[Checkpoint inhibitors neurological side effects]. / Complicaciones neurologicas de los inhibidores de punto de control inmunologico.

INTRODUCTION: Checkpoint inhibitors have dramatically transformed cancer treatment. However, due to the increasing number of tumors in which they are used, there is a high number of reported adverse effects. Among them, we highlight neurological side effects. In the approbatory clinical trials, they were thought to be sparse, but they may have been underestimated. AIM: To review the physiopathology and the incidence of neurological side effects due to the use of checkpoint inhibitors, as well as the clinical practice guidelines published in the last years. DEVELOPMENT: To review the published case reports of neurological side effects since the approval of checkpoint inhibitors, and our own experience. Moreover, we summarize the main clinical practice guidelines. CONCLUSIONS: Checkpoint inhibitors neurological side effects are frequent. A wide variety of central or peripheral nervous system symptoms may develop. In the setting of brain tumors, inflammation due to immune system activation might lead to pseudoprogression. Further studies are needed to better describe these neurological side effects, and to implement clinical guidelines.

TITLE: Complicaciones neurologicas de los inhibidores de punto de control inmunologico.Introduccion. Los inhibidores de punto de control inmunologico han supuesto un nuevo paradigma en el tratamiento de diferentes tipos de neoplasias. Sin embargo, con el uso creciente de estos farmacos, se estan observando diferentes efectos adversos. Entre ellos destacan los neurologicos, puesto que su frecuencia parece haberse infraestimado en los ensayos aprobatorios. Objetivo. Revisar la fisiopatologia y la incidencia de los efectos adversos neurologicos por inhibidores de punto de control neurologicos, asi como el abordaje basandose en diferentes guias clinicas. Desarrollo. Se revisan los casos que se han publicado desde la aprobacion de los farmacos y añadimos la experiencia de nuestro centro. A su vez, se hace un resumen de las diferentes guias publicadas de forma reciente. Conclusiones. Las complicaciones derivadas del uso de los inhibidores de punto de control inmunologico son frecuentes. Incluyen multiples cuadros de diferente gravedad, y pueden afectar a cualquier parte del sistema nervioso central y periferico. Ademas, en tumores del sistema nervioso, puede observarse un fenomeno de pseudoprogresion derivado de la inflamacion asociada. Queda pendiente realizar nuevos estudios para conocer en detalle estos efectos adversos y desarrollar guias clinicas con las que optimizar el manejo.

Late-onset anti-NMDA receptor encephalitis.

OBJECTIVE: To describe the clinical features and outcome of anti-NMDA receptor (NMDAR) encephalitis in patients ≥45 years old. METHOD: Observational cohort study. RESULTS: In a cohort of 661 patients with anti-NMDAR encephalitis, we identified 31 patients ≥45 years old. Compared with younger adults (18-44 years), older patients were more often male (45% vs. 12%, p < 0.0001), had lower frequency of tumors (23% vs. 51%, p = 0.002; rarely teratomas), had longer median time to diagnosis (8 vs 4 weeks, p = 0.009) and treatment (7 vs. 4 weeks, p = 0.039), and had less favorable outcome (modified Rankin Scale score 0-2 at 2 years, 60% vs. 80%, p < 0.026). In multivariable analysis, younger age (odds ratio [OR] 0.15, confidence interval [CI] 0.05-0.39, p = 0.0001), early treatment (OR 0.60, CI 0.47-0.78, p < 0.0001), no need for intensive care (OR 0.09, CI 0.04-0.22, p < 0.0001), and longer follow-up (p < 0.0001) were associated with good outcome. Rituximab and cyclophosphamide were effective when first-line immunotherapies failed (OR 2.93, CI 1.10-7.76, p = 0.031). Overall, 60% of patients older than 45 years had full or substantial recovery at 24 months follow-up. CONCLUSIONS: Anti-NMDAR encephalitis is less severe in patients ≥45 years old than in young adults, but the outcome is poorer in older patients. In this age group, delays in diagnosis and treatment are more frequent than in younger patients. The frequency of underlying tumors is low, but if present they are usually carcinomas instead of teratomas in younger patients. Early and aggressive immunotherapy will likely improve the clinical outcome.

Autoimmunity as a prognostic factor in sporadic adult onset cerebellar ataxia.

Cerebellar adult onset ataxia is a heterogeneous condition. The aim of this study was to ascertain if there is a heightened autoimmune background in patients with sporadic cerebellar ataxia of unknown origin, and if autoimmunity correlates with a more rapid evolution of the ataxia. We selected patients with sporadic progressive adult onset cerebellar ataxia with a follow-up of >5 years. As controls we included 43 patients with genetically demonstrated hereditary ataxia. All patients were tested for a panel of neuronal (onconeuronal, glutamate-decarboxylase [GAD], IgG/IgA transglutaminase 6 antibodies) and systemic non-neuronal antibodies (including IgG/IgA gliadin and transglutaminase 2, thyroperoxidase, thyroglobulin, antinuclear, striational, smooth muscle, mitochondrial, liver kidney microsomal, and parietal gastric cells antibodies). Correlation between the antibodies and disease progression was studied with Cox regression models and Kaplan-Meier plots. Forty-four patients were included. All patients were negative for onconeuronal or GAD antibodies. There were no significant differences between patients and controls in the prevalence of transglutaminase 6, 2, gliadin, or thyroid antibodies. However, when we studied the panel of systemic non-neuronal autoantibodies as a group, antibodies were more frequent in patients with sporadic ataxia (p = 0.018). The presence of one or more systemic non-neuronal antibodies correlated with a faster evolution to stage 2 (loss of independent gait) (p = 0.03) and shorter survival (p = 0.03) in patients with sporadic ataxia. We conclude that there is probably a heightened autoimmune background in some patients with sporadic cerebellar ataxia of unknown origin. The presence of systemic non-neuronal autoantibodies is a prognostic marker.

Degeneración cerebelosa paraneoplásica y anticuerpos anti-Yo / Paraneoplastic cerebellar degeneration and anti-Yo antibodies

No disponible

Peripheral nerve hyperexcitability: a clinical and immunologic study of 38 patients.

OBJECTIVE: We studied a case series of peripheral nerve hyperexcitability (PNH) aiming to describe clinical characteristics, immunologic and cancer associations, antibodies against neuronal antigens (voltage-gated potassium channel antibodies [VGKC-Abs] and other), and muscle biopsy findings. METHODS: Patients presenting with clinical and electrophysiologic signs of PNH were selected. We studied clinical and electrophysiologic features; a panel of non-neuronal organ-specific antibodies, immunofluorescence on rat nervous tissues, and radioimmunoprecipitation for VGKC-Abs; and muscle biopsies. RESULTS: Thirty-eight patients were included. After the exclusion of 6 cases with axonopathy of known origin, patients were subdivided according to the presence of electrophysiologic findings of motor axonopathy and association with cancer: axonopathic-PNH (group A: 12 patients), isolated nonparaneoplastic PNH (group B: 16 patients), and isolated paraneoplastic PNH (3 with thymoma and myasthenia gravis, 1 with thyroid carcinoma). PNH clinical features were similar in groups A and B. We found an overall high prevalence of clinical autoimmunity (33% of group A and 63% of group B) and systemic non-neuronal autoantibodies (42% of group A and 75% of group B). However, VGKC-Abs were only positive in 2 patients of group B. Ten patients underwent muscle biopsy, which showed inflammatory changes in 2 cases and nonspecific myopathic features in 8. CONCLUSIONS: PNH is a heterogeneous disorder involving the peripheral nerves in patients with a high propensity for developing autoimmunity. Associated muscle diseases are frequent in the form of myositis, myasthenia gravis, or nonspecific myopathic pathologic findings. VGKC-Abs were uncommon in this series.

[Limbic encephalitis: the new cell membrane antigens and a proposal of clinical-immunological classification with therapeutic implications]. / Encefalitis límbica: los nuevos antígenos y propuesta de una clasificación clinicoinmunológica con implicaciones terapéuticas.

INTRODUCTION: Most studies of patients with limbic encephalitis, paraneoplastic or not, use rigid clinical-radiological entry criteria or select patients previously known to have cancer or to harbor well characterized paraneoplastic antibodies. In practice this selection excludes a significant number of patients with autoimmune encephalitides, some of which may represent new disorders. METHODS: Review of the literature and our clinical experience with patients with limbic encephalitis. Description of the studies that led to the identification of new antibodies and antigens related to several types of autoimmune encephalitis. RESULTS: 82 % of prospectively identified patients with non-viral limbic encephalitis at our institution had 526 antibodies against proteins of the CNS. These antibodies were directed against two category of antigens: a) intracellular or classical paraneoplastic antigens (Hu, Ma2, among other), and b) cell membrane antigens including the voltage-gated potassium channels and the newly identified antigens of the neuropil of hippocampus. Each category of antigens included several subgroups with distinctive clinical-immunological associations. While the encephalitides related to intracellular antigens are predominantly mediated by cytotoxic T-cell mechanisms and are poorly responsive to treatment, those related to cell membrane antigens appear to be mediated by antibodies and often respond to treatment. Among the newly identified antigens, the NR1/NR2B heteromers of the NMDA receptor are of great interest due to their critical role in synaptic plasticity and memory. Patients with antibodies against these receptors are young women with benign-appearing cystic tumors of the ovary (mature or immature teratomas), who develop a severe and characteristic encephalitis that we report in detail. Despite the severity of the disorder, patients often recover after treatment of the tumor and immunotherapy. CONCLUSIONS: Approximately 40 % of patients with classical or atypical limbic encephalitis develop relevant immune responses that are not identified by currently available commercial tests. Different from the previously known paraneoplastic antigens, which location is intracellular and associate with syndromes that are poorly responsive to treatment, the newly identified antigens of the neuropil of hippocampus are in the neuronal cell membrane and the related syndromes, although severe and potentially lethal, often respond to treatment.

Encefalitis límbica: los nuevos antígenos y propuesta de una clasificación clinicoinmunológica con implicaciones terapéuticas / Limbic encephalitis: the new cell membrane antigens and a proposal of clinical-immunological classification with therapeutic implications

Introducción. La mayoría de las series publicadas de pacientes con encefalitis límbica autoinmune, paraneoplásica o no, utilizan criterios de inclusión clinicorradiológicos estrictos o seleccionan a pacientes con cáncer conocido o determinados anticuerpos antineuronales. En la práctica este tipo de selección excluye a un elevado número de pacientes con encefalitis autoinmunes, algunas de las cuales representan nuevas entidades clínicas. Métodos. Revisión de la literatura y de nuestra experiencia clínica con pacientes afectos de encefalitis límbica. Descripción de los estudios utilizados para identificar nuevos anticuerpos y antígenos asociados a varias formas de encefalitis autoinmunes. Resultados. El 82 % de los pacientes con encefalitis límbica no vírica prospectivamente identificados en nuestro centro tenían anticuerpos contra proteínas del sistema nervioso. Estos anticuerpos estaban dirigidos contra dos categorías de antígenos: a) antígenos intracelulares o paraneoplásicos clásicos (Hu, Ma2, entre otros), y b) antígenos de membrana neuronal, incluyendo los canales de potasio y los recientemente identificados «antígenos del neurópilo del hipocampo». Cada una de estas dos categorías de antígenos incluía a varios subgrupos con asociaciones clinicoinmunológicas características. Mientras que las encefalitis relacionadas con antígenos intracelulares son principalmente mediadas por respuestas citotóxicas (linfocitos T) y responden poco al tratamiento, las encefalitis relacionadas con antígenos de membrana parecen ser mediadas por anticuerpos y suelen mejorar con el tratamiento. Entre los antígenos recientemente identificados, los heterómeros NR1/NR2B de los receptores de glutamato (NMDA) son especialmente importantes debido a su papel crucial en mecanismos de plasticidad sináptica y memoria. La encefalitis que se asocia a anticuerpos contra estos receptores afecta predominantemente a mujeres jóvenes que suelen tener quistes de ovario de apariencia benigna (teratomas maduros o inmaduros) y desarrollan un síndrome neurológico característico y grave que describimos en detalle. A pesar de la gravedad del proceso, la recuperación es muy frecuente después de la extirpación del tumor e inmunoterapia. Conclusiones. Aproximadamente un 40 % de pacientes con encefalitis límbica clásica o atípica desarrollan respuestas inmunológicas relevantes que actualmente no se identifican en laboratorios comerciales. A diferencia de los antígenos paraneoplásicos previamente conocidos, cuya localización es intracelular y se asocian a síndromes que responden poco al tratamiento, los recientemente identificados antígenos del neurópilo del hipocampo se localizan en la membrana celular neuronal y los síndromes asociados, aunque graves, responden al tratamiento

Introduction. Most studies of patients with limbic encephalitis, paraneoplastic or not, use rigid clinical-radiological entry criteria or select patients previously known to have cancer or to harbor well characterized paraneoplastic antibodies. In practice this selection excludes a significant number of patients with autoimmune encephalitides, some of which may represent new disorders. Methods. Review of the literature and our clinical experience with patients with limbic encephalitis. Description of the studies that led to the identification of new antibodies and antigens related to several types of autoimmune encephalitis. Results. 82 % of prospectively identified patients with non-viral limbic encephalitis at our institution had 526 antibodies against proteins of the CNS. These antibodies were directed against two category of antigens: a) intracellular or classical paraneoplastic antigens (Hu, Ma2, among other), and b) cell membrane antigens including the voltage-gated potassium channels and the newly identified «antigens of the neuropil of hippocampus». Each category of antigens included several subgroups with distinctive clinical-immunological associations. While the encephalitides related to intracellular antigens are predominantly mediated by cytotoxic T-cell mechanisms and are poorly responsive to treatment, those related to cell membrane antigens appear to be mediated by antibodies and often respond to treatment. Among the newly identified antigens, the NR1/NR2B heteromers of the NMDA receptor are of great interest due to their critical role in synaptic plasticity and memory. Patients with antibodies against these receptors are young women with benign-appearing cystic tumors of the ovary (mature or immature teratomas), who develop a severe and characteristic encephalitis that we report in detail. Despite the severity of the disorder, patients often recover after treatment of the tumor and immunotherapy. Conclusions. Approximately 40 % of patients with classical or atypical limbic encephalitis develop relevant immune responses that are not identified by currently available commercial tests. Different from the previously known paraneoplastic antigens, which location is intracellular and associate with syndromes that are poorly responsive to treatment, the newly identified antigens of the neuropil of hippocampus are in the neuronal cell membrane and the related syndromes, although severe and potentially lethal, often respond to treatment

Autoimmune limbic encephalitis in 39 patients: immunophenotypes and outcomes.

BACKGROUND: About 40% of patients with limbic encephalitis do not have detectable CNS antibodies. Some of these patients have immune-mediated limbic encephalitis, but their frequency is unknown. AIMS: (1) To determine the spectrum of limbic encephalitis identified on clinical grounds in a single institution, and compare it with that in patients referred for antibody analysis. (2) To correlate clinical outcomes with the cellular location of the autoantigens. METHODS: Prospective clinical case studies. Immunohistochemistry with rat brain, live hippocampal neurones, HeLa cells expressing Kv potassium channels and immunoblot. RESULTS: In 4 years, 17 patients were identified in the Hospital of the University of Pennsylvania, Philadelphia, USA, and the serum or CSF samples of 22 patients diagnosed elsewhere were also studied. 9 of our 17 (53%) patients had antibodies to known neuronal antigens (paraneoplastic or voltage gated potassium channels (VGKCs)) and 5 (29%) to novel cell-membrane antigens (nCMAg) typically expressed in the hippocampus and sometimes in the cerebellum. Considering the entire series, 19 of 39 (49%) patients had antibodies to known antigens, and 17 (44%) to nCMAg. Follow-up (2-48 months, median 19 months) was available for 35 patients. When compared with patients with antibodies to intraneuronal antigens, a significant association with response to treatment was found in those with antibodies to cell-membrane antigens in general (VGKC or nCMAg, p = 0.003) or to nCMAg (p = 0.006). CONCLUSIONS: (1) 82% of patients with limbic encephalitis prospectively identified on clinical grounds had CNS antibodies; (2) responsiveness to treatment is not limited to patients with VGKC antibodies; (3) in many patients (29% from a single institution), the autoantigens were unknown but were found to be highly enriched in neuronal cell membranes of the hippocampus; and (4) these antibodies are associated with a favourable outcome.

Protein kinase Cgamma autoimmunity in paraneoplastic cerebellar degeneration and non-small-cell lung cancer.

BACKGROUND: The clinical and immunological profiles of patients with paraneoplastic cerebellar degeneration (PCD) and non-small-cell lung cancer (NSCLC) are not well known. OBJECTIVE: To review the clinical and immunological features of patients with PCD, NSCLC and without well-characterised onconeural antibodies. METHODS: The clinical features of nine patients with the diagnosis of classical PCD and NSCLC, included in our archives, were retrospectively reviewed. The presence of antibodies to cerebellar components was determined by immunohistochemistry and immunoblot of rat cerebellum. A cDNA library of human cerebellum was screened with the positive sera to identify the antigen. RESULTS: Nine patients with PCD and NSCLC were identified. Six patients were men, and the median age at diagnosis of PCD was 63 (range 47-73) years. PCD was completely reversed in two patients, and partially in one, after treatment of the tumour. The serum of one of the patients with PCD showed a unique reactivity with Purkinje cells. The screening of a cerebellar-expression library resulted in the isolation of protein kinase Cgamma (PKCgamma). PKCgamma immunoreactivity was not observed in the serum of 170 patients with non-paraneoplastic neurological syndromes, 27 patients with PCD, no onconeural antibodies and small-cell lung cancer, and 52 patients with NSCLC without paraneoplastic neurological syndromes. The NSCLC from 11 patients without PCD did not express PKCgamma at either the RNA or protein level. However, many cells of the NSCLC of the patient with PKCgamma antibodies expressed PKCgamma. CONCLUSION: PCD occurs in patients with NSCLC without typical onconeural antibodies and is associated with immune reactions against key proteins of the Purkinje cells.

Antibodies to Zic4 in paraneoplastic neurologic disorders and small-cell lung cancer.

OBJECTIVE: To determine whether serum Zic4 antibodies associate with paraneoplastic neurologic disorders (PND) and small-cell lung cancer (SCLC), and the association of these antibodies with other onconeuronal immunities associated with SCLC. DESIGN/METHODS: The authors studied 498 patients (215 with PND and 283 without PND or without cancer). The presence of antibodies was tested with immunoblots of Zic4, HuD, and CRMP5 proteins. The tumor expression of these proteins was determined by immunohistochemistry. RESULTS: Zic4 antibodies were identified in 61 patients. Ninety-two percent of patients with Zic4 antibodies had SCLC; detection of these antibodies segregated with the presence of PND (p = 0.031). Intrathecal synthesis of Zic4 antibodies was demonstrated in 5/7 patients with PND. None of 175 control patients without PND or cancer had Zic4 antibodies. Because of the robust association between Zic autoimmunity and SCLC, all patients were tested for other SCLC-related antibodies; concurrent Zic4, Hu, or CRMP5 antibodies occurred in the serum or CSF of 27% of SCLC patients with PND. Patients with isolated Zic4 antibodies were more likely to develop predominant cerebellar dysfunction than patients with several immunities (p < 0.001). Tumors of patients with and without onconeuronal antibodies coexpressed Zic, Hu, and CRMP5 proteins, indicating that the tumor expression of these antigens is necessary, but not sufficient, for immunologic activation. CONCLUSIONS: In patients with neurologic symptoms of unknown cause detection of Zic4 antibodies predicts a neoplasm, usually a SCLC, and suggests that the neurologic disorder is paraneoplastic. Detection of Zic4 antibodies often associates with anti-Hu or CRMP5 antibodies. Patients with isolated Zic4 antibodies are more likely to develop cerebellar dysfunction than those with concurrent immunities.

Hypocretin-1 CSF levels in anti-Ma2 associated encephalitis.

Idiopathic narcolepsy is associated with deficient hypocretin transmission. Narcoleptic symptoms have recently been described in paraneoplastic encephalitis with anti-Ma2 antibodies. The authors measured CSF hypocretin-1 levels in six patients with anti-Ma2 encephalitis, and screened for anti-Ma antibodies in patients with idiopathic narcolepsy. Anti-Ma autoantibodies were not detected in patients with idiopathic narcolepsy. Four patients with anti-Ma2 encephalitis had excessive daytime sleepiness; hypocretin-1 was not detectable in their cerebrospinal fluid, suggesting an immune-mediated hypocretin dysfunction.

Cerebellar degeneration and autoimmunity to zinc-finger proteins of the cerebellum.

The serum of a patient with subacute cerebellar dysfunction was used to probe a cDNA expression library and isolate two genes: Zic1 (zinc-finger of the cerebellum) and Zic4. The patient had intrathecal synthesis of Zic antibodies, suggesting that the Zic proteins were autoantigens of the neurologic disorder. The Zic proteins are involved in cerebellar development and are reported as being preferentially expressed by medulloblastomas. It was found that the expression of Zic proteins is enriched in, but not limited to, medulloblastomas and primitive neuroectodermal tumors.

[Antineural antibodies and paraneoplastic neurologic syndromes]. / Anticuerpos antineuronales y síndromes neurológicos paraneoplásicos.

The discovery that many paraneoplastic syndromes of the nervous system associate with the presence of specific antineuronal antibodies in the serum and cerebrospinal fluid of patients has facilitated the recognition of these disorders and attracted the interest of clinical and laboratory investigators. In this review, the authors discuss the most common immunological findings associated with paraneoplastic syndromes of the nervous system, and provide a practical clinical review of those associated with antineuronal antibodies.

Anticuerpos antineuronales y síndromes neurológicos paraneoplásicos / Antineural antibodies and paraneoplastic neurologic syndromes

El hallazgo de que muchos síndromes neurológicos paraneoplásicos se asocian con la presencia de anticuerpos antineuronales en el suero y el líquido cefalorraquídeo de los pacientes ha mejorado el diagnóstico de estos procesos, y ha atraído la atención de investigadores clínicos y de laboratorio. En este artículo, los autores describen los hallazgos inmunológicos más frecuentes en los síndromes paraneoplásicos del sistema nervioso, y presentan una revisión clínica práctica de los síndromes asociados a anticuerpos antineuronales (AU)

The discovery that many paraneoplastic syndromes of the nervous system associate with the presence of specific antineuronal antibodies in the serum and cerebrospinal fluid of patients has facilitated the recognition of these disorders and attracted the interest of clinical and laboratory investigators. In this review, the authors discuss the most common immunological findings associated with paraneoplastic syndromes of the nervous system, and provide a practical clinical review of those associated with antineuronal antibodies (AU)