Brain & Development 1995; 17; 114-6
H y p e r e k p l e x i a , a cause of n e o n a t a l apnea: a case report Jos6 Luiz Dias Gherpelli a,* Amaury Reis Nogueira Jr. a, Eduardo Juan Troster c, Alice Dagostinho Deutsch c, Clea Rodrigues Leon6 c, Mario Wilson Iervolino Brotto b, Aron Diament a, Jos6 Lauro Araujo Ramos c a Servi£o de Neurologia Infantil, Departamento de Neurologia, Hospital das Cllnicas da Faculdade de Medicina da Universidade de SKo Paulo, Caixa Postal 8091, SKo Paulo, 01065-970 SP, Brazil b Serviqo de Neurofisiologia, Departamento de Neurologia, Hospital das Clfnicas da Faculdade de Medicina da Universidade de S~o Paulo, S(to Paulo, SP, Brazil c Servigo de Neonatologia, Departamento de Pediatria, Hospital das Cffnicas da Faculdade de Medicina da Universidade de SKo Paulo, S~o Paulo, SP, Brazil
Received 27 January 1994; accepted 13 November 1994
We report a case of non-familial hyperekplexia which characteristically developed apnea and feeding difficulties in the neonatal period. The abnormal startle response was evident from the second week of life onwards. The infant showed a marked improvement of the startle response and muscle hypertonia with clonazepam. Clobazam was also tried with no apparent response. A prominent long latency C response was observed on EMG examination, suggesting a possible cortical neuronal hyperexcitability origin for the abnormal startle response observed in hyperekplexia. Keywords: H y p e r e k p l e x i a ; Myoclonus; I n f a n t a p n e a ; H i g h - r i s k n e w b o r n ; S t a r t l e r e s p o n s e
1. I N T R O D U C T I O N Startle is a common alerting reaction experienced by all humans. Except for minor interpersonal variations, a stereotyped motor pattern is seen consisting of facial grimacing, flexion of the head, elevation of the shoulders and flexion of the elbows, trunk and knees. Repeated stimulation tends to decrease the response but it never completely disappears. In infancy the intensity appears to be greater and the reaction similar to the Moro response. Startle disease or hyperekplexia is a rare, genetically determined disorder, with an autosomal dominant inheritance with variable expressivity, first described by Suhren et al. . There are several reports of sporadic cases of hyperekplexia [2-4]. In infants the disorder may be responsible for life-threatening episodes of apneic spells that can lead to the sudden infant death syndrome . In early life this disorder is frequently misdiagnosed as epilepsy or cerebral palsy. The hallmark of the disease is the presence of an abnormally exaggerated startle response to tactile, auditory and visual stimuli, together with a global
* Corresponding author. 0387-7604/95/$09.50 © 1995 Elsevier Science B.V. All rights reserved SSDI 0387-7604(94)00113-8
muscular hypertonia and hyperactive tendon reflexes. The abnormal startle response can be easily elicited by tapping the infant's nose. We report an infant with the sporadic form of hyperekplexia, who developed transient apneic spells and feeding problems in the immediate neonatal period.
2. C A S E R E P O R T The patient is a female, white infant, born at term, after an uneventful pregnancy, with a birth weight of 2,670 g and Apgar scores of 9 and 10. Her parents are unrelated and her only brother is a 3.5-year-old healthy child. In the first 2 days of life, she had several episodes of apneic spells with cyanosis, and vomiting with abdominal distention. In the third day, she developed fever, and the neurologic examination disclosed tremors, a severe global hypertonia with hyperactive tendon reflexes, and a positive Trousseau sign. The fever faded away spontaneously and she had no other cyanotic spells, but the hypertonia was more marked in the following days, leading to feeding difficulties that prompted the insertion of a nasogastric tube. Laboratory tests disclosed normal serum levels
J.L.D. Gherpelli et al. /Brain & Development 1995; 17:114-6
of calcium, magnesium, sodium, potassium, transaminases, glucose, alkaline phospha'~ase, urea, creatinine, direct and indirect bilirubin, serum lactate and pyruvate, blood gases and blood pH. Cranial ultrasound, CT scan, auditory and visual evoked potentials, and E E G were normal. Screening tests for inborn errors of amino acids, mucopolysaccharides and glucose metabolism in urine were negative. CSF examination disclosed a normal cell count and a protein of 74 mg%, but we performed no dosage of neurotransmitters. During the second week of life a startle reaction was observed after nose tapping ~md, although there were no other similar cases in the family background, a diagnosis of hyperekplexia was suggested. Clobazam was introduced at a dose of up to 10 m g / d a y with no positive results. The drug was discontinued and clonazepam was started at a dosage of 0.1 m g / k g / d a y , with marked improvement of the hypertonia and startle response. At 1 month of age, a video-EEG was performed and the tracing was normal throughout the examination, even when the startle response was elicited by tapping the infant's nose. At 1 month of age, she was able to feed from the bottle and, at 40 days, was discharged from the neonatal unit. At 4 months of age, her mother abruptly discontinued clonazepam for 3 days and noticed a marked increase in the startles frequency and worsening of the hypertonia, that improved after clonazepam was started again. At 5 months of age, a long loop reflex (LLR) study was performed by a method similar to that of Conrad and Aschoff  and Kelly et al. . The left median nerve was stimulated supra maximally by electrical pulses of 0.1 ms (cathode being distal) at the wrist, while the activity of the abductor pollicis brevis was recorded by surface electrodes in a belly tendon derivation. The LLR was tested with the muscle 'at rest', and several recordings were made in the patient to assure consistency. An augmented C response consistently occurred after median nerve stimulation, with a latency of 78 ms, after the F wave, but before the end of the silent period (Fig. 1). She is presently 1 year 3 months of age, receiving clonazepam 0.1 m g / k g / d a y , with a normal neurodevelopmental
quotient (she began to walk unsupported at 14 months and is able to say "mama and papa" and understands direct orders) and no startle response, although there is a mild global muscle hypertonia on the neurological examination. A MRI study was performed at 10 months of age showing normal brain images, including the brainstem.
3. D I S C U S S I O N About one hundred cases of hyperekplexia have been described in the literature. The frequency is probably higher, since some cases are misclassified as epilepsy or cerebral palsy during infancy. Affected individuals manifest hypertonia, exaggerated startle response, and intermittent apnea, all of them noticed either in the neonatal period or in the first months of life. A similar disorder starting later in childhood or in young adults and non-familial was described by Gastaut and Villeneuve . Andermann et al.  described the phenotypic variability of the disease and suggested classifying this syndrome into a major and minor form, the major form including hypertonia during infancy, excessive startle response, falling attacks without unconsciousness, generalized hyper-reflexia, episodic generalized shaking and insecure gait. The major form is one that affects babies, leading to lifethreatening episodes of apnea and the sudden infant death syndrome. The minor form is characterized by the presence of inconstant excessive startle response. Both forms can occur in the same family. Our infant had the major non-familial form of hyperekplexia. Our case illustrates the difficulties encountered in the diagnosis during the neonatal period. In the first week of life the characteristic startle response was not present, the apneic spells and hypertonia being the most conspicuous signs. The abnormal and characteristic startle response was evident only from the second week of life onwards. There are several reports of apnea of infancy and sudden infant death in infancy in families of hyperekplectic patients. Therefore, hyperekplexia should be part of the differential diagnosis in these circumstances. The apnea or respiratory difficulties observed during early infancy is secondary to bouts of massive myoclonus due to external stimuli that interfere with the respiratory muscle activity. Flexion of the infant's head and legs toward the trunk seems to inhibit the startles and thus allows the parents and medical personnel to control the acute episodes of apnea
Fig. 1. C response with a latency of 78 ms, after stimulation of the left median nerve at the wrist, with thumb in the 'rest' position. C, C response; M, motor response; F, F wave; LT, latency time; SL, silent period.
The startle response showed a marked decrease after the introduction of clonazepam in the present case, as well as an important decrease in muscle hypertonia. Therapeutic efficacy of clonazepam has been reported by several authors [4,8-10], although in other cases the response was less important or not observed at all . We tried clobazam, a drug tested in association with carbamazepine with good response in one of the cases reported by Brown et al. , without any beneficial effect. Trials with diazepam [2,3,9,12], nitrazepam [5,11], primidone , carbamazepine [4,11], phenytoin [2,4], phenobarbital [1-4] and valproic acid  with variable resuits were reported by several authors in cases of hyperekplexia, but clonazepam seems to be the most effective. The pathogenesis of the abnormal startle response is not
J.L.D. Gherpelli et al. /Brain & Development 1995; 17:114-6
fully understood. The conventional EEG and video-EEG showed no abnormal epileptic activity associated with the startle response in our patient. We found a prominent, high latency C response in the electromyography performed at 5 months of age in our patient. This finding strongly suggests an exaggerated LLR in this disorder. Assuming that LLR is of cortical origin, the electrophysiologic findings in our patient suggest increased cortical neuronal excitability as the basic pathophysiologic mechanism responsible for hyperekplexia. Markand et al.  also found a prominent C response in 6 familial cases and concluded that an increased cortical neuronal excitability was the basic pathophysiologic mechanism in hyperekplexia. Brown et al.  studied the startle response to auditory and somesthetic stimulation in 8 patients with hereditary or symptomatic hyperekplexia, observing disproportionately long latencies in the abnormal startle response to the hand and foot muscles and a peculiar muscle recruitment pattern that suggested convergence of the auditory and somesthetic stimuli on a common efferent system located in the brainstem. They suggested that this system would form the common final pathway for normal and abnormal startle responses. We did not find any other case with hyperekplexia in our patient's family (her parents and the 3-year-old brother had no abnormal startle response). Sporadic non-familial cases have been reported by several authors [2-4] and probably represent new mutations. The disease is inherited as an autosomal dominant trait with variable expressivity. Recently, Ryan et al. , using systematic linkage analysis in a family with hyperekplexia, found a tight linkage between the disease locus and a polymorphic genetic marker locus that has been physically mapped to chromosome 5 q33-q35.
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