A Rare Case of COVID-19 Related Acute Necrotizing Encephalopathy With the RANBP2 Mutation in a Pediatric Patient.

Acute necrotizing encephalopathy (ANE) is a rare childhood neurological disorder. The familiar type of ANE (ANE1) is associated with a mutation in the RANBP2 gene. Both SARS-CoV-2 and RANBP2 mutations are responsible for the manifestation of a hyper-inflammatory response that invades the central nervous system and plays a key role in the rapid progression of encephalopathy.

[Weston-Hurst syndrome. A case report and literature review]. / Síndrome de Weston Hurst. Reporte de un caso y revisión de la literatura.

Background: Acute disseminated encephalomyelitis is an autoimmune and demyelinating disease. It is rare in adults. It has 3 main variants. One of them is Weston-Hurst syndrome, also called acute hemorrhagic leukoencephalitis. The objective was to share the experience in the diagnostic and therapeutic approach of this rare disease, as well as make a review of the current bibliography, in order to collaborate in the knowledge of this disease. Clinical case: 27-year-old woman, with a viral respiratory infection 2 weeks prior to the development of a neurological syndrome characterized by paresthesia, motor deficit, status epilepticus and acute encephalopathy, progressing rapidly to coma, with evidence in MRI of diffuse hemorrhagic lesions in cerebral white matter with demyelination and peripheral edema. It was administered steroid treatment for 5 days, with improvement of symptoms, but with motor and sensory deficits persisting. Conclusion: Acute disseminated encephalomyelitis and its variants are rare entities, with an important range of differential diagnosis, which must be identified and quickly treated to avoid their lethal or disabling outcome.

Introducción: la encefalomielitis aguda diseminada es una enfermedad autoinmune y desmielinizante. Es rara en el adulto. Cuenta con tres variantes principales. Una de ellas es el síndrome de Weston Hurst, también conocido como leucoencefalitis hemorrágica aguda. El objetivo fue compartir la experiencia en el abordaje diagnóstico y terapéutico de esta rara enfermedad, así como hacer una revisión de la bibliografía actual, a fin de colaborar con el conocimiento de esta. Caso clínico: mujer de 27 años con cuadro de infección respiratoria viral 2 semanas previas al desarrollo de síndrome neurológico caracterizado por parestesias, déficit motor, estatus epiléptico y encefalopatía aguda, el cual progresó a estado de coma y evidenció en resonancia magnética lesiones difusas hemorrágicas en sustancia blanca cerebral con desmielinización y edema periférico. Se inició tratamiento con esteroides por 5 días con mejora de síntomas, aunque persistió el déficit motor y sensitivo. Conclusión: la encefalomielitis aguda diseminada y la variante hemorrágica de esta son entidades raras, con una importante gama de diagnóstico diferencial, que deben ser identificadas y tratadas de forma rápida para evitar su letal o incapacitante desenlace.

[Acute hemorrhagic leukoencephalitis with a subacute onset]. / Ostryi gemorragicheskii leikoentsefalit Khersta, variant podostrogo techeniya.

Acute hemorrhagic leukoencephalitis (AHLE), also called Hurst's encephalitis, is a rare demyelinating disease of the central nervous system characterized by rapid progression and acute inflammation of the white matter of the brain and spinal cord. AHLE is currently considered as a rare, most severe variant of acute disseminated encephalomyelitis. Clinically AHLE is characterized by a fulminant course with a rapid development of encephalopathy and multifocal neurological symptoms. AHLE is associated with high mortality rate that requires immediate and aggressive treatment initiation. This article describes a case of AHLE with an atypical course, a subacute form, which is extremely rarely described in the literature, with the progressive symptoms' development over several months. Due to delayed treatment initiation, unfortunately, a fatal outcome has been observed. Subsequent histological examination of the autopsy material confirmed the presence of a subacute form of AHLE in the patient.

[Acute hemorrhagic leukoencephalopathy. Case report]. / Leucoencefalopatía hemorrágica aguda. Reporte de caso.

Background: Acute hemorrhagic leukoencephalitis (AHLE) is an inflammatory disease of the brain, with a fulminant course that leads to a hemorrhagic demyelination of the central nervous system, having a poor prognosis and high mortality. Most of the times associated to crossed reactivity and molecular mimicry. Clinical case: : We present a case report of a previously healthy young woman with an acute and multifocal clinical course, preceded by a viral respiratory tract infection, followed by a rapid disease progression and a delay in the diagnosis. The clinical, neuroimaging and cerebrospinal fluid featured suggested the diagnosis of AHLE, despite efforts and management with immunosuppression and intensive care, the response to treatment was poor leaving the patient with a severe neurological impairment. Conclusion: There is little evidence regarding the clinical course and treatment of this disease, and more studies are needed to better characterize it and to provide further information about its prognosis and management. This paper gives a systematic review of the literature.

Introducción: la leucoencefalitis hemorrágica aguda (AHLE, por sus siglas en inglés) es una enfermedad inflamatoria del cerebro que conduce a una desmielinización hemorrágica del sistema nervioso central (SNC), de mal pronóstico y alta mortalidad. Muchas veces se asocia a diferentes patógenos que provocan un mimetismo molecular. Caso clínico: presentamos un caso de origen mexicano, que presento una clínica de una evolución aguda de tipo multifocal. Inicialmente asociado a un cuadro de origen infeccioso, aparentemente viral. Posterior a ese cuadro el paciente presenta una evolución tórpida, con retraso del diagnóstico. Acude con las manifestaciones clínicas, radiológicas y en líquido cefalorraquídeo compatibles con la enfermedad, aunque se da tratamiento inmunosupresor de manera energética la paciente presenta poca respuesta al tratamiento, con muchas secuelas por la enfermedad. Conclusión: existen poca evidencia sobre la evolución clínica y el manejo médico de la enfermedad y se necesitan más estudios para caracterizarla mejor y brindar más información sobre su pronóstico y manejo. En este artículo se provee una revisión sistemática de la bibliografía.

Biallelic variants in ribonuclease inhibitor (RNH1), an inflammasome modulator, are associated with a distinctive subtype of acute, necrotizing encephalopathy.

PURPOSE: Mendelian etiologies for acute encephalopathies in previously healthy children are poorly understood, with the exception of RAN binding protein 2 (RANBP2)-associated acute necrotizing encephalopathy subtype 1 (ANE1). We provide clinical, genetic, and neuroradiological evidence that biallelic variants in ribonuclease inhibitor (RNH1) confer susceptibility to a distinctive ANE subtype. METHODS: This study aimed to evaluate clinical data, neuroradiological studies, genomic sequencing, and protein immunoblotting results in 8 children from 4 families who experienced acute febrile encephalopathy. RESULTS: All 8 healthy children became acutely encephalopathic during a viral/febrile illness and received a variety of immune modulation treatments. Long-term outcomes varied from death to severe neurologic deficits to normal outcomes. The neuroradiological findings overlapped with ANE but had distinguishing features. All affected children had biallelic predicted damaging variants in RNH1: a subset that was studied had undetectable RNH1 protein. Incomplete penetrance of the RNH1 variants was evident in 1 family. CONCLUSION: Biallelic variants in RNH1 confer susceptibility to a subtype of ANE (ANE2) in previously healthy children. Intensive immunological treatments may alter outcomes. Genomic sequencing in children with unexplained acute febrile encephalopathy can detect underlying genetic etiologies, such as RNH1, and improve outcomes in the probands and at-risk siblings.

Two-year follow-up of a young male with possible acute hemorrhagic leukoencephalitis: A case report.

RATIONALE: Acute hemorrhagic leukoencephalitis (AHLE) is a rare but fetal fulminant demyelinating disease of unknown etiology. It is commonly regarded as a severe variant of acute demyelinating encephalomyelitis (ADEM). Its rapid clinical deterioration and high mortality appeal to clinicians to attach importance to early diagnosis. Immunosuppressive therapy is the main management to attenuate the autoimmune process, but with varied response and prognosis. PATIENT CONCERNS: A young male presented with moderate fever, headache and seizures after extraction of impacted teeth, and then deteriorated rapidly to deep coma. Initial magnetic resonance imaging (MRI) revealed multiple plaque-like lesions in bilateral cerebra, right thalamus and pontobulbar region with massive edematous swelling and multifocal small hemorrhagic foci. Inflammatory parameters in the peripheral blood were only mild higher with a pleocytosis in CSF. DIAGNOSIS: His clinical presentation, laboratory evaluation and radiological features were consistent with a suspected diagnosis of AHLE. INTERVENTIONS: He underwent pulse corticosteroids initially but failed to respond to it. However, his consciousness improved obviously when he was treated with multiple courses of intravenous injection of immunoglobulin (IVIG) combined with mycophenolate mofetil (MMF). OUTCOMES: The patient regained consciousness gradually on day 180 and was in minimally conscious state (MCS) during the two-year follow-up. LESSONS: AHLE presents distinctly from classical ADEM, and the situation may pose a diagnostic challenge. Clinicians should be vigilant in recognizing AHLE because of its rapid clinical deterioration and high mortality. We highlight the critical role of multimodal MRI, particularly susceptibility-weighted imaging (SWI) in the diagnosis of AHLE if cerebral biopsies are unavailable. Multiple courses of IVIG with MMF may be effective when early single pulse of corticosteroids fails. Individual who survives the initial insult may carry relatively good prognosis.

Acute Hemorrhagic Leukoencephalitis (AHLE): A Comprehensive Review on Causes, Symptoms, Link with COVID-19, Diagnosis, and Treatment.

Acute hemorrhagic leukoencephalitis (AHLE), also called Hurst disease, is a rare demyelinating disease of the central nervous system (CNS) marked by rapid progression and acute inflammation of the white matter. Due to the correlation in their suspected postinfectious autoimmune pathogenesis, it is regarded as the most severe form of acute disseminated encephalomyelitis (ADEM). Because this clinical scenario has a high mortality rate, aggressive and immediate treatment is required. Although the exact cause of AHLE is unknown, it usually occurs after a bacterial or viral infection, or, less frequently, after a measles or rabies vaccination. AHLE has been reported in patients with coronavirus disease 2019 (COVID-19) as a rare but serious neurological complication. However, due to the lack of evidence-based diagnostic criteria, diagnosis is difficult. The small number of cases described in the literature, which most likely reflects underreporting and/or low incidence, necessitates greater public awareness. Increased clinical suspicion and early imaging identification of this entity may allow clinicians to pursue more aggressive treatment options, potentially reducing fatal outcomes. This study focuses on symptoms and causes of AHLE, difference between AHLE and ADME, diagnosis and treatment of AHLE, and its link with COVID-19.

First case with RANBP2 biallelic mutation and severe acute necrotizing encephalopathy phenotype.

Familial acute necrotizing encephalopathy (ANE) is a rapidly progressive encephalopathy that can occur after common viral infections at different stages of life. The clinical findings of 2 siblings diagnosed with ANE were shared and the whole-exome-sequencing study of the index case was performed. It was confirmed by the Sanger method. We found the RANBP2 gene p.I656V variant homozygous in the index case. We found the variant in the parents as heterozygous. We argue that biallelic mutations in the RANBP2 gene may result in ANE with early onset and severe prognosis by increasing penetrance.

COVID-19 related acute necrotizing encephalopathy with extremely high interleukin-6 and RANBP2 mutation in a patient with recently immunized inactivated virus vaccine and no pulmonary involvement.

BACKGROUND: We report the first case of COVID-19 associated acute necrotizing encephalopathy (ANE) without pulmonary disease in a patient with an extremely high interleukin-6 (IL-6) level and Ran Binding Protein 2 (RANBP2) mutation. CASE PRESENTATION: A 29-year-old woman recently immunized with inactivated viral vaccine-BBIBP32-CorV (Sinopharm) presented with alteration of consciousness. Her body temperature was 37° Celsius, blood pressure 42/31 mmHg, heart rate 130 bpm, respiratory rate 20 per minute, and oxygen saturation 98%. Respiratory examination was unremarkable. Neurological examination revealed stupor but preserved brainstem reflexes. Non-contrast computerized tomography of the brain showed symmetrical hypodense lesions involving bilateral thalami and cerebellar hemispheres characteristic of ANE. No pulmonary infiltration was found on chest radiograph. SARS-CoV-2 was detected by PCR; whole genome sequencing later confirmed the Delta variant. RANBP2 gene analysis revealed heterozygous Thr585Met mutation. Serum IL-6 was 7390 pg/mL. Urine examination showed pyelonephritis. Her clinical course was complicated by seizure, septic shock, acute kidney injury, and acute hepatic failure. She later developed coma and passed away in 6 days. CONCLUSIONS: ANE is caused by cytokine storm leading to necrosis and hemorrhage of the brain. IL-6 was deemed as a prognostic factor and a potential treatment target of ANE in previous studies. RANBP2 missense mutation strongly predisposes this condition by affecting mitochondrial function, viral entry, cytokine signaling, immune response, and blood-brain barrier maintenance. Also, inactivated vaccine has been reported to precipitate massive production of cytokines by antibody dependent enhancement (ADE). The true incidence of COVID-19 associated ANE is not known as were the predictors of its development. We proposed these potential two factors (RANBP2 mutation and ADE) that could participate in the pathogenesis of ANE in COVID-19 apart from SARS-CoV2 infection by itself. Further study is needed to confirm this hypothesis, specifically in the post-vaccination period. Role of RANBP2 mutation and its application in COVID-19 and ANE should be further elaborated.

Acute Hemorrhagic Leukoencephalitis - A Rare but Fatal Form of Acute Disseminated Encephalomyelitis - Complicated by Brain Herniation: A Case Report and Literature Review.

BACKGROUND Acute hemorrhagic leukoencephalitis (AHLE) is a very rare fulminant post-infectious demyelinating disease of the CNS. We report an atypical presentation of AHLE involving unique brain areas 2 weeks following a viral upper-respiratory tract infection (URTI). Early diagnosis and proper management improve the prognosis of this disease, and AHLE can have a very poor prognosis and high mortality rate. CASE REPORT A 52-year-old male patient was referred for deteriorating consciousness 2 weeks after a viral URTI. An initial brain CT scan showed multiple patchy bilateral and diffuse hypodense areas including the cerebellar, occipital, parietal, and frontal lobes. The diagnostic workup also included CSF analysis and MRI of the brain, which revealed multiple areas of hemorrhagic involvement. Management included broad-spectrum antibiotics, acyclovir, mannitol, steroids, and plasmapheresis. On the fifth day of admission, brain CT showed severe diffuse edema and brain herniation. Unfortunately, despite prompt aggressive treatment measures, within 48 hours the patient died due to centrally-mediated hemodynamic instability. CONCLUSIONS We report a rare case of AHLE with a unique presentation and extensive unusual involvement of regions of periventricular and subcortical white matter, cerebellum, and midbrain. Early diagnosis along with appropriate management measures and intensive care can help decrease morbidity and mortality; therefore, prompt referral and high-level care should be sought for all patients who present with acute deteriorating consciousness. We hope that this report can help future studies to better characterize this rare disease and provide further guidance regarding prognosis and management.

Association of O blood type with the prognosis of acute necrotizing encephalopathy in childhood: A single-center cohort study.

BACKGROUND: Acute necrotizing encephalopathy (ANE) of childhood is a rare but critical disease with global distribution. Few studies have focused on investigating the relationship between O blood type and the prognosis of ANE. METHODS: We analyzed retrospectively the data of patients with ANE admitted to the Beijing Children's Hospital from March 2012 to February 2019. Baseline data, clinical characteristics, examination, treatment, and prognosis of O blood group were compared with those of the non-O blood group. Cox regression was used to observe the independent prognostic factors in ANE. RESULTS: Thirty-one ANE patients were recruited, and 8 (25.8%) of these patients were in the O blood group. The rest (n = 23; 74.2%) were in the non-O blood group. No significant differences were found in the demographic characteristics, clinical features, examinations, and treatments between the two groups (p > 0.05). At 28 days after discharge, the overall survival rate of the O blood group was significantly higher than that of the non-O blood group (χ2 = 5.630, p = 0.018). At 1 year after discharge, the survival quality of the O blood group was higher than that of the non-O blood group (p = 0.006). After adjusting for the confounding factors, Cox regression analysis showed that O blood type might be a protective factor in ANE [hazard ratio = 0.283, 95% CI = 0.081-0.988; p = 0.048]. CONCLUSIONS: O blood type may be a protective factor for patients with ANE.

Acute haemorrhagic leukoencephalitis (AHLE) - our experience and a short review.

BACKGROUND: Acute haemorrhagic leukoencephalitis (AHLE), a rare variant of acute disseminated encephalomyelitis (ADEM), often presents differently from classical ADEM, thereby posing a diagnostic challenge to the clinician. AIM: To report AHLE, its clinic-radiological manifestations, process of diagnosis and prognosis. METHOD AND RESULTS: Eight patients presented with altered sensorium, acute focal deficits with or without seizures. Initial workup showed evidence of haemorrhagic lobar or thalamic lesions in seven patients. All patients underwent extensive evaluation for collagen vascular disease and vasculitis profile, autoimmune encephalitis panel and aquaporin-4 antibody, which were found to be normal. Cerebrospinal fluid (CSF) biochemistry and microscopy was non-contributory and CSF viral PCRs, toxoplasma antibodies, cryptococcal antigen were also negative. All patients had progressively worsening sensorium and neurological deficits. Repeat MRIs showed increase in oedema in the lesions and appearance/expansion of haemorrhage in the thalamic/hemispherical lesions. All patients received intravenous methylprednisolone (IVMP) without any benefit. Four patients underwent plasmapheresis (PLEX), one received intravenous immunoglobulin (IVIG) and one received both second line immunotherapies, without significant improvement. Brain biopsy (performed in three patients) showed inflammatory demyelination and areas of haemorrhage, thus confirming the diagnosis. Six patients succumbed in 7-30 days of the illness, despite aggressive treatment and only two survived, albeit with a significant disability. CONCLUSION: AHLE is a rare, yet very severe variant of ADEM. MRI shows lesions with haemorrhages, oedema and mass effect and histology findings reveal inflammatory infiltrates, haemorrhagic foci and fibrinoid necrosis of vessel walls. Prognosis is worse as compared to the classic ADEM, with a high mortality rate. To the best of our knowledge, this is one of the largest series of AHLE to have been reported anywhere in the world. KEYMESSAGE: Acute encephalopathy, multifocal deficits accompanied by haemorrhagic CNS demyelinating lesions with oedema and mass effect are the key features of AHLE. It is a rare, yet very severe form of ADEM with very high morbidity and mortality.

Acute necrotizing encephalopathy of childhood: a single-center experience

Background/aim: Acute necrotizing encephalopathy is a rare type of acute encephalopathy characterized by multi-ocal brain lesions and associated severe neurological findings and various organ dysfunctions may accompany it. Materials and Methods: Patients with acute necrotizing encephalopathy of childhood diagnosed by pediatric neurology and pediatric intensive care at Sami Ulus Maternity, Child Health and Diseases Training and Research Hospital between 2007 and 2020 were included in this study. Results: Nine patients (six females, three males) with a mean age of 4.05 ± 1.94 years (age range 1­6.5) were included in this study. The interval range between fever and encephalopathy in patients was 1­4 days. Influenza A (3H1N1, one untyped) was detected in four patients, influenza B in three patients, and no cause was found in two patients. Major clinical findings other than febrile encephalopathy in all patients were a hemodynamic shock in seven patients, seizures in six patients, vomiting in five patients, dystonia in three patients, and flaccid paralysis in the upper extremity in one patient. Despite all our treatment approaches, including plasmapheresis, moderate to severe neurological sequelae was observed in all of our patients, who survived even with significant radiological improvement. Three patients for whom we could not perform plasmapheresis died. Conclusion: Our study revealed that thalamic involvement increased as the interval shortened, and brainstem involvement increased in patients over four years of age. The presence of persistent vomiting accompanying encephalopathy during the parainfectious period and plasmapheresis treatment being a treatment option that could prevent mortality were cautionary for our study.

Acute Disseminated Encephalomyelitis (ADEM): A Demyelinating Disease with Specific Morphological Features.

Acute disseminated encephalomyelitis (ADEM) is a rare immune-mediated inflammatory and demyelinating disorder of the central nervous system. Its characteristic perivenular demyelination and inflammation aid in the differential diagnosis with other inflammatory demyelinating diseases. Here, we present a clinical case of ADEM, summarize its histological hallmarks, and discuss pitfalls concerning the most important neuropathological differential diagnoses.