Immunotherapy in selected patients with Down syndrome disintegrative disorder.

Down syndrome disintegrative disorder (DSDD) is an increasingly identified condition characterized by cognitive decline, autistic characteristics, insomnia, catatonia, and psychosis in adolescents and young adults with Down syndrome. Previously we reported a higher rate of autoimmune thyroid disease in these patients compared with unaffected individuals with Down syndrome. We therefore hypothesized DSDD may in some cases be immune-mediated. Here we report four cases of DSDD treated with immunotherapy. Families were interviewed retrospectively for symptoms of cognitive decline, autism, catatonia, psychosis, and insomnia before and after treatment, using established scales where possible. Medical records were reviewed for evaluations and treatment. All four patients received intravenous immunoglobulin with or without additional immunotherapy. Significant improvements were seen in catatonia, insomnia, autistic features, cognition, and psychosis. In this small case series of patients with autoimmunity, core symptoms of DSDD improved significantly after immunotherapy. This supports the hypothesis that, in some patients, DSDD is immune-mediated. Immunotherapy should be considered in the treatment of DSDD, particularly in patients with a history of autoimmunity. WHAT THIS PAPER ADDS: Immunotherapy may improve symptoms of catatonia, insomnia, autism severity, cognitive decline, and psychosis in Down syndrome disintegrative disorder.

INMUNOTERAPIA EN PACIENTES SELECCIONADOS CON TRASTORNO DESINTEGRATIVO DEL SÍNDROME DE DOWN: El trastorno desintegrativo del síndrome de Down (TDSD) es una afección cada vez más identificada que se caracteriza por deterioro cognitivo, características autistas, insomnio, catatonia y psicosis en adolescentes y adultos jóvenes con síndrome de Down. Anteriormente informamos una tasa más alta de enfermedad tiroidea autoinmune en estos pacientes en comparación con las personas no afectadas con síndrome de Down. Por lo tanto, hipotetizamos que el TDSD puede, en algunos casos, estar inmunomediado. Aquí presentamos cuatro casos de TDSD tratados con inmunoterapia. Las familias fueron entrevistadas retrospectivamente para los síntomas de deterioro cognitivo, autismo, catatonía, psicosis e insomnio antes y después del tratamiento, utilizando escalas establecidas cuando sea posible. Los registros médicos fueron revisados ​​para evaluaciones y tratamiento. Los cuatro pacientes recibieron inmunoglobulina intravenosa con o sin inmunoterapia adicional. Se observaron mejoras significativas en catatonia, insomnio, características autistas, cognición y psicosis. En esta pequeña serie de casos de pacientes con autoinmunidad, los síntomas centrales de la TDSD mejoraron significativamente después de la inmunoterapia. Esto apoya la hipótesis de que, en algunos pacientes, la TDSD está inmunomediada. La inmunoterapia debe considerarse en el tratamiento de la TDSD, particularmente en pacientes con antecedentes de autoinmunidad.

IMUNOTERAPIA EM PACIENTES SELECIONADOS COM SÍNDROME DE DOWN E TRANSTORNO DESINTEGRATIVO: O transtorno desintegrativo na síndrome de Down (TDSD) é uma condição crescentemente identificada, caracterizada por declínio cognitivo, características autistas, insônia, catatonia, e psicose em adolescente e jovens adultos com síndrome de Down. Nós relatamos previamente uma taxa maior de doença autoimune da tireóide nestes pacientes comparados com indivíduos com síndrome de Down não afetados. Portanto, hipotetizamos que o TDSD pode, em alguns casos, ser imune-mediado. Aqui reportamos quatro casos de TDSD tratados com imunoterapia. As famílias foram entrevistadas retrospectivamente quanto a sintomas de declínio cognitivo, autismo, catatonia, psicose, e insônia antes e depois do tratamento, usando escalas estabelecidas quando possível. Os registros médicos foram revisados quanto a avaliações e tratamento. Todos os quatro pacientes receberam imunoglobulina intravenosa com ou sem imunoterapia adicional. Melhoras significativas foram vistas na catatonia, aspectos autistas, cognição, e psicose. Nesta pequena série de casos de pacientes com auto-imunidade, os sintomas centrais de TDSD melhoraram significativament após imunoterapia. Isso apóia a hipótese de que, em alguns pacientes, o TDSD é imuno-mediado. A imunoterapia deve ser considerada no tratamento do TDSD, particularmente em pacientes com história de autoimunidade.

Beyond biopsy for neurosarcoidosis: A review of blood and CSF biomarkers.

Neurosarcoidosis, a rare granulomatous disease, causes inflammation and damage to the central nervous system (CNS). A major diagnostic challenge in neurosarcoidosis is the absence of well-defined biomarkers. The need for biopsy to make the diagnosis can lead to delays and misdiagnosis if histopathology is inaccessible or indeterminate, highlighting the need for more accessible diagnostic indicators. The current gold standard for a "definite" neurosarcoidosis diagnosis requires biopsy of CNS tissue revealing non-caseating granulomas. However, such biopsies are inherently invasive and carry associated procedural risks. Notably, angiotensin-converting enzyme (ACE), commonly associated with systemic sarcoidosis, is recognized as a poor biomarker for neurosarcoidosis due to its lack of accuracy in the context of CNS involvement. Furthermore, imaging in neurosarcoidosis, while widely utilized and important for narrowing the diagnosis, lacks specificity. Decades of research have yielded molecular and immunologic biomarkers-soluble interleukin-2 receptor (IL-2R), serum amyloid A1, the CD4/CD8 ratio, neopterin, interferon-gamma (IFN-γ), and chemokine ligand 2 (CCL2)-that hold potential for improving diagnostic accuracy. However, these biomarkers are not yet established in clinical care as they may be difficult to obtain and are derived from small studies. They also suffer from a lack of specificity against other inflammatory and infectious central nervous system diseases. New biomarkers are needed for use alongside those previously discovered to improve diagnosis of this rare disease. This review synthesizes existing literature on neurosarcoidosis biomarkers, aiming to establish a foundation for further research in this evolving field. It also consolidates information on biomarkers of systemic sarcoidosis such as IL-8 and soluble CD40L that have not yet been studied in neurosarcoidosis but hold potential as markers of CNS disease.

Adalimumab as treatment for neurosarcoidosis: A case series.

Sarcoidosis is a disease characterized by non-caseating granulomas that can involve the central nervous system as neurosarcoidosis. This challenging disease is currently managed with high dose steroids, and sometimes the addition of infliximab. Other TNA-alpha inhibitors have not been studied as rigorously. We discovered ten neurosarcoidosis patients who were on an alternative TNA-alpha inhibitor, adalimumab. Eight patients had a positive response clinically and radiographically to adalimumab.

Neurosarcoidosis causing hydrocephalus: A case series.

Sarcoidosis is a granulomatous inflammatory disease that rarely affects the central nervous system as neurosarcoidosis. Neurosarcoidosis can affect any part of the nervous system causing a wide variety of clinical presentations ranging from seizures to optic neuritis. Here, we highlight rare cases of obstructive hydrocephalus in patients with neurosarcoidosis to make clinicians aware of this potential disease complication.

Neuromyelitis optica: Clinical course and potential prognostic indicators.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune neurological disorder associated with antibodies to aquaporin-4 (AQP4). NMOSD has been thought to follow a progressive disease course, with step-wise accumulation of disability over time, even in patients undergoing immunosuppressive/immunomodulatory therapy. The influence of factors such as AQP4 seropositivity, AQP4 serum titer levels, and administration of plasmapheresis on NMOSD prognosis is, as yet, unclear. METHODS: We performed a retrospective chart review of 53 persons with NMOSD at Duke University Hospital-collecting data on longitudinal disease course, imaging, demographics, and serum AQP4 titers (measured using the ELISA or FACS method). Most patients in our cohort were treated with high-dose corticosteroids and, following diagnosis, received maintenance immunosuppressive/immunomodulatory therapies. Longitudinal data on EDSS scores were used to calculate the slope of disability over time for each participant. We additionally investigated the correlation between initial AQP4 seropositivity, initial AQP4 serum titer levels, and treatment with plasmapheresis on disability progression for each participant. RESULTS: Contrary to current views on NMOSD disease course, the majority of our participants showed either no change (31.9%) or improvement (27.1%) in disability over time. Our results additionally revealed no significant association between clinical prognosis and initial AQP4 seropositivity (p = 0.830), initial AQP4 serum titer levels (p = 0.338), or administration of plasmapheresis (p = 0.1149). CONCLUSIONS: Our study presents a contemporary view of the clinical course of NMOSD and shows a more favorable view of its disease course than prior studies (performed before high-efficacy disease modifying therapies became widely-used for this patient population). Most patients in this study received treatment with high-dose corticosteroids following NMOSD flares, as well as a variety of maintenance immunosuppressive therapies. The results of this study cannot shed light on the disease course of untreated NMOSD. Our findings additionally challenge the theory that AQP4 seropositivity or serum titer levels at time of diagnosis may be used to effectively predict NMOSD prognosis. While we were unable to find evidence supporting a favorable effect of plasmapheresis administration on disease outcomes, further research is needed to determine the role plasmapheresis ought to play in the treatment of NMOSD.

Primary retinal pathology in multiple sclerosis as detected by optical coherence tomography.

Optical coherence tomography studies in multiple sclerosis have primarily focused on evaluation of the retinal nerve fibre layer. The aetiology of retinal changes in multiple sclerosis is thought to be secondary to optic nerve demyelination. The objective of this study was to use optical coherence tomography to determine if a subset of patients with multiple sclerosis exhibit primary retinal neuronopathy, in the absence of retrograde degeneration of the retinal nerve fibre layer and to ascertain if such patients may have any distinguishing clinical characteristics. We identified 50 patients with multiple sclerosis with predominantly macular thinning (normal retinal nerve fibre-layer thickness with average macular thickness < 5th percentile), a previously undescribed optical coherence tomography defined phenotype in multiple sclerosis, and compared them with 48 patients with multiple sclerosis with normal optical coherence tomography findings, 48 patients with multiple sclerosis with abnormal optical coherence tomography findings (typical for multiple sclerosis) and 86 healthy controls. Utilizing a novel retinal segmentation protocol, we found that those with predominant macular thinning had significant thinning of both the inner and outer nuclear layers, when compared with other patients with multiple sclerosis (P < 0.001 for both), with relative sparing of the ganglion cell layer. Inner and outer nuclear layer thicknesses in patients with non-macular thinning predominant multiple sclerosis were not different from healthy controls. Segmentation analyses thereby demonstrated extensive deeper disruption of retinal architecture in this subtype than may be expected due to retrograde degeneration from either typical clinical or sub-clinical optic neuropathy. Functional corroboration of retinal dysfunction was provided through multi-focal electroretinography in a subset of such patients. These findings support the possibility of primary retinal pathology in a subset of patients with multiple sclerosis. Multiple sclerosis-severity scores were also significantly increased in patients with the macular thinning predominant phenotype, compared with those without this phenotype (n = 96, P=0.006). We have identified a unique subset of patients with multiple sclerosis in whom there appears to be disproportionate thinning of the inner and outer nuclear layers, which may be occurring as a primary process independent of optic nerve pathology. In vivo analyses of retinal layers in multiple sclerosis have not been previously performed, and structural demonstration of pathology in the deeper retinal layers, such as the outer nuclear layer, has not been previously described in multiple sclerosis. Patients with inner and outer nuclear layer pathology have more rapid disability progression and thus retinal neuronal pathology may be a harbinger of a more aggressive form of multiple sclerosis.

Etiology of sarcoidosis: does infection play a role?

Sarcoidosis is a granulomatous inflammatory disorder of unclear etiology, which is known to affect multiple organ systems including the lungs, heart, skin, central nervous system, and eyes, among others. For this reason, sarcoidosis represents a systemic medical disorder that is clinically relevant to multiple medical sub-specialties. Despite extensive research, the etiology of sarcoidosis has yet to be elucidated, although most evidence supports that the pathogenetic mechanism of sarcoidosis is an aberrant immune response, driven by an unidentified antigen (or antigens) in genetically susceptible individuals. Multiple candidate etiologic agents, including microbial organisms and environmental agents, have been investigated, but study results are inconclusive. In this review, we describe the known histologic and immunologic features of sarcoidosis and discuss the evidence supporting a role for infectious processes in the pathogenesis of sarcoidosis.

Leber's Hereditary Optic Neuropathy Plus Causing Recurrent Myelopathy due to an MT-DN1 Mutation at G3635A.

A 51-year-old man with known Leber's hereditary optic neuropathy (LHON) presented with worsening lower extremity weakness and numbness. Following an episode of myelopathy two years before, he had been ambulating with a walker but over two weeks became wheelchair bound. He also developed a sensory level below the T4 dermatome to light touch, pinprick, and vibration. MRI of his cervical and thoracic spine showed a nonenhancing T2 hyperintense lesion extending from C2 to T12. At his presentation two years earlier, he was found to have a longitudinally extensive myelopathy attributed to his LHON. Genetic testing revealed a 3635 guanine to adenine mutation. MRI at that presentation demonstrated a C1-T10 lesion involving the central and posterior cord but, unlike the new lesion, did not involve the ventral and lateral horns. Given the similarity to his prior presentation and a negative evaluation for alternative etiologies, he was thought to have recurrent myelopathy secondary to Leber's Plus. To our knowledge, recurrent myelopathy due specifically to the G3635A mutation in Leber's Plus has not been reported previously.

Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease: Presentation and outcomes of adults at a single center.

BACKGROUND/INTRODUCTION: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a chronic demyelinating disorder that has been increasingly recognized since the serum antibody became commercially available in 2017. The most common clinical presentation is optic neuritis, and first line acute treatment is intravenous (IV) steroids. However, there are many questions that remain unanswered. For clinicians and patients, the primary question is whether relapses will occur and whether to treat with chronic therapy. METHODS: This retrospective chart review examined characteristics of thirty-three known adult MOGAD cases at a single institute. Data was collected on patient demographics, clinical presentation, objective diagnosis with MRI and serum antibody levels, acute and chronic treatment and disease outcomes. RESULTS: Our MOGAD cases revealed a slight female to male predominance of 1.5:1. No racial groups were affected disproportionately, and age of symptom onset spanned a large range with a median of 40 years. The most common clinical and radiologic presentation was optic neuritis followed by transverse myelitis and brainstem symptoms/lesions. IV methylprednisolone was used in the vast majority of cases for acute treatment. 83.3% of our patients were treated with chronic therapy at some point during their disease course. Therapies include rituximab, IVIG, ocrelizumab, mycophenolate mofetil and ofatumumab. The majority of our patients were treated with rituximab and we did not see a significant benefit of yearly relapse reduction for rituximab versus other therapies. Our cohort had a higher-than- expected percentage of cases with relapsing disease (56.3%) compared to monophasic (43.8%). DISCUSSION/CONCLUSION: Our study confirms prior data regarding the demographics, clinical presentation and radiologic presentation of MOGAD. There is no consensus on whether maintenance therapy should be started for MOGAD cases with a single clinical event. Our cohort showed a higher relapse rate than has been reported previously and all known relapses occurred within one year of diagnosis. More data is necessary to confirm risk of relapse in the years following diagnosis. In addition, further data on biomarkers are needed to predict the disease course could help guide management.

Visual dysfunction in multiple sclerosis correlates better with optical coherence tomography derived estimates of macular ganglion cell layer thickness than peripapillary retinal nerve fiber layer thickness.

BACKGROUND: Post-mortem analyses of multiple sclerosis (MS) eyes demonstrate prominent retinal neuronal ganglion cell layer (GCL) loss, in addition to related axonal retinal nerve fiber layer (RNFL) loss. Despite this, clinical correlations of retinal neuronal layers remain largely unexplored in MS. OBJECTIVES: To determine if MS patients exhibit in vivo retinal neuronal GCL loss, deeper retinal neuronal loss, and investigate correlations between retinal layer thicknesses, MS clinical subtype and validated clinical measures. METHODS: Cirrus HD-optical coherence tomography (OCT), utilizing automated intra-retinal layer segmentation, was performed in 132 MS patients and 78 healthy controls. MS classification, Expanded Disability Status Scale (EDSS) and visual function were recorded in study subjects. RESULTS: GCL+inner plexiform layer (GCIP) was thinner in relapsing-remitting MS (RRMS; n = 96, 71.6 µm), secondary progressive MS (SPMS; n = 20, 66.4 µm) and primary progressive MS (PPMS; n = 16, 74.1 µm) than in healthy controls (81.8 µm; p < 0.001 for all). GCIP thickness was most decreased in SPMS, and although GCIP thickness correlated significantly with disease duration, after adjusting for this, GCIP thickness remained significantly lower in SPMS than RRMS. GCIP thickness correlated significantly, and better than RNFL thickness, with EDSS, high-contrast, 2.5% low-contrast and 1.25% low-contrast letter acuity in MS. 13.6% of patients also demonstrated inner or outer nuclear layer thinning. CONCLUSIONS: OCT segmentation demonstrates in vivo GCIP thinning in all MS subtypes. GCIP thickness demonstrates better structure-function correlations (with vision and disability) in MS than RNFL thickness. In addition to commonly observed RNFL/GCIP thinning, retinal inner and outer nuclear layer thinning occur in MS.

Genetic or Autoimmune: POLG-Related Epilepsy Initially Treated as an Autoimmune Encephalitis, a Case Report.

Hospital neurologists participate at the forefront of managing fulminant acute and subacute onset epilepsy, frequently attributed to autoimmune encephalitis (AE). As the recognition of antibody-mediated AE grows, there is a growing number of patients who are treated as antibody-negative AE. While antibody-negative autoimmune processes should be considered in the setting of acute and subacute onset of fulminant epilepsy, other causes must be considered before subjecting patients to long-term immunomodulatory treatments and other potential therapeutic toxicities. We present the case of a previously healthy young man who presented with new-onset refractory seizures treated with escalating doses of anti-epileptic drugs as well as immunosuppression for presumed autoimmune epilepsy. He developed valproic acid induced hepatotoxicity requiring liver transplantation and was later found to have a POLG mutation. We discuss the presentation of POLG mutations as well as the diagnosis of seronegative autoimmune encephalitis. We highlight the need for a broad differential when evaluating new onset refractory seizures in an otherwise healthy person.

Profiling serum neurofilament light chain and glial fibrillary acidic protein in primary progressive multiple sclerosis.

This study examined the utility of serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) as biomarkers in primary progressive multiple sclerosis in context with clinical severity, progression, and treatment. Using a single-molecule array (Quanterix), serum protein concentrations were measured from twenty-five participants semiannually for five years. There was no association between levels of either biomarker and disease severity, disease duration, or treatment group. Enrollment sNfL level was not associated with future clinical worsening. Precedent clinical worsening was not associated with last sGFAP measurement. These results suggest a limited role for these biomarkers in primary progressive disease management.

B cell depletion and pregnancy: Review and applications for MS treatment.

Multiple sclerosis (MS) is a chronic autoimmune condition primarily affecting young adults. As there are numerous uncertainties faced by young women of childbearing age who are living with this chronic condition and the gender ratio is increasingly skewed towards women, it has become critical to define a clear approach to questions of disease management prior to and during pregnancy. With the approval of B cell depletion therapy for treatment of relapsing remitting and primary progressive MS, we explore the available data on using this type of therapy in the setting of pregnancy. We also provide recommendations regarding use of B-cell depleting therapies for patients who are considering or attempting conception.

The clinical presentation and treatment of MOG antibody disease at a single academic center: A case series.

OBJECTIVES: To describe the clinical presentation of MOG antibody disease (MOG-AD) in a series of patients at a single academic center. METHODS: We performed a retrospective review of patients with MOG antibodies. RESULTS: We review the clinical presentation of 11 patients with MOG antibodies. In patients seen at Duke University Health System with MOG antibodies, the most common presentation was optic neuritis. Rituximab was the most used treatment for long-term management. CONCLUSIONS: Our case series highlights the common presentation of MOG antibody disease (MOG-AD) at a single academic medical center.

Recurrent schilder's disease.

Schilder's disease is a rare and aggressive central nervous system demyelinating disorder that is typically monophasic and steroid responsive. Here, we present an unusual case of a teenager with Schilder's disease who was treated with corticosteroids and had a clinical and radiographic recurrence nearly one year after the initial presentation.

Neurosarcoidosis following Immune Checkpoint Inhibition.

Recently, immune checkpoint inhibitors have revolutionized cancer care by enhancing anti-tumor immunity. However, by virtue of stimulating the immune system, they can lead to immune-related adverse events (irAEs). Neurologic irAEs are uncommon but are becoming increasingly recognized and can be quite serious or even fatal. Furthermore, central nervous system (CNS) manifestations may be difficult to distinguish from CNS metastases, posing management challenges. Here, we describe a patient who developed exacerbation of sarcoidosis leading to CNS involvement following dual checkpoint blockade with nivolumab and ipilimumab for metastatic melanoma and review the relevant literature.

Nivolumab-Induced Autoimmune Encephalitis in Two Patients with Lung Adenocarcinoma.

Immune checkpoint inhibitors have improved patient survival outcomes in a variety of advanced malignancies. However, they can cause a number of immune-related adverse effects (irAEs) through lymphocyte dysregulation. Central nervous system (CNS) irAEs are rare, but as the number of indications for checkpoint inhibitors increases, there has been emergence of CNS immune-mediated disease among cancer patients. Given the relatively recent recognition of checkpoint inhibitor CNS irAEs, there is no standard treatment, and prognosis is variable. Therefore, there is a great need for further study of checkpoint inhibitor-induced CNS irAEs. Here, we present two unique cases of nivolumab-induced autoimmune encephalitis in patients with non-small cell lung cancer and review the available literature.

Currently approved and emerging oral therapies in multiple sclerosis: An update for the ophthalmologist.

Although our understanding of multiple sclerosis (MS) has grown substantially, its cause remains unknown. Nonetheless, in the past 3 decades, there have been tremendous advancements in the development of disease-modifying drugs (DMDs). In July 1993, the United States Food and Drug Administration approved the first disease-modifying drug-interferon ß- and there are currently 13 medications approved for use in relapsing MS. All the early medications are administered either as a subcutaneous or intramuscular injection, and despite the clinical efficacy and safety of these medications, many patients were hampered by the inconvenience of injections and injection-related side effects. In September 2010, the first oral DMD-fingolimod-was approved. Since then, 2 additional oral DMDs (teriflunomide and dimethyl fumarate) have been approved, and several other oral medications are being evaluated in extensive MS development programs. Because of frequent ocular involvement, ophthalmologists are often involved in the care of MS patients and therefore need to be aware of the current treatment regimens prescribed by neurologists, some of which can have significant ophthalmic adverse events. We update the current advancements in the treatment of MS and discuss the published clinical data on the efficacy and safety of the currently approved and emerging oral therapies in MS.