Isolated Lymphomatoid Granulomatosis of the Central Nervous System Mimicking Trigeminal Neuropathy, Bell's Palsy, and Glioblastoma in an Epstein-Barr-Negative Immunocompetent Host: A Case Report.

Lymphomatoid granulomatosis is an Epstein-Barr virus-associated lymphoproliferative B-cell neoplasm that typically involves multiple organ systems. This disease is exceedingly rare when confined to the central nervous system (CNS), usually presenting as a mass lesion or diffuse disease, with no existing standard of care. We present the case of a 67-year-old patient who had a unique and insidious course of isolated CNS lymphomatoid granulomatosis. The disease first presented with cranial neuropathies involving the trigeminal and facial nerves that were responsive to steroids both clinically and radiographically. Two years later, the disease manifested as a parietal mass mimicking high-grade glioma that caused homonymous hemianopsia. The patient underwent craniotomy for resection and was treated with rituximab after surgery. The patient has achieved progression-free survival more than three years after the surgery. Surgical debulking and post-procedural rituximab resulted in favorable survival in a case of isolated CNS lymphomatoid granulomatosis. An intracranial mass preceded by steroid-responsive cranial neuropathies should raise suspicion for lymphoproliferative disorder.

Severe Neuroinvasive West Nile Virus in Association With Anti-CD20 Monotherapy for Multiple Sclerosis.

OBJECTIVES: The objective of this study was to report on the development of neuroinvasive West Nile virus (WNV) infection in the context of anti-CD20 monotherapy for multiple sclerosis (MS). METHODS: This is a case series study. RESULTS: In 2021-2022, we observed 4 cases of neuroinvasive WNV infection in our patient population of 2009 patients with MS on ocrelizumab, compared with a total of 46 cases of neuroinvasive WNV infection reported in Pennsylvania and 40 in New Jersey. Odds were 258 times that of the general population (95% confidence interval 97-691), χ2 p < 0.0001). All were women aged 41-61 years with variable disease duration, level of disability, and duration of anti-CD20 therapy. All presented in summer/early fall with fever, headache, and encephalopathy consistent with meningoencephalitis. Three patients had acute cerebellitis. Two had anterior nerve root involvement progressing to quadriparesis, and 1 developed refractory nonconvulsive status epilepticus. All required intubation and experienced significant morbidity. All had CSF pleocytosis. Two patients were WNV IgM positive in both the serum and CSF, 1 patient had positive serum IgM and CSF metagenomic next-generation sequencing (mNGS), while 1 had positive CSF mNGS with negative serum and CSF antibodies. DISCUSSION: Neuroinvasive WNV infection can develop with anti-CD20 monotherapy in the absence of additional immunosuppression. WNV serologies may be negative in the setting of anti-CD20 treatment; in the appropriate clinical context, one should consider direct detection methods such as PCR or mNGS-based testing.

Early versus delayed treatment with glatiramer acetate: Analysis of up to 27 years of continuous follow-up in a US open-label extension study.

BACKGROUND: Glatiramer acetate (GA) is US-approved for relapsing multiple sclerosis. OBJECTIVES: To describe GA long-term clinical profile. To compare effectiveness of early start (ES) versus delayed start (DS; up to 3 years) with GA. METHODS: Phase 3 trial participants entered a randomized placebo-controlled period then an open-label extension (OLE) with GA. RESULTS: Overall, 208 out of 251 (82.9%) randomized participants entered the OLE; 24 out of 101 (23.8%, ES) and 28 out of 107 (26.2%, DS) participants completed the OLE. Median GA treatment was 9.8 (0.1-26.3) years. Annualized change in Expanded Disability Status Scale (EDSS) score was lower with ES versus DS (p = 0.0858: full study; p = 0.002; Year 5). Participants with improved/stable EDSS was consistently higher with ES versus DS: 40.3% versus 31.6% (p = 0.1590; full study); 70.8% versus 55.6% (p = 0.015; Year 5). ES prolonged time-to-6-month confirmed disease worsening (CDW) versus DS (9.8 vs 6.7 years), time-to-12-month CDW (18.9 vs 11.6 years), and significantly reduced time-to-second-6-month CDW (p = 0.0441). No new safety concerns arose. CONCLUSION: GA long-term treatment maintained clinical benefit with a similar safety profile to phase 3 results; a key limitation was that only 25% of participants completed the OLE. Early initiation of GA had sustained benefits versus delayed treatment.

Central Nervous System Infections in Immunocompromised Patients.

PURPOSE OF REVIEW: This article reviews current epidemiologic trends, clinical presentations, and diagnostic strategies for central nervous system (CNS) infections in human immunodeficiency virus-negative (HIV) patients immunocompromised by their underlying disease or by receipt of immunosuppressive or immunomodulating therapies. Three patient groups are considered: (1) cancer patients; (2) hematopoietic or solid organ transplantation recipients; and (3) patients with autoimmune or inflammatory conditions requiring therapies that alter the host immune response. RECENT FINDINGS: Clinical presentations, associated neuroimaging, and cerebrospinal fluid (CSF) abnormalities differ between immunocompromised and immunocompetent patients. Infections can trigger the emergence of neurotropic antibodies or inflammatory conditions due to treatment with cancer immunotherapies. Unbiased metagenomic assays to identify obscure pathogens help clinicians navigate the increasing range of conditions affecting the growing population of patients with altered immunity. Awareness of clinical presentations and disease and drug-specific risks is important for early diagnosis and intervention in these often life-threatening infections and their noninfectious mimes.

Neoplastic Myelopathies.

PURPOSE OF REVIEW: This article reviews the current classification system of primary spinal cord tumors and explores evolving diagnostic and therapeutic strategies for both primary tumors and metastatic tumors to various compartments of the spinal cord. RECENT FINDINGS: The 2016 World Health Organization classification system allows for more precise prognostication of and therapy for spinal cord tumors and has identified new entities, such as the diffuse midline glioma, H3 K27M mutant. Whole-exome sequencing reveals that the genetic background of primary glial spinal cord neoplasms differs from that of their intracranial histologic counterparts in ways that can potentially influence therapy. Targeted and immune checkpoint therapies have improved survival for patients with melanoma and lung cancer and have simultaneously produced novel complications by enhancing radiation toxicity in some cases and by facilitating the emergence of novel autoimmune and paraneoplastic syndromes involving the spinal cord, such as neuromyelitis optica spectrum disorder and syndromes associated with anti-Hu and collapsin response mediator protein-5 (CRMP-5) antibodies. These conditions must be distinguished from tumor or infection. Epidural spinal cord compression treatment paradigms have changed with the advent of robotic surgery and advances in radiation therapy. SUMMARY: Neoplastic myelopathies subsume a wide spectrum of pathologies. Neoplastic cord involvement may be primary or secondary and may be approached diagnostically by the particular spinal cord compartment localization. Primary spinal cord tumors account for only 2% to 4% of primary central nervous system tumors, ranging from low-grade glial neoplasms to malignant tumors. Metastatic malignancy to the epidural or leptomeningeal spaces is more common than primary cord tumors. Differential diagnoses arising in the course of evaluation for cord tumors include myelopathies related to radiation or chemotherapy and paraneoplastic syndromes, all of which are sources of significant morbidity. Knowledge of genetic syndromes and the biologic behavior of diverse histologies together with selective application of surgery, radiation, and targeted therapies can facilitate diagnosis, minimize surgical morbidity, and prolong quality of life.

Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR): 2020 Guidelines for the Prevention, Diagnosis and Treatment of Lyme Disease.

This evidence-based clinical practice guideline for the prevention, diagnosis, and treatment of Lyme disease was developed by a multidisciplinary panel representing the Infectious Diseases Society of America (IDSA), the American Academy of Neurology (AAN), and the American College of Rheumatology (ACR). The scope of this guideline includes prevention of Lyme disease, and the diagnosis and treatment of Lyme disease presenting as erythema migrans, Lyme disease complicated by neurologic, cardiac, and rheumatologic manifestations, Eurasian manifestations of Lyme disease, and Lyme disease complicated by coinfection with other tick-borne pathogens. This guideline does not include comprehensive recommendations for babesiosis and tick-borne rickettsial infections, which are published in separate guidelines. The target audience for this guideline includes primary care physicians and specialists caring for this condition such as infectious diseases specialists, emergency physicians, internists, pediatricians, family physicians, neurologists, rheumatologists, cardiologists and dermatologists in North America.

Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR): 2020 Guidelines for the Prevention, Diagnosis and Treatment of Lyme Disease.

This evidence-based clinical practice guideline for the prevention, diagnosis, and treatment of Lyme disease was developed by a multidisciplinary panel representing the Infectious Diseases Society of America (IDSA), the American Academy of Neurology (AAN), and the American College of Rheumatology (ACR). The scope of this guideline includes prevention of Lyme disease, and the diagnosis and treatment of Lyme disease presenting as erythema migrans, Lyme disease complicated by neurologic, cardiac, and rheumatologic manifestations, Eurasian manifestations of Lyme disease, and Lyme disease complicated by coinfection with other tick-borne pathogens. This guideline does not include comprehensive recommendations for babesiosis and tick-borne rickettsial infections, which are published in separate guidelines. The target audience for this guideline includes primary care physicians and specialists caring for this condition such as infectious diseases specialists, emergency physicians, internists, pediatricians, family physicians, neurologists, rheumatologists, cardiologists and dermatologists in North America.

Clinical Practice Guidelines by the Infectious Diseases Society of America, American Academy of Neurology, and American College of Rheumatology: 2020 Guidelines for the Prevention, Diagnosis, and Treatment of Lyme Disease.

This evidence-based clinical practice guideline for the prevention, diagnosis, and treatment of Lyme disease was developed by a multidisciplinary panel representing the Infectious Diseases Society of America (IDSA), the American Academy of Neurology (AAN), and the American College of Rheumatology (ACR). The scope of this guideline includes prevention of Lyme disease, and the diagnosis and treatment of Lyme disease presenting as erythema migrans, Lyme disease complicated by neurologic, cardiac, and rheumatologic manifestations, Eurasian manifestations of Lyme disease, and Lyme disease complicated by coinfection with other tick-borne pathogens. This guideline does not include comprehensive recommendations for babesiosis and tick-borne rickettsial infections, which are published in separate guidelines. The target audience for this guideline includes primary care physicians and specialists caring for this condition such as infectious diseases specialists, emergency physicians, internists, pediatricians, family physicians, neurologists, rheumatologists, cardiologists and dermatologists in North America.

A case series of PD-1 inhibitor-associated paraneoplastic neurologic syndromes.

Immune checkpoint inhibitors (ICIs) are highly efficacious for treating many solid tumor types. Because of their immune-activating mechanism of action, ICIs can trigger various immune-mediated toxicities. We present three cases: i) a woman with anti-Ri brainstem encephalitis; ii) a man with anti-Hu sensory neuronopathy; and iii) a woman with suspected combined anti-Hu and anti-NMDA paraneoplastic syndromes associated with the initiation of the ICIs pembrolizumab and nivolumab. These cases suggest that ICIs can induce both humoral and cell-mediated paraneoplastic neurologic syndromes. Identifying biomarkers that predict risk of developing ICI-associated paraneoplastic syndromes and the development of efficacious treatment strategies for neurologic ICI-toxicities are critical unmet needs.

Central Nervous System Infections Complicating Immunosuppression and Transplantation.

PURPOSE OF REVIEW: This article reviews infections associated with cancer treatments and immunosuppressive/immunomodulatory therapies used in both neoplastic and non-neoplastic conditions, including hematopoietic cell transplantation and solid organ transplantation. It provides a clinical approach to the most commonly affected patient groups based on clinicoanatomic presentation and disease-specific risks resulting from immune deficits and drugs received. RECENT FINDINGS: The clinical presentations, associated neuroimaging findings, and CSF abnormalities of patients with central nervous system infections who are immunocompromised may differ from those of patients with central nervous system infections who are immunocompetent and may be confused with noninfectious processes. Triggering of brain autoimmunity with emergence of neurotropic antibodies has emerged as a recognized parainfectious complication. New unbiased metagenomic assays to identify obscure pathogens help clinicians navigate the increasing range of conditions affecting the growing population of patients with altered immunity. SUMMARY: Despite evidence-based prophylactic regimens and organism-specific antimicrobials, central nervous system infections continue to cause significant morbidity and mortality in an increasing range of patients who are immunocompromised by their conditions and therapies. Multiple new drugs put patients at risk for progressive multifocal leukoencephalopathy, which has numerous imaging and clinical manifestations; patients at risk include those with multiple sclerosis, for whom infection risk is becoming one of the most important factors in therapeutic decision making. Efficient, early diagnosis is essential to improve outcomes in these often-devastating diseases.

Fragments of e-Cadherin as Biomarkers of Non-erosive Reflux Disease.

BACKGROUND: Approximately, 20% of patients with heartburn and normal endoscopic findings do not symptomatically improve on proton pump inhibitor (PPI) therapy making diagnosis and treatment uncertain. A biomarker distinguishing PPI-responsive from PPI-refractory heartburn is desirable. AIMS: We performed a pilot study assessing whether carboxy(C)-terminal fragments (CTFs) of e-cadherin in esophageal biopsies or amino(N)-terminal fragments (NTFs) of e-cadherin in serum could serve this purpose. METHODS: Twenty-nine patients with endoscopy-negative heartburn had esophageal biopsies for CTFs on Western blot and blood for serum NTFs on ELISA. All patients received dexlansoprazole 30 mg daily for 4 weeks, and heartburn was assessed by daily diary entry. Post-treatment blood samples were obtained for serum NTFs. A control group without GERD symptoms (n = 6) had biopsies for CTFs and a second control group (n = 20) blood serum for serum NTFs. RESULTS: Twenty-seven of 29 patients (93.1%) with endoscopy-negative heartburn, but 0 of 6 controls, were positive for CTFs. All patients and controls had measureable serum NTFs, but mean NTFs were significantly higher in those with PPI-responsive heartburn compared to those with PPI-refractory heartburn and controls. Following treatment, 24 of 29 (82.8) patients had relief of heartburn, which associated with a decline in mean NTFs compared to controls. NTFs in PPI-refractory patients (n = 5) were similar to controls before and after PPI therapy. CONCLUSIONS: When heartburn responds to PPI, elevated serum NTFs decline to normal. These data suggest that cleaved products of e-cadherin may serve as biomarkers of NERD. Further data are needed to assess and confirm this concept.

Epidemiology, Treatment, and Complications of Central Nervous System Metastases.

PURPOSE OF REVIEW: Neurologic problems resulting from systemic cancer metastases to brain parenchyma, dura, spinal cord, and leptomeninges are among the most common types of consultations addressed by neurologists. With patients surviving longer from systemic cancer, along with the rapidly evolving therapeutic options, the treatment of these devastating complications has become both more effective and more complicated. This article reviews current patterns of metastatic disease and the increasingly nuanced landscape of evolving therapies, their complications, and their impact on quality of survival. RECENT FINDINGS: Targeted therapies with tyrosine kinase inhibitors and immune checkpoint inhibitors and cytotoxic therapies directed at disease-specific chemosensitivity patterns have dramatically improved the prognosis of non-small cell lung cancer, melanoma, and breast cancer, but have led to some novel complications and altered recurrence patterns. Clinical trials suggest the superiority of hippocampal-avoidance radiation fields and the use of stereotactic radiosurgery over whole-brain radiation therapy to minimize long-term cognitive consequences of radiation therapy. Emerging data document tolerable safety when brain radiation is combined with immunotherapy. Chemotherapy can be a first-line treatment for some inoperable brain metastases, eliminating or deferring whole-brain radiation therapy. Stereotactic body radiation therapy is a new technique of radiation used for spinal and epidural metastases that spares spinal cord tissue while ablating tumors. SUMMARY: Metastases to the nervous system remain devastating, but their prognosis and therapies are more heterogeneous than previously appreciated. Neurologists now can offer more personalized prognostic information based on new stratification criteria, can predict drug complications relevant to the nervous system, and can provide critical partnership in the multidisciplinary effort to balance effective longer-term disease control with treatment-related adverse consequences.

Infections in Patients Receiving Multiple Sclerosis Disease-Modifying Therapies.

PURPOSE OF REVIEW: This paper will systemically review the risk of infections associated with current disease-modifying treatments and will discuss pre-treatment testing recommendations, infection monitoring strategies, and patient education. RECENT FINDINGS: Aside from glatiramer acetate and interferon-beta therapies, all other multiple sclerosis treatments to various degrees impair immune surveillance and may predispose patients to the development of both community-acquired and opportunistic infections. Some of these infections are rarely seen in neurologic practice, and neurologists should be aware of how to monitor for these infections and how to educate patients about medication-specific risks. Of particular interest in this discussion is the risk of PML in association with the recently approved B cell depleting therapy, ocrelizumab, particularly when switching from natalizumab. The risk of infection in association with MS treatments has become one of the most important factors in the choice of therapy. Balance of the overall risk versus benefit should be continuously re-evaluated during treatment.