Septin-5 and -7-IgGs: Neurologic, Serologic, and Pathophysiologic Characteristics.

BACKGROUND AND OBJECTIVES: We sought to determine clinical significance of neuronal septin autoimmunity and evaluate for potential IgG effects. METHODS: Septin-IgGs were detected by indirect immunofluorescence assays (IFAs; mouse tissue and cell based) or Western blot. IgG binding to (and internalization of) extracellular septin epitopes were evaluated for by live rat hippocampal neuron assay. The impact of purified patient IgGs on murine cortical neuron function was determined by recording extracellular field potentials in a multielectrode array platform. RESULTS: Septin-IgGs were identified in 23 patients. All 8 patients with septin-5-IgG detected had cerebellar ataxia, and 7 had prominent eye movement disorders. One of 2 patients with co-existing septin-7-IgG had additional psychiatric phenotype (apathy, emotional blunting, and poor insight). Fifteen patients had septin-7 autoimmunity, without septin-5-IgG detected. Disorders included encephalopathy (11; 2 patients with accompanying myelopathy, and 2 were relapsing), myelopathy (3), and episodic ataxia (1). Psychiatric symptoms (≥1 of agitation, apathy, catatonia, disorganized thinking, and paranoia) were prominent in 6 of 11 patients with encephalopathic symptoms. Eight of 10 patients with data available (from 23 total) improved after immunotherapy, and a further 2 patients improved spontaneously. Staining of plasma membranes of live hippocampal neurons produced by patient IgGs (subclasses 1 and 2) colocalized with pre- and post-synaptic markers. Decreased spiking and bursting behavior in mixed cultures of murine glutamatergic and GABAergic cortical neurons produced by patient IgGs were attributable to neither antigenic crosslinking and internalization nor complement activation. INTERPRETATION: Septin-IgGs are predictive of distinct treatment-responsive autoimmune central nervous system (CNS) disorders. Live neuron binding and induced electrophysiologic effects by patient IgGs may support septin-specific pathophysiology. ANN NEUROL 2022;92:1090-1101.

Immune-Mediated Myelopathies: A Review of Etiologies, Diagnostic Approach, and Therapeutic Management.

Myelopathy is a broad term used to describe a heterogeneous group of disorders that affects the spinal cord; the focus of this article will be a subgroup of these disorders with an autoimmune and inflammatory-based pathology. Symptoms typically develop over hours or days and then worsen over a matter of days to weeks, but sometimes can have a more insidious or subacute presentation, which can make the diagnosis more puzzling. Despite relatively low incidence rates, almost a third of affected patients are left with severely disabling symptoms. Prompt recognition of the underlying etiology is essential so that a specific targeted therapy can be implemented for optimal outcomes. The authors discuss a systematic approach to immune-mediated myelopathies, with a focus on the unique characteristics of each that may aid in diagnosis.

Diagnostic Testing in Central Nervous System Infection.

Patients with central nervous system (CNS) infection experience very high levels of morbidity and mortality, in part because of the many challenges inherent to the diagnosis of CNS infection and identification of a causative pathogen. The clinical presentation of CNS infection is nonspecific, so clinicians must often order and interpret many diagnostic tests in parallel. This can be a daunting task given the large number of potential pathogens and the availability of different testing modalities. Here, we review traditional diagnostic techniques including Gram stain and culture, serology, and polymerase chain reaction (PCR). We highlight which of these are recommended for the pathogens most commonly tested among U.S. patients with suspected CNS infection. Finally, we describe the newer broad-range diagnostic approaches, multiplex PCR and metagenomic sequencing, which are increasingly used in clinical practice.

Rapid Detection of Powassan Virus in a Patient With Encephalitis by Metagenomic Sequencing.

We describe a patient with severe and progressive encephalitis of unknown etiology. We performed rapid metagenomic sequencing from cerebrospinal fluid and identified Powassan virus, an emerging tick-borne flavivirus that has been increasingly detected in the United States.

Bedside Teaching in Neurology.

The patient's bedside offers an ideal venue for teaching the art of clinical neurology and modeling humanism and professionalism. However, bedside teaching is underutilized in modern medical education, despite evidence that learners desire more. Logistical challenges and lack of teacher confidence are commonly cited reasons, but both can be mitigated with a deliberate approach and sufficient experience. Well-executed bedside teaching can provide lasting lessons for learners while enhancing the patient experience, without affecting the efficiency or quality care delivery. In this review, we discuss the theory and evidence to support the use of bedside teaching, and subsequently delineate a framework for designing and executing effective bedside teaching in neurology.

HSV encephalitis-induced anti-NMDAR encephalitis in a 67-year-old woman: report of a case and review of the literature.

Herpes simplex virus (HSV) encephalitis can induce an autoimmune encephalitis mediated by autoantibodies against the N-methyl-D-aspartate receptor (NMDAR). Post-HSV NMDAR encephalitis and de novo NMDAR encephalitis have been more commonly described in children and young adults. We describe the case of a 67-year-old woman with post-HSV NMDAR encephalitis and review the relevant literature. Clinical, serological, neurophysiological, and imaging evaluations were undertaken in the evaluation of this patient. A literature review was performed. Nearly 2 months after a typical course of HSV encephalitis confirmed by HSV polymerase chain reaction studies from the spinal fluid and treated with intravenous acyclovir, a 67-year-old woman suffered neurological deterioration. There was no evidence of active HSV infection, but NMDAR antibodies were found in her serum and spinal fluid. The patient improved after initiation of immunosuppressive therapy. All patients who experience new or recurrent neurological symptoms following recovery from HSV encephalitis should be evaluated for post-infectious autoimmune encephalitis, including NMDAR encephalitis.

The Clinical Approach to Encephalitis.

Encephalitis has various etiologies, but viral infections and autoimmune disorders are the most commonly identified. Clinical signs, geographical clues, and diagnostic testing-including cerebrospinal fluid abnormalities and magnetic resonance imaging abnormalities-can be helpful in identifying the cause. Certain forms of encephalitis have specific treatments; hence, establishing a diagnosis rapidly and accurately is crucial. Here, we describe the clinical approach to diagnosing several common etiologies of encephalitis as well as treatment strategies.

Clinical approach to neurorheumatology.

Rheumatologic conditions are an important cause of both central and peripheral nervous system pathology. A thorough evaluation for an underlying rheumatologic process is an important component of a patient presenting with neurologic symptoms. In this review, the authors present an approach to evaluating rheumatologic conditions, focusing primarily on the history and physical examination. They focus on the most specific signs and symptoms that may help the neurologist assess whether an underlying rheumatologic process is present. In addition, they discuss the interpretation of such findings with an eye toward narrowing the differential diagnosis and directing further testing.

Neurosarcoidosis.

Sarcoidosis is an idiopathic multisystem granulomatous disorder. Neurologic manifestations in sarcoidosis are varied and making a diagnosis of neurosarcoidosis can be difficult as it mimics various other neurologic diseases. Knowledge of the syndromes associated with neurosarcoidosis can help guide the diagnostic evaluation. Definitive diagnosis requires neurologic tissue evidence of noncaseating granuloma, but in practice probable diagnosis is often made through nonneurologic biopsy and a characteristic syndrome and imaging. Treatment remains empiric, but new advances in immunologic therapy hold promise for effective and less-toxic regimens.

A neurologist's guide to safe use of immunomodulatory therapies.

Increased understanding of the pathogenesis of immune-mediated neurologic conditions with concomitant development of new therapeutic agents modulating various aspects of the immune system has resulted in the use of innovative therapies in the treatment of these diseases. These novel immunomodulatory therapeutic regimens also augment the potential for complications, including severe adverse effects.In this review, the authors address practical issues regarding management of patients with neuroimmunological conditions treated with immunomodulatory therapies, including glucocorticoids, methotrexate, azathioprine, mycophenolate, cyclophosphamide, rituximab, tumor necrosis factor-α inhibitors, and intravenous immunoglobulins. Particular focus is placed on their infectious and noninfectious adverse effects, contraindications, safety monitoring, risk surveillance, and preventive strategies in clinical practice.

Clinical aspects of headache in HIV.

BACKGROUND: Headaches are commonly seen in those patients with human immunodeficiency virus (HIV) and are the most common form of pain reported among HIV patients. There have been relatively few studies attempting to determine the rates and phenotypes of the headaches that occur in patients with HIV. DISCUSSION: Patients with HIV are susceptible to a much broader array of secondary headache causes, sometimes with atypical manifestations due to a dampened inflammatory response. The investigation of a headache in the HIV patient should be thorough and focused on making sure that secondary and HIV-specific causes are either ruled out or treated if present. CONCLUSION: An effective treatment plan should incorporate the use of appropriate pharmacological agents along with the integration of non-pharmacological therapies, such as relaxation and lifestyle regulation. When treating for headaches in patients with HIV, it is important to keep in mind comorbidities and other medications, especially combination antiretroviral therapy. For those with complicated headache histories, referral to a specialized headache center may be appropriate.

Pathophysiological mechanisms of headache in patients with HIV.

BACKGROUND: The pathophysiology of human immunodeficiency virus (HIV) is complex. The etiology of headache in the HIV population is often multifactorial, and attributing causality to specific pathophysiological mechanisms is challenging. Headaches can occur any time during the infection and may be primary (as in non-HIV-infected patients) or secondary (either from HIV directly or due to opportunistic disease). DISCUSSION: Direct HIV related headaches are due to the underlying viral pathophysiology. For example, acute meningitis can be seen during HIV-1 seroconversion. Headaches can occur during symptomatic HIV and also after an AIDS-defining illness. Late-stage HIV headache can occur without any pleocytosis. A correlation between viral load and neurological symptoms including headache has been suggested. There may be similar mechanisms involving migraine, tension-type headache, and HIV infection. CONCLUSION: Secondary HIV headaches can be related to opportunistic infections, malignancy, medications used to treat HIV, and immune restoration inflammatory syndrome.

Symmetric leukoencephalopathy associated with systemic lupus erythematosus: A systematic review of a distinctive neurorheumatologic syndrome.

BACKGROUND: A symmetric leukoencephalopathy can occur in the context of systemic lupus erythematosus (SLE), often as a first manifestation of underlying rheumatologic disease. Recognition of this distinctive syndrome can prompt investigation for SLE when undiagnosed, or prompt treatment initiation when the diagnosis is already known. Earlier recognition of this syndrome could lead to more effective treatment of the disease. METHODS: Clinical, laboratory, and radiographic features of three patients were described from an academic medical center in the United States with treatment dates between 2015 and 2022. A systematic review of literature from 1991 to 2023 yielded data for an additional 23 patients. RESULTS: Twenty-six total patients with symmetric leukoencephalopathy were included in this study. The median age of the patients was 37 years (range 10-69), 22 patients (85 %) were female, and 4 (15 %) were male. Fourteen of 26 patients (54 %) had this as the first clinical manifestation of SLE. Contrast enhancement was present on MRI brain in 3/26 (88 %) patients. Twenty patients (77 %) were treated with pulse-dose steroids, and all but one patient received some immunomodulatory therapy. Seven patients (27 %) progressed to death. No meaningful predictive differences were found between patients who survived and those who did not. CONCLUSIONS: In this case series and literature review patients developed symmetric leukoencephalopathy in systemic lupus erythematosus most often as the first clinical manifestation of SLE. Clinicians should consider this syndrome in any patient with acute onset of symmetric leukoencephalopathy on brain magnetic resonance imaging.

Imaging of Central Nervous System Autoimmune, Paraneoplastic, and Neuro-rheumatologic Disorders.

OBJECTIVE: This article provides an overview of the imaging modalities used in the evaluation of central nervous system (CNS) autoimmune, paraneoplastic, and neuro-rheumatologic disorders. An approach is outlined for interpreting imaging findings in this context, synthesizing a differential diagnosis based on certain imaging patterns, and choosing further imaging for specific diseases. LATEST DEVELOPMENTS: The rapid discovery of new neuronal and glial autoantibodies has revolutionized the autoimmune neurology field and has elucidated imaging patterns characteristic of certain antibody-associated diseases. Many CNS inflammatory diseases, however, lack a definitive biomarker. Clinicians should recognize neuroimaging patterns suggestive of inflammatory disorders, as well as the limitations of imaging. CT, MRI, and positron emission tomography (PET) modalities all play a role in diagnosing autoimmune, paraneoplastic, and neuro-rheumatologic disorders. Additional imaging modalities such as conventional angiography and ultrasonography can be helpful for further evaluation in select situations. ESSENTIAL POINTS: Knowledge of imaging modalities, both structural and functional, is critical in identifying CNS inflammatory diseases quickly and can help avoid invasive testing such as brain biopsy in certain clinical scenarios. Recognizing imaging patterns suggestive of CNS inflammatory diseases can also facilitate the early initiation of appropriate treatments to diminish morbidity and future disability.

Neurologic Complications of COVID-19.

OBJECTIVE: This article describes the spectrum of neurologic complications occurring in acute or postacute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as well as the neurologic risks and benefits of vaccination against SARS-CoV-2. LATEST DEVELOPMENTS: Early in the COVID-19 pandemic, reports of neurologic complications of COVID-19 began to surface. A variety of neurologic conditions have since been reported in association with COVID-19. Understanding of the underlying mechanism of COVID-19 neurologic involvement continues to evolve; however, the evidence seems to suggest that aberrant inflammatory responses may play a role. In addition to neurologic symptoms in acute COVID-19, neurologic post-COVID-19 conditions are increasingly recognized. The development of COVID-19 vaccines has been essential in preventing the spread of COVID-19. With increasing numbers of vaccine doses administered, various neurologic adverse events have been reported. ESSENTIAL POINTS: Neurologists must be aware of the potential acute, postacute, and vaccine-associated neurologic complications associated with COVID-19 and be poised to serve as integral members of multidisciplinary care teams for patients with COVID-19-related conditions.

Palato-Pharyngo-Laryngeal Rhythmic Myoclonus in Neuro-Behcet Syndrome: A Case Report.

OBJECTIVE: Behcet's syndrome (BS) is a chronic, relapsing multisystemic inflammatory perivasculitis and can affect any tissue, including the nervous system. Neuro-Behcet's syndrome (NBS) most commonly affects the CNS parenchyma and presents with a subacute brainstem syndrome that includes cranial neuropathies. Here we describe a rare case of palato-pharyngo-laryngeal myoclonus as a manifestation of NBS and discuss it from a laryngology perspective. METHODS: Case report at tertiary care center. Informed consent was obtained from patient. IRB approved as non-human subjects research. RESULTS: A 52-year-old male presented with a progressive history of ataxia, fatigue, apathy, dysphagia, depressed mood, dizziness, poor appetite, subjective fever and recurrent orogenital lesions. He was diagnosed with NBS and treated with methylprednisolone, followed by infliximab and methotrexate. Despite treatment, his severe spastic dysarthria, dysphagia, and aspiration worsened over the next few months, necessitating a gastrotomy tube. With concern for laryngospasm, he was referred to otolaryngology and found to have synchronous and symmetric palatal, pharyngeal, and laryngeal rhythmic myoclonus bilaterally at a frequency of 2 Hz with inappropriate vocal cord closure. Treatment with baclofen and a scopolamine patch improved his breathing and reduced choking events. CONCLUSIONS: Palato-pharyngo-laryngeal rhythmic myoclonus can be a presentation of brainstem NBS in the otolaryngology clinic. We theorize perivascular disease in NBS results in a brainstem lesion in the denato-rubro-olivary tract, which results in hypertrophic olivary degeneration and subsequent activation of the inferior olives oscillatory activity, causing palato-pharyngo-laryngeal rhythmic myoclonus. Common symptoms include significant dysarthria, dysphonia, and dysphagia with concern for obstructive sleep apnea and airway compromise. Treatments include pharmacologic therapy, laryngeal botox, and tracheostomy in cases of significant airway compromise.