Acute Encephalopathy in a 10-Year-Old Patient With Maple Syrup Urine Disease: A Challenging Diagnosis.

Maple syrup urine disease (MSUD) is a rare autosomal recessive metabolic disorder characterized by a deficiency in the branched-chain alpha-keto acid dehydrogenase complex, leading to the toxic accumulation of leucine, isoleucine and valine. Acute encephalopathy (AE) is a severe neurological disorder with diverse etiologies, demanding prompt identification and intervention. We present a unique case of a previously healthy teenage patient who developed AE during an influenza infection. Despite initial inconclusive investigations, the patient's condition rapidly deteriorated, requiring pediatric intensive care unit (PICU) admission. Diagnostic challenges included fluctuating mental status and refractory intracranial hypertension, ultimately necessitating decompressive craniectomy. Empirical treatments, including corticosteroids, tocilizumab, and plasmapheresis, were administered. Finally, clinical exome analysis revealed a pathogenic variant in homozygosity in the BCKDHA gene associated with MSUD type Ia. Her adult sister, experiencing similar symptoms in the same time period, did not survive. This case underscores the importance of considering metabolic disorders in AE etiology, even accounting for its various associated syndromes and usual prolonged diagnostic investigation, as prompt treatment initiation is vital for improved outcomes. Management of AE involves addressing seizures, systemic support and neuromonitoring, namely, intracranial pressure monitoring. Inborn errors of metabolism, like MSUD, should be considered, even if universally screened, as delayed diagnosis can result in prolonged hospitalization and significant morbidity.

Metabolic encephalopathies in children: A pragmatic diagnostic approach based on literature analysis.

Inborn errors of metabolism (IEM) in the general population are rare diseases. However, from the perspective of general pediatrics and pediatric intensive care units (PICUs), they are becoming a significant challenge both diagnostically and therapeutically. Clinically, there is a useful division of IEMs with neurological manifestations into 2 categories: acute and progressive encephalopathies. The extent of individual IEMs in these 2 groups varies, requiring different diagnostic strategies. Despite progress in development of diagnostic tools in IEM, initial diagnosis is made on the basis of basic laboratory tests, neuroradiological findings and metabolic screening. In settings of shortage of diagnostic resources and under time pressure, rational decisions should be made based on available clinical data. The text discusses diagnostic aspects of IEM presenting as metabolic encephalopathies, highlighting their significance in the context of general pediatric care and intensive care units (ICUs), and the challenges associated with diagnosis. It should be noted that the paper does not include a discussion of epileptic encephalopathies of IEM etiology, although some cases of metabolic encephalopathies may also present initially as epileptic encephalopathy.

Correction of In-Patient Severe Hypernatremia in an 81-Year-Old Female With Hypopituitarism.

Hypernatremia has been significantly associated with in-hospital mortality and discharge to long-term care facilities. The appropriate correction of electrolyte disturbances, especially sodium, is important to consider to prevent the addition of central nervous system disturbances, such as cerebral edema and eventual brain injury. The importance of maintaining a proper correction of hypernatremia has been well studied and used in clinical practice. Choosing to use a hypotonic solution is a key principle. It is of utmost importance to adjust the rate of correction based on the patient's symptoms, underlying etiology, and associated comorbidities. This case demonstrates how a correction formula was used and adjusted accordingly in an 81-year-old female with severe hypernatremia and metabolic encephalopathy with multiple comorbidities, including hypopituitarism. It is noteworthy to examine the correction rate, how it was calculated and delivered, and how the main cause of the hypernatremia was determined. Considering all these factors can help to properly administer any additional corrective medications, such as desmopressin (DDAVP) in a patient with diabetes insipidus (DI) secondary to hypopituitarism, or adjust the correcting rate based on signs, symptoms, and laboratory findings.

Delirium in older patients with COVID-19: Prevalence, risk factors and clinical outcomes across the first three waves of the pandemic.

OBJECTIVES: Delirium is a serious condition, which poses treatment challenges during hospitalisation for COVID-19. Improvements in testing, vaccination and treatment might have changed patient characteristics and outcomes through the pandemic. We evaluated whether the prevalence and risk factors for delirium, and the association of delirium with in-hospital mortality changed through the pandemic. METHODS: This study was part of the COVID-OLD study in 19 Dutch hospitals including patients ≥70 years in the first (spring 2020), second (autumn 2020) and third wave (autumn 2021). Multivariable logistic regression models were used to study risk factors for delirium, and in-hospital mortality. Differences in effect sizes between waves were studied by including interaction terms between wave and risk factor in logistic regression models. RESULTS: 1540, 884 and 370 patients were included in the first, second and third wave, respectively. Prevalence of delirium in the third wave (12.7%) was significantly lower compared to the first (22.5%) and second wave (23.5%). In multivariable-adjusted analyses, pre-existing memory problems was a consistent risk factor for delirium across waves. Previous delirium was a risk factor for delirium in the first wave (OR 4.02), but not in the second (OR 1.61) and third wave (OR 2.59, p-value interaction-term 0.028). In multivariable-adjusted analyses, delirium was not associated with in-hospital mortality in all waves. CONCLUSION: Delirium prevalence declined in the third wave, which might be the result of vaccination and improved treatment strategies. Risk factors for delirium remained consistent across waves, although some attenuation was seen in the second wave.

Glioblastoma Multiforme in a Patient With Alpha-1-Antitrypsin Deficiency.

Alpha-1 antitrypsin (A1AT) is a common genetic disease caused by a mutation in the SERPINA1 gene, predisposing patients to severe premature lung and liver disease. Higher expression of SERPINA1 has been associated with a poor prognosis in patients with high-grade glioblastoma. We present a woman in her 70s with a history of A1AT deficiency treated with weekly plasma-purified A1AT infusions, who presented with metabolic encephalopathy. A CT scan of the brain obtained during admission revealed a left frontal lobe mass measuring 1.1 cm. A craniotomy and resection of the lesion were performed, and the pathology studies revealed a glioblastoma multiforme, WHO grade IV. She is currently healing and awaiting treatment with temozolomide with concomitant radiation and tolerating treatment well.

Ceftriaxone-Induced Encephalopathy in a Patient With End-Stage Renal Disease on Hemodialysis.

Ceftriaxone-induced encephalopathy is a rare but known adverse effect secondary to neurotoxicity, especially in patients with end-stage renal disease (ESRD) on hemodialysis. The common presenting symptoms include myoclonus, psychosis, and seizures. We are presenting a case of a 77-year-old female patient who presented with confusion and jerky movements of her lips and extremities. Her initial workup was negative for stroke and seizure disorder. A probable diagnosis of ceftriaxone-induced encephalopathy was made using an Adverse Drug Reaction (ADR) probability scale (Naranjo scale) with a Naranjo score of 5. The patient's symptoms resolved after discontinuation of ceftriaxone. Ceftriaxone is a commonly used intravenous antibiotic in the inpatient setting, and thus clinicians should be aware of this rare adverse reaction in patients with ESRD.

Wernicke Encephalopathy Secondary to Hyperemesis Gravidarum in a 22-Year-Old Female Patient: A Case Report.

Wernicke encephalopathy is an acute, reversible neurological disorder, which, if untreated, can develop into Korsakoff syndrome. Commonly associated with alcohol use disorder, Wernicke encephalopathy is a metabolic disorder caused by a deficiency of thiamine, vitamin B1. This case report presents a clinical manifestation of Wernicke encephalopathy, in which a 22-year-old pregnant female with hyperemesis gravidarum and significant weight loss developed acute metabolic encephalopathy. Diagnostic imaging played an important role both in diagnosing the patient acutely in the hospital and during a follow-up visit one year after treatment.

Severe Hyperammonemia Due to Fecal Bowel Obstruction With a Congenital Portosystemic Shunt Resulting in Refractory Status Epilepticus and Cerebral Edema.

Hyperammonemic encephalopathy is a neurological emergency that can lead to seizures and cerebral edema. Although early interventions have been suggested, no clear criteria have been established. Herein, we report a case of severe non-hepatic hyperammonemia resulting in refractory status epilepticus within a day. A 79-year-old woman presented with acute altered mental status. Initial evaluation revealed septic shock and hyperammonemia due to fecal bowel obstruction with congenital portosystemic shunt. The patient was unresponsive to medical treatment and developed refractory status epilepticus. After surgical drainage with colostomy and a decrease in ammonia level, the patient developed cerebral edema and did not recover from the coma. Severe hyperammonemia warrants early intervention, especially in critically ill patients, with treatment of the cause and augmented removal of ammonia with renal replacement therapy.

Differences in functional network between focal onset nonconvulsive status epilepticus and toxic metabolic encephalopathy: application to machine learning models for differential diagnosis.

We aimed to compare network properties between focal-onset nonconvulsive status epilepticus (NCSE) and toxic/metabolic encephalopathy (TME) during periods of periodic discharge using graph theoretical analysis, and to evaluate the applicability of graph measures as markers for the differential diagnosis between focal-onset NCSE and TME, using machine learning algorithms. Electroencephalography (EEG) data from 50 focal-onset NCSE and 44 TMEs were analyzed. Epochs with nonictal periodic discharges were selected, and the coherence in each frequency band was analyzed. Graph theoretical analysis was performed to compare brain network properties between the groups. Eight different traditional machine learning methods were implemented to evaluate the utility of graph theoretical measures as input features to discriminate between the two conditions. The average degree (in delta, alpha, beta, and gamma bands), strength (in delta band), global efficiency (in delta and alpha bands), local efficiency (in delta band), clustering coefficient (in delta band), and transitivity (in delta band) were higher in TME than in NCSE. TME showed lower modularity (in delta band) and assortativity (in alpha, beta, and gamma bands) than NCSE. Machine learning algorithms based on EEG global graph measures classified NCSE and TME with high accuracy, and gradient boosting was the most accurate classification model with an area under the receiver operating characteristics curve of 0.904. Our findings on differences in network properties may provide novel insights that graph measures reflecting the network properties could be quantitative markers for the differential diagnosis between focal-onset NCSE and TME.

Association of Epileptiform Activity With Outcomes in Toxic-Metabolic Encephalopathy.

The clinical significance of epileptiform abnormalities (EAs) specific to toxic-metabolic encephalopathy (TME) is unknown. OBJECTIVES: To quantify EA burden in patients with TME and its association with neurologic outcomes. DESIGN SETTING AND PARTICIPANT: This is a retrospective study. A cohort of patients with TME and EA (positive) were age, Sequential Organ Failure Assessment Score, Acute Physiology and Chronic Health Evaluation II (APACHE-II) score matched to a cohort of TME patients without EA (control). Univariate analysis compared EA-positive patients against controls. Multivariable logistical regression adjusting for underlying disease etiology was performed to examine the relationship between EA burden and probability of poor neurologic outcome (modified Rankin Score [mRS] 4-6) at discharge. Consecutive admissions to inpatient floors or ICUs that underwent continuous electroencephalography (cEEG) monitoring at a single center between 2012 and 2019. Inclusion criteria were 1) patients with TME diagnosis, 2) age greater than 18 years, and 3) greater than or equal to 16 hours of cEEG. Patients with acute brain injury and cardiac arrest were excluded. MAIN OUTCOMES AND MEASURES: Poor neurologic outcome defined by mRS (mRS 4-6). RESULTS: One hundred sixteen patients were included, 58 with EA and 58 controls without EA, where matching was performed on age and APACHE-II score. The median age was 66 (Q1-Q3, 57-75) and median APACHE II score was 18 (Q1-Q3, 13-22). Overall cohort discharge mortality was 22% and 70% had a poor neurologic outcome. Peak EA burden was defined as the 12-hour window of recording with the highest prevalence of EAs. In multivariable analysis adjusted for Charlson Comorbidity Index and primary diagnosis, presence of EAs was associated with poor outcome (odds ratio 3.89; CI [1.05-14.2], p = 0.041). Increase in peak EA burden from 0% to 100% increased probability of poor discharge neurologic outcome by 30%. CONCLUSIONS AND RELEVANCE: Increasing burden of EA is associated with worse discharge outcomes in patients with TME. Future studies are needed to determine whether short-term treatment with anti-seizure medications while medically treating the underlying metabolic derangement improves outcomes.

A Case of Metformin-Associated Lactic Acidosis.

Metformin is a US FDA-approved oral anti-hyperglycemic medication used to treat non-insulin-dependent diabetes mellitus (NIDDM). Metformin, a biguanide drug, works by reducing glucose production in the liver, decreasing intestinal absorption, and improving insulin sensitivity, leading to lower blood glucose levels. Metformin is generally considered to be a medication with a good safety profile and high tolerability. However, metformin therapy is associated with an uncommon but potentially serious complication known as metformin-associated lactic acidosis (MALA), which is marked by severe lactic acid accumulation in the bloodstream. This case introduces an elderly female with multiple comorbidities who presented with confusion, malaise, and lethargy. Her laboratory findings revealed acute renal failure, severe metabolic acidosis, and significantly elevated lactic acid levels consistent with sepsis and possibly MALA. Aggressive resuscitation with fluids and sodium bicarbonate was initiated. Antimicrobial drugs were started for urinary tract infections. She subsequently required endotracheal intubation with invasive ventilation, pressor support, and continuous renal replacement therapy. Her condition gradually improved over several days. The patient ultimately recovered, and at the time of discharge, metformin was discontinued, and a sodium-glucose cotransporter-2 (SGLT-2) inhibitor was initiated. This case underscores the relevance of MALA as a potential complication of metformin therapy, particularly in patients with underlying kidney disease or other risk factors. Timely detection and prompt management of MALA can prevent progression to a critical stage and thus avoid potentially fatal outcomes.

The TANGO2 disease and the therapeutic challenge of acute arrhythmia management: a case report.

Background: TANGO2-related metabolic encephalopathy and arrhythmia are a rare, newly recognized, and likely under-diagnosed condition. First described in 2016, it is characterized by developmental delay and recurrent metabolic crisis. During these episodes, patients may present QTc prolongation and ventricular arrhythmias. Case summary: A 13-year-old female, with developmental delay, presented with severe rhabdomyolysis and an initially normal electrocardiogram (ECG). Due to the worsening of rhabdomyolysis, QTc prolongation was identified (QTc 570 ms) and oral ß-blocker therapy started. A non-sustained ventricular tachycardia developed, initially managed with magnesium and lidocaine. After a short period, an arrhythmic storm of polymorphic ventricular extrasystoles induced Torsade de Pointes (TdP) was triggered. A temporary percutaneous pacing lead was placed and esmolol infusion started. The electrical instability ran in parallel with the increasing severity of rhabdomyolysis and systolic ventricular function decline. Genetic testing identified a pathogenic variant in homozygosity in the TANGO2 gene. A stable sinus rhythm was achieved with metabolic and serum electrolytes optimization. ECG showed normalization of the QTc interval. Discussion: The full TANGO2-related phenotype emerges over time and the prognosis is linked to the appearance of ECG abnormalities. QT interval prolongation can lead to life-threatening ventricular tachycardias. The arrhythmia mechanism seems to be secondary to metabolite build-up in cardiomyocytes, which can explain the cardiac phenotype during the crisis which subsides after their resolution. In these patients, avoiding bradycardia is fundamental, since long QT-related TdP seems to be triggered by bradycardia and short-long-short ventricular premature beats (VPB). During an acute metabolic crisis, the management of arrhythmias relies on metabolic control.

Molecular Basis of Hyperammonemic Encephalopathy in Fibrolamellar Hepatocellular Carcinoma.

Hyperammonemic encephalopathy is a potentially fatal condition associated with fibrolamellar hepatocellular carcinoma. The mechanism involved in hyperammonemia in patients with fibrolamellar carcinoma was unclear until a possible physiopathological pathway was recently proposed. An ornithine transcarboxylase dysfunction was suggested as a result of increased ornithine decarboxylase activity induced by c-Myc overexpression. This c-Myc overexpression resulted from Aurora kinase A overexpression derived from the activity of a chimeric kinase that is the final transcript of a deletion in chromosome 19, common to all fibrolamellar carcinomas. We performed the analysis of the expression of all enzymes involved and tested for the mutation in chromosome 19 in fresh frozen samples of fibrolamellar hepatocellular carcinoma, non-tumor liver, and hepatic adenomatosis. The specific DNAJB-PRKACA fusion protein that results from the recurrent mutation on chromosome 19 common to all fibrolamellar carcinoma was detected only in the fibrolamellar carcinoma sample. Fibrolamellar carcinoma and adenomyomatosis samples presented increased expression of Aurora kinase A, c-MYC, and ornithine decarboxylase when compared to normal liver, while ornithine transcarbamylase was decreased. The proposed physiopathological pathway is correct and that overexpression of c-Myc may also be responsible for hyperammonemia in patients with other types of rapidly growing hepatomas. This gives further evidence to apply new and adequate treatment to this severe complication.

Contrast-Induced Encephalopathy: A Clinical Conundrum.

Contrast-induced encephalopathy (CIE) is a rare but well-known complication of mostly intra-arterial contrast administration and presents with a variety of neurological deficits due to disruption of the blood-brain barrier. We present a case of CIE after administration of intravenous contrast for computed tomography pulmonary angiogram (CTPE). A woman in her mid-70s with history of chronic obstructive pulmonary disease (COPD) presented with progressively worsening shortness of breath. She was diagnosed with multifocal pneumonia and started on IV antibiotics, IV steroids, and bilevel positive airway pressure (BiPAP) ventilation. A CTPE was done to rule out a pulmonary embolism during which she received 100 cc of Isovue 370 (iopamidol 76%), a low-osmolar, non-ionic, monomeric, iodine-based contrast agent. Within minutes of the contrast administration, the patient developed confusion and agitation with elevated blood pressure. Neurological evaluation revealed no gross focal motor or cranial nerve deficits and bilateral 2+ reflexes with mute plantar reflexes. Laboratory investigations were unchanged. She was shifted to the ICU but continued to remain drowsy and disoriented. CT brain done within two hours of onset revealed no intracranial abnormality. She was managed conservatively with IV fluids, neuro-checks, and blood pressure control. Her sensorium improved within 48 hours with supportive treatment. Repeat neuroimaging was not performed. She was discharged after four days with the resolution of her respiratory symptoms. CIE is a known but uncommon complication associated with the use of intraarterial contrast media but has been found to occur even after intravenous administration, which has been reported only once in literature. The presentation is highly variable, ranging from headache to coma, with transient cortical blindness being the most commonly identified. The diagnosis requires a high index of suspicion, and brain imaging is usually pathognomonic; however, cases in the absence of radiological signs have also been diagnosed. Typically, symptoms resolve within 48-72 hours and the disease runs a benign course, but cases of persistent neurological deficit and even cases of fatal cerebral edema have been reported.Treatment is usually supportive with intravenous hydra-tion and anticonvulsants and the occasional use of IV steroids and mannitol with favorable outcomes.

Citrullinemia, a rare cause of recurring encephalopathy.

An infant presented with recurrent episodes of encephalopathy, responding to nonspecific management of sepsis. High index of suspicion helped uncover underlying error of metabolism.

ECHS1 deficiency and its biochemical and clinical phenotype.

ECHS1 gene encodes a mitochondrial enzyme, short-chain enoyl-CoA hydratase (SCEH). SCEH is involved in fatty acid oxidation ([Sharpe and McKenzie (2018); Mitochondrial fatty acid oxidation disorders associated with short-chain enoyl-CoA hydratase (ECHS1) deficiency, 7: 46]) and valine catabolism ([Fong and Schulz (1977); Purification and properties of pig heart crotonase and the presence of short chain and long chain enoyl coenzyme A hydratases in pig and guinea pig tissues, 252: 542-547]; [Wanders et al. (2012); Enzymology of the branched-chain amino acid oxidation disorders: The valine pathway, 35: 5-12]), and the dysfunction of SCEH leads to a severe Leigh or Leigh-like Syndrome phenotype in patients ([Haack et al. (2015); Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement, 2: 492-509]; [Peters et al. (2014); ECHS1 mutations in Leigh disease: A new inborn error of metabolism affecting valine metabolism, 137: 2903-2908]; [Sakai et al. (2015); ECHS1 mutations cause combined respiratory chain deficiency resulting in Leigh syndrome, 36: 232-239]; [Tetreault et al. (2015); Whole-exome sequencing identifies novel ECHS1 mutations in Leigh, 134: 981-991]). This study aims to further describe the ECHS1 deficiency phenotype using medical history questionnaires and standardized tools assessing quality of life and adaptive skills. Our findings in this largest sample of ECHS1 patients in literature to date (n = 13) illustrate a severely disabling condition causing severe developmental delays (n = 11), regression (n = 10), dystonia/hypotonia and movement disorders (n = 13), commonly with symptom onset in infancy (n = 10), classical MRI findings involving the basal ganglia (n = 11), and variability in biochemical profile. Congruent with the medical history, our patients had significantly low composite and domain scores on Vineland Adaptive Behavior Scales, Third Edition. We believe there is an increasing need for better understanding of ECHS1 deficiency with an aim to support the development of transformative genetic-based therapies, driven by the unmet need for therapies for patients with this genetic disease.

The Impact of COVID-19 Infection on a Neurologically Compromised Male With Fahr's Disease Presenting With Acute Delirium and Aspiration Pneumonia: A Case Report.

Fahr's disease or idiopathic basal ganglia calcification is a rare, sporadic, genetically dominant, and inherited neurological condition that manifests with dysphagia and Parkinson's disease. The computed tomography (CT) scan is the method of choice to diagnose basal ganglia calcifications seen in Fahr's disease. This case report elaborates on the emergency management of a 58-year-old male patient with acute respiratory distress, acute delirium, schizophrenia, Fahr's syndrome, and history of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (coronavirus disease 2019 or COVID-19) infection. The patient's chest X-ray, laboratory workup, and vital signs were suggestive of aspiration pneumonia-induced sepsis and acute hypoxemic respiratory failure. Post-admission antibiotic management reduced sepsis complications without improving the altered mental status. A comprehensive clinical assessment suggested the attribution of Fahr's disease to the patient's aspiration pneumonia and other clinical complications. In addition, COVID-19 infection, sepsis-induced inflammatory processes, and pre-existing neurological compromise possibly deteriorated the patient's neurological outcomes, overall prognosis, and recovery.

Wernicke's encephalopathy secondary to hyperemesis gravidarum: A clinical challenge.

Wernicke's encephalopathy (WE) is an acute neurological condition characterized by a triad of ophthalmoplegia, ataxia and altered mental status. The underlying cause is thiamine deficiency, which may be due to multiple aetiologies. Thiamine is essential for carbohydrate and amino acid metabolism. Its deficiency shunts glucose to anaerobic pathways producing metabolic abnormalities. Diagnosing WE relies heavily on clinical suspicion. Magnetic Resonance Imaging can show some specific findings. We report this case of a 35 year old pregnant woman with gestational diabetes who was admitted in hospital for high blood sugar levels and electrolyte abnormalities. She had a history of ten miscarriages. From undergoing laparoscopic cholecystectomy for intractable vomiting to spontaneous expulsion of the foetus to being intubated for acidosis, her hospital stay was prolonged and eventful. Although the cause of her repeated miscarriages could not be established despite extensive workup, thiamine deficiency leading to Wernicke's encephalopathy was the most probable cause.

Case Report: Triphasic Waves in a 9-Year-Old Girl With Anti-NMDAR Encephalitis.

BACKGROUND: Triphasic waves (TWs) are mainly described in association with metabolic encephalopathy, especially hepatic encephalopathy. Now, as different conditions including non-metabolic and structural abnormalities have been reported to be associated with TWs, the presence of TWs becomes a non-specific finding for metabolic encephalopathy. CASE PRESENTATION: We report the first case of anti-NMDAR encephalitis in a 9-year-old girl presenting with TWs on EEG. The TWs background EEG lasted for about 12 h on the 40th day of the disease course. No epileptic wave was found during a series of EEG examinations. The child was discharged from the hospital and no neurological sequelae remained after a six-month follow-up. CONCLUSIONS: TWs are not specific to metabolic encephalopathy, but can also occur in children with autoimmune encephalitis. This case achieved a good prognosis after the early initiation of immunotherapy.