Motor neuron involvement in anti-Ma2-associated paraneoplastic neurological syndrome

Vogrig, Alberto; Joubert, Bastien; Maureille, Aurélien; Thomas, Laure; Bernard, Emilien; Streichenberger, Nathalie; Cotton, François; Ducray, François; Honnorat, Jérôme

doi:10.1007/s00415-018-9143-x

Cited by 34 publications

(27 citation statements)

References 41 publications

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“…Most of them were male, middle-age/elderly adults who developed a neurologic syndrome characterized by prominent limbic and diencephalic involvement, mainly associated with lung cancer. This clinical presentation is in line with both the original descriptions of the Ma2 syndrome 9,10,16,17 and the clinical features from the 44 remaining patients of our overall cohort. We, however, note 3 notable differences: (1) in the classic, paraneoplastic form, the neurologic syndrome is known to precede cancer diagnosis by several weeks to months.…”

Section: Discussionsupporting

confidence: 89%

“…Because the anti–Ma2-associated syndrome is characterized by atypical manifestations such as increased daytime sleepiness, hyperphagia, and weight gain, 10–12 it is important for the clinician to recognize the prominent features of this disease to avoid diagnostic pitfalls. These symptoms are related to the diencephalic involvement and need to be promptly differentiated from the clinical correlate of primary hypothyroidism, which is a much more common irAE that shares a similar presentation.…”

Section: Discussionmentioning

confidence: 99%

“…PNS with Abs targeting the intracellular Ma2 antigen characterizes a peculiar form of encephalitis with prominent involvement of limbic, brainstem, and diencephalic structures, usually in association with testicular or lung cancer. 9,10 Atypical manifestations including narcolepsy-cataplexy, weight gain, sexual dysfunction, and motor neuron syndrome were described and account for the difficulty in diagnosing anti–Ma2 antibody–associated PNS (Ma2-PNS). 9–12…”

mentioning

confidence: 99%

“…9,10 Atypical manifestations including narcolepsy-cataplexy, weight gain, sexual dysfunction, and motor neuron syndrome were described and account for the difficulty in diagnosing anti–Ma2 antibody–associated PNS (Ma2-PNS). 9–12…”

mentioning

confidence: 99%

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Increased frequency of anti-Ma2 encephalitis associated with immune checkpoint inhibitors

Vogrig

Fouret

Joubert

et al. 2019

Neurol Neuroimmunol Neuroinflamm

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152

136

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ObjectiveTo report the induction of anti–Ma2 antibody–associated paraneoplastic neurologic syndrome (Ma2-PNS) in 6 patients after treatment with immune checkpoint inhibitors (ICIs). We also analyzed (1) patient clinical features compared with a cohort of 44 patients who developed Ma2-PNS without receiving ICI treatment and (2) the frequency of neuronal antibody detection before and after ICI implementation.MethodsRetrospective nationwide study of all patients with Ma2-PNS developed during ICI treatment between 2017 and 2018.ResultsOur series of patients included 5 men and 1 woman (median age, 63 years). The patients were receiving nivolumab (n = 3), pembrolizumab (n = 2), or a combination of nivolumab and ipilimumab (n = 1) for treatment of neoplasms that included lung (n = 4) and kidney (n = 1) cancers and pleural mesothelioma (n = 1). Clinical syndromes comprised a combination of limbic encephalitis and diencephalitis (n = 3), isolated limbic encephalitis (n = 2), and a syndrome characterized by ophthalmoplegia and head drop (n = 1). No significant clinical difference was observed between our 6 patients and the overall cohort of Ma2-PNS cases. Post-ICI Ma2-PNS accounted for 35% of the total 17 Ma2-PNS diagnosed in our center over the 2017–2018 biennium. Eight cases had been detected in the preceding biennium 2015–2016, corresponding to a 112% increase of Ma2-PNS frequency since the implementation of ICIs in France. Despite ICI withdrawal and immunotherapy, 4/6 patients died, and the remaining 2 showed a moderate to severe disability.ConclusionsWe show a clear association between ICI use and increased diagnosis of Ma2-PNS. Physicians need to be aware that ICIs can trigger Ma2-PNS because clinical presentation can be challenging.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Increased frequency of anti-Ma2 encephalitis associated with immune checkpoint inhibitors

Vogrig

Fouret

Joubert

et al. 2019

Neurol Neuroimmunol Neuroinflamm

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152

136

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“…The presence of contrast enhancement at the mesial temporal lobe level in one of our patients is an interesting finding, which was previously reported in Ma2 antibody-associated syndrome. [25][26][27][28] The present study highlights the grim prognosis of patients with Ri-PNS: at 1 year, most of the French patients were unable to walk unassisted, and half of them died within 3 years of disease onset. These findings are in contrast with the favorable prognosis and good functional outcome suggested by others.…”

Section: Discussionmentioning

confidence: 60%

Clinical spectrum and diagnostic pitfalls of neurologic syndromes with Ri antibodies

Simard

Vogrig

Joubert

et al. 2020

Neurol Neuroimmunol Neuroinflamm

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ObjectiveTo describe the main syndrome and clinical course in a large cohort of patients with anti–Ri-associated paraneoplastic neurologic syndrome (Ri-PNS).MethodsTwenty-year retrospective nationwide study and systematic review of the literature.ResultsThirty-six patients with complete clinical information were identified (median age 66 years, range: 47–87 years). In this French cohort, the majority were women (78%). At onset, 4 main patterns were observed: cerebellar syndrome (39%), isolated tremor (24%), oculomotor disturbances (17%), and other symptoms (19%). Course was multistep for 78% of cases. At the time the disease reached the plateau phase (median 12 weeks, range: 1–64 weeks; 28% >3 months), 24 (67%) showed an overt cerebellar syndrome, which was isolated in 3 patients, and was most frequently (21/24 cases) part of a multisystem neurologic disease. Patients manifested a variety of movement disorders, including myoclonus (33%), dystonia (17%), either cervical or oromandibular, and parkinsonism (17%). Most patients had cancer (92%), mainly breast cancer (n = 22). Misdiagnoses concerned 22% of patients (n = 8) and included atypical parkinsonism (n = 2), MS (n = 2), Bickerstaff encephalitis (n = 1), hyperekplexia (n = 1), vestibular neuritis (n = 1), and functional neurologic disorder (n = 1). Survival at 12 months was 73% (95% CI [0.54–0.85]), at 24 months 62% (95% CI [0.41–0.78]), and at 36 months 47% (95% CI [0.25–0.65]). There was no major clinical difference between cases retrieved from the systematic review of the literature (n = 55) and the French cohort.ConclusionsRi-PNS is a multisystem neurologic syndrome with prominent cerebellum/brainstem involvement. Opsoclonus-myoclonus is less common than expected, and the disorder can mimic neurodegenerative diseases.

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

Gilligan,

Lesnick,

Guo

et al. 2024

Annals of Neurology

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ObjectivesTo report an autoimmune paraneoplastic encephalitis characterized by immunoglobulin G (IgG) antibody targeting synaptic protein calmodulin kinase‐like vesicle‐associated (CAMKV).MethodsSerum 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.ResultsOf 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.InterpretationCAMKV‐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

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Motor neuron involvement in anti-Ma2-associated paraneoplastic neurological syndrome

Cited by 34 publications

References 41 publications

Increased frequency of anti-Ma2 encephalitis associated with immune checkpoint inhibitors

Increased frequency of anti-Ma2 encephalitis associated with immune checkpoint inhibitors

Clinical spectrum and diagnostic pitfalls of neurologic syndromes with Ri antibodies

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

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