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Section Editor: Dr. Renu Suthar

May 2021

Title: Second intravenous immunoglobulin dose in patients with Guillain-Barré syndrome with poor prognosis (SID-GBS): a double-blind, randomised, placebo-controlled trial

Citation: Walgaard C, Jacobs BC, Lingsma HF, Steyerberg EW, van den Berg B, Doets AY, et al. Dutch GBS Study Group. Second intravenous immunoglobulin dose in patients with Guillain-Barré syndrome with poor prognosis (SID-GBS): a double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2021 Apr;20(4):275-283. doi: 10.1016/S1474-4422(20)30494-4.

Background: Treatment with one standard dose (2 g/kg) of intravenous immunoglobulin is insufficient in a proportion of patients with severe Guillain-Barré syndrome (GBS) and about 25% severely affected patients with GBS receive a second intravenous immunoglobulin dose (SID). Authors aimed to investigate whether a SID is effective in patients with GBS with a predicted poor outcome.

Methods: In this randomised, double-blind, placebo-controlled trial (SID-GBS), patients (≥12 years) with Guillain-Barré syndrome admitted to one of 59 participating hospitals in the Netherlands were included. Patients were included on the first day of standard intravenous immunoglobulin treatment (2g/kg over  5  days).  Only patients with a poor prognosis (modified Erasmus GBS outcome score of ≥6) were randomly assigned, via block randomization stratified  by  center,  to  SID  (2  g/kg  over  5  days)  or  to  placebo,  7–9  days  after  inclusion. Patients, outcome adjudicators, monitors, and the steering committee were masked to treatment allocation. The primary outcome measure was the Guillain-Barré syndrome disability score 4 weeks after inclusion. All patients in whom allocated trial medication was started were included in the modified intention-to-treat analysis.

Results: Between Feb 16, 2010, and June 5, 2018, 327 of 339 patients assessed for eligibility were included and 112 had a poor prognosis. Of those, 93 patients with a poor prognosis were included in the modified intention-to-treat analysis: 49 (53%) received SID and 44(47%) received placebo.  The mean GBS disability score was 4 (IQR 4-5) in both the groups with the adjusted odds ratio for improvement on the Guillain-Barré syndrome disability score at 4 weeks was 1·4 (95% CI 0·6–3·3; p=0·45). Patients given SID had more serious adverse events (35% vs 16% in the first 30 days), including thromboembolic events, than those in the placebo group. Four patients died in the intervention group (13–24 weeks after randomization).

Interpretation:  Adults with severe GBS with poor prognostic factors were not benefited with second course of intravenous immunoglobulin; moreover, it entails a risk of serious adverse events. Therefore, a second intravenous immunoglobulin course should not be considered for treatment of Guillain-Barre syndrome because of poor prognosis.

July 2020

Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: A randomised, double-blind, placebo-controlled trial.                                                                                                                                                                               Lagae L, Sullivan J, Knupp K, et al. Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: A randomised, double-blind, placebo-controlled trial. Lancet. 2020;394(10216):2243‐2254. doi:10.1016/S0140-6736(19)32500-0.

Methods: In this randomised, double-blind, placebo-controlled clinical trial, 119 children and young adults with Dravet syndrome were enrolled. After a 6-week observation period to establish baseline monthly convulsive seizure patients were randomly assigned in a 1:1:1 ratio to receive placebo (40), fenfluramine 0·2 mg/kg per day (40), or fenfluramine 0·7 mg/kg per day (39) in addition to the existing antiepileptic agents for 14 weeks. The primary outcome was the change in mean monthly frequency of convulsive seizures during the treatment period compared with baseline in the 0·7 mg/kg per day group versus placebo. The median reduction in seizure frequency was 74·9% in the fenfluramine 0·7 mg/kg group, 42·3% in the fenfluramine 0·2 mg/kg group, and 19·2% in the placebo group. The study met its primary efficacy endpoint, with fenfluramine 0·7 mg/kg per day showing a 62·3% greater reduction in mean MCSF compared with placebo (95% CI 47·7–72·8, p<0·0001); fenfluramine 0·2 mg/kg per day showed a 32·4% reduction in mean MCSF compared with placebo (95% CI 6·2–52·3, p=0·0209)

Interpretation: Fenfluramine was marketed in 1980’S as an anti-obesity medication and withdrawn in 1997 due to adverse effects of cardiac valulopathy and pulmonary artery hypertension. In this randomized placebo-controlled trial fenfluramine at dose of 0.7 mg/kg/day and 0.2 mg/kg/day in comparison to placebo led to significant reduction in the monthly convulsive seizure frequency. The maximum dose of fenfluramine used in this study was 26mg. More than 50% seizure reduction was noted in 68% patients receiving 0.7mg/kg/day and 38% patients receiving 0.2mg/kg/day of fenfluramine. The most common adverse events were decreased appetite, diarrhea, fatigue, lethargy, somnolence, and decreased weight. No cardiac adverse events were noted in this study. Low dose fenfluramine was effective in seizure reduction in patients with Dravet syndrome and was tolerated well.

Efficacy of levetiracetam, fosphenytoin, and valproate for established status epilepticus by age group (ESETT): a double-blind, responsive-adaptive, randomised controlled trial.

Citation: Chamberlain JM, Kapur J, Shinnar S, et al. Efficacy of levetiracetam, fosphenytoin, and valproate for established status epilepticus by age group (ESETT): a double-blind, responsive-adaptive, randomised controlled trial. Lancet. 2020;395(10231):1217‐1224. doi:10.1016/S0140-6736(20)30611-5.

Methods: In the Established Status Epilepticus Treatment Trial (ESETT) authors compared the efficacy and safety of levetiracetam, fosphenytoin, and valproate in >2-year-old patients. This multicentric, double-blind, response-adaptive, randomised controlled trial was conducted 58 hospital emergency departments across the USA. Patients with generalized convulsive status with persistent seizures of >5 minute despite adequate doses of benzodiazepines were enrolled. Patients were randomly assigned to receive levetiracetam, fosphenytoin, or valproate.

The primary outcome was absence of clinically apparent seizures with improved consciousness and without additional antiseizure medication at 1 h from start of drug infusion. A total of 462 patients were enrolled in this study, including 225 children <18 years old. 175 (38%) patients received levetiracetam, 142 (31%), fosphenyltoin, and 145 (31%) received valproate. The primary efficacy outcome was met in those treated with levetiracetam for 52% of children, with fosphenytoin in 49% children; and with valproate in 52% of children. No differences were detected in efficacy or primary safety outcome by drug within each age group.

Interpretation: This study provides class 1 evidence for second line agent for treatment of established status epilepticus. Levetiracetam, fosphenytoin and valproate have similar efficacy in all age group, with treatment success in approximately half of the patients. Any of the three drugs can be considered as a potential first-choice, second-line drug for benzodiazepine-refractory status epilepticus.

Levetiracetam Versus Phenobarbital for Neonatal Seizures: A Randomized Controlled Trial

Citation: Sharpe C, Reiner GE, Davis SL, et al. Levetiracetam versus phenobarbital for neonatal seizures: A randomized controlled trial. Pediatrics. 2020;e20193182. doi:10.1542/peds.2019-3182. (NEOLEV2)

Methods: For neonatal seizures, currently there is no US-FDA approved therapies. Levetiracetam has proven efficacy and an excellent safety profile in older patients; therefore, there is great interest in its use in neonates. Authors have studied the efficacy and safety of levetiracetam compared with phenobarbital for first-line treatment of neonatal seizures. NEOLEV2 is a multicenter, randomized, blinded, controlled, phase IIb efficacy, dose-escalation, and safety study of levetiracetam compared with phenobarbital in the first-line treatment of neonatal seizures.

The primary outcome measure was complete electroencephalographic seizure freedom for 24 hours. Infant between 36-44 week of age and >2.2 kg weight who are at risk for seizures were enrolled. Enrolled infant was monitored with continuous VEEG for electrical seizures. Those who had electrical seizures were randomly assigned to levetiracetam or phenobarbital group in 60:40 ratio. A total of 106 infants were enrolled in this study, and 83 were included for modified intention to treat primary endpoint efficacy analysis. In the phenobarbital group 24 among 30 (80%) remained seizure free for 24 hours, compared with 15 (out of 53, 28%) in the levetiracetam group (P-0.001; relative risk 0.35 [95% confidence interval: 0.22–0.56]; modified intention-to-treat population). A 7.5% improvement in efficacy was achieved with a dose escalation of levetiracetam from 40 to 60 mg/kg. More adverse effects were seen in subjects randomly assigned to phenobarbital (not statistically significant).

Interpretation: In the NEOLEV-2 study phenobarbital was more effective than levetiracetam for the treatment of neonatal seizures. Higher rates of adverse effects were seen with phenobarbital treatment. Hypotension, respiratory suppression, sedation, and requirement for pressor support, were more common in patients randomly assigned to phenobarbital.

Contributor: Dr. Naveen Sankhyan

October 2014-10-20
Coppola G et al. Current role of rufinamide in the treatment of childhood epilepsy: Literature review and treatment guidelines. Eur J Paediatr Neurol 2014 May 28. [Epub ahead of print]
The literature on the efficacy and safety of rufinamide in childhood-onset epilepsy syndromes currently includes approximately 600 paediatric patients.

Purpose: The literature on the efficacy and safety of rufinamide in childhood-onset epilepsy syndromes currently includes approximately 600 paediatric patients.

Results: Rufinamide is effective in decreasing the seizure frequency in the Lennox-Gastaut syndrome (LGS), especially tonic and atonic seizures. It might consequently be preferred to other drugs as a second-line treatment for LGS when drop-attacks are frequent. The mean responder rate in the published studies is 38% with seizure freedom achieved in 2.4% of patients. Rufinamide has shown some efficacy in epileptic encephalopathies other than LGS. It can be also effective as adjunctive therapy in children and adolescents with drug-resistant partial seizures. The available data suggest that rufinamide has an acceptable risk/benefit ratio with quite a low risk of aggravating seizures. Common adverse effects (somnolence, nausea and vomiting) are usually mild and self-limiting; they are more frequently observed during titration than in the maintenance phase, suggesting that low escalation rates might be associated with fewer adverse effects. Rufinamide appears to have a favourable cognitive profile compared with other antiepileptic drugs.

Conclusions and comment: This paper summarizes the views of a panel of experienced European epileptologists with regard to the current role of rufinamide in the treatment of childhood epilepsies. Rufinamide is only approved for adjunctive treatment of seizures associated with LGS in children 4 years of age and older. There are very few data on rufinamide treatment at the onset of LGS or early in the course of the disorder; whether early treatment will improve outcome has yet to be determined.


Chiang SS et al. Treatment outcomes of childhood tuberculous meningitis: a systematic review and meta-analysis. Lancet Infect Dis. 2014 Aug 6. pii: S1473-3099(14)70852-7. doi: 10.1016/S1473-3099(14)70852-7. [Epub ahead of print]

Methods: A systematic review and meta-analysis of childhood tuberculous meningitis studies published up to Oct 12, 2012. Included study reports that applied predefined diagnostic criteria and described treatment regimens and outcomes. Pooled risks of death during treatment and neurological sequelae among survivors is presented.

Findings: 19 studies met the inclusion criteria, with reported treatment outcomes for 1636 children. Risk of death was 19·3% (95% CI 14·0-26·1) and probability of survival without neurological sequelae was 36·7% (27·9-46·4). Among survivors, risk of neurological sequelae was 53·9% (95% CI 42·6-64·9). Diagnosis in the most advanced disease stage (3) occurred in 307 (47%) of 657 patients and was associated with worse outcomes than was earlier diagnosis. The most common findings at presentation were cerebrospinal fluid (CSF) leucocytosis (frequency 99·9%, 95% CI 68·5-100·0), CSF lymphocytosis (97·9%, 51·9-100·0), fever (89·8%, 79·8-95·2), and hydrocephalus (86·1%, 68·6-94·6). Frequency of CSF acid-fast-bacilli smear positivity was 8·9% (95% CI 5·0-15·4), and frequency of CSF culture positivity for Mycobacterium tuberculosis was 35·1% (16·8-59·2).

Comment: This is study which collates data of last several decades. This meta-analysis provides the framework to compare emerging data on outcome of TBM. Despite treatment, childhood tuberculous meningitis has very poor outcomes. Poor prognosis and difficult early diagnosis emphasise the importance of preventive therapy for child contacts of patients with tuberculosis and low threshold for empirical treatment of tuberculous meningitis suspects. Implementation of consensus definitions, standardised reporting of data, and high-quality clinical trials are needed to clarify optimum therapy.

May 2020

Safety, tolerability, and efficacy of Viltolarsen in boys with Duchenne muscular dystrophy amenable to exon 53 skipping: A phase 2 randomized clinical trial

Citation: Clemens PR, Rao VK, Connolly AM, et al. Safety, tolerability, and efficacy of viltolarsen in boys with duchenne muscular dystrophy amenable to exon 53 skipping: A Phase 2 Randomized Clinical Trial. JAMA Neurol. 2020; e201264. doi:10.1001/jamaneurol.2020.1264

Methods: In this phase 2 randomized clinical trial 16 boys with DMD received 40 mg/kg (low dose) or 80 mg/kg (high dose) of viltolarsen by weekly intravenous infusion. The initial 4 weeks of randomized clinical trial was double blind placebo controlled and subsequent 20 weeks were open label extension phase. The mean age of the boys with DMD was 7.4 (1.8) years. After 24 weeks of treatment, significant drug-induced dystrophin production was seen in both viltolarsen dose cohorts (40 mg/kg per week: mean [range] 5.7% [3.2-10.3] of normal; 80 mg/kg per week: mean [range] 5.9% [1.1-14.4] of normal). Viltolarsen was well tolerated; no serious adverse events or deaths occurred during the study. Compared to 65 age matched natural history controls, all 16 participants treated with viltolarsen showed significant improvements in timed function tests from baseline, including time to stand from supine, time to run/walk 10 m, and 6-minute walk test (viltolarsen: 28.9 m; control: −65.3 m) at the week 25 visit.

Interpretation: Exon 53 skipping is applicable in approximately 8% to 10% of patients with DMD, including those with deletions in exons 45-52, 47-52, 48-52, 49-52, 50- 52, and 52.4. In this phase 2 randomized controlled trial systemic treatment of boys with DMD amenable for exon 53 skipping with Viltolarsen induced expression of dystrophin protein. Western-blot analysis of dystrophin protein in the muscle biopsy at 24 weeks showed 5.7% & 5.9% dystrophin expression in boys with DMD treated with low and high dose Viltolarsen. Timed function test in viltolarsen treated group showed improvement in 6minute walk distance, 10-meter walk run time and time to stand from supine position.


Title: Vitamin B12, Folate, and Cognition in 6- to 9-Year-Olds: A Randomized Controlled Trial

Citation: Kvestad I, Taneja S, Upadhyay RP, et al. Vitamin B12, Folate, and Cognition in 6- to 9-Year-Olds: A Randomized Controlled Trial. Pediatrics. 2020;145(3):e20192316

Methods: The study is a follow-up of a factorial randomized, double-blind, placebo-controlled trial in 1000 North Indian children where children between age of 6 to 30 months were randomly assigned to receive a placebo or 1.8 µg of vitamin B12, 150 mg of folic acid, or both daily for 6 months. After 6 years, authors re-enrolled 791 of these children for cognitive assessments. Authors compared the scores of the main outcomes (the Wechsler Intelligence Scale for Children, the Crichton Verbal Scale, and subtests of the NEPSY-II) between the study groups, and also measured the associations between markers vitamin B metabolism (plasma cobalamin, folate, and total homocysteine concentrations). Authors reported no differences between the intervention groups and the placebo group on the cognitive outcomes. Plasma cobalamin, folate, and total homocysteine concentrations in early childhood were associated with the cognitive outcomes at follow-up in the unadjusted models. These associations disappeared in models adjusted for relevant confounders.

Interpretation: Results from this follow up study of a randomized, double-blind, placebo-controlled design suggest that vitamin B12 and folate supplementation in children between age 6 to 36 months doesn’t not have long lasting impact on the cognitive outcome of children at 6-9 years of age. Supplementation of vitamin B12 and folic acid in infants have limited public health relevance for long-term cognition.


Title: Selumetinib in children with inoperable plexiform neurofibromas

Citation: Gross AM, Wolters PL, Dombi E, et al. Selumetinib in Children with Inoperable Plexiform Neurofibromas. N Engl J Med. 2020;382(15):1430-1442. doi:10.1056/NEJMoa1912735.

Methods: An open-label, phase 2 trial of selumetinib was conducted in children with neurofibromatosis type 1 with plexiform neurofibromas to determine the objective response rate and clinical benefit. Children with neurofibromatosis type 1 with symptomatic inoperable plexiform neurofibromas received oral selumetinib twice daily at a dose of 25 mg/m2body-surface area on a continuous dosing schedule (28-day cycles). Volumetric magnetic resonance imaging and clinical outcome assessments (pain, quality of life, disfigurement, and function) were performed at least every four cycles. A total of 50 children (median age, 10.2 years; range, 3.5 to 17.4) were enrolled in this study. The most frequent neurofibroma-related symptoms were disfigurement (88%), motor dysfunction (66%), and pain (52%). A total of 35 patients (70%) had a partial response, and 28 (56%) had a durable response. Clinically meaningful improvements were seen in child-reported (38%) and parent-reported interference of pain in daily functioning (50%), and overall health-related quality of life (48%) as well as in functional outcomes of strength (56%) and range of motion (38%). Five patients discontinued treatment because of toxic effects possibly related to selumetinib, and 6 patients had disease progression. The most frequent toxic effects were nausea, vomiting, or diarrhea; an asymptomatic increase in the creatine phosphokinase level; acneiform rash; and paronychia.

Interpretation: In patients with neurofibromatosis dysfunction of the guanosine triphosphatase– activating protein neurofibromin leads to overactivation of the RAS pathway. Targeted inhibition of the RAS pathway with mitogen activated protein kinase inhibition has been successfully used preclinical model of neurofibromatosis type 1. Selective MEK inhibitor Selumetinib was effective in clinically meaningful reduction in pain, motor activity and quality of life in children with inoperable large plexiform neurofibroma.

EEG pattern in a child with Lissencephaly

Puneet Jain, Suvasini Sharma, Satinder Aneja

Pediatric Neurology, Department of Pediatrics, Kalawati Saran Children’s Hospital (LHMC), ew Delhi, India.

Email: [email protected]

An eight month old male presented with developmental delay and epileptic spasms for the last 3 months. He was the first child of non-consanguineous marriage. The antenatal and perinatal periods were uneventful. He achieved social smile at 5 months, partial neck holding at 6 months and was recognizing his mother and cooing at the time of presentation. There was no grasp. There was no regression of attained milestones. He started having flexor spasms since last 3 months. The spasms occurred in clusters which occurred mainly on waking up from sleep. He also had stiffness in the lower limbs which had been noticed for the last 2 months. This was non-progressive. Vision and hearing were normal. The family history was unremarkable.

On examination, the child had normal facies and no neurocutaneous markers. The weight and length were age appropriate. He had microcephaly (OFC 40 cm). The cranial nerve examination was normal. The tone was increased in all 4 limbs with brisk deep tendon reflexes and extensor plantar responses. Systemic examination was unremarkable. The MRI of the brain showed Lissencephaly with no gradient (Fig). The EEG showed diffuse high voltage alpha-frequency activity intermingled with beta-frequency activity (Fig).

Lissencephaly is a disorder of neuronal migration characterized by absent or abnormally wide gyri and abnormally thick cortex. Epilepsy is a major presentation of Lissencephaly syndromes and is usually drug-refractory. Three EEG patterns have been classically described in patients with Lissencephaly. The current case showed EEG pattern I. The characteristic EEG patterns along with the clinical findings may help neurologists to consider the diagnosis of Lissencephaly.

Suggested Reading

Menascua S, Weinstockb A, Farooq O, Hoffman H, Cortez MA. EEG and neuroimaging correlations in children with Lissencephaly. Seizure 2013;22:189-193

Isolated Pontine Involvement in Evolving Posterior Reversible Encephalopathy Syndrome

Ramesh Konanki, Lokesh Lingappa
Rainbow Hospital for Women and Children, Hyderabad

Email: [email protected]

A 8-year old previously healthy boy presented with fever, vomiting, bleeding gums and later, seizures on day 14 of illness. Child was noted to have hypertension, thrombocytopenia, hemolytic anemia, uremia and elevated serum lactate dehydrogenase suggestive of atypical hemolytic-uremic syndrome. He had repeated seizures and encephalopathy from day 14, requiring three antiepileptic drugs. The CT scan of brain on day 14 showed bulky, hypodense pons with normal supratentorial structures (figure 1A). MRI two days later showed hyperintensities involving pons and cerebellar peduncles (figure 1B). Repeat CT scan three days after MRI showed involvement of bilateral parietooccipital regions along with bulky pons (figure 1C). The hypertension, uremia, seizures and encephalopathy improved gradually with plasmapheresis. Repeat CT scan six weeks later showed complete resolution of signal changes in pons and parietooccipital regions, confirming the diagnosis of PRES.

Figure 1.
  •  CT scan on day 14 showing bulky, hypodense pons with obliteration of cisternal spaces (arrows);
  •  T2-weighted MRI on day 16 showing hyperintensities of pons and middle cerebellar peduncles (block arrows);
  •  CT scan on day 19 showing hypodensities asymmetrically involving parieto occipital regions (unshaded arrows)

Neonate with seizures

Aicardi Goutiere Syndrome: A case report

A four-year old boy, first child born to second-degree consanguineous couple presented with developmental delay, microcephaly and recurrent seizures from age of 5 months. The antenatal and perinatal periods were uneventful. He had episodes of fever associated altered sensorium and seizures for 1-2 weeks from 5 months onwards every 2-3 months. He had been treated as meningoencephalitis (previous reports not available). No family history of mental retardation or early childhood deaths. On examination, hypertelorism with horizontal oscillatory nystagmus, spasticity were noted. Rest of the examination was normal. Developmental evaluation gave developmental age of 6 months.

CSF analysis revealed lymphocytosis, with normal protein and glucose. No organisms were detected and negative for TORCH studies. CT scan (Fig. 1) and MRI of the brain (figure 2) are given below. The clinical and radiological findings in our patient, together with the CSF findings of an elevated lymphocytosis are highly suggestive of Aicardi- Goutiere’s syndrome.

AGS is an autosomal recessive progressive encephalopathy associated with basal ganglia calcification, white matter abnormality, CSF pleocytosis, and elevated CSF interferon- α. The main radiological differential diagnosis includes Cockayne syndrome, congenital infections, in particular congenital cytomegalovirus infection and toxoplasmosis and pseudo-TORCH syndrome.

Figure 1: CT scan showing spotty/punctate calcification in the basal ganglia, periventricular regions, parietal regions and cerebellar lobes bilaterally. Diffuse hypodense areas in bilateral frontal, parietal and temporal regions white matter. The cortical sulci, basal cisterns, and ventricular system are prominent, suggestive of cortical atrophy.

Figure 2: MRI scan of the brain showed diffuse symmetric, bilateral, white matter hyperintensities on T2-weighted images and T1 W images (Fig. 2) predominantly in the bilateral frontal, parietal and temporal subcortical white matter regions with paucity of white matter. Well defined cysts noted in the bilateral frontal and temporal regions. Thin rim of corpus callosum was seen.

Marin Amat sign

Dr. Puneet Jain and Dr. Sheffali Gulati,
Division of Pediatric neurology, All india institute of medical sciences (AIIMS), New delhi.
Email: [email protected]

A premorbidly normal, 8-years old girl presented with 5 days- history of deviation of angle of mouth towards right side and incomplete closure of the left eye. There was no history of ear discharge/vesicles, decreased hearing or parotid swelling. There was no history s/o other cranial nerve deficits, altered sensorium, seizures, headache, vomiting, weakness, sensory loss or unsteadiness. Examination revealed left CN VII palsy and Marin Amat sign. Fundoscopy and otoscopy was normal. Her MRI Brain was normal. Marin Amat sign, also called as “reverse Gunn phenomenon” is a synkinesia, seen with Bells palsy, due to aberrant regeneration of the facial nerve. (The video is available on personal request to the author)

Figure: Figure showing left facial nerve palsy

Neonate with Seizures and Encephalopathy

Ramesh Konanki, Lokesh Lingappa
Rainbow Children’s Hospital & Perinatal Centre, Hyderabad

A 5-day old baby girl, born at term gestation to 3rd degree consanguineous couple, appropriate for gestation, was admitted with complaints of seizures, poor feeding and lethargy. The peripartum was uneventful. At admission, baby was in peripheral circulatory failure, encephalopathy and respiratory distress. Baby was treated with antibiotics, antiepileptics (Phenobarbitone and Fosphenytoin), and mechanical ventilation. Investigations revealed metabolic acidosis, hyperammonemia (520 m.mol/l), arterial lactate 2.8 m.mol/l and hypoglecemia. Urine ketones were negative. The EEG showed diffuse cerebral dysfunction (Low amplitude indeterminate activity) with electrographic seizures and frequent brief ictal rhythmic discharges (BIRDs) arising from both hemispheres independently. Based on lab investigations and imaging findings possibility of IEM was considered. MRI images are given below. The blood amino acids and acylcarnitine profile (by TMS) revealed markedly elevated propionyl carnitine (C3), and elevated C3/C2 and C3/C16 ratios suggestive of methyl malonic academia/propionic acidemia.

Radiological differential diagnoses include ethyl malonic aciduria, 3-methyl glutaric aciduria, beta-keto thiolase deficiency, maple syrup urine disease (MSUD) and Leigh’s disease.

Figure 1: Axial T1-Weighted MRI showing hyperintense signal changes in bilateral putamina, subcortical white matter and peri-central sulcus white matter

Figure 2: DWI images showing areas of diffusion restriction involving medulla, dorsal pons, cerebellar peduncles, cerebellar vermis and dentate nuclei, midbrain, bilateral putamina and white matter adjacent to central sulci and splenium of corpus callosum.

L2-Hydroxy glutaric aciduria

L2-Hydroxy glutaric aciduria: An under recognized, slowly progressive

leucoencephalopathy of metabolic etiology

Lokesh Lingappa, Ramesh Konanki
Rainbow Children’s Hospital & Perinatal Centre, Hyderabad.

A 12-year old girl presented with initial motor delay, mild intellectual disability and seizures associated with fever. She had mild gait ataxia and incoordination, normal head size and fundus. MRI images are given here. Urine organic acids showed elevated L-2-hydroxyglutaric acid.

L2-OH glutaric aciduria is a neurometabolic disorder caused by deficiency of an FAD-linked, membrane-bound mitochondrial enzyme, L-2-hydroxyglutarate dehydrogenase. It commonly presents as mild developmental delay (motor and cognitive) that is either very slowly progressive or non-progressive, sometimes as static encephalopathy. In late childhood or adolescence, a slowly progressive neurological deterioration may be noted in the form of pyramidal, extrapyramidal, and cerebellar signs, and intellectual decline. Some children may present as learning disability in school age for the first time. These children may have seizures triggered by fever. This diagnosis should be suspected in children with relative megalencephaly, intellectual disability, mild gait disturbances, normal eyes, no evidence of peripheral neuropathy or organomegaly with no identifiable cause. MRI demonstrating leukoencephalopathy with predominant subcortical white matter involvement along with characterstic garland appearance of signal changes in the cerebellum (dentate nuclei involvement) and signal changes in bilateral globus pallidus one needs to suspect L2 hydroxy glutaric aciduria. The radiological differential diagnoses include Canavan disease and Kearns-Sayre syndrome, both of which almost always show brain stem involvement. The Urine organic acids by GCMS confirmed the diagnosis in the four of our cases with these classical MRI findings.

Figure: Axial T2 weighted MRI showing hyperintense signal changes involving bilateral dentate nuclei (A); and bilateral globi pallid, bilateral symmetric hemispheric white matter predominantly subcortical regions, more in frontoparietal lobes, sparing corpus callosum and internal caps