Unexplained Encephalopathy Research Articles

Newly discovered variants in unexplained neonatal encephalopathy.

The genetic background of neonatal encephalopathy (NE) is complicated and early diagnosis is beneficial to optimizing therapeutic strategy for patients. NE Patients with unclear etiology received regular clinical tests including ammonia test, metabolic screening test, amplitude-integrated electroencephalographic (aEEG) monitoring, brain Magnetic Resonance Imaging (MRI) scanning, and genetic test. The protein structure change was predicted using Dynamut2 and RoseTTAFold. 15 out of a total of 113 NE Patients were detected with newly reported pathogenic variants. In this sub-cohort, (1) seizure was the primary initial symptoms; (2) four patients had abnormal metabolic screening results, and two of them were also diagnosed with excessive blood ammonia concentration; (3) the brain MRI results were irregular in three infants and the brain waves were of moderate-severe abnormality in about a half of the patients. The novel pathogenic variants discovered in this study belonged to 12 genes, and seven of them were predicted to introduce a premature translation termination. In-silicon predictions showed that four variants were destructive to the protein structure of KCNQ2. Our study expands the mutation spectrum of genes associated with NE and introduces new evidence for molecular diagnosis in this newborn illness.

Posterior Reversible Encephalopathy Syndrome in a Patient with Septic Shock: A Case Report.

Posterior reversible encephalopathy syndrome (PRES) is a reversible condition with nonspecific neurologic and characteristic radiologic findings. Clinical presentation may include headache, nausea, vomiting, altered mental status, seizures, and vision changes. Diagnosis is confirmed through T2-weighted brain magnetic resonance imaging (MRI) showing bilateral hyperintensities in the white matter of posterior circulatory regions. We report a case of PRES in a patient suffering from complicated diverticulitis. Following medical management in the emergency department, the patient deteriorated, becoming hypotensive and altered. Bowel resection under general anesthesia was performed. Postoperative brain MRI demonstrated bilateral and symmetric T2 signal hyperintensities suggestive of PRES. Following supportive treatment, the patient was discharged from the surgical intensive care unit on postoperative day 21 with no residual deficits. It is important to recognize the nonspecific neurologic symptoms associated with PRES. Emergency physicians should suspect acute PRES when managing patients with prolonged or unexplained encephalopathy, while recognizing that hypertension need not be present.

Coronavirus disease 2019-associated acute necrotizing encephalopathy in a 9-year-old boy

Coronavirus disease 2019 (COVID-19) is associated with a variety of neurologic manifestations. Acute necrotizing encephalopathy (ANE) is a rare, life-threatening complication characterized by rapid deterioration of neurologic status following viral infection, such as influenza or human herpesvirus 6. Since the COVID-19 pandemic, a rise in ANE cases associated with the infectious disease has been reported in adult patients. We present a case of COVID-19-associated ANE in a 9-year-old boy. The patient experienced 3 days of fever and mild respiratory symptoms, followed by lethargy. Magnetic resonance imaging on day 4 showed hyperintensity in the bilateral thalami, midbrain, pons, hypothalamus, and cerebellum, along with some areas of hemorrhage. From the imaging findings, ANE was strongly suspected, leading to the initiation treatment involving a 5-day course of remdesivir and multiple immunomodulator therapies, including high-dose corticosteroids, intravenous immunoglobulin, tocilizumab, and 10 cycles of therapeutic plasma exchange. Subsequently, the patient gradually improved, experiencing only minor neurological sequelae and showing favorable radiologic improvement. In COVID-19-infected patients presenting neurologic symptoms, it is crucial to promptly suspect and investigate unexplained encephalopathy using neuroimaging. Early administration of immunomodulator therapy is vital for the diagnosis and optimizing clinical outcomes.

Rapid-Response Electroencephalography in Seizure Diagnosis and Patient Care: Lessons From a Community Hospital.

BACKGROUND: Nonconvulsive seizures are a major source of in-hospital morbidity and a cause of unexplained encephalopathy in critically ill patients. Electroencephalography (EEG) is essential to confirm nonconvulsive seizures and can guide patient-specific workup, treatment, and prognostication. In a 208-bed community hospital, EEG services were limited to 1 part-time EEG technician and 1 EEG machine shared between inpatient and outpatient settings. Its use was restricted to typical business hours. A nursing-led quality improvement (QI) project endeavored to enhance access to EEG by introducing a point-of-care rapid-response EEG program. METHODS: For this project, a multidisciplinary protocol was developed to deploy a Food and Drug Administration-cleared, point-of-care rapid-response EEG platform (Ceribell Inc) in a community hospital's emergency department and inpatient units to streamline neurodiagnostic workups. This QI project compared EEG volume, study location, time-to-EEG, number of cases with seizures captured on EEG, and hospital-level financial metrics of diagnosis-related group reimbursements and length of stay for the 6 months before (pre-QI, using conventional EEG) and 6 months after implementing the rapid-response protocol (post-QI). RESULTS: Electroencephalography volume increased from 35 studies pre-QI to 115 post-QI (3.29-fold increase), whereas the median time from EEG order to EEG start decreased 7.6-fold (74 [34-187] minutes post-QI vs 562 [321-1034] minutes pre-QI). Point-of-care EEG was also associated with more confirmed seizure diagnoses compared with conventional EEG (27/115 post-QI vs 0/35 pre-QI). This resulted in additional diagnosis-related group reimbursements and hospital revenue. Availability of point-of-care EEG was also associated with a shorter median length of stay. CONCLUSION: A nurse-led, rapid-response EEG protocol at a community hospital resulted in significant improvements in EEG accessibility and seizure diagnosis with hospital-level financial benefits. By expanding access to EEG, confirming nonconvulsive seizures, and increasing care efficiency, rapid-response EEG protocols can enhance patient care.

Diagnostic Yield of Combined Lumbar Puncture and Brain MRI in Critically Ill Patients With Unexplained Acute Encephalopathy: A Retrospective Cohort Study.

We sought to characterize the yield of combined LP and brain MRI (bMRI) in such patients as determined by both the frequency of abnormal results and the therapeutic efficacy of these investigations, that is, how often results changed management. Retrospective cohort study of medical ICU patients admitted to a tertiary academic center between 2012 and 2018 who had documented diagnoses of "AMS" and/or synonymous terms, no clear etiology of encephalopathy, and had undergone both LP and bMRI. The primary outcome was the frequency of abnormal diagnostic testing results determined objectively for LP using cerebrospinal fluid (CSF) findings and subjectively for bMRI through team agreement on imaging findings deemed significant through retrospective chart review. We subjectively determined the frequency of therapeutic efficacy. Finally, we analyzed the effect of other clinical variables on the likelihood of discovering abnormal CSF and bMRI findings through chi-square tests and multivariate logistic regression. One hundred four patients met inclusion criteria. Fifty patients (48.1%) had an abnormal CSF profile or definitive microbiological or cytological data by LP, 44 patients (42.3%) had bMRI with significant abnormal findings, and 74 patients (71.2%) had abnormal results on at least one of these investigations. Few clinical variables were associated with the abnormal findings in either investigation. We judged 24.0% (25/104) of bMRI and 26.0% (27/104) of LPs to have therapeutic efficacy with moderate interobserver reliability. Determining when to perform combined LP and bMRI in ICU patients with unexplained acute encephalopathy must rely on clinical judgment. These investigations have a reasonable yield in this selected population.

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

PurposeMendelian 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. MethodsThis 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. ResultsAll 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. ConclusionBiallelic 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.

CLINICAL CHARACTERISTICS OF PATIENTS WITH CORONAVIRUS INFECTION

In the context of the spread of COVID-19, it should be remembered that symptoms of unexplained encephalopathy, memory impairment, depression, apathy, peripheral nervous system and muscle damage should be interpreted as possible manifestations of the new coronavirus infection. Given the large number of people infected with MERS-CoV-2, a relative increase in the frequency of autoimmune lesions of the nervous system cannot be excluded in the near future (2, 3, 6). Further research is needed in this direction. It is safe to say that the clinical presentation of neurological diseases and syndromes caused by coronavirus infection is consistent with our usual ideas, in contrast to the results of neuroimaging and laboratory methods of further investigation (4,5). Of course, additional studies on larger groups of patients are needed to finally understand the mechanisms of development of complications, their degree of association with COVID-19, and the development of schemes for their treatment and subsequent rehabilitation.

Perinatal Stroke: Clinical Pearls and Future Directions

Perinatal strokes are disorders of cerebral vasculature occurring in the developing brain between 20 weeks of gestation and 28 days postnatally (Raju, 2007). This review describes specific types of perinatal strokes and includes up-to-date risk factors, clinical presentations, outcomes, and management including expert consensus and controversies. We will conclude with a discussion of new research focused on optimizing the quality of life for children with stroke and their families. Perinatal stroke can present acutely and should be considered for any newborn with unexplained encephalopathy or seizures, particularly those that are focal in nature. Presumed perinatal stroke syndromes present later in infancy with motor and sensory asymmetry. In either case, neuroimaging helps identify a specific perinatal stroke syndrome. Most perinatal stroke survivors experience long-term morbidity, inclusive of cerebral palsy (CP), epilepsy, cognitive and behavioural disabilities, and visual deficits. Significant progress has been made in understanding cerebrovascular injuries of the developing brain and the role of early rehabilitation in recovery. With limited preventative and acute treatment options available, long-term neurorehabilitation continues to be the focus of treatment. Equally important is to recognize the significant psychosocial impact of perinatal stroke on the entire family. Online resources and support systems are increasingly available through national and international pediatric stroke organizations.

Unexplained hyperammonemia and encephalopathy in the emergency department: Abernethy malformation in elderly patients.

Unexplained hyperammonemia and encephalopathy in the emergency department: Abernethy malformation in elderly patients.

NEUROLOGICAL ESSENCE OF HYPOTHYROIDISM

Thyroid disease commonly affects nervous system which can be easily recognized when there are frank signs of thyroid dysfunction. The clinical spectrum of hypothyroidism ranges from sub-clinical hypothyroidism to frank myxoedema coma in severe hypothyroidism. It is necessary to consider thyroid diseases in differential diagnosis when neurological manifestation express itself as unexplained encephalopathy, progressive cerebellar degeneration, polyneuropathy, psychosis or progressive cognitive decline and even dementia. Due to protean non-specic diverse manifestations, hypothyroidism may remain undiagnosed for many years hence proactive search and early replacement therapy helps in better therapeutic outcome. Congenital Hypothyroidism is potentially preventable and correctable form of metabolic cerebral disease and mental retardation necessitating neonatal screening for early detection and treatment.

Frequency of Nonconvulsive Seizures among Pediatric Systemic Cancer Patients with Acute Encephalopathy: Emergent Bedside EEG in Resource Constrained Communities

Purpose: To determine the incidence of nonconvulsive seizures (NCSz) among children with systemic cancer, who underwent unexplained acute severe encephalopathy (GCS≤8) during admission in ICUs and Neuro-ICUs.
 Study Design: Multicenter prospective observational study describing sub-clinical seizures and electroencephalographic (EEG) features of children (1-16 years) with acute unexplained encephalopathy who underwent emergent bedside EEG≥30min monitoring.
 Material and Methods: We conducted a prospective longitudinal observational study design and EEG assessment of 40 systemic cancer patients age ≤16years, consecutively diagnosed and admitted in intensive care units (ICUs) and neurointensive care units (Neuro-ICUs) of different cancer hospitals with unexplained acute impaired consciousness (GCS≤08) within ≤6hr of such deterioration. Bed-side EEG recordings of ≥30min were done according to the clinical scenario and the requirements of the treating neurologist/intensivist. Patients with brain tumor, brain metastasis, seizures or those with known cause of coma were excluded. Data surrounding clinical, electrographic, and treatment factors were collected Via a prospective systematic review of medical records and EEGs for correlation with diagnosis, change in the diagnosis and management.
 Results: Over a period of 2 years, 40 children, 22.5% 1-5yeras, 37.5% 6-10years, 40% 11-16years; boys 65% and girls 35%, who had systemic cancer with a median age of 9.8 years with unexplained acute deterioration of conscious level (GCS≤08). This cohort underwent bed-side EEG of ≥30 min, which was abnormal in 100% of the records. The main reasons for EEG requests were: 1) unexplained impaired consciousness 22(55%) and 2) reason one plus subtle convulsion 18(45%). The most common EEG abnormalities were invariant mixed theta-delta slowing (27.5%), followed by Low-amplitude delta pattern plus epileptiform discharges (20%) and there was electrographic evidence of EEG seizures in 17(42.5%) of the cohort. These electrographic seizures were present in 55.5% of 18 patients with subtle convulsions, whereas were documented only in 20% of the 22 patients without such movements. Electrographic seizures among patients with subtle convulsions responded to antiseizure drugs in 75% cases as compared 50% such response among patients without such convulsions.
 Conclusion: Emergent bed-side EEG record of ≥30 min is useful in systemic cancer patients admitted in NCUs and Neuro-ICUs with acutely impaired consciousness with or without abnormal body movements. Neurology consultation and EEG studies in these comatose patients provide useful diagnostic information.

Susac syndrome: A rare presentation

Susac syndrome is an autoimmune microangiopathy characterized by a triad of encephalopathy, sensori-neural hearing loss and varying degrees of branch retinal artery occlusion. A young male patient is described with features of focal neurological lesions and small superficial retinal haemorrhages and areas of retinal arteriolar endothelial inflammation appearing as Gass plaques. Susac syndrome presents with varying features involving brain, inner ear and retina. Fundus Fluorescein angiography should be performed in all patients with an unexplained encephalopathy to look for characteristic arteriolar wall changes.

Continuous Video Electroencephalography (EEG) for Event Characterization in Critically Ill Children.

To determine features of paroxysmal events and background electroencephalographic (EEG) abnormalities associated with electroclinical seizures in critically ill children who undergo continuous video EEG to characterize clinical events. This is a prospective study of critically ill children from July 2016 to October 2018. Non-neonates with continuous video EEG indication to characterize a clinical event were included. Patients with continuous video EEG to assess for subclinical seizures due to unexplained encephalopathy and those whose event of concern were not captured on continuous video EEG were excluded. The event to be characterized was taken from documented descriptions of health care providers and classified as motor, ocular, orobuccal, autonomic, and other. In patients with more than 1 component to their paroxysmal event, the events were classified as motor plus and nonmotor plus. One hundred patients met inclusion and exclusion criteria, with electroclinical seizures captured in 30% (30/100). The most common event to be characterized was an autonomic event in 32% (32/100). Asymmetry and epileptiform discharges were associated with electroclinical seizures (odds ratio [OR] 2.7, 95% confidence interval [CI] 1.1-6.5, P = .03; and OR 12.5, 95% CI 4.4-35.6, P < .0001). Autonomic events alone, particularly unexplained vital sign changes, were not associated with electroclinical seizures (OR 0.3, 95% CI 0.11-0.93, P = .03). Isolated autonomic events are unlikely to be electroclinical seizures. Details of the paroxysmal events in question can help decide which patient will benefit most from continuous video EEG based on institutional resources.

Hematopoietic Cell Transplantation for Adenosine Deaminase Severe Combined Immunodeficiency—Improved Outcomes in the Modern Era

Current treatment for adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID) includes enzyme replacement therapy (ERT), allogeneic hematopoietic stem cell transplant (HSCT), or ex vivo corrected autologous hematopoietic stem cell gene therapy. Historic data show HSCT survival is superior using unconditioned matched sibling and family compared to matched unrelated and haploidentical donors. Recent improvement in HSCT outcomes prompted us to retrospectively examine HSCT survival and long-term graft function in ADA-SCID transplanted at our center. Thirty-three ADA-deficient patients received HSCT between 1989 and 2020, with follow-up data to January 2021. Chemotherapy conditioning regimens were defined as myeloablative (MAC—busulfan/cyclophosphamide), reduced-toxicity myeloablative (RT-MAC—treosulfan-based, since 2007), or no conditioning. Serotherapy used included alemtuzumab (with or without other conditioning agents) or antithymocyte globulin (ATG). ERT was introduced routinely in 2010 until commencement of conditioning. Median age at HSCT was 3.2 (0.8–99.8) months. Twenty-one (63.6%) received stem cells from unrelated or haploidentical donors. Seventeen (51.5%) received chemotherapy conditioning and 16 (48.5%) received alemtuzumab. Median follow-up was 7.5 (0.8–25.0) years. Overall survival (OS) and event-free survival (EFS) at 8 years were 90.9% (95% CI: 79.7–100.0%) and 79% (55–91%), respectively. OS after 2007 (n = 21) was 100% vs 75% before 2007 (n = 12) (p = 0.02). Three (9.1%) died after HSCT: two from multiorgan failure and one from unexplained encephalopathy. There were no deaths after 2007, among those who received ERT and treosulfan-based conditioning pre-HSCT. Ten (30.3%) developed acute GvDH (3 grade II, 2 grade III); no chronic GvHD was observed. In the modern era, conditioned HSCT with MUD has a favorable outcome for ADA-deficient patients.

Inpatient Management of Encephalopathy.

Unexplained encephalopathy is a common occurrence in tertiary care centers and neurologic disorders should be considered after ruling out the infectious, toxic and metabolic etiologies. Neuroimaging combined with a thorough history and examination is often helpful in ruling out stroke and fulminant demyelinating encephalopathies. Autoimmune encephalopathy should be suspected in any patient with unexplained acute or subacute onset encephalopathy or rapidly progressing dementia. Anti-N-methyl-D-aspartate receptor (NMDA-R) encephalitis is the most studied form and Hashimoto encephalitis is the most controversial form of autoimmune encephalopathies. Obtaining a combined serum and Cerebrospinal fluid (CSF) autoantibody testing will increase the diagnostic yield of autoimmune and paraneoplastic encephalitis. When diagnosing NMDA receptor antibodies CSF is always more sensitive than serum and in contrast, voltage-gated potassium channel (VGKC) complex antibodies are more readily detectable in serum than in CSF. Neural-specific antibody tests frequently result after several weeks and treatment should be administered without a significant delay to prevent brain damage. Autoimmune encephalitis is often treatment responsive when immunotherapy (glucocorticoids, intravenous immune globulin, plasma exchange) is used in various combinations. The absence of inflammatory markers and autoantibodies in the serum or CSF may not rule out the possibility of paraneoplastic encephalopathies.

A case report of a first pregnant woman with late-onset multiple acyl-CoA dehydrogenase deficiency in Saudi Arabia

Background: Multiple acyl-CoA dehydrogenase deficiency (MADD), also known as glutaric aciduria II, is a rare autosomal recessively inherited disorder of inborn error of metabolism. It can mainly be presented in three phenotypes: severe neonatal onset with a dysmorphic feature, neonatal-onset without dysmorphic features, and less severe mild late-onset phenotype. Case presentation: A 34-year-old Saudi female previously healthy, Para 4, with severe metabolic acidosis, rhabdomyolysis intrapartum was presented to us. Her previous pregnancy history and deliveries were unremarkable; she has three healthy sons. Since the beginning of this pregnancy, she complained of fatigability and muscle weakness which was progressive with time. At 36 weeks of gestation, she was presented to the emergency room with labor pain. She deteriorated rapidly with significant drowsiness. Her arterial blood gas showed severe metabolic acidosis with a high anion gap and normal lactate. She was intubated and underwent emergency cesarean delivery under general anesthesia. After the operation, she was sent to the intensive care unit. She passed away after a few days. A molecular test confirmed the diagnosis of MADD. Conclusion: First, late-onset MADD is a rare, underdiagnosed disease in adults. Second, the biochemical diagnosis of late-onset MADD is challenging as it mimics medium chain acyl CoA dehydrogenase deficiency which makes the molecular diagnosis essential for diagnosis. Third, for any unexplained myopathy, cardiac dysfunction, encephalopathy, or metabolic acidosis, metabolic disorders must be considered as early consultation with metabolic service.

Managing encephalitis on the intensive care unit

Acute encephalitis although a rare syndrome in absolute numbers is a common differential diagnosis for unexplained encephalopathy in patients presenting to both neurological and general intensive care units. This talk will review management of the critically ill patient with suspected encephalitis. The broad differential diagnosis will be considered and diagnostic approaches to seek both infectious and immune-mediated causes for encephalitis discussed. The importance of antibody-mediated forms of encephalitis and differences in aetiologies of infectious encephalitis relating to geography will be emphasised. Both antimicrobial and immunomodulatory treatments for encephalitis will be reviewed. The importance of control of seizures and management of intracranial pressure will be outlined. The audience will be directed to guidelines from specialist societies for reference.

A Case of Unexplained Encephalopathy in a Kidney Transplant Recipient

A Case of Unexplained Encephalopathy in a Kidney Transplant Recipient

Hepatic Manifestations of Urea Cycle Disorders.

Content available: Author Interview and Audio Recording.

Chromosomal microarray and exome sequencing in unexplained early infantile epileptic encephalopathies in a highly consanguineous population

Aim To identify genetic causes for early infantile epileptic encephalopathies (EIEE) in Turkish children with mostly consanguineous parents. Methods In a selected EIEE group (N = 59) based on results of nongenetic and initial genetic testing with unexplained etiology, 49 patients underwent array-based comparative genomic hybridization (aCGH) and 49 patients underwent whole exome sequencing (WES) including 39 with negative aCGH results and 10 with WES-only. Results Diagnostic yield of aCGH and WES for pathogenic or likely pathogenic variants was 14.3% and 38.8%, respectively. Including de novo variants of uncertain significance linked to compatible phenotypes, increased the diagnostic yield of WES to 61.2%. Out of 38 positive variants, 18 (47.4%) were novel and 16 (42.1%) were de novo. Twenty-one (56.8%) patients had recessive variants inherited from mostly consanguineous healthy parents (85.7%). Fourteen (37.8%) of patients with diagnostic results had positive variants in established EIEE genes. Seizures started during neonatal period in 32.4% patients. Posture or movement disorders were comorbid with EIEE in 40.5% of diagnosed patients. We identified treatable metabolic disorders in 8.1% of patients and pathogenic variants in genes which support using targeted medicine in 19% of patients. Conclusions Detailed electro-clinical phenotyping led to expansion of some of the known phenotypes with non-neurological and neurological findings in addition to seizures, as well as suggestion of candidate genes (SEC24B, SLC16A2 and PRICKLE2) and a copy number variant (microduplication of Xp21.1p11.4). The high ratio of recessive inheritance could be important for family counseling.