Paraneoplastic Calmodulin Kinase-Like Vesicle-Associated Protein (CAMKV) Autoimmune Encephalitis.

OBJECTIVES: To report an autoimmune paraneoplastic encephalitis characterized by immunoglobulin G (IgG) antibody targeting synaptic protein calmodulin kinase-like vesicle-associated (CAMKV). METHODS: Serum and cerebrospinal fluid (CSF) samples harboring unclassified antibodies on murine brain-based indirect immunofluorescence assay (IFA) were screened by human protein microarray. In 5 patients with identical cerebral IFA staining, CAMKV was identified as top-ranking candidate antigen. Western blots, confocal microscopy, immune-absorption, and mass spectrometry were performed to substantiate CAMKV specificity. Recombinant CAMKV-specific assays (cell-based [fixed and live] and Western blot) provided additional confirmation. RESULTS: Of 5 CAMKV-IgG positive patients, 3 were women (median symptom-onset age was 59 years; range, 53-74). Encephalitis-onset was subacute (4) or acute (1) and manifested with: altered mental status (all), seizures (4), hyperkinetic movements (4), psychiatric features (3), memory loss (2), and insomnia (2). Paraclinical testing revealed CSF lymphocytic pleocytosis (all 4 tested), electrographic seizures (3 of 4 tested), and striking MRI abnormalities in all (mesial temporal lobe T2 hyperintensities [all patients], caudate head T2 hyperintensities [3], and cortical diffusion weighted hyperintensities [2]). None had post-gadolinium enhancement. Cancers were uterine adenocarcinoma (3 patients: poorly differentiated or neuroendocrine-differentiated in 2, both demonstrated CAMKV immunoreactivity), bladder urothelial carcinoma (1), and non-Hodgkin lymphoma (1). Two patients developed encephalitis following immune checkpoint inhibitor cancer therapy (atezolizumab [1], pembrolizumab [1]). All treated patients (4) demonstrated an initial response to immunotherapy (corticosteroids [4], IVIG [2]), though 3 died from cancer. INTERPRETATION: CAMKV-IgG is a biomarker of immunotherapy-responsive paraneoplastic encephalitis with temporal and extratemporal features and uterine cancer as a prominent oncologic association. ANN NEUROL 2024;96:21-33.

Engineered agrin attenuates the severity of experimental autoimmune myasthenia gravis.

INTRODUCTION: Agrin is essential for the formation and maintenance of neuromuscular junctions (NMJs). NT-1654 is a C-terminal fragment of mouse neural agrin. In this study, we determined the effects of NT-1654 on the severity of experimental autoimmune myasthenia gravis (EAMG). METHODS: EAMG was induced in female Lewis rats by immunization with the Torpedo acetylcholine receptor (tAChR) and complete Freund's adjuvant (CFA). NT-1654 was dissolved in phosphate-buffered saline (PBS) and injected daily subcutaneously into tAChR immunized rats during the first 10 days after immunization, and then every other day for the following 20 days. RESULTS: We showed that NT-1654 attenuated clinical severity, effectively promoted the clustering of AChRs at NMJs, and alleviated the impairment of NMJ transmission and the reduction of muscle-specific kinase (MuSK) in EAMG rats. DISCUSSION: We demonstrated that NT-1654 attenuated clinical severity, effectively promoted the clustering of AChRs at NMJs, and alleviated the impairment of NMJ transmission and the reduction of muscle-specific kinase (MuSK) in EAMG rats. Muscle Nerve 57: 814-820, 2018.

Interleukin-10 producing-B cells and their association with responsiveness to rituximab in myasthenia gravis.

INTRODUCTION: A subset of regulatory B cells in humans and mice has been defined functionally by their ability to produce interleukin (IL)-10. We characterized IL-10-producing B (B10) cells in myasthenia gravis (MG) patients and correlated them with disease activity and responsiveness to rituximab therapy. METHODS: Frequencies of B10 cells from MG patients and healthy controls were monitored by fluorescence-activated cell sorting (FACS). RESULTS: MG patients had fewer B10 cells than controls, which was associated with more severe disease status. Moreover, patients who responded well to rituximab therapy exhibited rapid repopulation of B10 cells, whereas in patients who did not respond well to rituximab, B10 cell repopulation was delayed. The kinetics of B10 cells were related to the responsiveness to rituximab in MG. CONCLUSIONS: We have characterized a specific subset of B10 cells in MG patients which may serve as a marker for disease activity and responsiveness to immune therapy.

Antibodies to myelin-associated glycoprotein (anti-Mag) in IgM amyloidosis may influence expression of neuropathy in rare patients.

We have examined whether antibodies to myelin-associated glycoprotein (anti-MAG) influence neuropathy occurrence and phenotype in primary (AL IgM) amyloidosis. Anti-MAG and the cross-reacted sulfoglucuronyl paragloboside antibodies (SGPG) were studied in 46 patients with IgM amyloidosis (21 with polyneuropathy), and 21 matched IgM MGUS (monoclonal gammopathies of undetermined significance) controls without neuropathy. We assessed the occurrence, phenotype of neuropathy, and attributes of nerve conduction and their relation to antibody activity. Twenty of 46 patients with IgM amyloidosis (7 with and 13 without polyneuropathy) had elevation of anti-MAG or SGPG by enzyme-linked immunosorbent assay (ELISA). Two of the polyneuropathy patients with IgM amyloidosis had antibodies to MAG based on Western blot (WB) positivity. One of these patients, with the highest anti-MAG titer, had a painful sensory ataxia, with prominent demyelination, and amyloid deposition in sural nerve. The other anti-MAG WB-positive amyloid patient had an axonal neuropathy and dysautonomia. Low levels of anti-MAG antibodies were found in 12 of 21 IgM MGUS controls without neuropathy (mean follow-up, 11 years). We conclude that finding serum anti-MAG antibodies does not exclude the diagnosis of primary amyloidosis. They do not appear to affect the occurrence or expression of polyneuropathy, except possibly in occasional cases with WB positivity.

Isolated amyloidosis presenting with lumbosacral radiculoplexopathy: description of two cases and pathogenic review.

In this study, we present two cases of infiltrative, localized amyloidosis involving lumbosacral root and plexus, e.g., isolated amyloidomas. Rare and poorly understood amyloidomas may occur in both neurologic and non-neurologic tissues. The described cases emphasize potential for localized peripheral amyloidomas: (1) potential for associated lambda light chain lymphoplasmacytic lymphoma association; (2) e isolated amyloidosis without evidence for systemic plasma cell dyscrasia; (3) features suggestive of potential pathogenesis; and (4) discussion of treatment options including immunotherapy and resection. The limited literature and experience among other cases is described.

Neoplastic lumbosacral radiculoplexopathy in prostate cancer by direct perineural spread: an unusual entity.

Neoplastic lumbosacral plexopathy occurs with some abdominal and pelvic malignancies. Patients present with severe pain radiating from the low back down to the lower extremities, and this progresses to weakness. Neoplastic lumbosacral plexopathy is virtually always associated with known malignancy or obvious pelvic metastatic disease. Uncommonly, prostate cancer can present as a lumbosacral plexopathy occurring through direct pelvic spread. We describe two cases of lumbosacral radiculoplexopathy from infiltrative prostate cancer without evidence of other pelvic or extraprostatic spread. The probable etiology of tumor spreading along prostatic nerves into the lumbosacral plexus (i.e., perineural spread) is discussed as are the potential mechanisms for this unusual mode of cancer dissemination.

Case of neuroleptic malignant-like syndrome precipitated by abrupt fava bean discontinuance.

Neuroleptic malignant-like syndrome (NMLS) is well described in the treatment of Parkinson's disease. The syndrome is characterized by fever, rigidity, autonomic instability, elevated creatine phosphokinase levels, and altered level of consciousness, which is usually precipitated by levodopa withdrawal. In recent years, patients have used fava beans to treat Parkinson's symptoms, because the beans contain appreciable amounts of levodopa and have been thought to be a safe adjunctive therapy. We describe a case of NMLS, which was precipitated by the abrupt cessation of fava bean ingestion.