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Anaesthetic implications of hyperekplexia--'startle disease'.

SUMMARY

This report describes anaesthesia for consanguineous siblings with the rare genetic condition hyperekplexia. This condition is also known as 'stiff baby syndrome' or 'startle disease' Hyperekplexia can present in major and minor forms and is caused by a mutation in chromosome 5 which results in a defect in the [alpha]-1 subunit of the inhibitory glycine receptors in the caudal pontine reticular formation leading to neuronal hyperexcitability. The patients present with a potentially life-threatening exaggerated startle reflex. Life-threatening spasms may be terminated by forced flexion of the head and legs towards the trunk. Anaesthesia management should avoid stimuli which trigger the reflex. Clonazepam and diazepam are used to prevent and control the spasms. Propofol and other agents with the ability to potentiate both GABA-ergic and glycinergic transmission may be appropriate choices for anaesthesia. Reaction to neuromuscular blockers may be unpredictable. Both our patients had relatively prolonged but otherwise uneventful recovery.

Key Words: anaesthesia, hyperekplexia

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Hyperekplexia, 'stiff baby syndrome' or 'startle disease' was first described in 1958 by Kirstein and Silfverskiold (1). The name hyperekplexia was suggested by Suhren et al in 1966 when they described this syndrome in a Dutch family (2). The affected children assume a generalised flexed posture with clenched fists and anxious stare. The episodes of stiffness may be associated with life-threatening complications such as apnoea, bradycardia, aspiration and complete heart block. Vigevano's manoeuvre (forced flexion of the head and legs towards the trunk) is known to be life-saving when prolonged stiffness impedes respiration'. Conducting anaesthesia in these patients without provoking acute episodes of spasm may be difficult. We present the details of two patients with hyperekplexia who presented for ocular surgery at our hospital and we discuss the anaesthetic implications of the disease.

CASE HISTORIES

Case 1

An eight-year-old male child weighing 29 kg, born of a consanguineous marriage presented to the ophthalmology department for strabismus surgery. He was born at full term without significant prenatal or labour associated complications. On the second day of life, he started having brief episodes of generalised stiffness, usually in response to stimuli such as a sudden loud voice, bright light or touching and tapping on the face. He would assume a flexed position of the body for a few seconds. There was no history of clonic movements or cyanosis during the episodes and they were not associated with any post-ictal phase. A therapeutic trial of phenobarbitone and sodium valproate for a presumed diagnosis of epilepsy was ineffective. On further evaluation, a diagnosis of hyperekplexia was made and therapy was changed to oral clonazepam with a reduction in his symptoms, although he still showed an exaggerated startle reflex in response to minor stimuli. Throughout his life he had a history of frequent unprovoked falls and delayed milestones. On examination, the child showed an exaggerated startle response with symmetrical myoclonic jerking of limbs on tapping the nasal tip or glabella. The patient had multiple healed scars over the body, presumably as a consequence of injuries related to spasms and falls. The remainder of the general and neurological examination was normal apart from brisk patellar reflexes. Haematological and biochemical investigations and screening tests for inborn errors of metabolism did not reveal any abnormality. An electroencephalogram showed intermittent left temporal slowing with no epileptogenic foci. A positron emission tomography scan showed evidence of hypometabolism in the left temporal lobe.

Clonazepam was continued on the day of surgery. The child was kept in a quiet pre-anaesthesia room. EMLA cream was used to minimise the stimulus of venous cannulation and midazolam 0.5 mg was given intravenously. The patient was not separated from his parents until he was anaesthetised. After applying routine monitors (ECG, pulse oximeter, NIBP), fentanyl 30 [micro]kg was given intravenously. Anaesthesia was induced with intravenous propofol in a titrated dose (total of 40 mg) and the airway was secured with a flexible LMA #2.5. Anaesthesia was maintained with isoflurane and nitrous oxide in oxygen. Ventilation was controlled without using nondepolarising muscle relaxants. Ketorolac 1 mg/kg was administered intramuscularly. Intraoperatively the child showed episodic dorsiflexion of the foot and abnormal movements of the fingers of the upper arm which were not related to the surgical stimuli. Otherwise the intraoperative course was uneventful. At the end of the surgery, the patient was allowed to breathe spontaneously and, after ensuring adequate ventilation, the airway was removed in a deep plane of anaesthesia. Although he was maintaining his airway and oxygen saturation, the patient was excessively sedated. Sedation scores improved gradually over the next two to three hours. He was observed until complete recovery and was discharged from hospital a day later.

Case 2

The younger sibling of the above child was six years old and weighed 17 kg. He started showing similar symptoms at the 23rd day of life that partially subsided after oral clonazepam therapy. The EEG of this younger sibling also showed intermittent bitemporal slowing (left >right). Anaesthetic management was similar except we did not administer midazolam in the preoperative period, as the child was cooperative. He also showed abnormal jerks under anaesthesia. Recovery was prolonged but uneventful.

DISCUSSION

The startle reflex is a normal reticular and cortical reflex elicited in newborns and infants, consisting of facial grimacing, blinking and some involuntary movements to a sudden stimulus. When such a reflex is pathologically exaggerated, resulting in tonic spasms, it is termed hyperekplexia or "startle disease" (4). This disorder is categorised into major and minor forms (4). The major form consists of an exaggerated startle response, momentary generalised muscular stiffness and hypertonia. Onset is usually soon after birth but it can present in fetal life as abnormal intrauterine movements. In the minor form, the startle response is exaggerated without any additional symptoms such as generalised stiffness. Our patients showed features of the major form of hyperekplexia.

Avoidance of the reflex resulting in hypertonic spasms is a major concern in these patients as it has been reported to be associated with life-threatening complications such as respiratory arrest, bradycardia, regurgitation, aspiration and heart blocks (5,6). Our anaesthesia plan was designed to avoid painful stimuli and minimise events such as sudden loud noises and bright lights in the perioperative period. Intravenous access was secured after local EMLA cream application and parental separation avoided until anaesthesia was induced.

Hyperekplexia is a genetic disorder. A mutation in the fifth chromosome results in a defect in the [alpha]-1 subunit of the inhibitory glycine receptors in the caudal pontine reticular formation leading to neuronal hyperexcitability. Glycine is an inhibitory transmitter particularly in the spinal cord and brainstem'. The abnormal startle reflex is probably related to the lack of inhibition by higher centres.

Hyperekplexia must be differentiated from other causes of neonatal hypertonia such as tetany, spastic cerebral palsy, Schwartz-Jample syndrome, severe perinatal asphyxia and spastic quadriparesis (5). Differential diagnosis between epileptic and nonepileptic paroxysmal disorders is fundamental, not only to allow correct management of patients, but also to avoid the burden of unnecessary investigations and antiepileptic medication.

Clonazapam (0.05 to 0.1 mg/kg/day) and diazepam are considered the drugs of choice and are effective in decreasing the severity of the symptoms but may not totally abolish them. They act by enhancing the GABA-gated chloride channel function and presumably compensate for the defective glycine-gated chloride channel in hyperekplexia (8). Thus anaesthetics that combine the ability to potentiate both GABA-ergic and glycinergic transmission might be of considerable utility in these patients. We used propofol for induction of anaesthesia in our patients. Propofol possesses antiepileptic properties, presumably related to GABA-mediated presynaptic and postsynaptic inhibition. Shea et al showed that intravenous propofol could compensate functionally for reduced glycine receptor response in a mouse model of hyperekplexia (9). They found that propofol can effectively reverse the functional and behavioural effects of hyperekplexia mutations in mice and concluded that propofol appears to be a promising lead compound for the rational design of drugs that target human hyperekplexia. The antiemetic property of propofol is also desirable for patients undergoing squint surgery.

Oguro et al studied the motor response to auditory and trigeminal stimulation in children with hyperekplexia (10). They found that taps on the supraorbital nerve elicited multiple startle patterns, probably by stimulation of structures of the eye supplied by trigeminal nerve branches. Inhalational induction of anaesthesia was thus avoided as application of a facemask may have some tapping action and provoke the reflex and its sequelae.

We avoided using nondepolarising muscle relaxants in our patients. Both our patients showed some mild limb jerks, which might be undesirable if the movement occurred at the surgical site. There are conflicting reports of the effects of suxamethonium on neuromuscular blockade in patients with hyperekplexia (11,12). Murphy et al also reported an abnormal degree of train-of-four fade in their patient with the use of sevoflurane as compared to that seen in normal children (12). Neuromuscular blocking drugs, whether depolarising or non-depolarising, should be used with caution and the effects monitored in children with hyperekplexia.

Clonazepam has synergistic respiratory depressive and sedative effects with other anaesthetic drugs especially opioids (13). Thus we used a low dose of fentanyl (1 [micro]g/kg) in both patients. Recovery was prolonged in both the patients. There has been one further report of anaesthesia in a child with hyperekplexia since the original submission of this paper (14).

Hyperekplexia is a rare disease and there are few reports of patients with hyperekplexia undergoing surgery under general anaesthesia. Anaesthetic management should include avoidance of any sudden stimuli, not just intraoperatively but in the whole of the perioperative period. Complications such as apnoea, bradycardia and regurgitation during episodes of spasm should be recognised early and managed with Vigevano's manoeuvre or pharmacological agents as appropriate. Anaesthetic drugs must be administered in titrated doses while considering their interaction with drug therapy for the disease. Due to the still unclear pharmacodynamics of neuromuscular blocking drugs in these patients, they may be avoided or used with caution.

Accepted for publication on December 17, 2007.

REFERENCES

(1.) Kirstein L, Silfverskiold B. A family with emotionally precipitated drop seizures. Acta Psychiatr Neurol Scand 1958; 33:471-476.

(2.) Suhren O, Bruyn GW, Tunyman JA. Hyperekplexia. A hereditary startle syndrome. Neurol Sci 1966; 3:577-605.

(3.) Vigevano F, Di Capua M, Dalla Bernardina B. Startle disease: an avoidable cause of sudden infant death. Lancet 1989; 1:216.

(4.) Bakker MJ, vanDijk JG, van den Maagdenberg AMJM, Tijssen MA. Startle syndromes. Lancet Neurology 2006; 5:513-524.

(5.) Shahabi NS. Neonatal hyperekplexia: a case report. Iranian Journal of Basic Medical Sciences 2003; 50:148-149.

(6.) McAbee GN, Kadakia SK, Sisley KC, Delfiner JS. Complete heart block in nonfamilial hyperekplexia. Pediatr Neurol 1995; 12:149-151.

(7.) Lapunzina P, Sanchez JM, Cabrera M, Moreno A, Delicado A, de Torres ML et al. Hyperekplexia (startle disease): a novel mutation (S270T) in the M2 domain of the GLRA1 gene and a molecular review of the disorder. Mol Diagn 2003; 7:125-128.

(8.) Zhou L, Chillag KL, Nigro MA. Hyperekplexia: a treatable neurogenetic disease. Brain Dev 2002; 24:669-674.

(9.) O'Shea SM, Becker L, Weiher H, Betz H, Laube B. Propofol restores the function of "hyperekplexic" mutant glycine receptors in Xenopus oocytes and mice. J Neurosci 2004; 24:2322-2327.

(10.) Oguro K, Hirano K, Aiba H. Trigeminally induced startle in children with hyperekplexia. Mov Disord 2005; 20:484-489.

(11.) Cook WP, Kaplan RE Neuromuscular blockade in a patient with stiff-baby syndrome. Anesthesiology 1986; 65:525-528.

(12.) Murphy C, Shorten G. Train of four fade in a child with stiff baby syndrome. Paediatr Anaesth 2000; 10:567-569.

(13.) Murray MJ, DeRuyter ML, Harrison BA. Opioids and benzodiazepines. Crit Care Clin 1995; 11:849-873.

(14.) Epbright B, Mayhew JF. Bilateral inguinal hernia repair in a child with hyperekplexia. Paediatr Anaesth 2007; 17:1099-1101.

R. GARG *, R. RAMACHANDRAN ([dagger]), P. SHARMA ([double dagger]) Department of Anaesthesia, All India Institute of Medical Sciences, Delhi, India

* M.D., D.N.B., Senior Resident. ([dagger]) M.D., Assistant Professor. ([double dagger]) M.D., D.N.B., Professor, Department of Opthalmology, Dr Rajendra Prasad Centre of Ophthalmologic Sciences.

Address for reprints: Dr R. Ramachandran, 112, Ashoka Enclave (Main), Faridabad, Haryana 121003, India.
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Author:Garg, R.; Ramachandran, R.; Sharma, P.
Publication:Anaesthesia and Intensive Care
Article Type:Clinical report
Geographic Code:9INDI
Date:Mar 1, 2008
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