Immune checkpoint inhibitors (ICIs) are oncologic treatments that may trigger or worsen paraneoplastic neurologic syndromes (PNSs). This study describes patients with CV2/CRMP5-PNS treated by ICI, compares the post-ICI group with ICI-naïve patients with CV2/CRMP5-PNS, and estimates the overall survival of ICI-treated patients with CV2/CRMP5-PNS, Hu-PNS, and Ma2-PNS. The medical records of patients positive for anti-CV2/CRMP5 antibodies were retrospectively reviewed at the French Reference Centre to identify those treated with ICI (2016-2024). Patients with a preexisting PNS were described separately from those with post-ICI PNS; the latter were then compared with ICI-naïve patients with CV2/CRMP5-PNS diagnosed in the same study period. An overall survival analysis between ICI-treated patients with CV2/CRMP5-PNS, Hu-PNS, and Ma2-PNS was performed. Fourteen patients with CV2/CRMP5-PNS treated with ICIs were included. Eight patients [median age, 73 years (range: 60-87); 87.5% men] developed post-ICI PNS after a median of 3.5 ICI cycles (range: 1-7). The frequency and distribution of clinical phenotypes (isolated neuropathy [n = 3] or a multifocal neurologic involvement [encephalopathy, limbic syndrome, brainstem syndrome, cerebellar syndrome, ocular syndrome, neuropathy, and/or dysautonomia; n = 5]) were similar to those of ICI-naïve CV2/CRMP5-PNS (n = 48). The frequency of severe presentations (modified Rankin Scale [mRS] score > 3) at diagnosis was similar between post-ICI patients and ICI-naïve patients with CV2/CRMP5-PNS (63% vs 48%, p = 0.7) and slightly higher at last visit in post-ICI patients (88% vs 54%, p = 0.12). Anti-CV2/CRMP5 antibodies were undetectable in the only patient with a pre-ICI serum sample. Among the 6 patients with preexisting CV2/CRMP5-PNS [median age, 66 years (range: 54-79); 50% men] who received ICIs, PNS symptoms worsened in 5 (83%) [median mRS increase of 1.5 points (range: 1-3)]. The median overall survival (22 months) was significantly longer in the ICI-treated patients with CV2/CRMP5-PNS compared with the Hu-PNS and Ma2-PNS groups (4 months and 8 months, respectively, p = 0.0069). ICIs may trigger the onset and exacerbate the progression of CV2/CRMP5-PNS. Post-ICI forms are clinically undistinguishable but possibly more severe than their ICI-naïve counterparts. Increased surveillance is needed in identifying preexisting PNSs, with extreme caution when considering ICI treatment. Post-ICI-induced PNSs have variable prognosis according to the associated onconeural autoantibodies. Opsoclonus is a rare oculomotor dyskinesia characterized by rapid, repetitive, conjugate eye movements that are involuntary, arrhythmic, chaotic, and multidirectional (horizontal, vertical, and torsional) without intersaccadic intervals. The movements appear most pronounced when the individual is awake and attempting fixation but persist during convergence, with closed eyelids, in darkness, and during sleep. Visual blur and oscillopsia commonly result from the large amplitude and high frequency of the oscillations. Opsoclonus differs from opsochoria, which involves dysconjugate eye movements, as well as ocular flutter, which is restricted to the horizontal plane. Unlike nystagmus, the phase moving the eye away from the target is always a saccade. When opsoclonus occurs with myoclonus or ataxia, encephalopathy, generalized tremor, or impaired cognition and behavioral changes, the presentation is classified as opsoclonus-myoclonus syndrome (OMS), also known as dancing eye and dancing feet syndrome. Often called "saccadomania," opsoclonus serves as a hallmark of central nervous system (CNS) dysfunction and frequently accompanies paraneoplastic, autoimmune, postinfectious, or toxic-metabolic disorders. Unlike typical nystagmus, which follows a rhythmic and directional pattern, opsoclonus consists of random, uncontrolled bursts of eye movement in all planes, making it highly specific for a neurological abnormality. Given this symptom's frequent association with systemic or neurological illness, early recognition and targeted investigations are crucial for identifying an underlying cause and initiating appropriate treatment. OMS is a rare but significant neuroinflammatory disorder in pediatric and adult populations. In children, neuroblastoma-associated OMS represents the most well-known form. In adults, paraneoplastic syndromes, viral encephalitis, and autoimmune encephalitis are frequent contributors. Dysfunction of the brainstem and cerebellar circuits, particularly the omnipause neurons of the pontine reticular formation, underlies the disorder, as these neurons normally suppress inappropriate saccadic activity. Damage to these inhibitory systems leads to disinhibition of the fastigial nucleus and burst neurons, causing excessive saccadic eye movements. This mechanism explains why opsoclonus often coexists with truncal ataxia, myoclonus, and cognitive dysfunction, all characteristic of OMS. Opsoclonus is an extremely rare neurological finding in pediatric and adult populations. The estimated incidence of OMS in children is 1 in 5 million per year, with most cases occurring between 12 months and 4 years of age. In pediatric patients manifesting with opsoclonus, neuroblastoma is identified in approximately 50% of cases, making this manifestation a paraneoplastic red flag that warrants immediate tumor screening. The early identification of opsoclonus has improved neuroblastoma detection, contributing to better survival rates and neurological outcomes and emphasizing the importance of timely diagnosis. In adults, the epidemiology varies, with paraneoplastic opsoclonus often linked to small cell lung cancer (SCLC), breast cancer, ovarian teratoma, and Hodgkin lymphoma. However, nonparaneoplastic cases are more prevalent, often occurring in postviral or postvaccination autoimmune encephalitis, toxic-metabolic syndromes, or idiopathic immune-mediated diseases. Opsoclonus rarely presents in isolation and frequently accompanies diffuse neurological dysfunction, necessitating a thorough interprofessional evaluation involving neurologists, ophthalmologists, oncologists, and immunologists. Dysfunction within the brainstem-cerebellar circuits underlies opsoclonus, particularly involving the fastigial nucleus, vestibulocerebellar tracts, and omnipause neurons in the pontine reticular formation. The fastigial nucleus plays a critical role in integrating ocular movements and posture. Lesions or autoimmune-mediated dysfunction affecting this structure disrupt saccadic control, leading to the characteristic disorganized bursts. Omnipause neurons in the nucleus raphe interpositus normally suppress saccades when the eyes are at rest. Damage to these inhibitory neurons removes this suppression, generating uncontrolled saccadic activity. Paraneoplastic opsoclonus is believed to result from autoantibodies targeting neuronal antigens, triggering widespread neuroinflammation in the brainstem and cerebellum. Anti-Hu and anti-Ri antibodies have been implicated in many cases, particularly those associated with SCLC and breast cancer. Opsoclonus arises from various pathological processes affecting the CNS, including immune-mediated, toxic-metabolic, and infectious mechanisms. As mentioned, this neurological sign may also occur as a paraneoplastic phenomenon associated with neuroblastoma in children and SCLC,  breast cancer, ovarian cancer, and lymphoma, particularly Hodgkin lymphoma, in adults. A systematic approach to the differential diagnosis is essential for guiding the appropriate workup and treatment strategy. Postinfectious and autoimmune etiologies have also been implicated. Viral encephalitis caused by West Nile virus, Epstein-Barr virus (EBV), Coxsackievirus, or COVID-19 has been reported as a trigger. Postvaccination immune-mediated encephalopathy and autoimmune encephalitis, including anti-N-methyl-D-aspartate receptor (anti-NMDA) encephalitis, anti-glutamic acid decarboxylase (anti-GAD) antibody-associated syndromes, and opsoclonus related to Sjögren syndrome, have also been described. Toxic and metabolic disturbances contribute to opsoclonus as well. Lithium toxicity, serotonin syndrome, and metabolic encephalopathies, including those due to hepatic or uremic dysfunction or severe vitamin B12 deficiency, have been linked to opsoclonus development. Certain medications, such as phenytoin, amiodarone, and metronidazole, have been associated with cerebellar toxicity leading to this manifestation. Structural and degenerative disorders associated with opsoclonus include brainstem infarcts, multiple sclerosis, and autoimmune demyelinating syndromes. Neurodegenerative conditions such as ataxia-telangiectasia, Creutzfeldt-Jakob disease (CJD), and progressive supranuclear palsy (PSP) have also been implicated. A comprehensive diagnostic approach is essential due to the strong association between opsoclonus and paraneoplastic or autoimmune syndromes. Brain and spine magnetic resonance imaging (MRI) is necessary to evaluate brainstem or cerebellar pathology and potential paraneoplastic syndromes. Paraneoplastic antibody testing, including anti-Hu, anti-Ri, and anti-Yo antibodies, aids in identifying autoantibody-mediated neurological conditions. In pediatric cases, neuroblastoma screening should include abdominal ultrasound, urine catecholamines such as vanillylmandelic acid (VMA) and homovanillic acid (HVA), and imaging with MRI or metaiodobenzylguanidine (MIBG) scanning. Cerebrospinal fluid (CSF) analysis and autoimmune testing, including oligoclonal bands, anti-GAD antibodies, and NMDA receptor antibodies, help identify immune-mediated etiologies. Opsoclonus represents a rare but clinically significant neurological disorder that frequently signals an underlying malignancy or immune-mediated process. Chaotic, multidirectional saccadic eye movements serve as an important neurological red flag, prompting urgent evaluation and targeted management. Early recognition remains critical, as timely tumor detection, immunotherapy, and supportive care significantly improve outcomes. Ongoing research into paraneoplastic and autoimmune mechanisms continues to advance treatment strategies, with targeted immunomodulatory therapies offering hope for better disease control and improved long-term prognosis.

Dysautonomia has been associated with paraneoplastic neurological syndrome (PNS)-related mortality in anti-Hu PNS, but its frequency and spectrum remain ill-defined. We describe anti-Hu patients with dysautonomia, estimate its frequency, and compare them to patients without dysautonomia. Patients with anti-Hu antibodies diagnosed in the study centre (1990-2022) were retrospectively reviewed; those with autonomic signs and symptoms were identified. Among 477 anti-Hu patients, 126 (26%) had dysautonomia (the only PNS manifestation in 7/126, 6%); gastrointestinal (82/126, 65%), cardiovascular (64/126, 51%), urogenital (24/126, 19%), pupillomotor/secretomotor (each, 11/126, 9%), and central hypoventilation (10/126, 8%). Patients with isolated CNS involvement less frequently had gastrointestinal dysautonomia than those with peripheral (alone or combined with CNS) involvement (7/23, 30% vs. 31/44, 70% vs. 37/52, 71%; P = 0.002); while more frequently central hypoventilation (7/23, 30% vs. 1/44, 2.3% vs. 2/52, 4%; P < 0.001) and/or cardiovascular alterations (18/23, 78% vs. 20/44, 45% vs. 26/52, 50%; P = 0.055). Median [95% CI] overall survival was not significantly different between patients with (37 [17; 91] months) or without dysautonomia (28 [22; 39] months; P = 0.78). Cardiovascular dysautonomia (HR: 1.57, 95% CI [1.05; 2.36]; P = 0.030) and central hypoventilation (HR: 3.51, 95% CI [1.54; 8.01]; P = 0.003) were associated with a higher risk of death, and secretomotor dysautonomia a lower risk (HR: 0.28, 95% CI [0.09; 0.89]; P = 0.032). Patients with cardiovascular dysautonomia dying ≤ 1 year from clinical onset had severe CNS (21/27, 78%), frequently brainstem (13/27, 48%), involvement. Anti-Hu PNS dysautonomia is rarely isolated, frequently gastrointestinal, cardiovascular and urogenital. CNS dysfunction, particularly brainstem, associates with lethal cardiovascular alterations and central hypoventilation, while peripheral involvement preferentially associates with gastrointestinal or secretomotor dysautonomia, being the latest more indolent.

Progressive multifocal leucoencephalopathy (PML) is a demyelinating disease caused by the John Cunningham (JC) virus, which may get reactivated under certain immunosuppressive states such as AIDS, immunomodulatory therapy and haematological malignancies. PML has been reported rarely even in immunocompetent individuals where no immunodeficiency was present. PML characteristically involves periventricular and juxtacortical white matter. Isolated cerebellar or brainstem PML may be seen rarely. We present a case of a man in his 70s who presented with rapidly progressive cerebellar ataxia, ptosis and bipyramidal signs. Investigations excluded a direct viral cerebellar infection, acute disseminated encephalomyelitis, paraneoplastic cerebellar degeneration or any structural cerebellar lesion. MRI PET study revealed the classical shrimp sign which raised the possibility of cerebellar PML, and the same was confirmed by a positive JC virus PCR in the cerebrospinal fluid. Our patient had no known immune-compromising state, but further workup revealed a low CD4 count suggestive of idiopathic CD4 lymphopenia. The case illustrates the importance of the shrimp sign on MRI, the possibility of cerebellar involvement of PML as well as the need to consider a differential diagnosis of PML even in individuals with no obvious immunocompromised state.

Antibodies against the neuronal protein Ma2 have been reported in a peculiar form of paraneoplastic encephalitis with prominent involvement of the limbic, brainstem, and diencephalic structures and usually associated with germ cell testicular, lung, or breast cancer. The diagnosis is frequently challenged by atypical clinical manifestations including parkinsonism, sleep disturbances, hypothalamic-pituitary dysfunctions, and motor neuron-like syndrome. In recent years, the advent of monoclonal antibodies targeting immune checkpoints has deeply changed the treatment of different tumors, especially melanoma and lung cancer. However, given their nature, an increasing number of neurological immune-related adverse events, including ocular motor abnormalities, have been described. Here, we report a woman with advanced non-small cell lung cancer treated with anti-PD-L1 durvalumab, presenting with an isolated pendular torsional nystagmus, in association with anti-Ma2 antibodies. This peculiar case widens our knowledge on the clinical presentation of anti-Ma2 encephalitis associated with checkpoint inhibitors.

Anti-Hu are the most frequent antibodies in paraneoplastic neurological syndromes, mainly associated with an often limited stage small cell lung cancer. The clinical presentation is pleomorphic, frequently multifocal. Although the predominant phenotypes are well characterized, how different neurological syndromes associate is unclear. Likewise, no specific study assessed the performance of new-generation CT and PET scanners for cancer screening in these patients. Herein, we aimed to describe the clinical pattern and cancer screening in a retrospective cohort of 466 patients with anti-Hu autoimmunity from the French Reference Centre on Paraneoplastic Neurological Syndromes registry. Clinical presentation, cancer screening and diagnosis were analysed. Among the 466 patients, 220 (54%) had multifocal neurological involvement. A hierarchical cluster analysis grouped the patients into (i) mainly limbic encephalitis, (ii) predominantly peripheral neuropathy and (iii) broad involvement of the nervous system (mixed group). Compared with limbic encephalitis and mixed groups, patients in the neuropathy group more frequently had a chronic onset of symptoms (29 versus 13 and 17%), elevated CSF proteins (83 versus 47 and 67%) and died from cancer progression (67 versus 15 and 28%; all P < 0.05). No significant difference in overall survival was observed between groups. Dysautonomia and brainstem signs were associated with a higher risk of death from the neurological cause; cancer diagnosis was the main predictor of all-cause death, especially when diagnosed within 2 years from clinical onset (all P < 0.05). Three hundred and forty-nine (75%) patients had cancer: in 295 (84%) neurological symptoms preceded tumour diagnosis, being lung cancer in 262 (89%), thereof small cell lung cancer in 227 (87%). First CT scan revealed lung cancer in 205/241 (85%), and PET scan shortened the interval to diagnosis when the initial CT scan was negative [7 months (1-66) in 27 patients versus 14 months (2-45) in 6; P < 0.001]. Although cancer diagnosis mostly occurred within 2 years from clinical onset, 13/295 (4%) patients exceeded that threshold. Conversely, 33 patients (7%) were 'cancer-free' after 2 years of follow-up. However, 13/33 (39%) had initial suspicious imaging findings that spontaneously regressed. In conclusion, although anti-Hu autoimmunity clinical presentation is mostly multifocal, we observed patients with a predominant limbic syndrome or isolated sensory neuropathy. Early implementation of PET scan shortens the interval to cancer diagnosis, which was the strongest predictor of death, especially if diagnosed ≤2 years from clinical onset. As cancer was diagnosed >2 years after clinical onset in few patients, screening should be extended up to 5 years. In addition, tumour regression was suspected in a substantial proportion of 'cancer-free' patients.