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Introduction: Genetic predisposition to autoimmune encephalitis with antibodies against N-methyl-D-aspartate receptor (NMDAR) is poorly understood. Given the diversity of associated environmental factors (tumors, infections), we hypothesized that human leukocyte antigen (HLA) and killer-cell immunoglobulin-like receptors (KIR), two extremely polymorphic gene complexes key to the immune system, might be relevant for the genetic predisposition to anti-NMDAR encephalitis. Notably, KIR are chiefly expressed by Natural Killer (NK) cells, recognize distinct HLA class I allotypes and play a major role in anti-tumor and anti-infection responses. Methods: We conducted a Genome Wide Association Study (GWAS) with subsequent control-matching using Principal Component Analysis (PCA) and HLA imputation, in a multi-ethnic cohort of anti-NMDAR encephalitis (n=479); KIR and HLA were further sequenced in a large subsample (n=323). PCA-controlled logistic regression was then conducted for carrier frequencies (HLA and KIR) and copy number variation (KIR). HLA-KIR interaction associations were also modeled. Additionally, single cell sequencing was conducted in peripheral blood mononuclear cells from 16 cases and 16 controls, NK cells were sorted and phenotyped. Results: Anti-NMDAR encephalitis showed a weak HLA association with DRB1*01:01~DQA1*01:01~DQB1*05:01 (OR=1.57, 1.51, 1.45; respectively), and DRB1*11:01 (OR=1.60); these effects were stronger in European descendants and in patients without an underlying ovarian teratoma. More interestingly, we found increased copy number variation of KIR2DL5B (OR=1.72), principally due to an overrepresentation of KIR2DL5B*00201. Further, we identified two allele associations in framework genes, KIR2DL4*00103 (25.4% vs. 12.5% in controls, OR=1.98) and KIR3DL3*00302 (5.3% vs. 1.3%, OR=4.44). Notably, the ligands of these KIR2DL4 and KIR3DL3, respectively, HLA-G and HHLA2, are known to act as immune checkpoint with immunosuppressive functions. However, we did not find differences in specific KIR-HLA ligand interactions or HLA-G polymorphisms between cases and controls. Similarly, gene expression of CD56dim or CD56bright NK cells did not differ between cases and controls. Discussion: Our observations for the first time suggest that the HLA-KIR axis might be involved in anti-NMDAR encephalitis. While the genetic risk conferred by the identified polymorphisms appears small, a role of this axis in the pathophysiology of this disease appears highly plausible and should be analyzed in future studies.
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Encefalitis Antirreceptor N-Metil-D-Aspartato , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Antígenos HLA , Células Asesinas Naturales , Receptores KIR , Humanos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Encefalitis Antirreceptor N-Metil-D-Aspartato/genética , Encefalitis Antirreceptor N-Metil-D-Aspartato/inmunología , Receptores KIR/genética , Femenino , Masculino , Adulto , Antígenos HLA/genética , Antígenos HLA/inmunología , Persona de Mediana Edad , Adulto JovenRESUMEN
In this report, we present a rare case of anti-Ma2-associated encephalitis concurrent with coronavirus disease 2019 (COVID-19) following breast cancer surgery. The patient exhibited minimal clinical symptoms of COVID-19 infection but developed seizures and altered mental status after surgery, leading to diagnosis of a classic paraneoplastic syndrome. This case highlights the possibility of paraneoplastic neurological syndrome even after cancer surgery and the need for careful consideration of post-acute infection syndromes when neurological symptoms occur following an infection.
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STUDY OBJECTIVES: We conducted a prospective study to quantify motor activity during sleep measured by actigraphy before and after 3 months of treatment with clonazepam in patients with video-polysomnography (vPSG) confirmed isolated rapid eye movement (REM) sleep behavior disorder (iRBD). METHODS: The motor activity amount (MAA) and the motor activity block (MAB) during sleep were obtained from actigraphy. Then, we compared quantitative actigraphic measures with the results of the REM sleep behavior disorder questionnaire for the previous 3-month period (RBDQ-3M) and of the Clinical Global Impression-Improvement scale (CGI-I), and analyzed correlations between baseline vPSG measures and actigraphic measures. RESULTS: Twenty-three iRBD patients were included in the study. After medication treatment, large activity MAA dropped in 39% of patients, and the number of MABs decreased in 30% of patients when applying 50% reduction criteria. 52% of patients showed more than 50% improvement in either one. On the other hand, 43% of patients answered "much or very much improved" on the CGI-I, and RBDQ-3M was reduced by more than half in 35% of patients. However, there was no significant association between the subjective and objective measures. Phasic submental muscle activity during REM sleep was highly correlated with small activity MAA (Spearman's rho = 0.78, p < .001) while proximal and axial movements during REM sleep correlated with large activity MAA (rho = 0.47, p = .030 for proximal movements, rho = 0.47, p = .032 for axial movements). CONCLUSIONS: Our findings imply that quantifying motor activity during sleep using actigraphy can objectively assess therapeutic response in drug trials in patients with iRBD.
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Clonazepam , Trastorno de la Conducta del Sueño REM , Humanos , Clonazepam/uso terapéutico , Actigrafía , Trastorno de la Conducta del Sueño REM/tratamiento farmacológico , Trastorno de la Conducta del Sueño REM/complicaciones , Estudios Prospectivos , Sueño REM , Actividad Motora/fisiologíaRESUMEN
STUDY OBJECTIVES: The pathomechanism of restless legs syndrome (RLS) is related to brain iron deficiency and iron therapy is effective for RLS; however, the effect of iron therapy on human brain iron state has never been studied with magnetic resonance imaging. This study aimed to investigate the change of brain iron concentrations in patients with RLS after intravenous iron therapy using quantitative susceptibility mapping (QSM). METHODS: We enrolled 31 RLS patients and 20 healthy controls. All participants underwent initial baseline (t0) assessment using brain magnetic resonance imaging, serum iron status, and sleep questionnaires including international RLS Study Group rating scale (IRLS). RLS patients underwent follow-up tests at 6 and 24 weeks (t1 and t2) after receiving 1000 mg ferric carboxymaltose. Iron content of region-of-interest on QSM images was measured for 13 neural substrates using the fixed-shaped method. RESULTS: RLS symptoms evaluated using IRLS were significantly improved after iron treatment (t0: 29.7 ± 6.5, t1: 19.5 ± 8.5, t2: 21.3 ± 10.1; p < .001). There was no significant difference in susceptibility values between the controls and RLS patients at t0. In the caudate nucleus, putamen, and pulvinar thalamus of RLS patients, the QSM values differed significantly for three timepoints (p = .035, .048, and .032, respectively). The post-hoc analysis revealed that the QSM values increased at t1 in the caudate nucleus (66.8 ± 18.0 vs 76.4 ± 16.6, p = .037) and decreased from t1 to t2 in the putamen (69.4 ± 16.3 vs 62.5 ± 13.6, p = .025). Changes in the QSM values for the pulvinar and caudate nuclei at t1 were positively and negatively correlated with symptomatic improvement, respectively (r = 0.361 and -0.466, respectively). CONCLUSIONS: Intravenous iron treatment results in changes in brain iron content which correlate to reductions in RLS severity. This suggests a connection between symptom improvement and the associated specific brain regions constituting the sensorimotor network.
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Deficiencias de Hierro , Síndrome de las Piernas Inquietas , Humanos , Hierro , Síndrome de las Piernas Inquietas/tratamiento farmacológico , Resultado del Tratamiento , Encéfalo/diagnóstico por imagen , Mapeo EncefálicoRESUMEN
Objective: To identify emotional and environmental factors that aggravate dream enactment behaviors (DEBs) in isolated rapid eye movement (REM) sleep behavior disorder (iRBD). Methods: In this cross-sectional study, a total of 96 polysomnography-confirmed iRBD patients (mean age, 68.5 years; men, 68%) and their caregivers completed questionnaires regarding potential aggravating factors related to DEBs, including emotion/feelings (stress, anger, anxiety, depressive mood, fatigue, pain), food (alcohol, caffeine, overeating in the evening, fasting/hunger), activities and sleep patterns (strenuous exercise, sex before bed, conflict/fighting, sleep deprivation, oversleeping, sleeping away from home, watching TV before bed), weather/environmental factors (cloudy or rainy weather, heat, cold, noise) and medication (skipping medication, taking hypnotics). Results: The patients reported that stress (61%) was the most aggravating factor for DEBs, followed by anxiety (56%), anger (51%), fatigue (49%), and watching TV before bed (46%). Similarly, the caregivers reported that these factors were most relevant to the aggravation of DEBs in the patients, although some factors were ranked differently. In the subgroup analyses, aggravating factors for DEBs did not differ by RBD symptom severity. Interestingly, the proportion of patients experiencing DEB aggravation by stress, anxiety and depressive mood was significantly higher in women than in men. Furthermore, depressed patients reported that stress and cloudy or rainy weather made DEBs worse than nondepressed patients. Conclusion: Our results suggest that DEBs in iRBD patients may be mainly aggravated by emotional factors. These negative effects appeared to be more prominent in female and depressed patients.
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OBJECTIVE: White matter (WM) tract-specific changes may precede gray matter loss in isolated rapid eye movement sleep behavior disorder (iRBD). We aimed to evaluate tract-specific WM changes using tract-specific statistical analysis (TSSA) and their correlation with clinical variables in iRBD patients. METHODS: This was a cross-sectional single-center study of 50 polysomnography-confirmed iRBD patients and 20 age- and sex-matched controls. We used TSSA to identify tract-specific fractional anisotropy (FA) and mean diffusivity (MD) in fourteen major fiber tracts and analyzed between-group differences in these values. Correlations between FA or MD values and clinical variables, including RBD symptom severity, depression and cognition, were evaluated. RESULTS: Patients with iRBD showed lower FA in the right anterior thalamic radiation (ATR) and higher MD in the bilateral ATR and right inferior fronto-occipital fasciculus (IF-OF) than controls after adjusting for age, sex, and years of education. MD values in the IF-OF positively correlated with scores on the Korean version of the Rapid Eye Movement Sleep Behavior Disorder Questionnaire-Hong Kong (RBDQ-KR, p = 0.042) and the Korean version of the geriatric depression scale (GDS-K, p = 0.002) in iRBD patients. Only GDS-K scores independently correlated with IF-OF MD values after adjusting for RBDQ-KR scores (adjusted p = 0.026). CONCLUSION: This study suggests WM microstructural disruption in the bilateral ATR and right IF-OF in patients with iRBD and that alterations in the IF-OF may contribute to depressive symptoms.
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Trastorno de la Conducta del Sueño REM , Sustancia Blanca , Humanos , Anciano , Sustancia Blanca/diagnóstico por imagen , Trastorno de la Conducta del Sueño REM/diagnóstico por imagen , Estudios Transversales , Anisotropía , Sustancia Gris/diagnóstico por imagenRESUMEN
BACKGROUND AND PURPOSE: Cognitive impairments are common in isolated rapid-eye-movement sleep behavior disorder (iRBD), in which the cholinergic system may play an important role. This study aimed to characterize the cortical cholinergic activity using resting-state functional connectivity (FC) of the nucleus basalis of Meynert (NBM) according to the cognitive status of iRBD patients. METHODS: In this cross-sectional study, 33 patients with polysomnography-confirmed iRBD and 20 controls underwent neuropsychological evaluations and resting-state functional magnetic resonance imaging. Thirteen of the iRBD patients had mild cognitive impairment (iRBD-MCI), and the others were age-matched patients with normal cognition (iRBD-NC). The seed-to-voxel NBM-cortical FC was compared among the patients with iRBD-MCI, patients with iRBD-NC, and controls. Correlations between average values of significant clusters and cognitive function scores were calculated in the patients with iRBD. RESULTS: There were group differences in the FC of the NBM with the left lateral occipital cortex and lingual gyrus (adjusted for age, sex, and education level). The strength of FC was lower in the iRBD-MCI group than in the iRBD-NC and control groups (each post-hoc p<0.001). The average NBM-lateral occipital cortex FC was positively correlated with the memory-domain score in iRBD patients. CONCLUSIONS: The results obtained in this study support that cortical cholinergic activity is impaired in iRBD patients with MCI. FC between NBM and posterior regions may play a central role in the cognitive function of these patients.
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Refractory status epilepticus (RSE) requires multimodal treatment approaches to achieve rapid seizure cessation and neuroprotection. A ketogenic diet (KD) has demonstrated efficacy as a nutritional therapeutic option for adult RSE. However, the group of adult RSE patients who would benefit from adopting a KD needs to be determined to appropriately select the patients indicated for a KD. Therefore, we conducted a nonrandomized retrospective cohort study to explore the therapeutic efficacy of a KD by investigating the moderation effect of a KD on the association between the clinical characteristics of RSE patients and their functional outcomes. This study investigated 140 RSE patients, including 32 patients treated with a KD; among these patients, 28 (81%) achieved seizure cessation. We found that KD moderated the reduction in the modified Rankin scale (mRS) score at discharge among patients who were older, had higher seizure severity scores, were under continuous intravenous anesthetic therapy (CIVAD), and had super-RSE. Age and seizure severity scores, but not CIVAD or super-RSE, were associated with a KD-moderated change in mRS score at 3 months. Thus, we consider that our study provides evidence of a neuroprotective effect of KD in the most severe RSE patients with very few remaining therapeutic options, but future randomized controlled trials in these subgroups of KD patients are necessary.
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Dieta Cetogénica , Fármacos Neuroprotectores , Estado Epiléptico , Adulto , Humanos , Estudios Retrospectivos , Fármacos Neuroprotectores/uso terapéutico , Estado Epiléptico/terapia , Convulsiones/tratamiento farmacológico , Terapia Combinada , Anestésicos Intravenosos/uso terapéutico , Anticonvulsivantes/uso terapéuticoRESUMEN
BACKGROUND: Neurological manifestations of COVID-19 are thought to be associated with the disease severity of COVID-19 and poor clinical outcomes. Dysregulated immune responses are considered to be mediating such complications. Our case illustrates multiple critical neurological complications simultaneously developed in a patient with non-severe COVID-19 and successful recovery with a multifaceted therapeutic approach. The cerebrospinal fluid (CSF) interleukin-6 (IL-6) level was temporally correlated with the clinical severity of the status epilepticus in our patient, suggesting a causal relationship. CASE PRESENTATION: A previously healthy 20-year-old female patient presented with a first-onset seizure. Concomitant non-severe COVID-19 pneumonia was diagnosed. CSF study showed lymphocytic pleocytosis with elevated IL-6 levels in CSF. During hospitalization under the diagnosis of autoimmune encephalitis, status epilepticus developed, and the seizure frequency was temporally correlated with the CSF IL-6 level. Furthermore, a new embolic stroke developed without a significant cardioembolic source. Contrary to the exacerbated COVID-19-associated neurological complications, COVID-19 pneumonia was cleared entirely. After treatment with antiseizure medications, antithrombotics, antiviral agents, and immunotherapy, the patient was discharged with near-complete recovery. CONCLUSION: Active serological, and radiological evaluation can be helpful even in non-severe COVID-19, and multidimensional treatment strategies, including immunotherapy, can successfully reverse the neurological complication.
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COVID-19 , Encefalitis , Estado Epiléptico , Accidente Cerebrovascular , Adulto , COVID-19/complicaciones , Femenino , Humanos , Interleucina-6 , Convulsiones/tratamiento farmacológico , Estado Epiléptico/diagnóstico , Estado Epiléptico/tratamiento farmacológico , Estado Epiléptico/etiología , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/terapia , Adulto JovenRESUMEN
Seizure is a common neurological presentation in patients visiting the emergency department (ED) that requires time for evaluation and observation. Timely decision and disposition standards for seizure patients need to be established to prevent overcrowding in the ED and achieve patients' safety. Here, we conducted a retrospective cohort study to predict early seizure recurrence in the ED (ES-RED). We randomly assigned 688 patients to the derivation and validation cohorts (2:1 ratio). Prediction equations extracted routine clinical and laboratory information from EDs using logistic regression (Model 1) and machine learning (Model 2) methods. The prediction equations showed good predictive performance, the area under the receiver operating characteristics curve showing 0.808 in Model 1 [95% confidential interval (CI): 0.761-0.853] and 0.805 in Model 2 [95% CI: 0.747-0.857] in the derivation cohort. In the external validation, the models showed strong prediction performance of 0.739 [95% CI: 0.640-0.824] in Model 1 and 0.738 [95% CI: 0.645-0.819] in Model 2. Intriguingly, the lowest quartile group showed no ES-RED after 6 h. The ES-RED calculator, our proposed prediction equation, would provide strong evidence for safe and appropriate disposition of adult resolved seizure patients from EDs, reducing overcrowding and delays and improving patient safety.
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Device-assisted enteroscopy (DAE) enables the direct visualization of small bowel lesions with histological diagnosis; however, few studies have described the diagnostic performance of enteroscopic biopsy. We investigated the diagnostic performance of enteroscopic biopsy. We used a nationwide multicenter enteroscopy database to identify patients who underwent DAE with biopsy for small bowel diseases. The patients were classified into the tumor and non-tumor groups according to the final diagnosis. They were also divided into diagnostic and non-diagnostic groups based on the enteroscopic biopsy results. The clinical significance of the first biopsy and histological diagnostic yield of DAE were analyzed. Among the 112 procedures investigated, 32 (28.9%) were diagnosed with tumors, and 80 (71.7%) were diagnosed with non-tumor diseases. The overall histological diagnostic yield of DAE was 43.7%. The histological diagnostic yield was significantly higher in the tumor than in the non-tumor group (81.2% vs. 28.8%, p < 0.001). The mean number of biopsies was significantly higher in the diagnostic than in the non-diagnostic group (5.6 ± 3.3 vs. 3.7 ± 2.1, p = 0.001). In the diagnostic group, 87.7% of the cases were histologically confirmed at the first biopsy. Therefore, the first biopsy should be performed carefully.
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OBJECTIVE: Mild cognitive impairment (MCI) was found in 30-50% of the isolated REM sleep behavior disorder (iRBD) patients. Furthermore, it is known that patients with Parkinson's disease have attention network defects. Given that iRBD is known to be the prodromal disease of α-synucleinopathies, our aim was to investigate whether there are attention network dysfunctions in iRBD patients following the presence of MCI. METHODS: 14 healthy controls, 48 iRBD patients, 24 with MCI and 24 without MCI, were included in this study. Attention network task (ANT) was used to assess alerting, orienting, and executive control networks. Event-related potentials (ERPs) and behavioral performances were recorded during the ANT. Parietal N1 and P3 components were analyzed to find effects of the three attention networks. RESULTS: IRBD patients without MCI showed neuropsychological, behavioral, and ERP results similar to those of healthy controls. On the other hand, iRBD patients with MCI showed a general decline in cognitive domains with no alerting effect (controls, p = 0.043; iRBD-noMCI, p = 0.014; iRBD-MCI, p = 0.130) while preserving orienting and executive control effect. Furthermore, iRBD patients with MCI had impairments in executive function and verbal memory domains, compared to iRBD patients without MCI. CONCLUSIONS: Our findings indicate that when cognition is reduced to MCI levels in iRBD patients, the attention network, especially the alerting component, is impaired. The attention network and cognition, on the other hand, can be preserved in iRBD patients due to the compensatory mechanism.
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Disfunción Cognitiva , Trastorno de la Conducta del Sueño REM , Sinucleinopatías , Cognición , Función Ejecutiva , HumanosRESUMEN
BACKGROUND: Campylobacter spp., common commensals in the gastrointestinal tract of animals, especially poultry, can cause acute gastrointestinal illness in humans through animal-to-human transmission. Although Campylobacter fetus, especially subspecies fetus, rarely leads to systemic infections such as bacteremia in immunocompromised patients, it is unclear whether Campylobacter fetus subspecies venerealis (Cfv) causes infectious diseases in humans. CASE PRESENTATION: A 28-year-old man with a history of chronic alcoholism visited the emergency department with weakness of the left extremities. The patient was clinically diagnosed with community-acquired bacterial meningitis. The organism from the blood culture was subsequently identified as Campylobacter fetus. On phylogenetic analysis, the 16S rRNA sequence showed 99.93% similarity with other Cfv 16S rRNA sequences. The patient had no exposure to identifiable sources except for close contact with a companion dog, which could have been a possible source of transmission. CONCLUSIONS: This case suggests that Cfv could lead to human systemic infections such as meningitis and that companion animals, in addition to well-known animal hosts, could be sources of transmission.
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Infecciones por Campylobacter , Campylobacter , Meningitis , Animales , Campylobacter/genética , Infecciones por Campylobacter/diagnóstico , Infecciones por Campylobacter/veterinaria , Campylobacter fetus/genética , Perros , Humanos , Mascotas , Filogenia , ARN Ribosómico 16S/genética , Adulto JovenRESUMEN
This study aimed to evaluate the sensitivity and prognostic value of arterial spin labeling (ASL) in a large group of status epilepticus (SE) patients and compare them with those of other magnetic resonance (MR) sequences, including dynamic susceptibility contrast (DSC) perfusion imaging. We retrospectively collected data of patients with SE in a tertiary center between September 2016 and March 2020. MR images were visually assessed, and the sensitivity for the detection of SE and prognostication was compared among multi-delay ASL, DSC, fluid-attenuated inversion recovery (FLAIR), and diffusion-weighted imaging (DWI). We included 51 SE patients and 46 patients with self-limiting seizures for comparison. Relevant changes in ASL were observed in 90.2% (46/51) of SE patients, a percentage higher than those for DSC, FLAIR, and DWI. ASL was the most sensitive method for initial differentiation between SE and self-limiting seizures. The sensitivity of ASL for detecting refractory SE (89.5%) or estimating poor outcomes (100%) was higher than those of other MR protocols or electroencephalography and comparable to those of clinical prognostic scores, although the specificity of ASL was very low as 9.4% and 15.6%, respectively. ASL showed a better ability to detect SE and predict the prognosis than other MR sequences, therefore it can be valuable for the initial evaluation of patients with SE.
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Encéfalo/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Marcadores de Spin , Estado Epiléptico/diagnóstico por imagen , Anciano , Mapeo Encefálico , Circulación Cerebrovascular , Imagen de Difusión por Resonancia Magnética/métodos , Electroencefalografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Perfusión , Imagen de Perfusión , Valor Predictivo de las Pruebas , Pronóstico , Curva ROC , Reproducibilidad de los Resultados , Estudios Retrospectivos , Sensibilidad y Especificidad , Resultado del TratamientoRESUMEN
We analyzed 136 patients (age, 67.5 ± 6.9 years; men, 59.6%) with idiopathic rapid eye movement sleep behavior disorder (iRBD). The results of the neuropsychological tests were not significantly different between APOE ε4 carriers and noncarriers, suggesting that the APOE ε4 allele was not associated with cognitive impairment in iRBD.
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Apolipoproteína E4/genética , Disfunción Cognitiva/genética , Trastorno de la Conducta del Sueño REM/genética , Trastorno de la Conducta del Sueño REM/psicología , Anciano , Alelos , Apolipoproteína E4/sangre , Estudios Transversales , Femenino , Genotipo , Humanos , Masculino , Pruebas NeuropsicológicasRESUMEN
Treatment of super-refractory status epilepticus (SRSE) is associated with various complications of anaesthetic coma therapy. This study aimed to describe the factors affecting the prognosis, especially in-hospital mortality, of patients receiving pentobarbital coma therapy for the treatment of SRSE. This was a retrospective cohort study conducted in a single tertiary referral centre with patients who received pentobarbital coma therapy for the treatment of SRSE from 2006 to 2018. Exploratory analyses were performed for clinical, laboratory, electrographic, and radiological factors for the entire cohort and were compared between the mortality and survivor groups. In total, 19 patients were enrolled, and five (26.3%) patients died in the hospital. The maximal pentobarbital infusion dose was higher in the mortality group than in the survivor group (4.4±1.0 mg/kg/h vs. 2.9±1.4 mg/kg/h, respectively; p=0.025). The high-dose pentobarbital infusion group (>3.75 mg/kg/h) underwent longer mechanical ventilation (24 [20-36.75] vs. 41 [28-70], p=0.025) and blood culture results were more frequently positive, suggestive of septicaemia (8.3% vs. 57.1%, p=0.038). The group of SRSE patients treated with pentobarbital coma therapy who died in the hospital received a higher pentobarbital infusion dose compared to survivors; a complication of high-dose pentobarbital infusion was septicaemia. Considering the high rate of septicaemia observed, systematic treatment strategies focusing on infectious complications should be established and implemented. The association between maximal pentobarbital infusion dose and in-hospital mortality needs to be further validated.