David Michelson

Evidence Report: Genetic and metabolic testing on children with global developmental delay Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society

Objective: To systematically review the evidence concerning the diagnostic yield of genetic and metabolic evaluation of children with global developmental delay or intellectual disability (GDD/ID). Methods: Relevant literature was reviewed, abstracted, and classified according to the 4-tiered American Academy of Neurology classification of evidence scheme. Results and Conclusions: In patients with GDD/ID, microarray testing is diagnostic on average in 7.8% (Class III), G-banded karyotyping is abnormal in at least 4% (Class II and III), and subtelomeric fluorescence in situ hybridization is positive in 3.5% (Class I, II, and III). Testing for X-linked ID genes has a yield of up to 42% in males with an appropriate family history (Class III). FMR1 testing shows full expansion in at least 2% of patients with mild to moderate GDD/ID (Class II and III), and MeCP2 testing is diagnostic in 1.5% of females with moderate to severe GDD/ID (Class III). Tests for metabolic disorders have a yield of up to 5%, and tests for congenital disorders of glycosylation and cerebral creatine disorders have yields of up to 2.8% (Class III). Several genetic and metabolic screening tests have been shown to have a better than 1% diagnostic yield in selected populations of children with GDD/ID. These values should be among the many factors considered in planning the laboratory evaluation of such children.

Practice Parameter: Evaluation of the child with microcephaly (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society

Objective: To make evidence-based recommendations concerning the evaluation of the child with microcephaly. Methods: Relevant literature was reviewed, abstracted, and classified. Recommendations were based on a 4-tiered scheme of evidence classification. Results: Microcephaly is an important neurologic sign but there is nonuniformity in its definition and evaluation. Microcephaly may result from any insult that disturbs early brain growth and can be seen in association with hundreds of genetic syndromes. Annually, approximately 25,000 infants in the United States will be diagnosed with microcephaly (head circumference <−2 SD). Few data are available to inform evidence-based recommendations regarding diagnostic testing. The yield of neuroimaging ranges from 43% to 80%. Genetic etiologies have been reported in 15.5% to 53.3%. The prevalence of metabolic disorders is unknown but is estimated to be 1%. Children with severe microcephaly (head circumference <−3 SD) are more likely (∼80%) to have imaging abnormalities and more severe developmental impairments than those with milder microcephaly (−2 to −3 SD; ∼40%). Coexistent conditions include epilepsy (∼40%), cerebral palsy (∼20%), mental retardation (∼50%), and ophthalmologic disorders (∼20% to ∼50%). Recommendations: Neuroimaging may be considered useful in identifying structural causes in the evaluation of the child with microcephaly (Level C). Targeted and specific genetic testing may be considered in the evaluation of the child with microcephaly who has clinical or imaging abnormalities that suggest a specific diagnosis or who shows no evidence of an acquired or environmental etiology (Level C). Screening for coexistent conditions such as cerebral palsy, epilepsy, and sensory deficits may also be considered (Level C). Further study is needed regarding the yield of diagnostic testing in children with microcephaly.

The effect of assessment method and respondent population on utilities elicited for Gaucher Disease

Measured preferences have been reported to vary with the method of elicitation and respondent population surveyed. We elicited utilities for Gaucher disease using a multimedia implementation of the time trade-off, standard gamble, and a conceptually different, largely untested approach, the risk-risk trade-off, from those who are healthy, those with a chronic illness and those with Gaucher disease. The risk-risk trade-off produced significantly lower utilities than the other two preference assessment methods and had the poorest test-retest reliability. The respondents self-rated current health state utility was the most important determinant of utility values elicited by the time trade-off and standard gamble for the hypothetical health states. Our results do not support the use of our implementation of the risk-risk trade-off method. In eliciting preferences for hypothetical health states from the general population, the subjective rating of a respondents own health state should be considered in determining representative population groups.

Tethered cord syndrome in childhood: diagnostic features and relationship to congenital anomalies

Abstract Tethered Cord Syndrome (TCS) is a stretch-induced functional disorder of the spinal cord that often develops and presents in childhood in association with spinal dysraphism. While the subtlety with which TCS can present makes it challenging to diagnose, awareness of the common neurological, musculoskeletal and urologic symptoms are of great value to the clinician, and can aid timely referral for neurosurgical evaluation. This article reviews these symptoms, as well as the clinical and radiological findings of the most common dysraphic conditions associated with TCS.

Use of opioids in asphyxiated term neonates : Effects on neuroimaging and clinical outcome

Perinatal asphyxia is a common cause of neurologic morbidity in neonates who are born at term. Asphyxiated neonates are frequently treated with analgesic medications, including opioids, for pain and discomfort associated with their care. On the basis of previous laboratory studies suggesting that opioids may have neuroprotective effects, we conducted a retrospective review of medical records of 52 neonates who were admitted to our neonatal intensive care unit between 1995 and 2002 and had undergone magnetic resonance imaging (MRI) of the brain. Our review revealed that 33% of neonates received morphine or fentanyl. The neonates who received opioids also had experienced hypoxic/ischemic insults of greater magnitude as suggested by higher plasma lactate levels and lower 5-min Apgar scores. It is interesting that the MRI studies of neonates who were treated with opioids during the first week of life demonstrated significantly less brain injury in all regions studied. More important, follow-up studies of a subgroup of opioid-treated neonates whose MRI scans were obtained in the second postnatal week had better long-term neurologic outcomes. Our results suggest that the use of opioids in the first week of life after perinatal asphyxia have no significant long-term detrimental effects and may increase the brains resistance to hypoxic-ischemic insults.

Neurodevelopmental disorders and genetic testing: Current approaches and future advances

Genetic testing for intellectual disability, global developmental delay and other neurodevelopmental disorders has advanced considerably in the last five to ten years and can be an important diagnostic tool for clinicians. This article provides a clinical and ethical framework for understanding these advances, future directions and the current limitations of these approaches. Ann Neurol 2013;74:164–170

Cerebral Folate Deficiency Presenting as Adolescent Catatonic Schizophrenia: A Case Report

Cerebral folate deficiency presents during infancy with irritability, deceleration of head growth, seizures, and progressive cognitive and motor impairment. Although low serum folate levels have been found in patients with schizophrenia, we describe the first case of cerebral folate deficiency presenting as catatonic schizophrenia. A 13-year-old previously healthy boy presented to our hospital with a 17-month history of schizophrenic symptoms with progressively worsening catatonia. On admission, he demonstrated near-complete mutism, frequent enuresis and encopresis, and severe psychomotor retardation. Our initial diagnostic evaluations, including brain magnetic resonance imaging, electroencephalogram, and routine metabolic tests, were normal. A lumbar puncture done to look for neurotransmitter defects or cerebral folate deficiency revealed low levels of 5-methyltetrahydrofolate (31 nmol/L; reference range, 40-150 nmol/L). He also had elevated titers of folate receptor-blocking antibodies. He was treated for the next 9 months with 5-formyltetrahydrofolate (folinic acid), but his catatonia was unchanged.

Gliomatosis cerebri mimicking Rasmussen encephalitis. Case report.

Gliomatosis cerebri (GC) is a distinct malignant neuroepithelial neoplasm that is rarely found in children. The authors present the case of an 11-year-old girl in whom the initial presentation suggested possible early Rasmussen encephalitis (RE), but in whom a diagnosis of GC was made instead after examination of a brain biopsy specimen. Despite advances in magnetic resonance (MR) imaging and MR spectroscopy, this case shows the limitations of clinical and neuroimaging diagnosis and the essential role of biopsy procedures when early RE is suspected.