Pathogenic Variants in NUP214 Cause "Plugged" Nuclear Pore Channels and Acute Febrile Encephalopathy.

We report biallelic missense and frameshift pathogenic variants in the gene encoding human nucleoporin NUP214 causing acute febrile encephalopathy. Clinical symptoms include neurodevelopmental regression, seizures, myoclonic jerks, progressive microcephaly, and cerebellar atrophy. NUP214 and NUP88 protein levels were reduced in primary skin fibroblasts derived from affected individuals, while the total number and density of nuclear pore complexes remained normal. Nuclear transport assays exhibited defects in the classical protein import and mRNA export pathways in affected cells. Direct surface imaging of fibroblast nuclei by scanning electron microscopy revealed a large increase in the presence of central particles (known as "plugs") in the nuclear pore channels of affected cells. This observation suggests that large transport cargoes may be delayed in passage through the nuclear pore channel, affecting its selective barrier function. Exposure of fibroblasts from affected individuals to heat shock resulted in a marked delay in their stress response, followed by a surge in apoptotic cell death. This suggests a mechanistic link between decreased cell survival in cell culture and severe fever-induced brain damage in affected individuals. Our study provides evidence by direct imaging at the single nuclear pore level of functional changes linked to a human disease.

Developing a mouse model of acute encephalopathy using low-dose lipopolysaccharide injection and hyperthermia treatment.

IMPACT STATEMENT: Acute encephalopathy (AE), mainly reported in East Asia, is classified into four categories based on clinical and neuropathological findings. Among them, AE caused by cytokine storm is known as the severest clinical entity that causes cerebral edema with poor prognosis. Because suitable and convenient model animal of AE had not been developed, the treatment of patients with AE is not established. In the present study, we established a simple and convenient protocol to mimic AE due to cytokine storm. Our model animal should be useful to elucidate the pathogenesis of AE.

Influenza A (H1N1)-associated severe complications; hemolytic uremic syndrome, myocarditis, acute necrotizing encephalopathy.

Influenza is a generally self-limited infection agent that only rarely causes severe complications. To increase awareness about its serious complications, we report three cases of influenza A (H1N1) infection complicated with hemolytic uremic syndrome, myocarditis and acute necrotizing encephalopathy. In all three cases, nasopharyngeal samples confirmed influenza A (H1N1) infection by antigen test and multiplex PCR detection. The first case, a 3-year-old girl, had respiratory distress, anemia, thrombocytopenia and renal failure at admission, and was diagnosed with hemolytic uremic syndrome. Supportive treatment and oseltamivir did not prevent the development of chronic renal failure. The second case, a 5-year-old girl admitted with lethargia and flu-like symtoms and was diagnosed with myocarditis and cardiogenic shock. Oseltamivir and supportive treatment including extra-corporeal membrane oxygenation (ECMO) failed. She died on the 3rd day of admission. The third case, a 21-month-old boy, presented with decreased level of consciousness and was diagnosed with acute necrotizing encephalopathy with the aid of cranial magnetic resonance imagining (MRI). He was discharged without any neurological sequelae three weeks after admission. It should be kept in mind that influenza virus does not always cause a self-limited flu. Multidisciplinary management, early diagnosis and antiviral treatment are critical for the disease and to prevent its life-threatening complications.

The inter-rater reliability and prognostic value of coma scales in Nepali children with acute encephalitis syndrome.

Background Acute encephalitis syndrome (AES) is a common cause of coma in Nepali children. The Glasgow coma scale (GCS) is used to assess the level of coma in these patients and predict outcome. Alternative coma scales may have better inter-rater reliability and prognostic value in encephalitis in Nepali children, but this has not been studied. The Adelaide coma scale (ACS), Blantyre coma scale (BCS) and the Alert, Verbal, Pain, Unresponsive scale (AVPU) are alternatives to the GCS which can be used. Methods Children aged 1-14 years who presented to Kanti Children's Hospital, Kathmandu with AES between September 2010 and November 2011 were recruited. All four coma scales (GCS, ACS, BCS and AVPU) were applied on admission, 48 h later and on discharge. Inter-rater reliability (unweighted kappa) was measured for each. Correlation and agreement between total coma score and outcome (Liverpool outcome score) was measured by Spearman's rank and Bland-Altman plot. The prognostic value of coma scales alone and in combination with physiological variables was investigated in a subgroup (n = 22). A multivariable logistic regression model was fitted by backward stepwise. Results Fifty children were recruited. Inter-rater reliability using the variables scales was fair to moderate. However, the scales poorly predicted clinical outcome. Combining the scales with physiological parameters such as systolic blood pressure improved outcome prediction. Conclusion This is the first study to compare four coma scales in Nepali children with AES. The scales exhibited fair to moderate inter-rater reliability. However, the study is inadequately powered to answer the question on the relationship between coma scales and outcome. Further larger studies are required.

Acute Encephalitis Syndrome in Adults and Its Correlation with Cytokine Levels in the Serum and Cerebrospinal Fluid.

Acute encephalitis syndrome (AES) is a major health problem in developing countries including India. Neuronal injury in encephalitis is attributed to direct toxicity from pathogens and proinflammatory cytokines. In this study, we assessed cytokine levels in serum and cerebrospinal fluid (CSF), and their correlation with clinical symptoms. In our study, patients with AES for a duration of less than 2 weeks underwent brain imaging followed by CSF analysis for routine parameters and viral studies. We assessed interleukin (IL)-6, IL-10, and regulated on activation, normal T cell expressed and secreted (RANTES) levels in the serum samples of all patients and in 50 CSF samples and compared them with serum cytokine levels of 64 age- and sex-matched controls. Of the 87 AES patients, 13 had Japanese encephalitis (JE). Serum IL-6, IL-10, and RANTES levels were significantly elevated in patients with AES compared with that in controls. Serum IL-10 levels were significantly reduced while RANTES levels were significantly elevated in patients who died. CSF IL-6 and IL-10 levels were significantly elevated in the non-JE group compared with that in JE patients. RANTES levels in the CSF were high in patients who had no seizures. IL-10 exerts its anti-inflammatory effect by modulating the innate and adaptive immune response, thus limiting the production of pro-inflammatory cytokines. Higher IL-10 levels were found to be protective in patients with acute encephalitis.