Child Neurology: A case illustrating the role of imaging in evaluation of sudden infant death
Sarah M. Kranick, MD,
Jaya Ganesh, MD,
Curtis R. Coughlin, II, MS and
Daniel J. Licht, MD
From the Department of Neurology (S.M.K.), Hospital of the University of Pennsylvania, Philadelphia; Section of Biochemical Genetics (J.G., C.R.C.), Division of Child Development, and Division of Neurology (D.J.L.), Children’s Hospital of Philadelphia, PA.
Address correspondence and reprint requests to Dr. Sarah Kranick, Human Motor Control Section, National Institute of Neurological Disorders and Stroke, NIH, Bldg. 10, Rm. 7D42, 10 Center Dr., MSC 1428, Bethesda, MD 20892 mattes1{at}mail.nih.gov
A previously healthy 5-month-old girl was found face down onthe bed by her grandmother. Two hours earlier she had actednormally and was placed on her back to nap. She was found tobe apneic and pulseless by Emergency Medical Services and regaineda pulse after 45 minutes of cardiopulmonary resuscitation.
She was born full-term via spontaneous vaginal delivery to a30-year-old gravida 1 para 1. Her newborn screen was normal.By maternal report, she was meeting milestones. She had no recentinfections and immunizations were up to date. She was breastfedexclusively. Her only medication was Poly-Vi-Sol with iron.There were no smokers or pets in her household. The parentswere a mixed race (Asian/Caucasian) couple with no family historyof cardiac or neurologic disease or sudden death.
Physical examination revealed reactive pupils but absent oculocephalicand corneal reflexes, gag, and cough. There was no withdrawalfrom pain or purposeful movement. She was not dysmorphic. Herliver was percussed 4 cm below the costal margin. A dilatedophthalmoscopic examination showed trace optic nerve head pallorbut no other abnormality.
The differential diagnosis of a prolonged arrest in an infantincludes respiratory, cardiac, infectious, neurologic, metabolic,and traumatic events. Cultures must be obtained for sepsis ormeningoencephalitis. Cardiac conduction anomalies may be detectedon EKG, although paroxysmal arrhythmias would not necessarilybe detected after the event. While familial arrhythmia syndromessuch as long-QT syndrome or Wolff-Parkinson-White syndrome maybe revealed by family history, sudden cardiac death in childrenmay also be due to sporadic mutations in cardiac ion channelgenes and provoked by fever, as in Brugada syndrome. Structuralheart disease, leading to apnea or embolism, can be evaluatedby echocardiography. Metabolic or neuromuscular diseases causingrespiratory distress may be associated with dysmorphisms, hypotonia,hypoglycemia, metabolic acidosis, ketosis, or hyperammonemia;evaluation should include serum amino acids, urine organic acids,and lactate and pyruvate levels. The newborn screen must bereviewed for inborn errors of metabolism; although not testedin all states, fatty acid oxidation disorders such as very-long-chainacyl-coA dehydrogenase deficiency can present with sudden deathwhen cardiac energy metabolism becomes impaired (Pennsylvaniascreening information: www.perkinelmergenetics.com/newbornscreening.htm).Toxic screens are warranted even without a known ingestion.While status epilepticus may not be seen on EEG if extensivedamage has occurred, neuroimaging may show underlying pathologyprovoking a seizure, such as strokes or hemorrhages, tumors,or traumatic brain injury. Nonaccidental trauma or smothering(unintentional or intentional) must be suspected in any suddeninfant death.
Initial noncontrast head CT showed subtle midbrain hypodensities(figure). Laboratory studies revealed initial arterial pH of7.03, arterial lactate of 4.2 mg/dL, and albumin of 2.9 mg/dL(norms: lactate 0.5–1.6 mmol/L; albumin 3.1–4.2g/dL). The initial arterial lactate improved to 1.9 mg/dL priorto the lumbar puncture. CSF showed 8 white blood cells (47%monocytes, 33% lymphocytes), 2 red blood cells, protein 94 mg/dL,glucose 43 mg/dL (serum glucose 61 mg/dL), lactate 2.4 mmol/L(norms: CSF protein 15–40 mg/dL, glucose 32–82 mg/dLor 60% of serum, lactate 0.7–2.0 mmol/L; CSF leukocytes>6/mL is considered abnormal in children older than 3 months1).Serum ammonia was 13 µmol/L (norm: 9–33 µmol/L).Blood, urine, and CSF cultures showed no growth. CSF herpessimplex virus and enterovirus PCRs were negative. Serum andurine drug screens were negative for acetaminophen, salicylates,tricyclic antidepressants, ethyl alcohol, cannabinoids, opiates,cocaine, benzodiazepines, barbiturate, amphetamines, phencyclidine,and methadone. Her serum amino acids, urine organic acids, andacylcarnitine profile were all normal. Urine ketones were negative.
Figure Neuroimaging depicting lesions of different ages
Initial head CT showing hypodensities in the midbrain (white arrow, A). MRI of the brain showing an area of restricted diffusion in the left thalamus (open arrow, right panel, B) not correlating to the apparent diffusion coefficient map (open arrow, left panel, B), implying that this is an older lesion than the acute diffusion-restricting infarcts seen throughout the white matter (white arrows, B). Also seen are T2 hyperintensities in the dorsal midbrain (white arrow, left panel, C), periaqueductal grey matter (white arrow, right panel, C), and substantia nigra (open arrow, C).
Her initial EEG was flat with gradual return of some continuousactivity over 48 hours. EKG showed no conduction defects andechocardiography revealed a structurally and functionally normalheart. Abdominal ultrasound revealed normal hepatic echotexture.
In addition to the extensive white matter infarcts typicallyseen after prolonged arrest, her brain MRI performed 3 daysafter her arrest also revealed infarcts of various ages in theleft thalamus and the dorsal brainstem suspicious for a mitochondrialcytopathy (figure). A muscle biopsy was performed. Mitochondrialenzyme activities were within normal range. Quantitative mitochondrialDNA analysis showed a reduced amount of DNA, but the degreeof reduction was not sufficient to diagnose a primary mitochondrialdepletion syndrome (mtDNA sequencing, MitoMet oligo aCGH: BaylorCollege of Medicine; quantitative PCR, mitochondrial enzymeactivities: Columbia University). Her parents decided to withdrawcare, and her heart stopped beating shortly after extubation.
In the evaluation of an infant who has had a prolonged arrest,neurologists are frequently consulted. Determining the etiologyis of critical importance given the risk to future siblingsif there is genetically inherited disease or child abuse. Thediagnosis of sudden infant death syndrome (SIDS) requires othercauses to be ruled out; by definition, SIDS is any sudden unexplaineddeath in an infant less than 1 year old, for which no causecan be found, despite thorough history and examination includingautopsy and examination of the scene of death.2 One recent articleproposed that the relative risk of recurrent SIDS, reportedbetween 1.7 and 10.1, has been overestimated in part due toflawed investigations into these deaths.3 Too frequently thediagnosis of SIDS may be made before appropriate evaluationshave been completed, and physicians may feel uncomfortable pursuingautopsies if parents object.
While the evaluation of sudden death in an infant requires autopsy,examination of the scene of death, and detailed history, theevaluation of an infant who has been resuscitated after a prolongedarrest is not clearly defined. More has been written on thediagnostic evaluation of an apparent life-threatening event(ALTE), defined as an acute change in breathing that was frighteningto the caretaker including some combination of apnea, colorchange, change in muscle tone, choking, or gagging. While someSIDS deaths are due to respiratory causes, SIDS and ALTE aredifferentiated epidemiologically by multiple factors, includingthe decrease in SIDS, but not ALTE, after the Back to Sleepcampaign.4 The differential diagnosis listed above for prolongedarrest is meant as a guide and is unlikely to be all-encompassing.
While several factors in this case suggested a metabolic disorder,including hepatomegaly, depressed albumin, and elevated lactate,these are nonspecific findings that could follow prolonged arrest.An MRI was obtained not because of any protocol necessitatingneuroimaging after prolonged arrest, but because the familyfelt that they needed to see more evidence of brain damage beforeconsidering withdrawal of care. While profound hypoxia can produceischemic lesions such as these, the varying ages of the diffusion-weightedimaging abnormalities in this case raised the suspicion of amitochondrionopathy, especially given the location of theselesions in the dorsal brainstem and periaqueductal gray matterand that hypodensities were seen in the midbrain on CT on arrival.5
If resuscitation efforts had failed in our patient, she mayhave been classified as SIDS. She was found in the prone position,the most significant risk factor for SIDS, although she didnot have other risk factors, such as male gender, African Americanor Native American race, prematurity, or exposure to secondhandsmoke.6 In this case, an MRI that was intended to be prognosticactually widened the differential diagnosis, which had significantimplications for genetic counseling. Parents should be informedthat the risk of future children being affected, even when aspecific genetic or metabolic cause has not been identified,is small but not trivial. This case illustrates that while theevaluation of an infant after prolonged arrest varies widelybetween institutions and from case to case, there may be a rolefor neuroimaging.
Dr. Kranick, Dr. Ganesh, and C.R. Coughlin report no disclosures.Dr. Licht receives research support from the NIH [NINDS K23NS052380 (Principal Investigator)] and the Dana Foundation andhas served as a medical expert for defense and plaintiff attorneys.
Disclosure: Author disclosures are provided at the end of thearticle.
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