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.

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.

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.

Clinical approach to neuro-rheumatology.

Recognizing the neurologic manifestations of systemic rheumatologic diseases and certain isolated autoimmune neurologic diseases poses challenges to the clinician. Using a systematic approach allows the clinician to diagnose these conditions more readily and to initiate treatment more rapidly. Specific neurological syndromes frequently associated with rheumatologic or specific autoimmune conditions can suggest the diagnosis. A targeted history and examination can identify neurological and systemic clues that help to identify an underlying rheumatologic condition. Judicious use of laboratory and radiographic studies can help confirm suspected diagnoses. This article will review some of the neurological syndromes typical of rheumatologic disease and outline an approach to evaluating for unknown rheumatologic disease in this context.

Neurosarcoidosis: Pathophysiology, Diagnosis, and Treatment.

Although often regarded as a protean illness with myriad clinical and imaging manifestations, neurosarcoidosis typically presents as recognizable syndromes that can be approached in a rational, systematic fashion. Understanding of neurosarcoidosis has progressed significantly in recent years, including updated diagnostic criteria and advances in treatment. The diagnosis of neurosarcoidosis is established by the clinical syndrome, imaging and histopathological findings, and exclusion of other causes. Mounting evidence supports the use of tumor necrosis factor inhibitors as an important addition to the therapeutic armamentarium, along with glucocorticoids and steroid-sparing cytotoxic immunosuppressants. In this narrative review, we summarize recent advances in the diagnosis and treatment of neurosarcoidosis.

Single Center Experience with Isolated Spinal Cord Neurosarcoidosis.

INTRODUCTION: Isolated spinal cord neurosarcoidosis is extremely rare. The potential implications of long-term immunosuppressant therapy make correct diagnosis imperative. However, there are challenges inherent in isolated spinal cord involvement that require a multidisciplinary approach. Here we present the largest series of definite and possible isolated spinal neurosarcoidosis and discuss our institutional experience in managing this rare but morbid condition. METHODS: A retrospective review was performed to identify all neurosarcoidosis cases starting from 2002 to 2020 at our institution. Patients were screened for cases of isolated spinal neurosarcoidosis. A descriptive analysis was performed for each case. RESULTS: A total of 64 cases of neurosarcoidosis were identified. The spine was involved in 26 (40.6%) patients. Only 4 (6.3%) cases had isolated spinal cord involvement. A full medical and imaging workup was performed in determining isolated spinal cord involvement. Three patients subsequently underwent surgical biopsy, and 1 did not undergo biopsy because of patient preference. One of the patients who underwent biopsy had an initial nondiagnostic biopsy and had a repeat biopsy. Corticosteroids were employed in all cases with additional immunosuppressive agents for maintenance therapy and refractory cases. All showed radiographic improvement and were clinically stable to improved. CONCLUSION: Isolated spinal cord involvement of neurosarcoidosis is rare and can present challenges in diagnosis. A biopsy can be performed when necessary. However, a biopsy of the spinal cord carries inherent risks and may not always be possible or result in a nondiagnostic sample. In the setting of high clinical suspicion, maximal medical therapy is still employed.

Enhanced Virus Detection and Metagenomic Sequencing in Patients with Meningitis and Encephalitis.

Meningitis and encephalitis are leading causes of central nervous system (CNS) disease and often result in severe neurological compromise or death. Traditional diagnostic workflows largely rely on pathogen-specific tests, sometimes over days to weeks, whereas metagenomic next-generation sequencing (mNGS) profiles all nucleic acid in a sample. In this single-center, prospective study, 68 hospitalized patients with known (n = 44) or suspected (n = 24) CNS infections underwent mNGS from RNA and DNA to identify potential pathogens and also targeted sequencing of viruses using hybrid capture. Using a computational metagenomic classification pipeline based on KrakenUniq and BLAST, we detected pathogen nucleic acid in cerebrospinal fluid (CSF) from 22 subjects, 3 of whom had no clinical diagnosis by routine workup. Among subjects diagnosed with infection by serology and/or peripheral samples, we demonstrated the utility of mNGS to detect pathogen nucleic acid in CSF, importantly for the Ixodes scapularis tick-borne pathogens Powassan virus, Borrelia burgdorferi, and Anaplasma phagocytophilum. We also evaluated two methods to enhance the detection of viral nucleic acid, hybrid capture and methylated DNA depletion. Hybrid capture nearly universally increased viral read recovery. Although results for methylated DNA depletion were mixed, it allowed the detection of varicella-zoster virus DNA in two samples that were negative by standard mNGS. Overall, mNGS is a promising approach that can test for multiple pathogens simultaneously, with efficacy similar to that of pathogen-specific tests, and can uncover geographically relevant infectious CNS disease, such as tick-borne infections in New England. With further laboratory and computational enhancements, mNGS may become a mainstay of workup for encephalitis and meningitis. IMPORTANCE Meningitis and encephalitis are leading global causes of central nervous system (CNS) disability and mortality. Current diagnostic workflows remain inefficient, requiring costly pathogen-specific assays and sometimes invasive surgical procedures. Despite intensive diagnostic efforts, 40 to 60% of people with meningitis or encephalitis have no clear cause of CNS disease identified. As diagnostic uncertainty often leads to costly inappropriate therapies, the need for novel pathogen detection methods is paramount. Metagenomic next-generation sequencing (mNGS) offers the unique opportunity to circumvent these challenges using unbiased laboratory and computational methods. Here, we performed comprehensive mNGS from 68 prospectively enrolled patients with known (n = 44) or suspected (n = 24) CNS viral infection from a single center in New England and evaluated enhanced methods to improve the detection of CNS pathogens, including those not traditionally identified in the CNS by nucleic acid detection. Overall, our work helps elucidate how mNGS can become integrated into the diagnostic toolkit for CNS infections.

Vascular Involvement in Neurosarcoidosis: Early Experiences From Intracranial Vessel Wall Imaging.

BACKGROUND AND OBJECTIVES: Cerebrovascular manifestations in neurosarcoidosis (NS) were previously considered rare but are being increasingly recognized. We report our preliminary experience in patients with NS who underwent high-resolution vessel wall imaging (VWI). METHODS: A total of 13 consecutive patients with NS underwent VWI. Images were analyzed by 2 neuroradiologists in consensus. The assessment included segment-wise evaluation of larger- and medium-sized vessels (internal carotid artery, M1-M3 middle cerebral artery; A1-A3 anterior cerebral artery; V4 segments of vertebral arteries; basilar artery; and P1-P3 posterior cerebral artery), lenticulostriate perforator vessels, and medullary and deep cerebral veins. Cortical veins were not assessed due to flow-related artifacts. Brain biopsy findings were available in 6 cases and were also reviewed. RESULTS: Mean patient age was 54.9 years (33-71 years) with an M:F of 8:5. Mean duration between initial diagnosis and VWI study was 18 months. Overall, 9/13 (69%) patients had vascular abnormalities. Circumferential large vessel enhancement was seen in 3/13 (23%) patients, whereas perforator vessel involvement was seen in 6/13 (46%) patients. Medullary and deep vein involvement was also seen in 6/13 patients. In addition, 7/13 (54%) patients had microhemorrhages in susceptibility-weighted imaging, and 4/13 (31%) had chronic infarcts. On biopsy, 5/6 cases showed perivascular granulomas with vessel wall involvement in all 5 cases. DISCUSSION: Our preliminary findings suggest that involvement of intracranial vascular structures may be a common finding in patients with NS and should be routinely looked for. These findings appear concordant with previously reported autopsy literature and need to be validated on a larger scale.

Consensus disease definitions for neurologic immune-related adverse events of immune checkpoint inhibitors.

Expanding the US Food and Drug Administration-approved indications for immune checkpoint inhibitors in patients with cancer has resulted in therapeutic success and immune-related adverse events (irAEs). Neurologic irAEs (irAE-Ns) have an incidence of 1%-12% and a high fatality rate relative to other irAEs. Lack of standardized disease definitions and accurate phenotyping leads to syndrome misclassification and impedes development of evidence-based treatments and translational research. The objective of this study was to develop consensus guidance for an approach to irAE-Ns including disease definitions and severity grading. A working group of four neurologists drafted irAE-N consensus guidance and definitions, which were reviewed by the multidisciplinary Neuro irAE Disease Definition Panel including oncologists and irAE experts. A modified Delphi consensus process was used, with two rounds of anonymous ratings by panelists and two meetings to discuss areas of controversy. Panelists rated content for usability, appropriateness and accuracy on 9-point scales in electronic surveys and provided free text comments. Aggregated survey responses were incorporated into revised definitions. Consensus was based on numeric ratings using the RAND/University of California Los Angeles (UCLA) Appropriateness Method with prespecified definitions. 27 panelists from 15 academic medical centers voted on a total of 53 rating scales (6 general guidance, 24 central and 18 peripheral nervous system disease definition components, 3 severity criteria and 2 clinical trial adjudication statements); of these, 77% (41/53) received first round consensus. After revisions, all items received second round consensus. Consensus definitions were achieved for seven core disorders: irMeningitis, irEncephalitis, irDemyelinating disease, irVasculitis, irNeuropathy, irNeuromuscular junction disorders and irMyopathy. For each disorder, six descriptors of diagnostic components are used: disease subtype, diagnostic certainty, severity, autoantibody association, exacerbation of pre-existing disease or de novo presentation, and presence or absence of concurrent irAE(s). These disease definitions standardize irAE-N classification. Diagnostic certainty is not always directly linked to certainty to treat as an irAE-N (ie, one might treat events in the probable or possible category). Given consensus on accuracy and usability from a representative panel group, we anticipate that the definitions will be used broadly across clinical and research settings.

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.

CNS vasculopathies: Challenging mimickers of primary angiitis of the central nervous system.

Primary angiitis of the central nervous system (CNS) is an inflammatory vasculopathy affecting the brain and spinal cord. It is a difficult diagnosis to make because of its insidious nonspecific course and its multiple mimics. This review identifies and discusses some noninfectious mimickers of primary CNS angiitis, including: reversible cerebral vasoconstriction syndrome, Sneddon's Syndrome, amyloid-beta-related angiopathy, Susac Syndrome, and neurosarcoidosis. Each condition will be reviewed in terms of epidemiology, pathology, clinical presentation, diagnostic approach, and treatment. Distinguishing these mimics from the primary angiitis of the CNS is important for proper treatment and prognosis.

Association Between Immunosuppressive Treatment and Outcomes of Cerebral Amyloid Angiopathy-Related Inflammation.

Importance: Cerebral amyloid angiopathy-related inflammation (CAA-ri), a distinct subtype of cerebral amyloid angiopathy, is characterized by an autoimmune reaction to cerebrovascular ß-amyloid deposits. Outcomes and response to immunosuppressive therapy for CAA-ri are poorly understood. Objective: To identify clinical, neuroimaging, laboratory, pathologic, or treatment-related associations with outcomes after an episode of CAA-ri. Design, Setting, and Participants: A retrospective cohort study of prospectively identified individuals who presented from July 3, 1998, to November 27, 2017, with a median follow-up of 2.7 years (interquartile range, 1.0-5.5 years). The study included 48 consecutive patients with CAA-ri meeting diagnostic criteria who had at least 1 disease episode and subsequent outcome data. No patients refused or were excluded. Exposures: Prespecified candidate variables were immunosuppressive therapies, cerebrospinal fluid pleocytosis, magnetic resonance imaging findings of recent infarcts or contrast enhancement, and histopathologic evidence of vessel wall inflammation. Main Outcomes and Measures: Clinical improvement and worsening were defined by persistent changes in signs or symptoms, radiographic improvement by decreased subcortical foci of T2 hyperintensity or T1 enhancement, and radiographic worsening by increased subcortical T2 hyperintensity, T1 enhancement, or infarcts. Disease recurrence was defined as new-onset clinical symptoms associated with new imaging findings. Results: The 48 individuals in the study included 29 women and had a mean (SD) age of 68.9 (9.9) years. Results of presenting magnetic resonance imaging revealed that 10 of 29 patients with CAA-ri (34%) had T1 contrast enhancement, 30 of 32 (94%) had subcortical T2 hyperintensity (22 of 30 [73%] asymmetric), 7 of 32 (22%) had acute or subacute punctate infarcts, and 27 of 31 (87%) had microbleeds. Immunosuppressive treatments after first episodes included corticosteroids (33 [69%]), cyclophosphamide (6 [13%]), and mycophenolate (2 [4%]); 14 patients (29%) received no treatment. Clinical improvement and radiographic improvement were each more likely in individuals treated with an immunosuppressive agent than with no treatment (clinical improvement: 32 of 34 [94%] vs 7 of 14 [50%]; odds ratio, 16.0; 95% CI, 2.72-94.1; radiographic improvement: 24 of 28 [86%] vs 4 of 14 [29%]; odds ratio, 15.0; 95% CI, 3.12-72.1). Recurrence was less likely if CAA-ri was treated with any immunosuppressant agent than not (9 of 34 [26%] vs 10 of 14 [71%]; hazard ratio, 0.19; 95% CI, 0.07-0.48). When controlling for treatment, no variables were associated with outcomes aside from an association between APOE ɛ4 and radiographic improvement (odds ratio, 4.49; 95% CI, 1.11-18.2). Conclusions and Relevance: These results from a relatively large series of patients with CAA-ri support the effectiveness of immunosuppressive treatment and suggest that early treatment may both improve the initial disease course and reduce the likelihood of recurrence. These results raise the possibility that early blunting of CAA-ri and the autoimmune response may have long-term benefits for the subsequent disease course.

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.

A Consensus Guideline to Support Resident-as-Teacher Programs and Enhance the Culture of Teaching and Learning.

BACKGROUND: Methods for assessing residents as teachers are limited, and it can be difficult to discern optimal curricula for training residents as educators. A guideline may be a tool to assess resident-as-teacher programs and to help enhance a culture of teaching and learning. OBJECTIVE: We developed a consensus guideline to assess academic medical centers' resident-as-teacher programs and teaching environments. METHODS: Faculty representing 8 specialties from 5 teaching hospitals created a guideline for resident-as-teacher programs through an iterative expert consensus development process. To assess local resident-as-teacher practices, the guideline was administered as an online survey to program directors from 47 residency programs at 5 hospitals. The survey included 26 items addressing curricula, educational climate, financial support, assessment, professional development, and promotion. RESULTS: Forty-nine percent of residency programs surveyed completed the questionnaire, representing 65% of specialties (17 of 26). Respondents reported that residents were required to participate in a teaching orientation in 78% of programs (18 of 23) and were evaluated on teaching in 91% (21 of 23). There were special educational programs and teaching awards in 91% of programs (21 of 23), respectively. All programs included evaluations of faculty teaching, which were linked to faculty annual reviews in 52% of programs (12 of 23), but to faculty promotion or salary in only 22% of programs (5 of 23). CONCLUSIONS: We developed a resident-as-teacher consensus guideline that could provide a road map for program directors and institutions to think broadly about how they educate residents and fellows as teachers.

Building a neuroinfectious disease consensus curriculum.

OBJECTIVE: To delineate a comprehensive curriculum for fellowship training in neuroinfectious diseases, we conducted a modified Delphi approach to reach consensus among 11 experts in the field. METHODS: The authors invited a diverse range of experts from the American Academy of Neurology Neuro-Infectious Diseases (AAN Neuro-ID) Section to participate in a consensus process using a modified Delphi technique. RESULTS: A comprehensive list of topics was generated with 101 initial items. Through 3 rounds of voting and discussion, a curriculum with 83 items reached consensus. CONCLUSIONS: The modified Delphi technique provides an efficient and rigorous means to reach consensus on topics requiring expert opinion. The AAN Neuro-ID section provided the pool of diverse experts, the infrastructure, and the community through which to accomplish the consensus project successfully. This process could be applied to other subspecialties and sections at the AAN.

Infectious Myelopathies.

Infectious diseases are an important cause of spinal cord dysfunction. Infectious myelopathies are of growing concern given increasing global travel and migration and expanding prevention and treatment with vaccinations, antibiotics, and antiretrovirals. Clinicians must recognize these pathologies because outcomes can dramatically improve with prompt diagnosis and management. We provide a complete review of the most frequent infectious agents that can affect the spinal cord. For each pathogen we describe epidemiology, pathophysiology, anatomic location, characteristic clinical syndromes, diagnostic approach, treatment, and prognosis. The review includes spinal imaging from selected cases.

Helminthic Infections of the Central Nervous System.

PURPOSE OF REVIEW: This article discusses select helminthic parasitic infections that may affect the central nervous system and reviews the epidemiology, neurologic presentation, recommended diagnostic testing, and treatment approach to these infections. RECENT FINDINGS: Emigration from and travel to areas endemic for helminthic infections that affect the nervous system has led to increased incidence of parasitic neurologic disease in developed countries, necessitating that neurologists be familiar with the diagnostic and therapeutic approach to these diseases. Evidence is emerging on the optimal treatment for neurocysticercosis, which varies based on the form of the disease in the nervous system. SUMMARY: Parenchymal neurocysticercosis is a leading cause of acquired epilepsy worldwide, and extraparenchymal neurocysticercosis is responsible for many cases of hydrocephalus. Recognition of the different stages and locations of neurocysticercosis is essential for proper management. Similarly, schistosomiasis constitutes a major cause of myelopathy in endemic areas and requires prompt diagnosis and treatment to avoid permanent deficits.

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.