Mogamulizumab for Treatment of Human T-lymphotropic Virus Type 1-Associated Myelopathy/Tropical Spastic Paraparesis: A Single-Center US-based Series.

BACKGROUND: Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic neurological condition characterized by progressive myelopathic symptoms including spasticity, pain, weakness, and urinary symptoms, without proven treatments. Mogamulizumab (MOG) is a monoclonal antibody that binds CCR4 and leads to the clearance of HTLV-1-infected CCR4+ cells. A phase 1-2a study in Japan evaluated MOG for the treatment of HAM/TSP and reported decreases in HTLV-1 proviral load and neuroinflammatory markers, with clinical improvement in some participants. METHODS: We administered MOG 0.1 mg/kg every 8 weeks to individuals with HAM/TSP as a compassionate and palliative treatment. Patients who received MOG had (1) a positive peripheral HTLV-1 antibody, (2) progressive myelopathic symptoms, and (3) a diagnosis of HAM/TSP. RESULTS: Four female patients, ages 45-68, received MOG (range, 2-6 infusions) between 1 November 2019 and 30 November 2022. Two patients with <3 years of symptoms had milder disease, with Osame scores <4. The other 2, with >7 years of symptoms, had Osame scores >5. One patient, with 6 total treatments, received dose-reduced MOG after she developed a rash at the initial dose. The 2 patients with milder baseline disease reported symptomatic improvement and saw reductions in Osame and/or modified Ashworth scale scores during follow-up. The other 2 patients showed no improvement. All 4 developed rashes after receiving MOG-a treatment-limiting event in some cases. CONCLUSIONS: Clinical trials are needed including diverse patient populations to assess the potential role of MOG for HAM/TSP. Our findings may help inform the development of these trials.

Peripheral Neuropathies in Infectious Diseases.

Peripheral nerve disorders may be the presenting manifestation of a systemic infection, and early recognition of these syndromes is essential for prompt diagnosis and treatment. Mechanisms associated with infectious disorders of the peripheral nerve are often complex and multiple, with secondary inflammation, direct infectious invasion of nerves, and toxicities of antimicrobial medications playing a role. Here, we provide a complete review of the most common infectious pathogens that can affect the peripheral nerves.

A 44-year-old man with eye, kidney, and brain dysfunction.

Retinal vasculopathy with cerebral leukodystrophy (RVCL) is a rare, autosomal dominant condition caused by mutations of TREX1 (3-prime repair exonuclease-1). The phenotypic expressions range from isolated retinal involvement to varying degrees of retinopathy, cerebral infarction with calcium depositions, nephropathy, and hepatopathy. We report a case of RVCL caused by a novel TREX1 mutation. This patient's multisystem presentation, retinal involvement interpreted as "retinal vasculitis," and improvement of neuroimaging abnormalities with dexamethasone led to the accepted diagnosis of a rheumatologic disorder resembling Behçet disease. Clinicians should consider RVCL in any patient with retinal capillary obliterations associated with tumefactive brain lesions or nephropathy.

Recurrence of progressive multifocal leukoencephalopathy despite immune recovery in two HIV seropositive individuals.

We present two cases of recurrent progressive multifocal leukoencephalopathy (PML) in patients with long standing virally suppressed human immunodeficiency virus (HIV) and normal CD4+ T cell count who were taking stable regimens of highly active antiretroviral therapy (HAART). This has significant implications for other patients with a past history of PML, not just those with HIV but also those on medications such as natalizumab or fumarates.

Neuro-Behçet disease and autoinflammatory disorders.

Misregulation of innate immunity leads to autoinflammation. Behçet disease is an autoinflammatory condition involving recurrent attacks of inflammation in skin, eyes, joints, and even the nervous system. The etiology may involve vascular inflammation. Central nervous system involvement in neuro-Behçet disease (NBD) comes in the form of parenchymal NBD or nonparenchymal NBD. The parenchymal form has a predilection for the brainstem, diencephalon and cerebral hemispheres, and represents a meningoencephalitis thought to be related to small vessel vasculitis. Cerebral venous sinus thrombosis, arising from a vasculitic process of large veins, comprises the majority of vascular NBD cases. The rarer monogenetic autoinflammatory syndromes are characterized by periodic fever, and typically present in the pediatric population. Neurologic involvement in these syndromes typically presents in the form of an aseptic meningitis. Treatment of autoinflammatory disorders involves immune modulation with corticosteroids, disease-modifying antirheumatic medications, and increasingly antibodies targeting cytokines like tumor necrosis factor α and interleukin 1.

A case of immunotherapy-responsive autoimmune hemichorea.

INTRODUCTION: Subacute adult-acquired hemichorea is a striking presentation with a broad differential, including ischemic, metabolic, and inflammatory causes. CASE: We encountered a 74-year-old woman with rapid onset of hemichorea and associated encephalopathy. Following a thorough workup without identification of clear imaging or laboratory abnormalities, we empirically treated with IVIg. Her hemichorea dramatically improved. Due to relapses of hemichorea, she required repeat immunotherapy with IVIg or high dose steroids followed by maintenance mycophenolate. DISCUSSION: This case of seronegative autoimmune hemichorea highlights the importance of a high index of suspicion for an inflammatory etiology of chorea when other causes are ruled out and performing an immunotherapy trial.

Steroid-Responsive Parkinsonism and Encephalopathy: A Case Report.

We describe a patient who presented with rapidly progressive parkinsonism and encephalopathy and was diagnosed with seronegative autoimmune encephalitis (AE). Subacute parkinsonism as a manifestation of seronegative AE is uncommon with only a handful of similar cases published in literature. A 71-year-old man presented with severe flu like symptoms, rapidly progressive cognitive decline and was found to have parkinsonian features on examination. Initial brain magnetic resonance imaging (MRI) was unremarkable however, cerebrospinal fluid (CSF) analysis revealed a lymphocytic pleocytosis and elevated protein level. Thorough searches for neural antibodies and infectious pathogens were negative. His symptoms fluctuated initially but markedly improved within days of starting prednisone and dramatically worsened after prednisone was tapered off. His CSF pleocytosis also improved on prednisone. Relapses again resolved with resumption of prednisone. The scope of autoimmune neurology Is constantly evolving, and physicians should be aware of the diverse and heterogenous clinical presentations of autoimmune encephalitis. We aim to emphasize the importance of ruling out autoimmune encephalitis in patients presenting with acute or subacute parkinsonism. This case additionally reinforces that negative antibody tests do not exclude the diagnosis of AE.

Contrasting Cases of HIV Vasculopathy Associated Fusiform Aneurysms.

Background: Human Immunodeficiency Virus (HIV) vasculopathy encompasses the development of aneurysms, stenosis and vessel occlusions. Intracranial fusiform aneurysms in Human Immunodeficiency Virus (HIV) were originally described in children; however, HIV-associated aneurysms are increasingly recognized in adults. Purpose: We present two cases to highlight the spectrum of severity and outline instructive clinical courses. Results: Case one is a 52-year-old woman with HIV, Acquired Immunodeficiency Syndrome (AIDS)-defining progressive multifocal leukoencephalopathy (PML) and an 18 years course of cerebral aneurysms, aneurysm thrombosis and the development of right middle cerebral artery (MCA) moyamoya pattern collaterals. Case two is a 55-year-old man with AIDS-defining cerebral toxoplasmosis, complicated by IRIS and anterior and posterior circulation fusiform aneurysm formation. Conclusions: The combination of both fusiform abnormalities and Moyamoya, discussed in our first case has not been previously described. In comparison, our second case actually demonstrated improvement in vasculopathy after nine-months of antiretroviral therapy (ART) adherence.

Case Report and Clinical Reasoning: Fulminant Liver Failure and Invasive Aspergillosis Following Ocrelizumab Treatment in a 21 Year-Old Woman.

We present the case of a 21 year-old woman with newly diagnosed relapsing-remitting multiple sclerosis who is given a single dose of ocrelizumab and placed on moderate-dose steroids with subsequent development of hepatic failure who goes on to develop highly fulminant systemic and central nervous system (CNS) aspergillosis. Ocrelizumab has no documented association with aspergillus infection, and moderate-dose steroids less often lead to such fulminant disease, but liver failure is associated with often-fatal aspergillus infection. We emphasize that liver failure is an underrecognized immune dysregulated state that predisposes to bacterial and fungal infections and suggest changes in diagnostic reasoning that could be considered in patients with multiple modalities of immunosuppression.

Treatment of IgG4-related disease-associated hypertrophic pachymeningitis with intrathecal rituximab: a case report.

IgG4-related disease-associated hypertrophic pachymeningitis (IgG4RD-HP) is a fibroinflammatory autoimmune disorder in which diagnosis is difficult without biopsy. Guidance on management of disease refractory to glucocorticoids and intravenous rituximab is limited. We present the case of a 68-year-old woman with IgG4RD-HP who developed sensorineural hearing loss with associated bulky basilar pachymeningeal enhancement. Her cerebrospinal fluid was inflammatory and had an elevated IgG4 concentration, strongly suggestive of IgG4RD-HP. Biopsy of involved meninges was not possible due to surgical risk. Over years she developed bilateral optic neuropathies and hydrocephalus, requiring intravenous rituximab and ventriculoperitoneal shunt. Her disease was refractory to glucocorticoids. Despite maintenance intravenous rituximab, she developed slowly progressive symptoms of intracranial hypertension and hydrocephalus with persistently inflammatory spinal fluid. Switching to intrathecal rituximab therapy led to dramatic improvement in gait and headache and reduced pachymeningeal bulk and metabolic activity. In patients with IgG4RD-HP refractory to glucocorticoids and intravenous rituximab, intrathecal rituximab may be an efficacious therapy.

Autoimmune and Paraneoplastic Chorea: A Review of the Literature.

Autoimmune chorea syndromes represent a vast array of paraneoplastic, parainfectious and idiopathic disorders. It is increasingly apparent that familiarity with these disorders is critically important, as they may be treatable or may be part of a syndrome requiring further work-up and monitoring. These disorders are mediated by an aberrant immunologic attack with resultant neuronal dysfunction, manifesting as chorea. These conditions are typically accompanied by other neurologic or systemic manifestations. In this review we outline the clinical features, epidemiologic factors, and delineate the specific antibodies associated with each of these autoimmune mediated disorders. We highlight up to date information regarding this heterogeneous group of disorders, including a discussion of parainfectious Sydenham's chorea; paraneoplastic syndromes associated with CRMP-5 (collapsin response mediated protein-5/CV2) and ANNA-1 (antineuronal nuclear antibody / Hu) antibodies, in addition to neuronal antibody-associated disorders including anti-NMDAR, LGI1 (leucine-rich glioma inactivated-1) and CASPR2 (contactin associated protein-2). We discuss the more recently described entities of IgLON5, which has evidence of both immunologic and degenerative pathophysiology, in addition to PDE-10A antibody-associated chorea. We also outline chorea secondary to systemic diseases including Systemic Lupus Erythematosus (SLE) and Primary Antiphospholipid Syndrome (PAPS). We provide a framework for diagnosis and treatment.

Spinomedullary Weston Hurst Syndrome After COVID-19 and Influenza Co-Infection: A Case Report.

The neurological complications of coronavirus disease 2019 (SARS-CoV-2, COVID-19) have so far included a range of para- and post-infectious neuroinflammatory syndromes inclusive of all components of the neuraxis and peripheral neuromuscular system. In comparison to the para-infectious manifestations of anosmia, ageusia, encephalopathy, and encephalitis, cases of post-infectious ADEM have rarely been reported and have most commonly affected the supratentorial component with or without spinal cord involvement. In this report, we describe a case of isolated involvement of the cervicothoracic spinal cord and medulla, occurring in association with microhemorrhages and hemosiderin deposition in the medulla, that presented fulminantly and required aggressive immunotherapy to control the inflammatory attack. We compare and contrast this case against prior reports of acute hemorrhagic leukoencephalitis (Weston Hurst syndrome) and review the atypical features of neuroinflammation reported to occur following COVID-19 infection.

Case Report of Spinal Cord Involvement in Susac Syndrome Masquerading as a Multiple Sclerosis Mimic.

We present a unique case of a 59-year-old woman with atypical Susac syndrome and prominent involvement of the spinal cord. She initially presented with progressive headaches, lower extremity weakness and hearing loss. Her MRI brain showed multiple enhancing lesions and her MRI spine showed a T8 enhancing lesion as well as a C2 cord infarct. She was treated with IV methylprednisolone with initial stabilization. However, she developed worsening encephalopathy and lower extremity weakness. Her repeat MRI brain showed new bilateral enhancing lesions and subacute infarcts. Given the increased burden of new lesions, she underwent a brain biopsy, which showed perivascular chronic inflammation within a small vessel distribution. Additionally, fluorescein angiography revealed bilateral branch retinal arterial occlusion (BRAO) and an audiogram demonstrated bilateral sensorineural hearing loss. She was diagnosed with Susac syndrome and treated with IV cyclophosphamide with improvement in her clinical exam. Spinal cord involvement is extremely rare for Susac syndrome, which commonly manifests as the classic triad of encephalopathy, BRAO and hearing loss. Her presentation with myelopathy highlights the importance of considering atypical presentations of well-established syndromes for optimal diagnosis and management.

Ischemic stroke in neurosarcoidosis: A retrospective cohort analysis.

BACKGROUND: Cerebrovascular disease is rarely reported in neurosarcoidosis and constitutes one of its least well-described forms, though recognition for it has grown in the last decade with recent studies estimating a higher frequency of occurrence than previously known. METHODS: Patients with ischemic stroke were included if the mechanism was directly attributable to sarcoidosis of the CNS. Patients were excluded if an alternative stroke etiology was of equal or higher likelihood than CNS sarcoidosis. RESULTS: Neurologic disease was the initial presenting manifestation of sarcoidosis in 8/11 (72.7%), and ischemic stroke was an inaugural manifestation of sarcoidosis in 4/11 (36.4%). Small vessel disease was the predominant ischemia subtype (10/11, 90.9%) with pontine perforating vessels (6/11, 54.5%) and lenticulostriate arteries (3/11, 27.3%) being the vasculature most often affected. Vessels with a more rostral supratentorial distribution were uncommonly affected. Common neuroinflammatory accompaniments included leptomeningitis (10/11, 90.9%) and cranial nerve disease (3/11, 27.3%). Recurrent strokes occurred in 8/11 (72.7%), and recurrent neuroinflammation occurred in 7/11 (63.6%). Antiplatelet drugs were used in 6/11 (54.5%) patients. Most (10/11, 90.9%) required at least two lines of immunosuppression to achieve inflammatory disease remission in this context; infliximab was the most successfully employed immunosuppressant (7/8 treatment courses, 87.5%). Recurrent strokes occurred in 8/11 (72.7%) patients, and a second inflammatory attack occurred in 7/11 (63.6%) patients. The presenting median modified Rankin Scale score of 4.0 improved to 2.0 over a median period of follow-up of 52.0 months. CONCLUSION: Ischemic strokes in neurosarcoidosis occur in a caudal-to-rostral distribution, tend to affect small caliber blood vessels that lack collateral blood flow, and typically associate with inflammatory leptomeningeal disease. The risk for relapse in the forms of stroke or neuroinflammation are high in this neurosarcoidosis phenotype.

Adalimumab for CNS sarcoidosis: single-center experience and literature review.

BACKGROUND: Tumor necrosis factor (TNF) alpha is critical in the development of granulomas and multiple recent reports have highlighted the role of infliximab, an infused TNF alpha inhibitor, in the treatment of neurosarcoidosis. As a self-injected TNF alpha inhibitor, adalimumab has certain advantages over infused medications, including greater patient freedom and autonomy. Experience with adalimumab is not well reported in the literature. OBJECTIVE: To report clinical experience with adalimumab in the treatment of central nervous system (CNS) sarcoidosis by combining observations in our center with those that have been reported in the literature. METHODS: Patients were identified from the Mass General Brigham Research Patient Data Registry and in the literature by searching PubMed. Patients with CNS manifestations of sarcoidosis treated with adalimumab were included for retrospective review and analyzed for baseline characteristics, treatment indications, outcomes, and adverse effects. RESULTS: Adalimumab was commonly started after failure of or intolerance to infliximab and methotrexate. Of those with adequate follow-up, 5/10 ultimately improved, remission was maintained in 3/10, and 2/10 with active disease remained stable without further worsening. One patient suffered a relapse, likely multifactorial in etiology, but has remained relapse free on adalimumab for 10 months subsequently. Three patients ultimately discontinued adalimumab. CONCLUSIONS: Preliminary evidence suggests that adalimumab may be a reasonable therapeutic option for patients with neurosarcoidosis affecting the CNS, including those with medically refractory disease.