Clinical manifestations

Presentation and course

Benign sleep myoclonus of infancy (BSMI) usually presents in the first month of life, typically within the first two weeks, and may begin as early as a few hours after birth (07). The myoclonic movements are present during all sleep states (active, quiet, and intermediate) but are most frequent during quiet sleep and least frequent during active sleep (35; 19; 14). They usually continue for two to four months, and rarely into early childhood (12; 37). One third of the cases do not resolve by three months of life (24). Maneuvers such as rocking in a head-to-toe direction and repetitive sound stimuli have been described as activating procedures for benign sleep myoclonus (10; 29). The neurologic examination is usually normal. The disorder follows a benign course and subsides spontaneously without leading to developmental delay, neurologic deficits, or seizures (10; 37; 26). Infants with myoclonic jerks of the extremities in NREM or quiet sleep during the first months of life with spontaneous disappearance within three to four months have revealed completely normal psychomotor development, cognitive function, and EEG, confirming the self-limited and nonepileptic nature of benign sleep myoclonus (39; 28; 26). The myoclonus is intermittent, repetitive, synchronous, and bilateral, or seldom unilateral. It often involves mainly the distal portions of the upper extremities with flexion of fingers, wrists, and elbow (07).

Less commonly, there is involvement of the lower extremities with dorsiflexion of the ankles, or all four extremities (28). Abdominal or axial musculature may also be affected (35). In most cases, jerking lasts for no more than 20 seconds, but it may recur at intervals during the night (07) and may even simulate a status epilepticus (38). Jerks frequently occur in four to five clusters, recurring every two to three seconds before they cease spontaneously. They may be triggered by noise and are sometimes made worse by gentle restraint (11; 03). They are not associated with eye deviation, oral movement, apnea, color change, or crying (10).

In a retrospective study of 38 newborns with benign sleep myoclonus of infancy (or benign neonatal sleep myoclonus), Paro-Panjan and Neubauer found that myoclonic jerks usually started between day one and day 16 (median three days) and that they were mostly bilateral, synchronous, and symmetrical in distribution and never involved the facial muscles (29). The jerks occurred only during sleep, especially when the child was drowsy or fell asleep, but also when the child had been asleep for more than 20 minutes, before waking, or in different stages of sleep. Neurologic evaluation remained usually normal, and EEG performed during the jerks in two children showed no paroxysmal activity. In this study, benign sleep myoclonus disappeared between the age of two weeks and 10 months (median two months), and follow-up examinations between three and 12 months of age revealed normal neurologic assessment in 30 infants and mildly abnormal neurologic signs in eight (29). These clinical features were confirmed in a sample of 18 infants with benign sleep myoclonus of infancy (or benign neonatal sleep myoclonus) (20). Myoclonus was evident during sleep in all the infants, but in two infants it was also observed during the transition from sleep to awakening. Moreover, four infants had lateralized myoclonus, and two had myoclonus involving the head and face. Again, EEGs were always normal during the myoclonus. The main clinical manifestations and outcomes were reaffirmed in a report of 15 Japanese cases (37). The age at onset ranged from one to 18 days in healthy full-term neonates. In all but one patient, sleep myoclonus resolved by six months. At the final evaluation (mean about three years), 14 of the 15 patients showed normal development; none presented epilepsy. Of note, the long-term follow-up showed that migraine occurred after five years of age in five cases and cyclic vomiting syndrome occurred in two cases. Moreover, a high incidence of migraine was revealed in the patients’ parents. The authors suggest that benign sleep myoclonus can be related to migraine (37).

Prognosis and complications

Benign sleep myoclonus of infancy has a benign course and usually resolves by seven months of age (07; 37). There is no evidence of neurologic deficits or increased incidence of seizures in later life (10; 23; 37; 14; 26). There is a case report of a boy who had febrile convulsions and sleep myoclonus in the first year of life, and he subsequently developed astatic and myoclonic seizures at the age of 13 months (27). A complex partial seizure occurred for the first time at three years of age. Abnormality on CT scan, EEG paroxysms, and delayed development were noted. The benign sleep myoclonus in this case was probably unrelated to the subsequent myoclonic-astatic seizures. Nonetheless, benign neonatal myoclonus resolves during the first year of life and does not persist into adulthood (33; 23; 37). In a study, the long-term follow-up showed that migraine occurred after five years of age in five cases out of 15 and cyclic vomiting syndrome occurred in two cases (37). Moreover, a high incidence of migraine was revealed in the patients’ parents. The authors suggest that benign sleep myoclonus can be related to migraine.

Biological basis

Etiology and pathogenesis

The etiology is unknown. The condition may be familial: five siblings have been reported affected in a family, all showing normal psychomotor development, cognitive functions, and EEG at a three to 10-year follow-up neurologic examination (39); three members were affected in another family (09). Three families with recurrence of benign sleep myoclonus of infancy (or benign neonatal sleep myoclonus) in two or more individuals were described in 2012; the three pedigrees were suggestive of autosomal dominant inheritance (02). Microsatellite markers were used to determine a possible link to the loci for KCNQ2 and KCNQ3, the two genes that cause most cases of benign familial neonatal seizures. The loci for KCNQ2 and KCNQ3 were excluded. The conclusions were that benign sleep myoclonus can show autosomal dominant inheritance and is not allelic with benign familial neonatal seizures (02). Benign sleep myoclonus of infancy has not been associated with prenatal or perinatal complications (10; 37). Remarkably, in a survey of infants with neonatal abstinence syndrome (born to opioid-dependent mothers) and treated with opioids or sedatives, a high frequency of benign neonatal myoclonus was disclosed (67% vs. 2.6% in control infants) (18). Neurologic examinations and cerebral ultrasound scans were, however, normal in these infants, and EEG showed no signs of epileptic activity. Myoclonic jerks in benign neonatal sleep myoclonus can evoke EEG potentials on vertex electrodes corresponding to somatosensory responses, comparable to those described in the literature as late somatosensory evoked responses in full-term newborns (22).

The biological basis is unknown. The myoclonic jerks may be triggered by changes in brainstem reticular activating system activity that occur in association with initiation and synchronization of normal sleep (10) or may be due to a transient immaturity or imbalance involving the serotonergic system (35). Evidence may also implicate a dysfunction in the opiate system (18). A polymyographic study in one case suggested that benign sleep myoclonus of infancy was probably generated in the cervical spinal cord (15). The authors’ hypothesis was that during sleep, a threshold for spinal myoclonic activity is crossed as supraspinal inhibitory control is reduced in a young and still immaturely myelinated brain.

Epidemiology

Most reports state that the incidence of benign sleep myoclonus of infancy (or benign neonatal sleep myoclonus) is not known. Two reports estimated an incidence that varies between 0.8 and 3.0 cases per 1000 (24). In the International Classification of Sleep Disorders, third edition (ICSD-3), the reported incidence is 3.7 per 10,000 live births; males are affected more than females by a ratio of about 2:1 (05).

Prevention

No means of prevention are known.

Differential diagnosis

Confusing conditions

In children younger than five years of age, behavioral events and parasomnias represent the most common mimickers of epilepsy (21). In particular, myoclonic jerks can occur in a variety of seizure disorders. The differential diagnosis in the neonatal period and in the first months of life includes seizures due to drug withdrawal, infantile spasms (West syndrome), benign myoclonus of early infancy, benign myoclonic epilepsy of infancy, benign familial neonatal convulsions, essential myoclonus, cerebral gangliosidoses, neonatal hyperekplexia, myoclonic encephalopathy of infancy, and reflex myoclonic epilepsy in infancy (06; 13; 34; 14; 26). Benign sleep myoclonus of infancy, which in severe cases may mimic serial seizures, can be distinguished from the other disorders by its occurrence only during sleep, by observing the quality of jerks and their possible provocation by sound or by shaking the child and cessation on arousal, and by the normal EEGs and neurologic examination and its benign course (10; 11; 29; 08; 17; 37; 01; 04). Moreover, no history of maternal drug use and no family history of myoclonus are recorded. Instead, West syndrome is characterized by infantile spasms that appear before one year of age, an abnormal EEG with hypsarrhythmia, and a poor prognosis (25). Hyperekplexia (startle disease) is a rare nonepileptic disorder characterized by an exaggerated persistent startle reaction to unexpected auditory, somatosensory, and visual stimuli, generalized muscular rigidity, and nocturnal myoclonus (32). It can present in fetal life as abnormal intrauterine movements, or later at any time from the neonatal period to adulthood. Electroencephalography may show fast spikes initially during the tonic spasms, followed by slowing of background activity with eventual flattening. In summary, ictal video-EEG is the gold standard for classification of infantile paroxysms as epileptic or nonepileptic, avoiding overtreatment for benign nonepileptic manifestations and facilitating targeted treatment of infantile epilepsies (16). In neonatal seizures due to drug withdrawal, the jerking movement is stimulus-sensitive, not sleep-dependent, and often associated with tremulousness. Infantile spasms (West syndrome) usually occur in an older age group (three months or older), and the myoclonus occurs in both awake and asleep states. Developmental arrest and a hypsarrhythmic EEG pattern are characteristic in infantile spasms. Benign myoclonus of infancy occurs only during the awake state. Benign myoclonic epilepsy of infancy is associated with attacks during wakefulness and sleep, and ictal EEGs show generalized spike- or polyspike-and-wave discharges (36; 06; 31). Early myoclonic encephalopathy can be associated with nonketotic hypoglycemia and pyridoxine dependency (40). Most reveal significant EEG abnormalities including suppression-burst or multiple paroxysmal abnormalities with a random asynchronous attenuation pattern.

Diagnostic workup

The diagnosis of benign sleep myoclonus of infancy is based on clinical features. Laboratory studies, sleep and awake EEG, and neuroimaging examinations are normal (10). Benign sleep myoclonus of infancy (BSMI), alternately named benign neonatal sleep myoclonus, is classified in the third edition of the International Classification of Sleep Disorders (ICSD-3) in the section on sleep-related movements disorders (05). The ICSD-3 diagnostic criteria are as follows:

Management

The disorder generally does not interfere with sleep. It slowly vanishes without sequelae and without medications (28). Anticonvulsant treatment is not recommended and may worsen the condition (35; 11; 20).