Debopam Samanta

Evidence-based decision support for neurological diagnosis reduces errors and unnecessary workup.

Using vignettes of real cases and the SimulConsult diagnostic decision support software, neurologists listed a differential diagnosis and workup before and after using the decision support. Using the software, there was a significant reduction in error, up to 75% for diagnosis and 56% for workup. This error reduction occurred despite the baseline being one in which testers were allowed to use narrative resources and Web searching. A key factor that improved performance was taking enough time (>2 minutes) to enter clinical findings into the software accurately. Under these conditions and for instances in which the diagnoses changed based on using the software, diagnostic accuracy improved in 96% of instances. There was a 6% decrease in the number of workup items accompanied by a 34% increase in relevance. The authors conclude that decision support for a neurological diagnosis can reduce errors and save on unnecessary testing.

Dry beriberi preceded Wernicke's encephalopathy: Thiamine deficiency after laparoscopic sleeve gastrectomy

In recent times, pediatric obesity has become widely prevalent. If first-line treatment with lifestyle modification fails, bariatric surgery may be indicated for severely obese patients. Many patients now travel abroad to get these surgeries done. Some of these patients receive inadequate postoperative care. We described a morbidly obese 17-year-old girl who had a laparoscopic sleeve gastrectomy procedure for weight loss. Due to severe nausea, she stopped her multivitamin supplementation. Within a few weeks, she developed symptoms of dry beriberi was soon followed by classic symptoms of Wernicke′s encephalopathy. The prompt diagnosis was made with confirmation from serum thiamine level and brain magnetic resonance imaging. Thiamine supplementation reversed ophthalmological symptoms promptly. However, the patient needed inpatient rehabilitation for neuropathy. This case describes that thiamine deficiency can occur after restrictive bariatric surgery, despite lower risk of malnutrition in the absence of intestinal bypass procedure. This report highlights that in the presence of risk factors: dietary noncompliance, inadequate follow-up, and severe nausea with and without vomiting can precipitate the development of Wernicke′s encephalopathy, even after restrictive surgery. Physicians may increasingly encounter thiamine and other nutrient deficiencies in increasing numbers due to increasing prevalence of obesity disorders and availability of bariatric surgeries. This report also emphasized the importance of identifying vague sensory symptoms in thiamine deficiency.

De novo R853Q mutation of SCN2A gene and West syndrome

SCN2A mutations can cause benign familial neonatal–infantile seizures and various epileptic encephalopathies. We report an infant with de novo SCN2A mutation, who presented with epileptic spasms, and later developed focal and myoclonic seizures. This report highlights the importance of genomic screening in patients with West syndrome (WS), emergence of a broad phenotype of SCN2A mutations, and importance of further investigation of the genotype–phenotype correlation of mutations to advance our understanding of pathophysiologic mechanism of seizures.

Myoclonic epilepsy evolved into West syndrome: a patient with a novel de novo KCNQ2 mutation

KCNQ2 mutations causing benign familial neonatal convulsions were initially described more than 10 years ago but more recently reports suggest that early infantile encephalopathy can also be caused by the same genetic mutation. We report an infant with de novo KCNQ2 mutation who presented with drug responsive myoclonic epilepsy in early infancy but later had a presentation consistent with West syndrome including hypsarrhythmia and electrodecrement pattern during spasms. This report highlights the importance of genomic screening in patients with infantile epileptic encephalopathy and the emergence of a broad phenotype of KCNQ2 mutations.

Electroencephalographic findings in KBG syndrome: a child with novel mutation in ANKRD11 gene

KBG syndrome is characterized by intellectual impairment and various craniofacial, skeletal and other minor physical anomalies (Table 1) [1]. Recently, mutations in the ANKRD11 gene encoding ankyrin repeat domain 11, was found to be the genetic mutation associated with this syndrome. Neurologic involvement with developmental delay, seizures, EEG abnormalities and prominent neuropsychiatric features has been described. EEG abnormalities have been previously described as mostly nonspecific in the literature. We report a case of KBG syndrome with evolution of EEG findings over 6 years in a pediatric patient.

Infantile spasms in Williams-Beuren syndrome with typical deletions of the 7q11.23 critical region and a review of the literature.

Williams–Beuren syndrome (WBS), a contiguous-genedeletion disorder, is caused by 1.5–1.8 Mb heterozygous deletion of chromosome 7q11.23. Epilepsy has been rarely reported with the standard deletion, whereas larger deletions with telomeric extension can have severe cognitive delay and severe epilepsy including infantile spasms (IS). Recently, Nicita et al. reported epilepsy as a possible feature in association with typical deletion; however, less than ten cases of IS have been reported with the smaller typical deletion of WBS and there is a dearth of literature on critical review of these cases [1].

Intractable epileptic spasms in a patient with Pontocerebellar hypoplasia: Severe phenotype of type 2 or another subtype?

Introduction: Pontocerebellar hypoplasia (PCH) involves a diverse range of etiologies including a group of single gene disorders. Mutations in the tRNA splicing endonuclease complex (TSEN) 54 gene can be responsible for PCH type 2, 4 and 5. The more common and less severe PCH 2 phenotype is caused by homozygosity for the common missense mutation A307S, while the severe phenotype seen in type 4 and 5 is caused by compound heterozygosity of the A307S mutation along with a nonsense or splice site mutation. Report: We report a 4- month-old girl who presented with epileptic spasms that remained intractable to several antiepileptic medications. Magnetic Resonance Imaging (MRI) brain showed fairly severe hypoplasia with superimposed atrophy of the cerebellum and brainstem with prominent extra-axial fluid spaces. Extensive metabolic testing was negative. Commercial testing for PCH via TSEN54 gene revealed missense mutation of Ala307Ser. A novel sequence variant, designated c.17_40 del, was also found and was predictive of an in-frame deletion of eight amino acids. Follow-up over 2 years revealed intractable epileptic spasms, progressive microcephaly and development of prominent choreoathetosis. Conclusion: This case report describes a rare case of PCH with overlapping features of the less severe PCH2 and the more severe PCH4/5 phenotype. It also adds another new entity in the list of genetic conditions where West syndrome and pontocerebellar hypoplasia can be seen together, emphasizing the need for further investigations of the genotype-phenotype correlation of mutations in order to advance our understanding of the pathophysiologic mechanism in these rare conditions.

A 15-year-old with seizures: late diagnosis of pyridoxine-dependent epilepsy

A 15-year-old boy with history of epilepsy and developmental delay was admitted to the hospital for recurrent seizures. He had history of seizure with fever, predominantly with minor gastrointestinal or upper respiratory tract infections, since the age of 5 months. He had several episodes of focal seizures and was treated with phenobarbital, levetiracetam, lamotrigine, and topiramate until he was 3 years old. Subsequently, he had only rare convulsive seizures in the setting of febrile illness. He was never treated with pyridoxine. Routine electroencephalography showed right and left, independent, frontal sharp epileptiform discharges. Brain magnetic resonance imaging (MRI) was normal. He remained seizure free from age 9 to 14 years, and during that period he was weaned off of all antiepileptic medications. He had mild cognitive delay requiring special assistance in class, mild visual motor integration delay with both visual perceptual and motor coordination difficulty, and mild difficulty in social interaction. Just after he turned 15, he started to have seizures again, and levetiracetam was restarted. On the morning of the admission, he started to have headache, nausea, vomiting and subjective fever, which was followed by repetitive convulsive jerking later that day. He was brought to the emergency room and subsequently admitted to the intensive care unit. Approximately, 15–30 brief seizures of 1–3 min duration were captured daily over the next 7 days, characterized by a slight movement of the head towards right followed by rhythmic opening and closing of mouth and rhythmic eyelid blinking, with or without progression to whole-body convulsion (Fig. 1). Several antiepileptic medications were administered including lorazepam, levetiracetam, fosphenytoin, lacosamide, phenobarbital, and midazolam continuous intravenous infusion. Hematology, chemistry, cerebrospinal fluid, toxicology, infection, neuroimaging studies were non-contributory. Eventually, the patient became seizure free with a combination of antiepileptic medications: levetiracetam, phenytoin, and lacosamide. Patient went home after 3 weeks stay in a short-term disability unit. Due to unknown nature of his epilepsy, epilepsy gene panel was sent for sequencing and deletion and duplication analysis of 70 genes. ALDH7A1 heterozygous pathogenic variant p.Glu427Gln (E427Q) and likely pathogenic variant pTrp203Gly (W203G) were detected, which suggested a diagnosis of pyridoxine-dependent epilepsy. Both mutations cause semi-conservative amino acid substitutions and alter highly conserved positions in the protein to abolish enzyme activity. Each parent is confirmed as a carrier of one mutation each, and a-aminoadipic semialdehyde (aAASA) in urine was elevated at 1.52 mmol/mol creatinine (range\0.5 mmol/mol creatinine). Patient was started on 150 mg BID dose of pyridoxine as well as folinic acid 25 mg two times daily. Patient remained completely seizure free in 6 month follow-up. The ALDH7A1 gene is the only known gene in which pathogenic variants are known to cause pyridoxine-dependent epilepsy (PDE). This gene encodes antiquitin which plays a role in detoxification of aldehydes and lysine catabolism, and its mutation leads to an accumulation of D1-piperideine-6-carboxylase, which inactivates pyridoxal 5-phosphate [1]. Pyridoxal 5-phosphate is an essential cofactor in many neurotransmitter metabolism enzymatic reactions. PDE can cause intractable seizures in neonates, & Debopam Samanta dsamanta@uams.edu

Clinicopathologic findings of CARS2 mutation

OBJECTIVES We describe a 13-year-old girl with a past medical history of epilepsy, intellectual impairment, dysphagia with gastric tube dependence, and autism spectrum disorder who presented with focal status epilepticus. METHODS Video-electroencephalography revealed left occipital pseudoperiodic epileptiform discharges and frequent seizures originating from the left hemisphere. The seizure was refractory to antiepileptic medications and pharmacologic coma. Subsequently, left occipital lobectomy was done. Extensive evaluation including whole exome sequencing, histopathologic examination of brain and muscle samples, mitochondrial DNA content analysis of tissue sample was completed to detect the etiology. RESULTS Skeletal muscle mitochondrial DNA content (qPCR) analysis showed approximately 37% of the mean value of age and tissue matched control group consistent with a mitochondrial depletion syndrome. Microscopic examination of the brain showed cortical abnormalities that largely consisted of infarct-like pathology in a laminar manner, abnormalities of neuronal distribution, and white matter changes. Compound heterozygous mutations of the CARS2 gene were identified by whole exome sequencing; V52G variant [p.Val52Gly (GTG>GGG):c.155 T>G in exon 1] was inherited from the mother and T188M variant[p.Thr188Met (ACG>ATG): c.563 C>T in exon 5] was inherited from the father. CONCLUSION This is the first detailed clinicopathologic description of the Alpers-Huttenlocher syndrome phenotype from CARS mutations.

Influenza B-associated acute necrotizing encephalopathy of childhood: a report from North America.

Central nervous system manifestation of influenza virus infection can be meningitis, encephalitis, or encephalopathy. Newland et al. [1] reported the incidence of influenzarelated neurologic complications as approximately four cases per 100,000 child-years in a geographical area of North America. Seizures were the most common presentation in this cohort with small number of patients with encephalopathy, post-infectious encephalopathy, stroke secondary to hypotension, and aseptic meningitis. Encephalopathy is characterized by absence of inflammation in the brain and composed of several subtypes such as acute necrotizing encephalopathy (ANE), Reye’s syndrome, and hemorrhagic shock and encephalopathy. Though, ANE is frequently reported from Far East countries, less than 10 cases were reported from western countries. A 3-year-old boy, with history of prematurity and very mild spastic diplegia, presented with mental status changes and posturing. He had low-grade fever and sore throat for 1 day, but at the presentation, he had a rapidly progressive neurologic deterioration with unresponsiveness and eye deviation that progressed to prominent extensor posturing. There was no family history of consanguinity, recurrent infections, immune deficiency or early infant deaths. His immunization was up-to-date. Vitals were following: temperature 101 F, heart rate 120, respiratory rate 44, blood pressure 117/60, and pulse oximetry 92 %. Due to subsequent poor respiratory effort, he was sedated and intubated in the emergency department. Neurologic examination was limited due to sedation, but sluggishly reacting symmetric pupil, facial symmetry, baseline increased tone of lower extremities could be appreciated. Tendon reflexes were 2? and bilateral positive Babinski’s reflex was noted. Extensive laboratory investigations were done and significant positive findings were: throat swab positive for influenza B by PCR, white blood cells 3.5 K/ll (normal range 6–17 K/ll), lymphocyte 60 % (50–56 %), magnetic resonance imaging (MRI) brain revealed prominent and fairly symmetrical T2/FLAIR signal abnormalities in the cerebellar peduncles, thalamus, midbrain and pons, and to a lesser extent in the left caudate (Fig. 1). MR spectroscopy did not reveal a prominent lactate peak. Cerebrospinal fluid (CSF) exam revealed 0 (normal 0–5/L) white blood cell, 0 red blood cells, protein 67 (normal 20–70 mg/dL) and glucose 137. Liver enzymes were significantly elevated: AST 750 (normal 20–60 U/L), ALT 2683 (normal 5–45 U/L), but coagulation parameters, bilirubin 0.3 (0.2–1.4 mg/dL), and ammonia 16 (29–57 lmol/L) were normal. Electroencephalography monitoring had not revealed any seizure activity and was most consistent with sedated sleep. Lactic acid was not elevated. CSF was negative for influenza and other viral agents. Serological tests for other viral antibodies were negative also. He had a prolonged and complicated 6-week course in the hospital. He received broad spectrum antibiotic and antiviral coverage initially as well as intravenous immunoglobulin and steroid taper. At discharge, he was ambulatory up to 300 feet with a reverse rolling walker. He was able to remove and replace block on peg board and was getting intensive help from a speech therapist for oral motor skills and progressive swallow skills. His extreme agitation, during initial part of the admission, showed improvement. He was more spastic requiring daily & Debopam Samanta dsamanta@uams.edu