Ferritin as an Effective Predictor of Neurological Outcomes in Children With Acute Necrotizing Encephalopathy.

BACKGROUND: Acute necrotizing encephalopathy (ANE) is a fulminant disease with poor prognosis. Cytokine storm is the important phenomenon of ANE that affects the brain and multiple organs. The study aimed to identify whether hyperferritinemia was associated with poor prognosis in patients with ANE. METHODS: All patients with ANE had multiple symmetric lesions located in the bilateral thalami and other regions such as brainstem tegmentum, cerebral white matter, and cerebellum. Neurological outcome at discharge was evaluated by pediatric neurologists using the Pediatric Cerebral Performance Category Scale. All risk factors associated with poor prognosis were further analyzed using receiver operating characteristic curve analysis. RESULTS: Twenty-nine patients with ANE were enrolled in the current study. Nine (31%) patients achieved a favorable neurological outcome, and 20 (69%) patients had poor neurological outcomes. results The group of poor neurological outcome had significantly higher proportion of shock on admission and brainstem involvement. Based on multivariate logistic regression analysis, ferritin, aspartate aminotransferase (AST), and ANE severity score (ANE-SS) were the predictors associated with outcomes. The appropriate cutoff value for predicting neurological outcomes in patients with ANE was 1823 ng/mL for ferritin, 78 U/L for AST, and 4.5 for ANE-SS. Besides, comparison analyses showed that higher level of ferritin and ANE-SS were significantly correlated with brainstem involvement (P < 0.05). CONCLUSIONS: Ferritin may potentially be a prognostic factor in patients with ANE. Hyperferritinemia is associated with poor neurological outcomes in patients with ANE and ferritin levels more than 1823 ng/mL have about eightfold increased risk of poor neurological outcome.

[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 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.

Pediatric recurrent acute necrotizing encephalomyelitis, RANBP2 genotype and Sars-CoV-2 infection: Diagnosis, pathogenesis and targeted treatments from a case study.

Acute necrotizing encephalopathy (ANE) is a rare disease not yet described in children with Covid-19. RANBP2 gene variations are implicated in recurrences in the genetic form of ANE, the so called ANE1. We report the first case of pediatric ANE1 following Sars-CoV-2 infection. She had a first episode at 2 years of age following influenza type A with full recovery, many other respiratory and non-respiratory febrile viral infections without recurrences and a severe recurrence following Sars-CoV-2 infection, suggesting a potentiation effect on cytokine cascade. Her MRI showed the typical pattern of injury resembling that of mitochondrial disorders, and supported the role of RANBP2 in mitochondrial homeostasis. This case rises attention on diagnostic challenges and offers several interesting tips for discussion about new perspectives in pathogenesis and targeted treatments.

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.

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.

Encephalopathy as a prognostic factor in adults with acute disseminated encephalomyelitis following COVID-19.

Numerous reports support the possible occurrence of acute disseminated encephalomyelitis (ADEM) following COVID-19. Herein, we report a case of ADEM in a 53-year-old man 2 weeks after SARS-CoV-2 infection. We reviewed the reports of adult cases of ADEM and its variant acute necrotizing hemorrhagic leukoencephalitis (ANHLE) to check for possible prognostic factors and clinical/epidemiological peculiarities. We performed a descriptive analysis of clinical and cerebrospinal fluid data. Ordinal logistic regressions were performed to check the effect of clinical variables and treatments on ADEM/ANHLE outcomes. We also compared ADEM and ANHLE patients. We identified a total of 20 ADEM (9 females, median age 53.5 years) and 23 ANHLE (11 females, median age 55 years). Encephalopathy was present in 80% of ADEM and 91.3% of ANHLE patients. We found that the absence of encephalopathy predicts a better clinical outcome in ADEM (OR 0.027, 95% CI 0.001-0.611, p = 0.023), also when correcting for the other variables (OR 0.032, 95% CI 0.001-0.995, p = 0.05). Conversely, we identified no significant prognostic factor in ANHLE patients. ANHLE patients showed a trend towards a worse clinical outcome (lower proportion of good/complete recovery, 4.5% vs 16.7%) and higher mortality (36.4% vs 11.1%) as compared to ADEM. Compared to pre-pandemic ADEM, we observed a higher median age of people with post-COVID-19 ADEM and ANHLE, a shorter interval between infection and neurological symptoms, and a worse prognosis both in terms of high morbidity and mortality. Despite being affected by the retrospective nature of the study, these observations provide new insights into ADEM/ANHLE following SARS-CoV-2 infection.

Acute Disseminated Encephalomyelitis and Acute Hemorrhagic Leukoencephalitis Following COVID-19: Systematic Review and Meta-synthesis.

BACKGROUND AND OBJECTIVES: Since the onset of the COVID-19 pandemic, a growing number of reports have described cases of acute disseminated encephalomyelitis (ADEM) and acute hemorrhagic leukoencephalitis (AHLE) following infection with COVID-19. Given their relatively rare occurrence, the primary objective of this systematic review was to synthesize their clinical features, response to treatments, and clinical outcomes to better understand the nature of this neurologic consequence of COVID-19 infection. METHODS: Patients with a history of COVID-19 infection were included if their reports provided adequate detail to confirm a diagnosis of ADEM or AHLE by virtue of clinical features, radiographic abnormalities, and histopathologic findings. Cases purported to be secondary to vaccination against COVID-19 or occurring in the context of a preexisting relapsing CNS demyelinating disease were excluded. Case reports and series were identified via PubMed on May 17, 2021, and 4 additional cases from the authors' hospital files supplemented the systematic review of the literature. Summary statistics were used to describe variables using a complete case analysis approach. RESULTS: Forty-six patients (28 men, median age 49.5 years, 1/3 >50 years old) were analyzed, derived from 26 case reports or series originating from 8 countries alongside 4 patient cases from the authors' hospital files. COVID-19 infection was laboratory confirmed in 91% of cases, and infection severity necessitated intensive care in 67%. ADEM occurred in 31 cases, whereas AHLE occurred in 15, with a median presenting nadir modified Rankin Scale score of 5 (bedridden). Anti-MOG seropositivity was rare (1/15 patients tested). Noninflammatory CSF was present in 30%. Hemorrhage on brain MRI was identified in 42%. Seventy percent received immunomodulatory treatments, most commonly steroids, IV immunoglobulins, or plasmapheresis. The final mRS score was ≥4 in 64% of patients with adequate follow-up information, including 32% who died. DISCUSSION: In contrast to ADEM cases from the prepandemic era, reported post-COVID-19 ADEM and AHLE cases were often advanced in age at onset, experienced severe antecedent infection, displayed an unusually high rate of hemorrhage on neuroimaging, and routinely had poor neurologic outcomes, including a high mortality rate. Findings are limited by nonstandardized reporting of cases, truncated follow-up information, and presumed publication bias.

Acute Necrotizing Encephalopathy as a Complication of Chikungunya Infection.

BACKGROUND: Acute necrotizing encephalopathy (ANE) is a rapidly progressive encephalopathy seen commonly in children triggered by various prodromal viral infections, most common being influenza virus and Human herpes virus-6. OBJECTIVE: We report two rare cases of ANE preceded by Chikungunya infection. CASES: A 13-year old girl presented with a three-day history of headache, fever, seizures, and altered sensorium. Another 42-year old man presented with two days history of fever and altered sensorium. Both were suspected to have viral encephalitis. Evaluation revealed serum positivity for Chikungunya virus. In both cases, diagnosis was clinched by characteristic bilateral symmetrical thalamic lesions with central necrosis and hemorrhage along with lesions in cerebral white matter, brainstem, and cerebellum. CONCLUSIONS: ANE is reported to have high morbidity and mortality. To the best of our knowledge, this is the first report of ANE post-Chikungunya infection. Apart from being rare etiologically, the patients had excellent response to steroids.

Spectrum of Neurological Manifestations in Covid-19: A Review.

COVID-19, in most patients, presents with mild flu-like illness. Elderly patients with comorbidities, like hypertension, diabetes, or lung and cardiac disease, are more likely to have severe disease and deaths. Neurological complications are frequently reported in severely or critically ill patients with comorbidities. In COVID-19, both central and peripheral nervous systems can be affected. The SARS-CoV-2 virus causes the disease COVID-19 and has the potential to invade the brain. The SARS-CoV-2 virus enters the brain either via a hematogenous route or olfactory system. Angiotensin-converting enzyme two receptors, present on endothelial cells of cerebral vessels, are a possible viral entry point. The most severe neurological manifestations, altered sensorium (agitation, delirium, and coma), are because of hypoxic and metabolic abnormalities. Characteristic cytokine storm incites severe metabolic changes and multiple organ failure. Profound coagulopathies may manifest with ischemic or hemorrhagic stroke. Rarely, SARS-CoV-2 virus encephalitis or pictures like acute disseminated encephalomyelitis or acute necrotizing encephalopathy have been reported. Nonspecific headache is a commonly experienced neurological symptom. A new type of headache "personal protection equipment-related headache" has been described. Complete or partial anosmia and ageusia are common peripheral nervous system manifestations. Recently, many cases of Guillain-Barré syndrome in COVID-19 patients have been observed, and a postinfectious immune-mediated inflammatory process was held responsible for this. Guillain-Barré syndrome does respond to intravenous immunoglobulin. Myalgia/fatigue is also common, and elevated creatine kinase levels indicate muscle injury. Most of the reports about neurological complications are currently from China. COVID-19 pandemic is spreading to other parts of the world; the spectrum of neurological complications is likely to widen further.

COVID-19 and Headache: A Primer for Trainees.

OBJECTIVE: To summarize for the trainee audience the possible mechanisms of headache in patients with COVID-19 as well as to outline the impact of the pandemic on patients with headache disorders and headache medicine in clinical practice. BACKGROUND: COVID-19 is a global pandemic caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2, of which a large subset of patients features neurological symptoms, commonly headache. The virus is highly contagious and is, therefore, changing clinical practice by forcing limitations on in-person visits and procedural treatments, more quickly shifting toward the widespread adaptation of telemedicine services. DESIGN/RESULTS: We review what is currently known about the pathophysiology of COVID-19 and how it relates to possible mechanisms of headache, including indirect, potential direct, and secondary causes. Alternative options for the treatment of patients with headache disorders and the use of telemedicine are also explored. CONCLUSIONS: Limited information exists regarding the mechanisms and timing of headache in patients with COVID-19, though causes relate to plausible direct viral invasion of the nervous system as well as the cytokine release syndrome. Though headache care in the COVID-19 era requires alterations, the improved preventive treatment options now available and evidence for feasibility and safety of telemedicine well positions clinicians to take care of such patients, especially in the COVID-19 epicenter of New York City.

COVID-19: A Global Threat to the Nervous System.

In less than 6 months, the severe acute respiratory syndrome-coronavirus type 2 (SARS-CoV-2) has spread worldwide infecting nearly 6 million people and killing over 350,000. Initially thought to be restricted to the respiratory system, we now understand that coronavirus disease 2019 (COVID-19) also involves multiple other organs, including the central and peripheral nervous system. The number of recognized neurologic manifestations of SARS-CoV-2 infection is rapidly accumulating. These may result from a variety of mechanisms, including virus-induced hyperinflammatory and hypercoagulable states, direct virus infection of the central nervous system (CNS), and postinfectious immune mediated processes. Example of COVID-19 CNS disease include encephalopathy, encephalitis, acute disseminated encephalomyelitis, meningitis, ischemic and hemorrhagic stroke, venous sinus thrombosis, and endothelialitis. In the peripheral nervous system, COVID-19 is associated with dysfunction of smell and taste, muscle injury, the Guillain-Barre syndrome, and its variants. Due to its worldwide distribution and multifactorial pathogenic mechanisms, COVID-19 poses a global threat to the entire nervous system. Although our understanding of SARS-CoV-2 neuropathogenesis is still incomplete and our knowledge is evolving rapidly, we hope that this review will provide a useful framework and help neurologists in understanding the many neurologic facets of COVID-19. ANN NEUROL 2020;88:1-11 ANN NEUROL 2020;88:1-11.

COVID-19-related acute necrotizing encephalopathy with brain stem involvement in a patient with aplastic anemia.

OBJECTIVE: To describe a novel case of coronavirus disease 2019 (COVID-19)-associated acute necrotizing encephalopathy (ANE) in a patient with aplastic anemia where there was early brain stem-predominant involvement. METHODS: Evaluation of cause, clinical symptoms, and treatment response. RESULTS: A 59-year-old woman with a background of transfusion-dependent aplastic anemia presented with seizures and reduced level of consciousness 10 days after the onset of subjective fever, cough, and headache. Nasopharyngeal swab testing for severe acute respiratory syndrome coronavirus (SARS-CoV-2) was positive, and CT during admission demonstrated diffuse swelling of the brain stem. She required intubation and mechanical ventilation for airway protection, given her reduced level of consciousness. The patient's condition deteriorated, and MRI on day 6 demonstrated worsening brain stem swelling with symmetrical hemorrhagic lesions in the brain stem, amygdalae, putamina, and thalamic nuclei. Appearances were consistent with hemorrhagic ANE with early brain stem involvement. The patient showed no response to steroid therapy and died on the eighth day of admission. CONCLUSIONS: COVID-19 may be associated with an acute severe encephalopathy and, in this case, was considered most likely to represent an immune-mediated phenomenon. As the pandemic continues, we anticipate that the spectrum of neurologic presentation will broaden. It will be important to delineate the full clinical range of emergent COVID-19-related neurologic disease.

Scoping review of prevalence of neurologic comorbidities in patients hospitalized for COVID-19.

OBJECTIVE: The emergence of coronavirus disease 2019 (COVID-19) presents a challenge for neurologists caring for patients with preexisting neurologic conditions hospitalized for COVID-19 or for evaluation of patients who have neurologic complications during COVID-19 infection. We conducted a scoping review of the available literature on COVID-19 to assess the potential effect on neurologists in terms of prevalent comorbidities and incidence of new neurologic events in patients hospitalized with COVID-19. METHODS: We searched MEDLINE/PubMed, CINAHL (EBSCO), and Scopus databases for adult patients with preexisting neurologic disease who were diagnosed and hospitalized for COVID-19 or reported incidence of secondary neurologic events following diagnosis of COVID-19. Pooled descriptive statistics of clinical data and comorbidities were examined. RESULTS: Among screened articles, 322 of 4,014 (8.0%) of hospitalized patients diagnosed and treated for COVID-19 had a preexisting neurologic illness. Four retrospective studies demonstrated an increased risk of secondary neurologic complications in hospitalized patients with COVID-19 (incidence of 6%, 20%, and 36.4%, respectively). Inconsistent reporting and limited statistical analysis among these studies did not allow for assessment of comparative outcomes. CONCLUSION: Emerging literature suggests a daunting clinical relationship between COVID-19 and neurologic illness. Neurologists need to be prepared to reorganize their consultative practices to serve the neurologic needs of patients during this pandemic.