haut de page

mise à jour du
22 mai 2003
Pediatrics in Review
2000; 21; 5; 173-177
Index of suspicion
Hassib Narchi
Saudi Aramco Al-Hasa Health Center, Mubarraz, Saudi Arabia


You are called by the nursery nurse to evaluate a 3-day-old infant who has fed poorly since shortly after birth and seems to be unusually "tight." The girl was born to unrelated parents at term by breech delivery after an uneventful pregnancy. The tetanus immunization status of her mother is up-to-date, and there is no history of drug abuse. The family history is unremarkable, and her six older siblings are healthy. Birthweight was 3.2 kg, and her Apgar scores were 6 and 9 at 1 and 5 minutes, respectively; no resuscitation was required.
Physical examination reveals an irritable infant who has no dysmorphic features but whose sucking and swallowing are poor. There is generalized hypertonicity that is more pronounced when the baby is awake and disappears during sleep. The tendon reflexes are brisk, and the startle reflex is exaggerated. No other abnormalities are noted.
The results of multiple investigations, including blood gases, serum glucose, calcium, electrolytes, complete blood count, cerebrospinal fluid (CSF) studies, and urine toxicology screening for opiates, barbiturates, cocaine, and amphetamines, all are normal. Blood and CSF bacteriologic cultures remain negative. Cranial ultrasonography and electroencephalography (EEG) during the hypertonic episodes yield normal findings, as do nerve conduction velocity studies. Additional testing rules out gastroesophageal reflux. Electromyography shows an almost permanent muscular activity, even during rest, with occasional periods of electric quietness.
The association of generalized muscular rigidity, hypertonia in flexion, and an exaggerated startle response, in the absence of other identified disorders, in this infant led to the diagnosis of hyperexplexia, and oral diazepam was prescribed at a dose of 0.5 mg every 8 hours. Her feeding pattern improved quickly, and her muscle tone decreased progressively over the next few months. At 2 weeks of age, electromyography was repeated and revealed normal patterns. The child's developmental milestones and the results of the neurologic examination were entirely normal at 1 year of age.
Hyperexplexia, known also as hyperekplexia or stiff-baby syndrome, is a rare autosomal dominant neurologic disorder. It manifests at birth with generalized muscular rigidity, hypertonia in flexion with closed fists, and an exaggerated startle response. These signs typically are heightened by the slightest stimulus, including nose tapping, and disappear with sleep. Hypertonia diminishes during the first 2 to 3 years of life. Motor retardation often is present without intellectual deficit. There is an increased risk of congenital dislocation of the hips and also of umbilical, inguinal, and hiatal hernia (which can be a risk factor for aspiration) due to increased abdominal pressure. Sudden death has occurred in patients who have hyperexplexia and may be related to complete heart block and apnea during seizure-like episodes. Dramatic improvement follows the use of diazepam or clonazepam.
Findings on EEG, nerve conduction velocity studies, and evoked potential testing (somatosensory, brainstem, and cortical) are normal. Electromyography shows a pattern of sustained muscular activity with intermittent periods of electrical quiet. The sustained muscular activity disappears with benzodiazepine treatment.
Current pathogenetic hypotheses for hyperexplexia include the presence of abnormalities in the brain stem inhibitory system and neuromediator or receptor dysfunction. The physiology is believed to involve increased excitability of reticularneurons in the brainstem (and possibly in the spinal cord), leading to exaggerated primitive withdrawal reflexes. Hyperexplexia is the first human disease shown to result from mutations within a neurotransmitter gene. CSF gamma-aminobutyric acid (GABA) levels were reported to be low in affected patients, and because clonazepam acts through the GABA type-A receptors, a genetic defect in the GABA neurotransmitter receptor is thought to be the cause of this disorder.
The condition is linked to a DNA marker on the long arm of chromosome 5 and is associated with point mutations at the channel-forming segment M2 of the glycine receptor alpha-1 subunit GLRA1. Both recessive and dominant mutations in GLRA1 have been found in affected individuals. Mutation analysis of GLRA1 also is likely to be useful as an aid to genetic counseling and in the diagnostic evaluation of neonatal hypertonia.
The differential diagnosis in a newborn who has increased muscle tone is extensive. Tonic seizures may occur after birth asphyxia or meningitis or in patients who have Metabolic abnormalities, but they do not increase with stimuli or decrease
with sleep, and findings on the EEG usually are diagnostic. Neonatal drug withdrawal syndrome usually occurs 24 to 72 hours after birth and may be suspected by maternal behavior or drug history as well as by the presence of other signs in the neonate, such as diaphoresis, high pitched cry, sneezing, yawning, ravenous appetite, vomiting, diarrhea, and poor temperature regulation.
Drug withdrawal is confirmed by a urine toxicology screen. Neonatal tetanus is very rare and may occur in infants of incompletely immunized mothers. It usually is associated with an infected umbilical stump, and symptoms do not occur in the first week of life. Opisthotonos and trismus may be prescrit, and the dorsal and facial muscles are affected more frequently than the limbs. The symptoms do not disappear during sleep. Congenital arthro gryposis may result from neuromuscular pathology and may be accompanied by polyhydramnios. In these patients, the limbs are frozen in a fixed deformity (flexion or extension), and this positioning is not influenced by stimuli or sleep.
Sandifer syndrome is associated with gastroesophageal reflux and manifests as torticollis and arching of the body.Patients who have hyperexplexia may have apneic spells. Apnea is very unusual in terrn infants in the absence of birth asphyxia, seizures, central nervous system hemorrhage or malformation, or sepsis. Apparent life-threatening events or near-sudden infant death syndrome occur after the neonatal period and may be associated with apnea and cardiorespiratory arrest, but startle reactions and muscular rigidity do not occur.
Data regarding drug therapy is scanty, anecdotal, and not derived from randornized double-blind studies. Benzodiazepines, primarily clonazepam, are the drugs used most often, with clinicians initiating therapy at dosages that can control severe Symptoms, then titrating the dose to obtain the desired clinical response. There are no forma] guidelines for the duration of therapy. Most authors begin to taper the dose as soon as clinical improvement has been achieved, although therapy up 1 to 3 years of age has been reported. Some authors recommend a clonazepam dose of 0.05 to 0. 1 mg/kg per day.
Hyperexplexia should be considered in the evaluation of neonates and infants who have suspected seizures, apnea, aspiration pneumonia, hyperexcitability, and near-miss sudden infant death syndrome. By diagnosing this condition correctly, the clinician may spare the patient unnecessary investigation and allow him or her to receive specific treatment and subsequent supervision. Families need to be informed of the genetic nature of the disorder, which may recur in future pregnancies.