Derived from the Greek words: “hyper,” meaning excessive, and “ekplexia,” meaning panic, hyperekplexia is a hereditary disorder characterized by exaggerated startle reflex in response to acoustic, tactile, and other stimuli.1–4 First described in 1958 by Kirstein and Silfverskiold,5 4 members of a family were observed to experience sudden falls provoked by surprise, fear, and stress.4
We report the case of a parturient with a clinical diagnosis of hyperekplexia who underwent successful vaginal delivery managed by the anesthesiology and neonatology service teams from initial antenatal consultation to labor and delivery to hospital discharge. Written and verbal consent for publication were obtained from the patient.
A 38-year-old gravida 6 para 1 (G6P1) presented for antenatal anesthesia consultation at 36 weeks’ gestation regarding her diagnosis of familial hyperekplexia. Since her own birth, her symptoms have included generalized stiffness, hypertonia, and hyperreflexia. Within a few hours after birth, she was transferred to a special care nursery because of generalized stiffness and excessive startle to auditory and tactile stimuli. These symptoms persisted into adulthood. Multiple members of her family have also experienced exaggerated startle symptoms, including her mother, maternal grandmother, and her own 3-year-old son. As part of her workup, the patient had a normal brain magnetic resonance imaging. In addition, she had a normal sleep-deprived electroencephalogram with provoked startle, showing no epileptiform activities during the attack. There were no abnormal laboratory tests to suggest an underlying etiology. During the startling episodes, she was unable to perform voluntary movements but her consciousness was always preserved.
For most of her adult life, her startle attacks were due to unexpected or overwhelming auditory, tactile, and other stimuli. These stimuli have included sudden slamming of doors, sudden alarm from an electronic device, sudden unexpected touch, or sudden change in temperature. She even described having startling episodes from receiving cold IV solutions. During a startle attack, her arms become fully extended, her head becomes fixed, and her lower extremities become rigid with loss of voluntary control. Each episode typically lasts several seconds, during which she is fully conscious but cannot move. The hypertonic muscle contractions are intensely painful. After the hypertonia, tremors and myalgia ensue in all her extremities, sometimes lasting several hours after the episode. The frequency of these attacks depends on her immediate environment, but in a typical day she will have 3 to 4 such attacks. Although clonazepam and paroxetine help control her symptoms, they do not fully attenuate them. During pregnancy, the doses were decreased due to increased somnolence and concerns for fetal adverse effects at a higher dosage.
During her first pregnancy in 2010, her providers were aware of her condition but found no literature to guide her care. Although the plan was for early initiation of epidural labor analgesia, artificial rupture of membrane (ROM) was performed at 3 cm cervical dilation due to minimal cervical changes performed before consulting the anesthesia service. Immediately after ROM, the contractions began with high intensity, triggering sustained tensing of her legs, arms, and hips with each contraction. By the time the anesthesiologist arrived, she was unable to flex her hips and had total body muscle pain from repeated startle attacks. The anesthesiologist successfully placed an epidural catheter, but it required 45 minutes to do so. After the epidural placement, she was much more comfortable and subsequently had an uncomplicated vaginal delivery of a baby boy. The baby boy developed feeding discoordination shortly after birth, excessive startling response at 2 weeks, with generalized stiffness and hypertonia after a startled response. These symptoms increased with handling and disappeared during sleep.
The patient also described a long-standing history of autonomic instability, including postural hypotension, orthostatic sinus tachycardia, presyncopal, and syncope episodes. These symptoms were not problematic in the first pregnancy. In the current pregnancy, these symptoms worsened during the second trimester, resulting in an intolerance of prolonged standing and exercise. Extensive workup by her cardiologist and endocrinologist during her current pregnancy did not reveal any underlying etiology for the autonomic dysfunction.
During the second trimester, assessment with a Holter monitor revealed sinus tachycardia up to 140 beats per minute. In an attempt to increase her intravascular volume, her cardiologist recommended a dietary supplement of 6 salt tablets per day to increase her serum sodium. The cardiologist also recommended compression leggings and that she maintain adequate fluid intake throughout pregnancy. Medications taken during pregnancy included clonazepam and paroxetine for hyperekplexia, levothyroxine for hypothyroidism, vitamin D, prenatal vitamins, and iron.
Physical examination during consultation was unremarkable. Airway and spine examinations revealed no anatomic predictors of difficult laryngoscopy or neuraxial placement. The plan was for her to receive an early epidural analgesia for her upcoming labor and delivery, continue all her medications for hyperekplexia, and consult with the neonatology service regarding neonatal monitoring plans.
The patient returned at term in spontaneous labor. The anesthesiology and neonatology service teams were notified immediately upon her arrival. The nursing team was educated on her diagnosis and potential implications. Upon arrival of the anesthesiologist to her labor room, she was already positioned calmly in a sitting position. In addition to establishing a rapport with the patient and her husband, every step during establishment of epidural analgesia including skin sterilization, local anesthetic infiltration, and epidural needle insertion were initiated only after meticulous verbal forewarning. A lumbar epidural catheter was placed successfully on the first attempt. After a negative test dose with 3 mL of 1.5% lidocaine with 1:200,000 epinephrine, the patient was placed in lateral position with left uterine displacement. Fifteen milliliters of bupivacaine 0.125% with 2 mcg/mL of fentanyl was administered in fractionated dosing while maintaining close monitoring of her arterial blood pressure. Once she became comfortable, the obstetricians were notified and artificial ROM was performed.
Four hours later, the patient delivered a baby girl (Apgar scores of 9 and 9 at 1 and 5 minutes, respectively) with the neonatology team immediately available. The baby was transferred and observed in the neonatal intensive care unit for 24 hours without problems, and both patient and her baby were discharged on postpartum day 4.
Almost 6 decades after the first case of hyperekplexia was reported, the molecular basis of hyperekplexia has become elucidated. We now understand hyperekplexia to be a genetic disorder inherited as an autosomal dominant or recessive pattern with almost complete penetrance.1,2,6
Symptoms of hyperekplexia can manifest before birth as abnormal intrauterine movements7,8 or immediately after delivery in the neonatal period. Neonates may present with tonic spasms mimicking generalized tonic seizures, hypertonia, and developmental delays.4,9 Infants with hyperekplexia may have difficulties feeding and swallowing. In severe cases, the stiffening episodes may lead to sudden death due to apnea, aspiration pneumonia, and cardiac irregularities, including severe bradycardia and complete heart block.10–12 Adult patients may present with abnormal flexor and/or extensor muscle response on startling, leading to sudden falls with preservation of consciousness.13
The underlying pathophysiology of hyperekplexia is a diminished glycinergic input leading to disinhibition.2,14 Altered glycinergic neurotransmission may be caused by a mutation in the genes (GLRA1 and GLRB) encoding the postsynaptic inhibitory glycine receptors subunits GlyRα1 and GlyRβ, respectively; the gene (SLC6A5) encoding the presynaptic glycine transporter GlyT2; or the genes (GPHN and ARHGEF9) encoding the glycine receptor clustering proteins gephyrin and collybistin, respectively.2,10 Severe recurrent apnea is more frequent in neonates at risk for inheriting the GLRB and SLC6A5 mutations. Therefore, early genetic testing for symptomatic neonates and preconception counseling for parents who carry these mutations are recommended.6
A number of case reports on hyperekplexia have been published, with a majority of them describing the management of hyperekplexia during the immediate neonatal4,10,15 and early childhood8,16–18 period. A few reports described hyperekplexia during adolescence1,19 and in adults.20 To our knowledge, this is the first case report on the management of hyperekplexia involving a pregnant patient during labor and delivery.
The differential diagnosis for excessive startle or hypertonia is wide and may include paroxysmal extreme pain disorder, startle epilepsy, stiff person syndrome, conversion disorder, Tourette syndrome, Crisponi syndrome, or a peculiar neuropsychiatric condition that is restricted to defined social or ethnic groups such as Franco-Canadian lumberjack communities termed Jumping Frenchmen of Maine or Latah Syndrome.21 Similarities and differences of these conditions compared with hyperekplexia are described elsewhere.3
Our patient, and other affected members of her family, displayed symptomatology that met the criteria for a clinical diagnosis of hyperekplexia, using published clinical diagnostic data3,6 (Table 1). The role of genetic testing is a newly emerging addition to our understanding of this unique syndrome. Our patient had negative genotyping for GLRA1 and GLRB mutations. She was not tested for other less common but known mutations, such as SLC6A5, GPHN, and ARHGEF9. Gene-negative cases of hyperekplexia have been described in the literature.6 Moreover, hyperekplexia is a rare condition, there may be other genes or mutations involved that have not yet been discovered.6
The primary goals of anesthetic management for parturients with hyperekplexia include (1) minimizing unexpected stimuli7 and emotional stress21 that may be caused by abrupt movement, excessive pain, or commotion during emergency cesarean delivery; (2) coordinating communications in advance among anesthesiology, obstetric, neonatology, neurology, and nursing teams; (3) establishing close communication and rapport with the patient; and (4) anticipating potential need for neonatal rescue medication or maneuver during hypertonic crisis.
We recommended early epidural analgesia for this patient upon learning about her poor experience with multiple startle attacks from intense contractions during her first delivery. Anesthetic plans were discussed with the patient in the event of an urgent and emergent cesarean delivery, including the need for spinal or general anesthesia if epidural anesthesia was not feasible. As such, in a patient with hyperekplexia, we found no reported contraindication for either spinal or general anesthesia in the literature. However, given that this patient had autonomic insufficiency, neuraxial placement in the lateral position and close hemodynamic monitoring was considered in the event of a cesarean delivery. If time allows, a sequential combined spinal epidural anesthesia may be one option to avoid the rapid sympathectomy introduced by single-shot spinal anesthesia.22
There is no information on the effects of general anesthesia in adult patients with hyperekplexia. One case report described a 5-month-old infant with hyperekplexia demonstrating marked resistance to succinylcholine after inhaled induction and maintenance of anesthesia with halothane but a normal response to pancuronium and neostigmine.17 A subsequent case report in a 16-month-old infant did not observe this resistance with succinylcholine but found an exaggerated train-of-four fade after inhaled induction and maintenance of anesthesia with sevoflurane.18 Based on the limited reports in the literature, it is not possible to draw conclusions on the effect of general anesthetic and neuromuscular blocking drugs in patients with hyperekplexia.23
During acute attacks when there is impending apnea or cardiac arrest, forced truncal flexion, also known as the Vigevano maneuver, has been reported to be successful in terminating neonatal hypertonic crisis.24 Benzodiazepines have been used with variable success, but clonazepam has been reported to be highly effective.19,25 In our patient, the Vigevano maneuver (flexing of limbs and head toward trunk to mitigate symptoms of an acute attack) would have been difficult to perform, and it has not been shown to be effective in adults.24 Instead, we had IV midazolam readily available for the treatment of acute symptoms, recognizing that midazolam has never been reported in the literature to be effective in treating hypertonia from hyperekplexia.
Autonomic reactions have been described in patients with hyperekplexia, with an increase in arterial blood pressure and heart rate during hypertonic crisis.26 Details of autonomic function outside the acute attacks are not well documented. Our patient had a history of autonomic insufficiency, with an unclear etiology. Because of the paucity of information in the literature, whether autonomic insufficiency is a comorbid condition of patients with hyperekplexia or whether pregnancy itself may affect hyperekplexia disease activity is currently unknown.
Babies born to mothers with hyperekplexia should be monitored for signs of excessive startles, feeding discoordination, chest wall rigidity, and apnea.27 The neonatology service team should be notified in advance so that equipment for intubation and mechanical ventilation is available. Intravenous benzodiazepines could be prepared in anticipation of an acute crisis.
In summary, hyperekplexia is a rare hereditary disorder of altered glycinergic neurotransmission with potentially important anesthetic considerations. Optimal maternal and neonatal management involve understanding factors that may precipitate acute attacks, using strategies that can minimize these triggers and communicating these concerns with all members of the labor and delivery team.
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