A newborn infant with hypertonic episodes

CASE PRESENTATION

A 3-hour-old neonate was admitted to the neonatal intensive care unit following a cyanotic spell with hypertonia noted during her first breastfeed.

The patient was delivered by spontaneous vaginal delivery at term. At birth she had respiratory depression requiring brief positive pressure ventilation. Apgars were 3¹8⁵. Mother was a healthy 29-year-old G2P0 with normal antenatal ultrasounds and protective serologies. Her previous pregnancy was a third trimester stillbirth.

On assessment the patient had significant and frequent episodes of hypertonia with associated tachycardia and subsequent desaturations with bradycardia requiring bag mask ventilation. The nature of these events suggested seizures and the patient was empirically treated with lorazepam. However, multiple episodes were captured on video electroencephalography (EEG), which did not show any electrographic seizure activity.

Infectious, cardiac, metabolic and neurologic workups were undertaken. The full septic workup, newborn screen and metabolic workup were all negative. There was no structural heart disease and the Holter monitoring was normal. Brain Magnetic Resonance Imaging on day 1 showed white matter edema, which improved on repeat imaging.

The patient was noted to have generalized hypertonia when awake and normal tone during sleep. She had a high-pitched cry, intermittent stridor and feeding difficulties. Further clinical observation confirmed the diagnosis.

DISCUSSION: HYPEREKPLEXIA

The presentation of this patient appeared clinically as seizures, however video EEG is the gold standard for diagnosis of seizures and multiple captured events showed no EEG seizure activity. As such, the differential diagnosis for seizures was explored. Jitteriness and tremors are the most common paroxysmal motor phenomena in neonates. Unlike seizures these do not cause autonomic changes and they can be stopped by restraint of the affected limb (1). Benign sleep myoclonus consists of nonepileptic myoclonic jerks that occur only during sleep and can be aborted by rousing the patient (1). Paroxysmal extreme pain disorder is an autosomal disorder characterized by episodes of stiffening secondary to extreme pain, which can lead to apneas. It is associated with autonomic changes with flushing and harlequin color change (1). Any cause of neonatal apnea can mimic a seizure. Cardiac causes of dysrhythmia and syncope can result in cerebral hypoxemia and secondary hypoxic phenomena (1). Gastroesophageal reflux disease can result in Sandifer’s syndrome, abnormal movements related to feeding (1).

In consultation with the Neurology service, this patient was diagnosed with Hyperekplexia. This diagnosis was made based on the presence of tonic desaturation episodes, generalized hypertonia during the day with normal tone during sleep with myoclonic jerks. She demonstrated an exaggerated startle response to tapping on the nose, and intermittent responsiveness to the Vigevano manoeuvre. Abnormal laryngospasm was seen on laryngoscopy, which was thought to be secondary to hypertonicity.

Hyperekplexia is a rare genetic disorder with core clinical feature of hypertonia and an exaggerated startle reflex with subsequent stiffness (2,3). Hypertonia is present only when the patient is awake and presents immediately after birth (2). The clinical hallmark is the exaggerated startle reflex characterized by extension of the head followed by flexion spasms on the extremities and neck, which is seen in response to tapping on the nose (2). This response does not habituate. Other associated features include nocturnal myoclonus, hyper-alert gaze, herniae and hip dislocation (3). Last trimester intrauterine startle may be present (3).

Hyperekplexia is clinically important because it has been identified as a cause of sudden infant death (3). Infant death in hypekplexia occurs during tonic neonatal cyanotic episodes due to central and obstructive apnea. The Vigevano manoeuvre, or forced flexion of the head and legs toward the trunk, is a potentially life-saving manoeuvre in hyperekplexia as it aborts tonic episodes (3). The diagnosis is made on clinical assessment with pertinent negatives including normal laboratory testing, normal brain imaging and normal EEG (2,3).

Hyperekplexia is caused by genetic mutations of the glycine receptor or transporter (2). It can be autosomal dominant or recessive (2). In this patient genetic testing for the five genes known to be associated with hyperekplexia (SLC6A5, GLRB, GLRA1, GPHN, ARHGEF99) were negative. The exact incidence of gene negative disease is unknown (2).

Treatment of hyperekplexia is with clonazepam, a GABARA1 agonist (2,3). It decreases excess startle reflex, decreases stiffness and decreases the risk of sudden infant death syndrome. The natural history of hyperekplexia is toward improvement in hypertonicity over the first 3 years of life (2,3). Motor milestone development may be delayed, but often catches up once hypertonicity decreases. Speech and learning may also be affected. The excessive startle response typically persists and can lead to recurrent falls (2,3).

With clonazepam this patient significantly improved with decreased startle, normalization of tone and an improved sleep study. The patient was safely discharged home with apnea monitoring and after a number of months clonazepam was attempted to be weaned. However, the excess startle response returned and the previous dose was reintroduced. The patient continues to be followed by a paediatric neurologist.

CLINICAL PEARLS

1. EEG should be performed in all neonates with suspected seizure. If clinical uncertainty persists then Video EEG telemetry should be performed to capture an event for EEG correlation. If there is no EEG correlation seen, then one must rethink their diagnosis of seizure.

2. Hyperekplexia is a rare, but important diagnosis with characteristic features and treatment available.

3. Recognizing the key clinical features of hyperekplexia can help prevent sudden infant death syndrome.