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Case Reports Indian Pediatrics 2002; 39:773-776 |
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Hyperekplexia: A Non-epileptic Startle Disorder |
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S.B. Rajadhyaksha V.B. Bahl
Hyperekplexia is an uncommon neurological entity that is often confused with epilepsy in infancy. Most cases have a familial predisposition. It is characterized by episodic stiffness, apnea in the neonatal period, hypertonia and exaggerated nonhabituating startle in response to unexpected auditory, visual or somatosensory stimuli. It has relatively benign long-term outcome despite the stormy and perplexing neonatal course. Five children belonging to three families who presented recently to the epilepsy unit at a children’s hospital are described here. Case Reports Case 1 and II The first case, a 5 week old baby was the second child of non-consanguineous Muslim parents. She was born at term, cried immediately and was breastfed soon after. As per history and the hospital notes she had brief seizure like episodes on day 2. There was no fever, alteration in color, breathing, feeding pattern or activity. The blood levels of glucose and calcium were normal. She had similar episodes on day 10 and one month of age and was treated with phenobarbitone. The mother also informed that the baby was excessively jittery and startled unduly to minor stimulti such as touch. There was episodic stiffening of the body occuring for a few minutes several times a day. At presentation the baby was alert, with normal weight, length and head circumference. She was jittery with mild hypertonia, hyperreflexia and flexor plantar response. On lightly tapping the bridge of the nose with a finger, there was an exaggerated startle response with symmetrical myoclonic jerking of limbs which did not habituate with repeated stimulation at intervals of one second. She had no evidence of birth asphyxia, intracranial hemorrhage or tetany. Metabolic studies were normal. MRI scan showed no structural anomaly of brain with myelination appropriate for age. Video-EEG with repeated nasal tapping demonstrated the excessive startle response with its associated muscle artifact and absence of epileptiform activity or any autonomic change. In view of a clinical diagnosis of hyperekplexia, the infant was treated with clonazepam at 0.02 mg/kg/day. EMG performed subsequently was normal. After 3 weeks, there was a marked decrease in the startle response with no further seizure-like stiffening episodes and muscle tone was normal. At 3 months, the neurodevelopment assessment showed a moderate delay of central coordination. At 6 months an improvement in motor skills was noted with a marked reduction of the exaggerated startle response. Second case, the elder brother of first case also had pathological startle with jerking of the four limbs most noticeable on tapping the dorsum of nose. The parents were concerned about his safety as he startled easily and used to fall to the ground to auditory stimuli especially from vehicular traffic. As a newborn, he was jittery, had apneic episodes, was ‘tight’, but did not have any seizures or feeding problems. There was no neuro-developmental delay. EMG and video EEG were normal. His audiogenic startle and resultant falls were abolished to the satisfaction of his parents after oral clonazepam was started at 0.03 mg/kg/day. Both parents and other family members were unaffected.
Case III and IV: This brother-sister pair aged 5 weeks and 2 years 3 month respectively had a normal birth history, born to non-consanguineous Muslim parents. The boy presented to us with complaints of excessive startle and episodic stiffening. There was an identical neonatal history in his older sister. Video-EEG was normal. The generalized flexor spasm in response to nasal tapping without habituation was evident in both. On clonazepam, both showed improvement in startle response at 6 months follow up. Mild motor delay was noted in the boy, while his sister was functioning at an age appropriate development level. Both parents were asymptomatic and family history was not contributory.
Case V: A male infant, first child born out of a normal delivery to third degree consanguineous parents with no significant family history, was admitted with complaints of recurrent tightness and apneic spells from day 4 of life. On examination, he was active and had a non-habituating startle reflex on repeated glabellar tapping. The muscle tone was variable and deep tendon jerks were brisk. Video EEG did not show epileptiform activity, was started on clonazepam but was lost to follow-up. Discussion
Hereditary hyperekplexia, as a major form manifests in the newborn period. A relatively benign minor variety with excessive non-habituating startle is seen in older individuals(1,2). This disorder presents at or soon after birth with exaggerated startle in response to minor stimulti, apneic spells and hypertonia which may be continuous or episodic. The three younger infants in our series had episodic hypertonia only in awake state without a setting of perinatal asphyxia, seizures, sepsis, central nervous system hemorrhage or malformation. Other nonepileptic conditions like benign neonatal myoclonus (occurs only in sleep) and neonatal tetanus were excluded. Stimulus-evoked myoclonus seen with severe central nervous system dysfunction and the exaggerated Moro’s response seen in spastic quadriparetic children was also ruled out(3). The possibility of neonatal seizures was excluded as the episodes were state related, could be induced and video EEG did not show any ictal correlate. However, children and adults with hyperekplexia can manifest with tonic and clonic generalized attacks with cyanosis, repeated myoclonic jerks and prolonged seizures(2,3). Typically, hypertonia decreases within a few months and disappears by 2-3 years, which may result in motor lag during infancy as observed in both our infants. Delayed walking and slight mental retardation has also been described(1,3). The exaggerated startle response may persist even up to adulthood and an increased association of hernias and congenital dislocation of the hip has been noted. Rarely, hyperekplexia may present antenatally with abnormal intrauterine movements and a peculiar fetal position(2,4). The affected older siblings of our cases had no hypertonia, were functioning at an age-appropriate development level which excluded the diagnosis of pathological startle of Tay Sach’s disease. However, symptoms were not innocuous as loud sounds provoked frequent falls and injuries. Parents of all the cases were asymptomatic without a history of stiffening or abnormal startle.
The inheritance is autosomal dominant with variable penetrance, and both major and minor forms may be seen in the same family(2,5). Recessively inherited and sporadic forms of the disorder are also seen. All our cases appear to be familial as indicated by the affected sibling pairs, and a history of consanguineous parentage in the fifth child. Late-onset forms of generalized stiffness with momentary loss of postural control leading to unexpected falls ‘en statue’ termed ‘hereditary stiff-man syndrome’ and varied neurological conditions with brainstem dysfunction with pathological startle termed ‘symptomatic hyperekplexia’ have also been reported in adult literature(6). Hyperekplexia is the first human disease shown to result from mutation within a neurotransmitter gene, in the alpha l subunit of the inhibitory glycine receptor on chromosome 5 (5q33-q35)(7). Recessive cases differing in their alpha l subunit and compound heterozygotes have also been described. Low CSF GABA level is linked to the therapeutic response to clonazepam which potentiates GABA transmission(8). EEG, nerve conduction velocity and evoked potential testing are mostly normal in hyperekplexia(1,9). Occasionally EEG recording shows nonspecific temporal theta activity or bilateral runs of polyspike-slow waves followed by brief flattening of background activity(10,11). Electro-myography (EMG) may indicate periodic sustained muscle contraction with intermittent quiet periods and a normal response is seen following benzodiazepine treatment. A prominent long latency C response has also been described(12). Muscle artifacts on video EEG can be mistaken for true epileptiform discharge and a simultaneous EEG-EMG may help discriminate movement artifacts(13). Proton magnetic resonance spectroscopic imaging (MRSI) studies have shown reduced intensity of neuronal markers as evidence of frontal region dysfunction in hyperekplexia(14,15). Resolution of the disorder with time and treatment is usual and supports the diagnosis. Treatment is easy and effective with clonazepam or diazepam. Basal hypertonia and frequency of startle episodes reduce markedly. No definite guidelines exist regarding duration of therapy but the drug can be tapered slowly once the symptoms subside(16). Valproate and piracetam have been used with some success. Occasionally, a baby can die of cardiopulmonary arrest if a tonic episode occurs in sleep and this can be terminated by a life saving maneuver of sudden forcible flexion of the head and neck(11). Contributors: VBB carried out the workup, follow up, literature review and also drafted the manuscript. SBR was responsible for diagnosis, supervision and overall management. She will stand as the guarantor for the manuscript. Funding: None. Competing interests: None stated.
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