Neurologic complications in herpes simplex encephalitis: clinical, immunological and genetic studies.

Patients with herpes simplex virus (HSV) encephalitis (HSE) often develop neuronal autoantibody-associated encephalitis (AE) post-infection. Risk factors of AE are unknown. We tested the hypotheses that predisposition for AE post-HSE may be involved, including genetic variants at specific loci, human leucocyte (HLA) haplotypes, or the blood innate immune response against HSV, including type I interferon (IFN) immunity. Patients of all ages with HSE diagnosed between 1 January 2014 and 31 December 2021 were included in one of two cohorts depending on whether the recruitment was at HSE onset (Spanish Cohort A) or by the time of new neurological manifestations (international Cohort B). Patients were assessed for the type of neurological syndromes; HLA haplotypes; blood type I-IFN signature [RNA quantification of 6 or 28 IFN-response genes (IRG)] and toll-like receptor (TLR3)-type I IFN-related gene mutations. Overall, 190 patients (52% male) were recruited, 93 in Cohort A and 97 in Cohort B. Thirty-nine (42%) patients from Cohort A developed neuronal autoantibodies, and 21 (54%) of them developed AE. Three syndromes (choreoathetosis, anti-NMDAR-like encephalitis and behavioural-psychiatric) showed a high (≥95% cases) association with neuronal autoantibodies. Patients who developed AE post-HSE were less likely to carry the allele HLA-A*02 (4/21, 19%) than those who did not develop AE (42/65, 65%, P = 0.0003) or the Spanish general population (2005/4335, 46%, P = 0.0145). Blood IFN signatures using 6 or 28 IRG were positive in 19/21 (91%) and 18/21 (86%) patients at HSE onset, and rapidly decreased during follow-up. At Day 21 after HSE onset, patients who later developed AE had higher median IFN signature compared with those who did not develop AE [median Zs-6-IRG 1.4 (0.6; 2.0) versus 0.2 (-0.4; 0.8), P = 0.03]. However, a very high median Zs-6-IRG (>4) or persistently increased IFN signature associated with uncontrolled viral infection. Whole exome sequencing showed that the percentage of TLR3-IFN-related mutations in patients who developed AE was not different from those who did not develop AE [3/37 (8%) versus 2/57 (4%), P = 0.379]. Multivariate logistic regression showed that a moderate increase of the blood IFN signature at Day 21 (median Zs-6-IRG >1.5 but <4) was the most important predictor of AE post-HSE [odds ratio 34.8, interquartile ratio (1.7-691.9)]. Altogether, these findings show that most AE post-HSE manifest with three distinct syndromes, and HLA-A*02, but not TLR3-IFN-related mutations, confer protection from developing AE. In addition to neuronal autoantibodies, the blood IFN signature in the context of HSE may be potentially useful for the diagnosis and monitoring of HSE complications.

Anti-Zic4 paraneoplastic cerebellar degeneration in a patient with EGFR-mutated NSCLC: a case report.

Paraneoplastic cerebellar degeneration (PCD) is one of the most prevalent neurological paraneoplastic syndromes, typically associated with small cell lung cancer (SCLC). PCD is thought to be caused by proteins expressed by tumor cells which trigger an antibody-mediated immune response. Despite PCD being commonly associated with anti-Yo, anti-Hu and anti-Tr/DNER antibodies, PCD is the most prevalent paraneoplastic syndrome in patients harboring anti-Zic4 antibodies. We report what, to our knowledge, is the first known case of anti-Zic4 mediated PCD in a patient with EGFR-mutated metastatic non-small cell lung cancer (NSCLC). Our patient was in complete response (CR) to targeted therapy and presented to the emergency room with drowsiness, unsteady gait and memory lapses. The diagnostic work-up revealed a diffuse cerebellar atrophy in the MRI, ruling out brain metastasis and leptomeningeal carcinomatosis. A body-CT scan showed no signs of recurrent disease. The cerebrospinal fluid (CSF) was within normal parameters. An onconeural antibody panel was conducted in a peripheral blood sample, detecting high levels of anti-Zic4 antibody by indirect immunofluorescence (IFI), results later confirmed by immunoblot testing. With the suspected diagnosis of an anti-Zic4 PCD, the case was discussed with the neurology department and treatment with high dose methylprednisolone was initiated. Considering the lack of substantial clinical benefit, the patient was then treated with intravenous immunoglobulins (IVIG) for 5 days, showing modest improvement. At this time, the patient presented minor disease relapse in the form of a sub-centimetric pulmonary nodule. Despite one cycle of chemotherapy, the patient's neurological condition deteriorated leading to fatal pneumonia secondary to progressive dysphagia. There is scarce evidence of paraneoplastic syndromes in EGFR-mutated NSCLC. Further research is warranted to stablish a possible association between anti-Zic4 and the EGFR molecular pathway.

Amnesia global aguda como forma exclusiva de presentación de infarto talámico: un reto diagnóstico / Acute global amnesia as an exclusive presenting symptom of thalamic infarct: a diagnostic challenge

Introducción. La amnesia aguda aislada es una forma excepcional de presentación del ictus talámico. Se analizan el perfil clínico, el diagnóstico, el tratamiento y el pronóstico de estos pacientes. Casos clínicos. Revisión retrospectiva de los casos de infarto talámico que se presentaron exclusivamente como amnesia aguda en nuestro hospital terciario universitario (n = 3) y revisión de casos similares en PubMed (n = 20). El 48% presentaba al menos un factor de riesgo de ictus (hipertensión arterial, dislipidemia, diabetes mellitus, fibrilación auricular o ictus previo). La amnesia fue anterógrada en tres casos (13%) y global en los otros 20 (87%). El infarto se detectó en estudio de neuroimagen en las primeras 24 horas en un paciente (4%) y posteriormente en los demás, y la media de días hasta el diagnóstico fue de 11. La tomografía computarizada inicial fue normal en cinco (22%) pacientes. Precisaron estudio por resonancia magnética ocho (35%) casos para detectar el infarto. De éstos, cuatro sujetos se estudiaron directamente con resonancia magnética. La amnesia presentó una mejoría clara en ocho (35%) pacientes, y la recuperación fue completa en tres (13%). Las secuelas mnésicas que interferían la capacidad funcional se presentaron en 15 pacientes (65%). La clínica persistió menos de 24 horas en dos pacientes (9%). Ningún caso recibió tratamiento revascularizador en fase aguda. Conclusión. Los infartos talámicos que comienzan de forma exclusiva con amnesia presentan notables dificultades diagnósticas que repercuten negativamente en su tratamiento en la fase aguda. Estos infartos pueden producir un déficit mnésico funcionalmente discapacitante en un porcentaje elevado de pacientes

Introduction. Isolated acute amnesia is an exceptional presenting symptom of thalamic stroke. This study analyses the clinical profile, the diagnosis, the treatment and the prognosis of these patients. Case reports. We conducted a retrospective review of the cases of thalamic infarct that presented exclusively as acute amnesia in our university tertiary hospital (n = 3) and a review of similar cases in PubMed (n = 20). 48% presented at least one risk factor of stroke (arterial hypertension, dyslipidaemia, diabetes mellitus, atrial fibrillation or a previous stroke). Amnesia was anterograde in three cases (13%) and global in the remaining 20 (87%). The infarct was detected in neuroimaging studies carried out within the first 24 hours in one patient (4%) and later in all the others; the average time until a diagnosis was established was 11 days. The initial CT scan was normal in five patients (22%). Eight cases (35%) required magnetic resonance imaging to detect the infarct. Of these, four subjects were studied directly with MR imaging. Amnesia clearly improved in eight patients (35%), and three of them (13%) made a full recovery. Fifteen patients (65%) presented mnemonic sequelae that interfered with their functional capacity. The clinical picture lasted less than 24 hours in two patients (9%). None of the cases received revasculisation therapy in the acute phase. Conclusion. The diagnosis of thalamic infarcts that begin exclusively with amnesia is very difficult and this has negative repercussions on their treatment in the acute phase. These infarcts can produce a functionally disabling memory deficit in a high percentage of patients

Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and retrospective analysis.

BACKGROUND: Herpes simplex encephalitis can trigger autoimmune encephalitis that leads to neurological worsening. We aimed to assess the frequency, symptoms, risk factors, and outcomes of this complication. METHODS: We did a prospective observational study and retrospective analysis. In the prospective observational part of this study, we included patients with herpes simplex encephalitis diagnosed by neurologists, paediatricians, or infectious disease specialists in 19 secondary and tertiary Spanish centres (Cohort A). Outpatient follow-up was at 2, 6, and 12 months from onset of herpes simplex encephalitis. We studied another group of patients retrospectively, when they developed autoimmune encephalitis after herpes simplex encephalitis (Cohort B). We compared demographics and clinical features of patients who developed autoimmune encephalitis with those who did not, and in patients who developed autoimmune encephalitis we compared these features by age group (patients ≤4 years compared with patients >4 years). We also used multivariable binary logistic regression models to assess risk factors for autoimmune encephalitis after herpes simplex encephalitis. FINDINGS: Between Jan 1, 2014, and Oct 31, 2017, 54 patients with herpes simplex encephalitis were recruited to Cohort A, and 51 were included in the analysis (median age 50 years [IQR 5-68]). At onset of herpes simplex encephalitis, none of the 51 patients had antibodies to neuronal antigens; during follow-up, 14 (27%) patients developed autoimmune encephalitis and all 14 (100%) had neuronal antibodies (nine [64%] had NMDA receptor [NMDAR] antibodies and five [36%] had other antibodies) at or before onset of symptoms. The other 37 patients did not develop autoimmune encephalitis, although 11 (30%) developed antibodies (n=3 to NMDAR, n=8 to unknown antigens; p<0·001). Antibody detection within 3 weeks of herpes simplex encephalitis was a risk factor for autoimmune encephalitis (odds ratio [OR] 11·5, 95% CI 2·7-48·8; p<0·001). Between Oct 7, 2011, and Oct 31, 2017, there were 48 patients in Cohort B with new-onset or worsening neurological symptoms not caused by herpes simplex virus reactivation (median age 8·8 years [IQR 1·1-44·2]; n=27 male); 44 (92%) patients had antibody-confirmed autoimmune encephalitis (34 had NMDAR antibodies and ten had other antibodies). In both cohorts (n=58 patients with antibody-confirmed autoimmune encephalitis), patients older than 4 years frequently presented with psychosis (18 [58%] of 31; younger children not assessable). Compared with patients older than 4 years, patients aged 4 years or younger (n=27) were more likely to have shorter intervals between onset of herpes simplex encephalitis and onset of autoimmune encephalitis (median 26 days [IQR 24-32] vs 43 days [25-54]; p=0·0073), choreoathetosis (27 [100%] of 27 vs 0 of 31; p<0·001), decreased level of consciousness (26 [96%] of 27 vs seven [23%] of 31; p<0·001), NMDAR antibodies (24 [89%] of 27 vs 19 [61%] of 31; p=0·033), and worse outcome at 1 year (median modified Rankin Scale 4 [IQR 4-4] vs 2 [2-3]; p<0·0010; seizures 12 [63%] of 19 vs three [13%] of 23; p=0·001). INTERPRETATION: The results of our prospective study show that autoimmune encephalitis occurred in 27% of patients with herpes simplex encephalitis. It was associated with development of neuronal antibodies and usually presented within 2 months after treatment of herpes simplex encephalitis; the symptoms were age-dependent, and the neurological outcome was worse in young children. Prompt diagnosis is important because patients, primarily those older than 4 years, can respond to immunotherapy. FUNDING: Mutua Madrileña Foundation, Fondation de l'Université de Lausanne et Centre Hospitalier Universitaire Vaudois, Instituto Carlos III, CIBERER, National Institutes of Health, Generalitat de Catalunya, Fundació CELLEX.

Síndrome del cóndilo occipital como primera manifestación de un carcinoma hepatocelular metastásico. Presentación de dos casos / Occipital condyle syndrome as the first symptom of a metastatic hepatocellular carcinoma. Two case reports

Introducción. El síndrome del cóndilo occipital consiste en la presencia de cefalea occipital unilateral que empeora con los movimientos cefálicos y se acompaña de parálisis del XII par ipsilateral. La infiltración de la base del cráneo por metástasis óseas se encuentra entre sus etiologías, especialmente las que afectan por infiltración al nervio hipogloso en su paso a través del canal óseo. Casos clínicos. Se presentan dos casos clínicos de síndrome del cóndilo occipital secundario a un hepatocarcinoma metastásico. El primero, un varón de 52 años con cirrosis hepática secundaria a hepatopatía por virus de la hepatitis C, con síndrome del cóndilo occipital como síntoma inicial en un hepatocarcinoma diseminado; y el segundo, un varón de 56 años, tras recidiva de un hepatocarcinoma después de un trasplante hepático, a pesar de no cumplir los criterios de Milán. Conclusión. El síndrome del cóndilo occipital es un síntoma de alarma y requiere realizar un estudio completo mediante pruebas de imagen, puesto que puede ser la primera manifestación de un hepatocarcinoma oculto (AU)

Introduction. Occipital condyle syndrome consists of the presence of unilateral occipital headache exacerbated by moving the head and is accompanied by paralysis of the ipsilateral hypoglossal nerve. One of its causes is infiltration of the base of the skull by bone metastases, especially those affecting the hypoglossal nerve due to infiltration as it passes through the osseous canal. Case reports. We report two clinical cases of occipital condyle syndrome secondary to metastatic hepatocarcinoma. The first is that of a 52-year-old male with liver cirrhosis secondary to liver pathology caused by hepatitis C virus with occipital condyle syndrome as the presenting symptom in disseminated hepatocarcinoma. The second case is that of a 56-year-old male after recurrence of hepatocarcinoma following a liver transplant, despite not fulfilling the Milan criteria. Conclusion. Occipital condyle syndrome is an alarm symptom and requires a thorough study by means of imaging tests, since it may be the first symptom of an undetected hepatocarcinoma (AU)

Association of anti-Yo, anti-Hu and antiSOX1 antibodies in CSF in a patient with limbic and paralimbic encephalitis in the setting of small cell lung carcinoma: case presentation with review of the literatura

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El tarantismo en España en el siglo XVIII: latrodectismo y sugestión / Tarantism in Spain in the eighteen century: latrodectism and suggestion

Introducción. El tarantismo es la enfermedad producida por la picadura de la tarántula, en la que la música de la tarantela desencadena un baile involuntario. Se conoce en Italia desde el siglo XVI. Objetivo. Analizar el tarantismo descrito en España a finales del siglo XVIII, atendiendo especialmente a sus aspectos neurológicos, y proponer su explicación médica y psicopatológica. Desarrollo. En 1782 hubo una epidemia de afectados por picadura de tarántula en España. Médicos españoles describieron correctamente los efectos clínicos, idénticos a los provocados por la picadura de la araña viuda negra (Latrodectus tredecimguttatus), identificada en la época como tarántula. Los casos descritos por Francisco Xavier Cid curaban con el baile involuntario provocado por la tarantela, como se describía en Italia desde el siglo xvi. Interpretamos el efecto curativo de este baile en España como un fenómeno de sugestión. En los pacientes españoles no se producían los trastornos del comportamiento, las recidivas periódicas ni la afectación colectiva descritos por autores italianos, y que sugieren un fenómeno histérico, probablemente continuación de la manía danzante de la Edad Media. Conclusiones. El tarantismo descrito en España en el siglo XVIII incluye dos fenómenos distintos: los síntomas sistémicos producidos de la mordedura de la tarántula, que es en realidad un latrodectismo, y el efecto curativo de la tarantela, lo cual se explica por un fenómeno de sugestión. Los trastornos psíquicos falsamente asociados a la picadura de la tarántula observados en Italia, de origen histérico, no estuvieron presentes en los casos españoles de tarantismo del siglo XVIII (AU)

Introduction. Tarantism is the disease caused by the bite of the tarantula, in which the music tarantella triggers an involuntary dance. It is known in Italy since the sixteenth century. Aim. To analyze the tarantism reported in Spain at the end of the eighteenth century, with special attention to its neurological aspects, and to propose its medical and psychopathological explanation. Development. An epidemic of people affected by the tarantula bite occurred in Spain in 1782. Spanish doctors described appropriately the clinical effects, identical to those produced by the bite of the spider black widow (Latrodectus tredecimguttatus), which was at that time identified as a tarantula. The cases reported by Francisco Xavier Cid cured with the involuntary dance triggered by the tarantella, as was described in Italy since the sixteenth century. Our interpretation is that this curative effect of dance in Spain was induced by suggestion. In Spanish patients there were no behavioral disturbances, periodic recurrences or collective involvement as those reported by Italian authors, which suggest an hysterical phenomenon, probably a continuation of the dancing mania of the Middle Age. Conclusions. Tarantism reported in Spain in the eighteenth century includes two different phenomena: the systemic symptoms produced by the tarantula bite, which is actually latrodectism, and the curative effect of the tarantella, explained by suggestion. The psychiatric disturbances, with a hysterical nature, falsely associated to the tarantula bite, observed in Italy, were not present among the Spanish cases of tarantism in the eighteenth century (AU)

Substantia Nigra Echogenicity Predicts Response to Drug Withdrawal in Suspected Drug-Induced Parkinsonism.

INTRODUCTION: Response to drug withdrawal in patients with suspected drug-induced parkinsonism (DIP) is of prognostic and therapeutic importance, but cannot be predicted solely on clinical information. The aim of this study was to validate SN hyperechogenicity (SN+) assessed by transcranial sonography as a predictor of response to drug withdrawal in this group of patients. METHODS: Patients were diagnosed according to previously published criteria and prospectively included in the study. All patients were followed until complete recovery of parkinsonian symptoms or at least for 6 months after discontinuation of the offending drug and then diagnosed as DIP or parkinsonism following neuroleptic exposure (PFNE). Transcranial sonography (TCS) findings were compared with the clinical diagnosis. RESULTS: Sixty patients comprised the group for the final analysis. Sixteen patients were classified as PFNE and 44 as DIP. The area of SN echogenicity was significantly increased in the PFNE group (0.23 cm2; standard deviation [SD]: 0.04), compared to the DIP group (0.14 cm2; SD, 0.05; one-way analysis of variance; P < 0.001). Normal SN was significantly associated with complete recovery after withdrawal of the parkinsonism-inducing drug (P < 0.0005). Accuracy of SN+ to distinguish PFNE from DIP was: sensitivity 81.2%; specificity 84.1%; positive predictive value 47.4%; and negative predictive value 96.2%. CONCLUSIONS: We believe that SN+ assessed with TCS is a valid prognostic marker in the setting of suspected DIP. It is a nonexpensive, feasible technique that can be implemented for proper counseling and guidance of treatment decisions.

Utilización de haloperidol en un paciente con síndrome de encefalomiopatía mitocondrial, acidosis láctica y episodios parecidos a ictus (síndrome MELAS) / Using haloperidol in a patient with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS síndrome)

El síndrome de MELAS (del inglés: mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes) es una enfermedad de herencia materna caracterizada por una alteración en la cadena respiratoria mitocondrial. Además de la encefalopatía, la miopatía y los fenómenos que simulan ictus, entre sus síntomas también se encuentran manifestaciones psiquiátricas, sobre todo deterioro cognitivo, trastornos afectivos, psicosis y ansiedad. Debido a la escasa prevalencia de esta enfermedad, existen pocas referencias respecto al tratamiento de sus síntomas psiquiátricos. Muchos de los neurolépticos empleados en la práctica clínica habitual han demostrado toxicidad únicamente in vitro sobre la cadena respiratoria mitocondrial, por lo que su uso se desaconseja en estos pacientes. Presentamos un caso de un varón con diagnóstico de síndrome de MELAS mediante estudio genético que demostró la mutación A3243G de MELAS en el gen MT-TL1 del ADN mitocondrial. El paciente, además de las manifestaciones clásicas de la enfermedad, presentaba agitación psicomotriz, insomnio y alteraciones conductuales agudas con heteroagresividad, que, tras el ensayo de múltiples fármacos, únicamente lograron controlarse mediante la administración intravenosa de haloperidol, sin empeorar las manifestaciones neurológicas de la enfermedad. El presente caso evidencia que el empleo de haloperidol en el tratamiento agudo de las manifestaciones psiquiátricas de las enfermedades mitocondriales puede ser seguro y eficaz (AU)

Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome is a maternally inherited disease characterised by an anomaly in the mitochondrial respiratory chain complex. Apart from encephalopathy, myopathy and stroke-like episodes, these patients can also develop psychiatric symptoms such as dementia, affective disorders, psychosis, and anxiety phenomena. Because of the low prevalence of this syndrome, there are few references about the management of its psychiatric comorbidity. In mitochondrial diseases, neuroleptic agents are not recommended because they have demonstrated in vitro toxicity over the mitochondrial respiratory chain. The case is presented of a patient with a diagnosis of MELAS syndrome confirmed by the detection of a A3243G mutation in the MT-TL1 gene encoding part of the mitochondrial DNA. This patient did not only show the classic manifestations of the disease, but also presented with psychomotor agitation, insomnia and behavioural disturbances with aggressiveness. Several drugs were ineffective, but intravenous haloperidol induced remission without worsening of the neurological manifestations. This case suggests that haloperidol may be safe and effective for the acute control of psychiatric symptoms in mitochondrial syndromes (AU)

[Gustavo Pittaluga and the expedition to study sleeping sickness in the Spanish territories of the Gulf of Guinea (1909)]. / Gustavo Pittaluga y la expedición para el estudio de la enfermedad del sueño en los territorios españoles del golfo de Guinea (1909).

INTRODUCTION: Sleeping sickness, or human African trypanosomiasis, caused an important mortality at the beginnings of the twentieth century. For this reason the European colonial countries organized several scientific expeditions which contributed decisively to the knowledge of the disease. AIM: To study the first investigation performed in Spain on African trypanosomiasis and in the field of tropical medicine, which was accomplished by a scientific expedition to the Spanish territories in the Gulf of Guinea organized by Cajal in 1909. DEVELOPMENT: The parasitologist Gustavo Pittaluga, who became one of the most outstanding figures in Spanish medicine and public health during the first third of the twentieth century, commanded the expedition. Other members were Luis Rodriguez Illera and Jorge Ramon Fananas, Cajal's son. Along four months they travelled through the Spanish territories of Guinea, collecting clinical and epidemiological information on sleeping sickness and other diseases, and examining a great number of patients, who had hematological and parasitological studies performed. In the clinical description of the 14 cases of trypanosomiasis studied we have found the first description of the opsoclonus-myoclonus syndrome. A pathological study of the brain was performed in one case. In addition, important entomological studies and experimental investigations on trypanosomiasis were also performed. CONCLUSIONS: This expedition took place in the context of the impulse of renovation of Spanish science headed by Cajal through the Junta de Ampliacion de Estudios, recently created. In the investigations performed in Guinea, Pittaluga demonstrated a high scientific standard in the fields of clinical medicine, hygiene, parasitology and entomology, comparable with other contemporary European studies.