Paraneoplastic encephalitis: clinically based approach on diagnosis and management

Paraneoplastic neurological syndromes (PNSs) comprise a subset of immune-mediated nervous system diseases triggered by an underlying malignancy. Each syndrome usually shows a distinct clinical presentation and outcome according to the associated neural antibodies. PNSs generally have a subacute onset with rapid progression and severe neurological disability. However, some patients may have hyperacute onset or even show chronic progression mimicking neurodegenerative diseases. Updated diagnostic criteria for PNS have been recently established in order to increase diagnostic specificity and to encourage standardisation of research initiatives related to PNS. Treatment for PNS includes oncological therapy and immunomodulation to halt neurological deterioration although current treatment options are seldom effective in reversing disability. Nevertheless, growing knowledge and better understanding of PNS pathogenesis promise better recognition, earlier diagnosis and novel treatment strategies. Considering that PNSs provide a model of effective anticancer immunity, the impact of these studies will extend far beyond the field of neurology

Cytokine dynamics and targeted immunotherapies in autoimmune encephalitis

Autoimmune encephalitides constitute a diverse group of immune-mediated central nervous system disorders mainly characterized by the presence of antibodies targeting neuronal or glial antigens. Despite the notable contribution of antibody discovery to the understanding of their physiopathology, the specific immune cells and inflammatory mediators involved in autoimmune encephalitis are still poorly defined. However, cytokines have recently emerged as crucial signalling molecules in the pathogenesis of autoimmune encephalitis. Cytokines are biologically active, soluble, low-molecular-weight proteins or glycoproteins involved in a wide variety of physiological functions, including central nervous system development and homeostasis, immune surveillance, as well as proliferation and maturation of immune cells. Since unbalanced cytokine expression is considered a hallmark of many autoimmune central nervous system disorders, their identification and quantification has become an essential element in personalized medicine applied to the field of neuroimmunology. Several studies have explored the cytokine profile of autoimmune encephalitis, but their interpretation and comparison is challenging due to their small sample sizes and extremely high heterogeneity, especially regarding the cytokines analysed, type of sample used, and associated neural antibody. Only the cytokine profile of anti-N-methyl-D-aspartate receptor encephalitis has extensively been investigated, with findings suggesting that, although humoral immunity is the main effector, T cells may also be relevant for the development of this disorder. A better understanding of cytokine dynamics governing neuroinflammation might offer the opportunity of developing new therapeutic strategies against specific immune cells, cytokines, antibodies, or intracellular signalling cascades, therefore leading to better outcomes and preventing undesired side effects of the presently used strategies. In this review, we first summarize the current knowledge about the role of cytokines in the pathogenesis of autoimmune encephalitis, combining theoretical analysis with experimental validations, to assess their suitability as clinical biomarkers. Second, we discuss the potential applicability of the novel targeted immunotherapies in autoimmune encephalitis depending on the immunobiology of the associated antibody, their limitations, as well as the main limitations that should be addressed in future studies

Immunomodulation in the acute phase of autoimmune encephalitis

Autoimmune encephalitides constitute an emerging group of diseases for which the diagnosis and management may be challenging, and are usually associated with antibodies against neuroglial antigens used as biomarkers. In this review, we aimed to clarify the diagnostic approach to patients with encephalitis of suspected autoimmune origin in order to initiate early immunotherapy, and to summarize the evidence of current immunotherapies and alternative options assessed for refractory cases. Currently, the general therapeutic approach consists of steroids, IVIG, and/or plasma exchange as first-line medications, which should be prescribed once a diagnosis of possible autoimmune encephalitis is established. For patients not responding to these treatments, rituximab and cyclophosphamide are used as second-line immunotherapy. Additionally, alternative therapies, chiefly tocilizumab and bortezomib, have been reported to be useful in particularly refractory cases. Although the aforementioned approach with first and second-line immunotherapy is widely accepted, the best therapeutic strategy is still unclear since most available evidence is gathered from retrospective non-controlled studies. Moreover, several predictors of good long-term prognosis have been proposed such as response to first-line therapies, modified Rankin score lesser than 4 at the worst neurologic status, no need for admission in intensive care unit, and early escalation to second-line immunotherapy. Thus, the lack of solid evidence underlines the necessity of future well-conducted trials addressing both the best therapeutic regimen and the outcome predictors, but since autoimmune encephalitides have a relatively low incidence, international collaborations seem imperative to reach a reasonable study population size

Novelties in Autoimmune and Paraneoplastic Cerebellar Ataxias: Twenty Years of Progresses

Major advances in our knowledge concerning autoimmune and paraneoplastic cerebellar ataxias have occurred in the last 20 years. The discovery of several neural antibodies represents an undeniable contribution to this field, especially those serving as good biomarkers of paraneoplastic neurological syndromes and those showing direct pathogenic effects. Yet, many patients still lack detectable or known antibodies, and also many antibodies have only been reported in few patients, which makes it difficult to define in detail their clinical value. Nevertheless, a notable progress has additionally been made in the clinical characterization of patients with the main neural antibodies, which, although typically present with a subacute pancerebellar syndrome, may also show either hyperacute or chronic onsets that complicate the differential diagnoses. However, prodromal and transient features could be useful clues for an early recognition, and extracerebellar involvement may also be highly indicative of the associated antibody. Moreover, important advances in our understanding of the pathogenesis of cerebellar ataxias include the description of antibody effects, especially those targeting cell-surface antigens, and first attempts to isolate antigen-specific T-cells. Furthermore, genetic predisposition seems relevant, although differently involved according to cancer association, with particular HLA observed in non-paraneoplastic cases and genetic abnormalities in the tumor cells in paraneoplastic ones. Finally, immune checkpoint inhibitors used as cancer immunotherapy may rarely induce cerebellar ataxias, but even this undesirable effect may in turn serve to shed some light on their physiopathology. Herein, we review the principal novelties of the last 20 years regarding autoimmune and paraneoplastic cerebellar ataxias

Miller-Fisher syndrome after SARS-CoV-2 infection.

On March 11th, 2020, the WHO declared the SARS-Cov-2 pandemic. Syndromes have been detected in relation to COVID-19 such as encephalitis, acute necrotizing hemorrhagic encephalopathy and cerebrovascular complications. There are also cases of peripheral nervous system involvement. Our case would be the 3rd patient with MFS associated with COVID-19 as far as we know. We present a 51 years old female diagnosed with MFS two weeks after COVID-19. RTPCR to SARS-CoV-2 was negative but IgG was positive. Most of the cases were mild or moderate with typical signs and symptoms. All were treated with IV immunoglobulin with good response in most cases. Despite the short evolution time of the cases surviving the current pandemic, the description of cases of post-infectious neurological syndromes suggests that this is probably not an infrequent complication in the subacute stage of Covid-19 disease

Miller‐Fisher syndrome after SARS‐CoV‐2 infection

On March 11th, 2020, the WHO declared the SARS-Cov-2 pandemic. Syndromes have been detected in relation to COVID-19 such as encephalitis, acute necrotizing hemorrhagic encephalopathy and cerebrovascular complications. There are also cases of peripheral nervous system involvement. Our case would be the 3rd patient with MFS associated with COVID-19 as far as we know. We present a 51 years old female diagnosed with MFS two weeks after COVID-19. RTPCR to SARS-CoV-2 was negative but IgG was positive. Most of the cases were mild or moderate with typical signs and symptoms. All were treated with IV immunoglobulin with good response in most cases. Despite the short evolution time of the cases surviving the current pandemic, the description of cases of post-infectious neurological syndromes suggests that this is probably not an infrequent complication in the subacute stage of Covid-19 disease

Paraneoplastic neurological syndromes associated with renal or bladder cancer: case series and PRISMA-IPD systematic review

Background: The link between paraneoplastic neurological syndromes (PNS) and renal cell and bladder cancer (RCC/BC) is rare and uncertain. Our aim was to clinically evaluate, in light of the updated PNS criteria, these uncommon associations. Methods: Retrospective nationwide cohort chart review study and systematic review of the literature. Results: After excluding 5 patients due to the diagnosis of another co-occurrent malignancy, 10/18 patients with RCC and 8/18 patients with BC were identified. A total of 31 cases were previously published, yielding an overall series of 27/49 RCC and 22/49 BC patients. There was a predominance of cerebellar syndromes in both cancers (10/27, 37% for RCC; 9/22, 41% for BC), followed by encephalitis in 9/27 (33%) patients with RCC and encephalomyelitis/sensory neuronopathy in 5/22 (23%) patients with BC. The detection of high-risk Abs was more frequent among BC patients (16/19, 84% vs. 3/13, 23% in RCC, p = 0.0009), Ri antibodies being the most frequent thereof. After applying the updated PNS criteria, patients with BC met highest degrees (possible, probable, and definite) of certainty for PNS diagnosis (20/22, 91% vs. 16/27, 59% in RCC, p = 0.021). Conclusion: A second neoplasm should always be ruled out before establishing the diagnosis of PNS in patients with RCC or BC. However, while this association remains dubious for most patients with RCC, a casual role is more probable in patients with BC and high-risk antibodies presenting with cerebellar ataxia, brainstem encephalitis or encephalomyelitis/sensory neuronopathy

Análisis de letalidad por COVID-19 en pacientes con demencia neurodegenerativa

Introduction: The elderly population is the group most threatened by COVID-19, with the highest mortality rates. This study aims to analyse the case fatality of COVID-19 in a cohort of patients with degenerative dementia. Methods: We conducted a descriptive case-control study of a sample of patients diagnosed with primary neurodegenerative dementia. Results: Twenty-four of the 88 patients with COVID-19 included in the study died: 10/23 (43.4%) patients diagnosed with dementia and 14/65 (21.5%) controls; this difference was statistically significant. Discussion: Our results suggest that case fatality of COVID-19 is significantly higher among patients with primary degenerative dementia than in other patients with similar mean ages and comorbidities.Proyecto COV20/00157 financiado por fondo COVID-19 del Instituto de Salud Carlos III. España.YesIntroducción: La población anciana es la más amenazada por COVID-19, con mayores tasas de mortalidad. El objetivo de este trabajo es analizar la letalidad en una cohorte de pacientes de COVID-19 con demencia degenerativa. Métodos: Hicimos un estudio descriptivo de casos-control de una muestra de pacientes diagnosticados con demencias neurodegenerativas primarias. Resultados: De los 88 pacientes incluidos en el estudio, 24 pacientes con COVID-19 fallecieron: 10/23 (43,4%) eran pacientes con diagnóstico de demencia y 14/65 (21,5%) pacientes del grupo control, una diferencia estadísticamente significativa. Discusión: La letalidad por COVID-19 entre los pacientes con demencia degenerativa primaria es significativamente mayor en comparación con otros pacientes con edades medias y comorbilidades similares, según nuestro estudio