin, CV2 (collapsin response 2, also known as collapsin response mediator protein-5 [CRMP5]), VGCC (voltage-gated calcium channel), GAD65 (glutamic acid decarboxylase 65-kDa isoform), AP3B2 (adaptor protein 3B2, also known as anti-Nb), MAP1B (microtubule-associated protein 1B antibody, also known as anti-PCA-2), and neurochondrin antibodies. Antibodies targeting cell-surface or synaptic antigenic targets described in the article include DNER (delta/notchlike epidermal growth factor related receptor; antigen to anti-Tr), CASPR2 (contactin-associated proteinlike 2), septin-5, Homer-3, and mGluR1 (metabotropic glutamate receptor 1). The vestibulocerebellar presentation is largely indistinguishable among these conditions and is characterized by subacute onset of cerebellar symptoms over weeks to months. The diagnosis of autoimmune vestibulocerebellar syndromes is based on a combination of clinical and serological features, with a limited role for neuroimaging. Subtle eye movement abnormalities can be an early feature in many of these disorders, and therefore a meticulous vestibulo-ocular examination is essential for early and correct identification. Cancer occurrence and its type are variable and depend on the autoantibody detected and other cancer risk factors. Treatment comprises immunotherapy and cancer-directed therapy. Acute immunotherapies such as intravenous immunoglobulin, plasma exchange, and steroids are used in the initial phase, and the use of long-term immunosuppression such as rituximab may be necessary in relapsing cases. Outcomes are better if immunotherapy is started early. The neurologic prognosis depends on multiple factors.

Acute Disseminated Encephalomyelitis (ADEM) and Increased Intracranial Pressure Associated With Anti-Myelin Oligodendrocyte Glycoprotein Antibodies.

BACKGROUND: Antibodies to the myelin oligodendrocyte glycoprotein (MOG) have been identified in about 40% of children with acute disseminated encephalomyelitis (ADEM). The objective of this report is to describe three individuals with fulminant ADEM complicated by increased intracranial pressure associated with the presence of the anti-MOG antibodies. METHODS: This is a retrospective case series. Informed consent was obtained from the concerned patients or caregivers. RESULTS: High intracranial pressure associated with ADEM in the presence of MOG antibodies can result in cerebral edema, herniation, prolonged hospital stay (average intensive care unit stay: 22 days, average hospital stay: 50.6 days), and long-term disability. CONCLUSION: Increased intracranial pressure complicating MOG antibody-related ADEM is a unique finding in our cases. This can complicate the clinical picture of ADEM and confers high morbidity. Long-term immunosuppression is warranted in selected cases with persistent seropositivity.

Spontaneous Carotid Cavernous Fistula in Young Female with Anti-thrombin III Deficiency.

A 27-year-old female patient presented with headache, vomiting, and visual disturbances who was evaluated and detected to have a direct carotid cavernous fistula (CCF). Secondary causes were ruled out, and she was treated with coil occlusion and glue injection. A month after almost complete clinical recovery, she developed deep vein thrombosis of left thigh. Subsequent work-up revealed antithrombin III (ATIII) deficiency in her. To the best of our knowledge, this is the first reported case of ATIII deficiency associated with CCF. This case shows the importance of working up for a primary etiology if any, to prevent further complications after surgery.

Fungal mediated biotransformation reduces toxicity of arsenic to soil dwelling microorganism and plant.

Rhizospheric and plant root associated microbes generally play a protective role against arsenic toxicity in rhizosphere. Rhizospheric microbial interaction influences arsenic (As) detoxification/mobilization into crop plants and its level of toxicity and burden. In the present investigation, we have reported a rhizospheric fungi Aspergillus flavus from an As contaminated rice field, which has capability to grow at high As concentration and convert soluble As into As particles. These As particles showed a reduced toxicity to soil dwelling bacteria, fungi, plant and slime mold. It does not disrupt membrane potential, inner/outer membrane integrity and survival of the free N2 fixating bacteria. In arbuscular mycorrhiza like endophytic fungi Piriformospora indica, these As particles does not influence mycelial growth and plant beneficial parameters such as phosphate solubilizing enzyme rAPase secretion and plant root colonization. Similarly, it does not affect plant growth and chlorophyll content negatively in rice plant. However, these As particles showed a poor absorption and mobilization in plant. These As particle also does not affect attachment process and survival of amoeboid cells in slime mold, Dictyostelium discoideum. This study suggests that the process of conversion of physical and chemical properties of arsenic during transformation, decides the toxicity of arsenic particles in the rhizospheric environment. This phenomenon is of environmental significance, not only in reducing arsenic toxicity but also in the survival of healthy living organism in arsenic-contaminated rhizospheric environment.

Atypical Anti-MOG syndrome with aseptic meningoencephalitis and pseudotumor cerebri-like presentations.

OBJECTIVE: To describe 2 atypical cases with Anti-MOG antibody related demyelinating syndrome. METHODOLOGY: Case series. RESULTS: We present two cases. Case 1 is an 18-year-old woman who presented with headache, blurred vision, and papilledema and was initially diagnosed with pseudotumor cerebri syndrome. CSF showed mildly elevated opening pressure and lymphocytic pleocytosis and a diagnosis of aseptic meningitis was considered. MRI brain and spinal cord revealed longitudinally extensive bilateral simultaneous optic neuritis and multiple spinal cord lesions. Case 2 is a 28-year old man who presented initially with unilateral optic neuritis followed by aseptic meningitis three weeks later and subsequently acute disseminated encephalomyelitis (ADEM). Serology was positive for Anti-MOG antibody on a cell-based assay in both these cases. DISCUSSION: Although bilateral optic neuritis has been well described in MOG related disorders, aseptic meningitis and pseudotumor cerebri-like syndromes are notable alternate presentations. The presence of eosinophils in the CSF (in the first patient) is a unique finding in our case series. CONCLUSION: In a patient with an aseptic meningitis like presentation, the presence of optic neuritis, brain and/or spinal cord lesions should raise suspicion for an MOG-Ab related syndrome.

Unique characteristics of optical coherence tomography (OCT) results and visual acuity testing in myelin oligodendrocyte glycoprotein (MOG) antibody positive pediatric patients.

BACKGROUND: Optic nerve involvement in anti-myelin oligodendrocyte glycoprotein antibody associated syndrome (MOG ab syndrome) tends to have unique features. Few studies have reported optical coherence tomography (OCT) measures like retinal nerve fiber layer thickness findings in the setting of pediatric MOG ab syndrome. OBJECTIVES: The aim of this study is to compare visual acuity between MOG ab positive and MOG ab negative pediatric cohorts and examine correlations with OCT findings. METHODS: We included outpatients less than 18 years of age who had optic neuritis (ON) of at least one eye and who completed visual testing and OCT in the study. ON was defined based on clinical or OCT findings. Antibody testing was obtained using cell-based assay. The primary analyses of interest investigated differences in low-contrast visual acuity stratified by the defined RNFL ranges and by antibody positivity. RESULTS: We analyzed 28 eyes from 14 anti-MOG ab patients (MOG-ON cohort), 18 eyes from 9 anti-AQP4 ab (AQP4-ON cohort) patients and 26 eyes from 13 patients who tested negative for both the antibodies (seronegative ON cohort). MOG-ON eyes with zero reported clinical events had lower RNFL thickness, than the minimum RNFL thickness of either the seronegative-ON or AQP4-ON eyes with zero clinical attacks in most retinal segments. Within the lowest range of the RNFL (RNFL <50 um) in most retinal segments, the MOG-ON cohort had a statistically significant greater visual acuity relative to the AQP4 cohort. CONCLUSIONS: Patients with anti-MOG antibody mediated CNS disorders can suffer from subclinical ON events with significant reductions in RNFL. Despite equally significant damage to the optic nerve, MOG-Ab positive patients have relatively preserved visual acuity.

Anti-Myelin Oligodendrocyte Glycoprotein Antibody Associated With Gray Matter Predominant Transverse Myelitis Mimicking Acute Flaccid Myelitis: A Presentation of Two Cases.

BACKGROUND: Anti-myelin oligodendrocyte glycoprotein (MOG) antibody associated disorders frequently manifest as optic neuritis, transverse myelitis, and acute disseminated encephalomyelitis. While their clinical phenotypes overlap with relapsing inflammatory Central nervous system (CNS) conditions such as multiple sclerosis and neuromyelitis optica spectrum disorder, MOG-related syndromes frequently occur in a younger age group. In children, longitudinally extensive transverse myelitis (LETM) is less specific for anti-aquaporin-4 associated neuromyelitis optica spectrum disorder, and has also been reported in pediatric multiple sclerosis, idiopathic transverse myelitis, and acute flaccid myelitis. METHODS: We summarize two patients with positive MOG antibodies and myelitis. RESULTS: We identified two individuals with anti-MOG associated LETM that demonstrate primarily gray matter involvement. Clinically these patients exhibited hyperreflexia and had rapid improvement with immunotherapies. CONCLUSIONS: Anti-MOG diseases can cause LETM with gray matter predominance mimicking acute flaccid myelitis, but clinically these patients can have retained reflexes and respond favorably to immunotherapies.

MOG antibody disease: A review of MOG antibody seropositive neuromyelitis optica spectrum disorder.

MOG antibody disease is an autoimmune disease of the central nervous system associated with a serological antibody against MOG, myelin oligodendrocyte glycoprotein. MOG is a glycoprotein expressed on the outer membrane of myelin and solely found within the central nervous system, including in the brain, optic nerves and spinal cord. Clinically, the disease resembles neuromyelitis optica spectrum disorders in the predilection for relapses of optic neuritis and transverse myelitis. In addition, acute disseminated encephalomyelitis (ADEM) is a well-recognized phenotype of MOG antibody disease in children. In recent studies around the world where MOG testing is available, up to 42% of NMOSD patients who test seronegative for the AQP4 antibody test positive for MOG antibodies. MOG antibody disease has thus recently emerged as a distinct entity carved out of the patient population diagnosed with NMOSD. In this review, we examine the history of the MOG antibody and its relevance to demyelinating disease, as well as compare the clinical, radiographic and serological profiles of patients with MOG antibody with patients with AQP4 antibody.

Emerging drugs for primary progressive multiple sclerosis.

INTRODUCTION: The identification of effective therapies for progressive forms of multiple sclerosis (MS) has remains a priority and challenge for the global MS community. Despite a few proposed mechanisms, a more complete understanding of the mechanisms involved in the pathogenesis of these MS phenotypes, animal models that incorporate these pathogenic characteristics, novel trial designs, drug repurposing strategies, and new models of collaboration between clinical and basic science personnel may be required in identifying effective therapies. Areas covered: Here, we review the current knowledge on putative pathogenic mechanisms in primary progressive MS (PPMS). Also, the rationale and outcomes of key phase II or III trial initiatives in PPMS are summarized. Future perspectives are outlined. Expert opinion: The recent approval of ocrelizumab is a major milestone forward in the therapy of PPMS. One reason for success of this drug is appropriate patient selection. The ultimate goal in PPMS therapy should be the reversal of disability, and the arrest of disease progression. Our current understanding of PPMS suggests that a combination of immune-modulatory, myelin-restorative, and neuro-regenerative therapies particularly early in the disease course would be a reasonable strategy. Finally, selection of appropriate patients, selection of appropriate outcomes and monitoring therapy is again crucial for success of therapeutic strategies.

Distal renal tubular acidosis in Sjögren's syndrome.

Interstitial nephritis and immune complex-mediated glomerulonephritis are the two common renal manifestations of primary Sjögren's syndrome (SS). Here, we discuss three cases of primary SS where presenting manifestation was distal renal tubular acidosis. The possibility of an underlying autoimmune disorder should be considered in a patient presenting with distal tubular acidosis or recurrent hypokalemic periodic paralysis as treatment of primary disease improves the outcome of illness.

A Callosal Catastrophe: Toxic Leukoencephalopathy Associated with Thermogenic Weight Loss Supplement Use.

BACKGROUND: The use of weight loss drugs and dietary supplements is common, but safety profiles for these drugs are largely unknown. Reports of toxicity have been published, and the use of these agents should be considered in clinical differential diagnoses. METHODS: We report the case of a patient with toxic leukoencephalopathy and hyponatremia associated with oral consumption of a thermogenic dietary supplement and essential oils. RESULTS: A 30-year-old woman presented after 2 days of headache, blurred vision, photophobia, vomiting, and hand spasms. She was taking a thermogenic dietary supplement daily for 6 months as well as a number of essential oils. Examination revealed mild right sided ataxia and diffuse hyperreflexia. Neuroimaging demonstrated bilaterally symmetric T2 hyperintensities of the corpus callosum and periventricular white matter. Approximately 18 h after admission she became unresponsive with brief extensor posturing and urinary incontinence. She partially recovered, but 1 h later became unresponsive with dilated nonreactive pupils and extensor posturing (central herniation syndrome). She was intubated, hyperventilated, and given hyperosmotic therapy. Emergent imaging showed diffuse cerebral edema. Intracranial pressure was elevated but normalized with treatment; she regained consciousness the following day. She was extubated one day later and discharged on hospital day 5. She was seen 2 months later with no further symptoms and a normal neurologic examination. CONCLUSIONS: The pathophysiology of this patient's hyponatremia and toxic leukoencephalopathy is unknown. However, physicians must be aware of the association between thermogenic dietary supplements and toxic leukoencephalopathy. Vigilance for life-threatening complications including hyponatremia and cerebral edema is critical.

Occult renal cell carcinoma presenting as carcinomatous polyarthritis.

Carcinomatous polyarthritis (CP) is a rare paraneoplastic disorder which can be associated with various solid tumors and can even precede detection of the underlying malignancy. A 54-year-old male presented with migratory asymmetric inflammatory polyarthritis and high-grade fever for 6 months. On evaluation, he was diagnosed to have renal cell carcinoma (RCC). CP as an initial presentation of RCC was not described previously.