Acute Neurologic Dysfunction in Critically Ill Children: The PODIUM Consensus Conference

CONTEXT Acute neurologic dysfunction is common in critically ill children and contributes to outcomes and end of life decision-making. OBJECTIVE To develop consensus criteria for neurologic dysfunction in critically ill children by evaluating the evidence supporting such criteria and their association with outcomes. DATA SOURCES Electronic searches of PubMed and Embase were conducted from January 1992 to January 2020, by using a combination of medical subject heading terms and text words to define concepts of neurologic dysfunction, pediatric critical illness, and outcomes of interest. STUDY SELECTION Studies were included if the researchers evaluated critically ill children with neurologic injury, evaluated the performance characteristics of assessment and scoring tools to screen for neurologic dysfunction, and assessed outcomes related to mortality, functional status, organ-specific outcomes, or other patient-centered outcomes. Studies with an adult population or premature infants (≤36 weeks' gestational age), animal studies, reviews or commentaries, case series with sample size ≤10, and studies not published in English with an inability to determine eligibility criteria were excluded. DATA EXTRACTION Data were abstracted from each study meeting inclusion criteria into a standard data extraction form by task force members. DATA SYNTHESIS The systematic review supported the following criteria for neurologic dysfunction as any 1 of the following: (1) Glasgow Coma Scale score ≤8; (2) Glasgow Coma Scale motor score ≤4; (3) Cornell Assessment of Pediatric Delirium score ≥9; or (4) electroencephalography revealing attenuation, suppression, or electrographic seizures. CONCLUSIONS We present consensus criteria for neurologic dysfunction in critically ill children.

Diagnosis of Classic Homocystinuria in Two Boys Presenting with Acute Cerebral Venous Thrombosis and Neurologic Dysfunction after Normal Newborn Screening

Homocystinuria, caused by cystathionine β-synthase deficiency, is a rare inherited disorder involving metabolism of methionine. Impaired synthesis of cystathionine leads to accumulation of homocysteine that affects several organ systems leading to abnormalities in the skeletal, cardiovascular, ophthalmic and central nervous systems. We report a 14-month-old and a 7-year-old boy who presented with neurologic dysfunction and were found to have cerebral venous sinus thromboses on brain magnetic resonance imaging (MRI)/magnetic resonance venogram (MRV) and metabolic and hypercoagulable work-up were consistent with classic homocystinuria. The 14-month-old boy had normal newborn screening. The 7-year-old boy initially had an abnormal newborn screen for homocystinuria but second tier test that consisted of total homocysteine was normal, so his newborn screen was reported as normal. With the advent of expanded newborn screening many treatable metabolic disorders are detected before affected infants and children become symptomatic. Methionine is the primary target in newborn screening for homocystinuria and total homocysteine is a secondary target. Screening is usually performed after 24–48 h of life in most states in the US and some states perform a second screen as a policy on all tested newborns or based on when the initial newborn screen was performed. This is done in hopes of detecting infants who may have been missed on their first screen. In the United Kingdom, NBS using dried blood spot is performed at 5 to 8 days after birth. It is universally known that methionine is a poor target and newborn screening laboratories have used different cutoffs for a positive screen. Reducing the methionine cutoff increases the sensitivity but not necessarily the specificity of the test and increasing the cutoff will miss babies who may have HCU whose levels may not be high enough to be detected at their age of ascertainment. It is not clear whether adjusting methionine level to decrease the false negative rates combined with total homocysteine as a second-tier test can be used effectively and feasibly to detect newborns with HCU. Between December 2005 and December 2020, 827,083 newborns were screened in Kentucky by MS/MS. Kentucky NBS program uses the postanalytical tools offered by the Collaborative Laboratory Integrated Reports (CLIR) project which considers gestational age and birthweight. One case of classical homocystinuria was detected and two were missed on first and second tier tests respectively. The newborn that had confirmed classical homocystinuria was one of twenty-three newborns that were referred for second tier test because of elevated methionine (cutoff is >60 µmol/L) and/or Met/Phe ratio (cutoff is >1.0); all 23 dried blood spots had elevated total homocysteine. One of the subjects of this case report had a normal methionine on initial screen and the other had a normal second-tier total homocysteine level. The performance of methionine and total homocysteine as screening analytes for homocystinuria suggest that it may be time for newborn screening programs to consider adopting next generation sequencing (NGS) platforms as alternate modality of metabolic newborn screening. Because of cost considerations, newborn screening programs may not want to adopt NGS, but the downstream healthcare cost incurred due to missed cases and the associated morbidity of affected persons far exceed costs to newborn screen programs. Since NGS is becoming more widely available and inexpensive, it may be feasible to change testing algorithms to use Newborn Metabolic NGS as the primary mode of testing on dry blood specimens with confirmation with biochemical testing. Some commercial laboratories have Newborn Screening Metabolic gene panel that includes all metabolic disorders on the most comprehensive newborn screening panel in addition to many other conditions that are not on the panel. A more targeted NGS panel can be designed that may not cost much and eventually help avoid the pitfalls associated with delayed diagnosis and cost of screening.

Congenital hypoparathyroidism misdiagnosed as infantile seizure

The occurrence of seizure in children is a common neurologic dysfunction and finding the underlying aetiology is critically important as it determines the prognosis and outcome of the seizure and also guides therapeutic strategies. Parathyroid hormone (PTH) plays key role in the complex controlling mechanisms regulating calcium and phosphate balance. An insufficient circulating PTH level is a common cause of hypocalcaemia. A 3-months-old infant was referred to our endocrine unit with recurrent seizures, body stiffness, noisy breathing and bilateral cataract. He was previously been diagnosed as epilepsy in a syndromic child. Biochemical investigation revealed hypoparathyroidism, brain MRI was suggestive of decrease myelination for age, EEG revealed normal study, and a diagnosis of congenital hypoparathyroidism was confirmed. After calcium and vitamin D replacement, the infant improved and was seizure free off antiepileptic therapy. This case therefore explores an unusual case of seizure disorder. It further highlights the fact that not all epilepsies are cryptogenic or genetic epilepsy, therefore treatable acute symptomatic etiologies should be adequately searched.

‘Fifth Day Fits’ (FDF) – Biotinidase Deficiency is Probably the New Name

Neonatal Seizures, the most critical of neonatal neurologic dysfunction, has aetiology of varying prognoses. The diagnosis of underlying aetiology is most critical. With use of genetic studies, better imaging technologies, better cortical electrical activity mapping and biochemical advancement, every attempt in diagnosing a cause is made.