The Journal of Maternal-Fetal & Neonatal Medicine
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Epileptic and non-epileptic paroxysmal motor phenomena in newborns Carlotta Facini, Carlotta Spagnoli & Francesco Pisani To cite this article: Carlotta Facini, Carlotta Spagnoli & Francesco Pisani (2016): Epileptic and non-epileptic paroxysmal motor phenomena in newborns, The Journal of Maternal-Fetal & Neonatal Medicine, DOI: 10.3109/14767058.2016.1140735 To link to this article: http://dx.doi.org/10.3109/14767058.2016.1140735
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Date: 16 March 2016, At: 11:15
http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, Early Online: 1–8 ! 2016 Taylor & Francis. DOI: 10.3109/14767058.2016.1140735
REVIEW ARTICLE
Epileptic and non-epileptic paroxysmal motor phenomena in newborns Carlotta Facini, Carlotta Spagnoli, and Francesco Pisani
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Child Neuropsychiatry Unit, Neuroscience Department, University of Parma, Parma, Italy
Abstract
Keywords
Objective: The aim of this study is to provide an extensive overview of the clinical features of neonatal paroxysmal motor phenomena, both self-limited, related to the immaturity of the central nervous system, and pathological (epileptic and non-epileptic), in order to help the diagnostic approach. Methods: We reviewed the scientific literature about epileptic and non-epileptic paroxysmal motor phenomena in newborns. Results: Paroxysmal motor phenomena in newborns represent a challenge for the clinicians due to the different underlying pathophysiological mechanisms. A proper differential diagnosis is required. Conclusions: There are some clinical features that may help clinicians with the differentiation among physiological and pathological, epileptic, and non-epileptic events. However, further investigations are often needed to identify the cause. A continuous synchronized video– electroencephalogram (EEG)–recording, interpreted by an expert in neonatal neurology, remains the gold standard to prove the epileptic origin of a paroxysmal motor phenomenon.
Newborns, neonatal paroxysmal motor phenomena, seizures
Introduction Newborns display lots of sudden, mostly short-lasting involuntary movements and alterations of muscle tone, involving various parts of the body (Table 1). These paroxysmal motor phenomena could be due to the immaturity of the central nervous system (CNS) or they could be pathological, epileptic or non-epileptic in origin (Table 1). The knowledge of all these conditions is important for the clinicians in order to make a proper differential diagnosis. In this review, we will give a complete overview of the clinical features of neonatal paroxysmal motor phenomena, focusing on the differential diagnosis among physiological and pathological, epileptic, and non-epileptic events, to help the clinical diagnostic approach.
Self-limited paroxysmal motor phenomena in newborn During the neonatal period, there is still an incomplete maturation of the corticospinal tract, explaining the reduced effectiveness in the inhibitory control on the motor system and the consequent tendency of the newborns, particularly if preterms, to exhibit paroxysmal movements which are agerelated and self-limited [2]. The overview of these Address for correspondence: Carlotta Facini, Unita` Operativa di Neuropsichiatria Infantile, Dipartimento Materno-Infantile, Azienda Ospedaliero-Universitaria di Parma, Via Gramsci 14, 43126 Parma (PR), Italy. Tel: +39 521 702205. Fax: +39 521 704708. E-mail: [email protected]
History Received 22 June 2015 Revised 5 January 2016 Accepted 7 January 2016 Published online 12 February 2016
phenomena is possible after a careful exclusion of pathological diagnoses. Tremor During the first days of life, tremors are reported in 2/3 of healthy infants as an isolated sign and they gradually improve with increasing post-conceptional age [3,17]. Physiological tremors are fine and they are stopped with a gentle passive flexion and restraint of the affected limb or by suckling stimulation test [2,22]. The underlying mechanisms could be an exaggerated muscle stretch reflex, due to immaturity of spinal inhibitory pathways or the adaptative presence of elevated norepinephrine level [23,24]. Benign neonatal sleep myoclonus (BNSM) It is a benign and quite common condition, affecting 0.8–3/1000 full-term and near-term newborns and can be mistaken for epilepsy and even for status epilepticus if prolonged [1,2,7,25]. Therefore, it is important to know the distinctive features of this clinical form. BNSM may be present in neurologically normal, healthy infants [7,17] and it is characterized by myoclonic jerks involving the limbs, most frequently generalized and symmetric but sometimes affecting only one limb or a side [7]. These paroxysmal movements only occur during sleep, mainly in quiet sleep, and they stop with arousal [7]. The onset is during the first 2 weeks of life and the resolution occurs spontaneously within the sixth month of age [1,2]. Rocking or repetitive sound stimuli may
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Table 1. Clinical presentation and etiology of neonatal paroxysmal motor phenomena.
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Paroxysmal motor phenomena
Clinical presentation
Etiology
Tremor and jitteriness
Tremor: an involuntary, rhythmic oscillatory movement of equal amplitude around a fixed axis. Jitteriness: recurrent tremors [1,2].
Myoclonus
Positive myoclonus: brief, shock-like, irregular and arrhythmic muscle jerk, with higher amplitude than tremor. Negative myoclonus: brief lapse of muscle contraction. It may be focal, segmental, multifocal, or generalized. It may occur at rest or during muscular activity [2,5,6].
Startle reflex
Rapid sequence of movements: grimacing and blinking, flexion of neck, trunk, hips and knees, arms adduction and fists clenching, in response to unexpected stimuli [10,11]. Paroxysmal tonic upgaze: episodes of sustained upward deviation of the eyes, often associated with incomplete downward eye movements on attempted downgaze. Paroxysmal tonic downgaze: prolonged downward eye deviation [2,13]. The tonic eye deviation can be also along the horizontal axis [14,15]. Opsoclonus is an irregular and chaotic oscillation of the eyes in any direction [2,13]. A sudden and uncontrolled contraction of the diaphragm, causing the breath to be quickly drawn and then immediately cut off by a closing of the throat.
– Physiological. – Pathological non-epileptic (hypoxic–ischemic encephalopathy, intracranial hemorrhage, hypoglicemia, hypocalcemia, sepsis, hypothermia, hyperthyroidism, drug withdrawal, familial trembling of the chin [1–4]). – Physiological: benign neonatal sleep myoclonus – Pathological, non-epileptic (hypoxic–ischemic encephalopathy, intraventricular hemorrhage, glycine encephalopathy, benzodiazepines or opiates withdrawal symptom [1,2,7,8]. – Epileptic (e.g. early myoclonic encephalopathy, EME, presents with focal myoclonus as the primary seizure type) [2,9]. – Physiological. – Pathological non-epileptic when excessive (genetically inherited or sporadic hyperekplexia) [1,10,12]. – Benign (few cases of brief episodes of paroxysmal tonic upgaze or downgaze, both in response to stimuli and of transient opsoclonus have been described in healthy children [13]. Pathological non-epileptic (e.g. opsoclonus can be a sign of visual loss, hypoxic–ischemic encephalopathy and herpes simplex encephalitis) [13]. – Epileptic [15]. Usually physiological. It could be a sign of non-ketotic hyperglycinemia when it is associated with neurological symptoms such as lethargy, poor feeding, hypotonia, and seizures [2]. – Physiological [16]. – Expression of brainstem release phenomena, due to the immaturity of the inhibitory control pathways or to neocortical injuries; they could represent subcortical seizures [17]. – Epileptic when associated with clonic movements of other body parts [15]. Tongue fasciculations are a sign of hypoxic–ischemic encephalopathy, Mo¨bius syndrome and spinal muscular atrophy [13,18]. – Pathological non-epileptic (a severe asphyxia, an inherited metabolic disease or an acute bilirubin encephalopathy involving the basal ganglia [13,17,19]; neocortical malformations or damages determining a disinhibition of subcortical motor pathways [17]; intrauterine cocaine exposure or gastro-esophageal reflux, identifying a Sandifer’s syndrome [2,13]. – Epileptic (hypoxic–ischemic encephalopathy, intraventricular hemorrhage, cerebral strokes, cerebral malformations, central nervous system infections, acute metabolic disorders, inborn metabolic diseases and epileptic syndromes with neonatal onset, including benign familial neonatal seizures, early myoclonic encephalopathy and early infantile epileptic encephalopathy [20]. – Bilateral tonic stiffening and multifocal clonic movements often do not correlate with EEG discharges, but are associated with encephalopathy [21].
Ocular movement disorders
Hiccups
Oral–buccal–lingual repetitive movements
Repetitive movements of chewing, swallowing, sucking. Fasciculations (small, local, involuntary muscular contraction visible under the skin) of the tongue [13]. Regular, rhythmic tongue twitching.
Paroxysmal dystonia
Episodes of sustained muscle contractions causing twisting and repetitive movements or abnormal postures.
Tonic seizures
Focal tonic seizures present with sustained asymmetric posturing of the limb or trunk or sustained deviation of the eyes. Generalized bilateral tonic seizures consist in hyperextension or, less commonly, flexion of the upper and lower extremities or hyperextension of the legs and flexion of the arms, sometimes associated with axial hyperextension [14,15].
Clonic seizures
Repetitive, rhythmic (1–4 jerks per second) twitching of facial, limb or axial musculature, involving circumscribed muscle groups (focal) or shifting from a muscle group to another one in a random manner (multifocal) [14,15]. Movements of ‘‘cycling’’, ‘‘boxing’’, ‘‘pedaling’’, ‘‘swimming’’.
Complex motor automatisms
They could be the expression of brainstem release phenomena, due to the immaturity of the inhibitory control pathways or to neocortical injuries, or they could represent subcortical seizures, not detectable by surface EEG recording [17].
Paroxysmal motor phenomena in newborns
DOI: 10.3109/14767058.2016.1140735
provoke the motor phenomenon that, moreover, could be exacerbated by holding the affected limbs or administering benzodiazepines [2,7]. To explain the origin of this phenomenon, both an immaturity in the network involved in the motor control during sleep and a genetic component, due to the existence of familial cases, have been proposed [1,2,25]. The electroencephalogram (EEG) and the psychomotor development of the affected newborns are both normal [1,25].
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Startle reflex Healthy newborns are prone to present startle reflex, with prompt habituation, in response to a sudden, more often auditive, stimulus [10]. It is a brainstem reflex that originates in the bulbopontine reticular formation and that gradually undergoes the inhibitory control of the corticospinal motor pathways [11]. It has probably the meaning of a basic alerting reaction [10]. The onset of the startle reflex is contemporary to the Moro reflex and it becomes more noticeable by the time of its disappearance [10]. Upgaze and downgaze movements They may be present in healthy newborns. Hahn has described brief upgaze movements, lasting a few seconds, after the sudden appearance of a visual stimulus into the visual field or during baths with water poured on the face [13]. These cases could represent an uncoupling of the normal Bell’s phenomenon with the eyelid closure [13]. A fast downward eye deviation in response to various stimuli or during feeding is possible, with spontaneous remission [26]. Opsoclonus A few cases of isolated, transient opsoclonus in healthy newborns have been described [13]. Hiccups Newborns show a tendency to hiccup as part of a physiological mechanism, starting in utero, involved in the maturation of the inspiratory muscles [2,27]. Repetitive sucking movements Sucking reflex is a brainstem-mediated reflex that develops around the 25th week of gestation, taking an essential part in competent oral feeding and in coordinating effective breathing and swallowing [16]. It consists of automatic stereotypic movements that sometimes could be particularly repetitive and prolonged, resembling motor automatisms of pathological origin or subtle seizures.
Pathological non-epileptic paroxysmal motor phenomena in newborn Tremor and jitteriness Tremors and jitteriness can be clinical manifestations of pathological neonatal conditions such as hypoxic–ischemic encephalopathy, intracranial hemorrhage, hypoglicemia, hypocalcemia, sepsis, hypothermia, hyperthyroidism, and drug withdrawal (opiates, serotonin reuptake inhibitors, marijuana, cocaine, inhaled volatile substances) [1,2,3].
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There is also an autosomal dominant form of tremor, called familial trembling of the chin, that involves the perioral muscles, particularly during crying [1,4]. Pathological tremors, especially in the context of a mild asphyxia or of an intracranial hemorrhage, are usually coarse [1,3]. In the suspect of an underlying condition causing the tremor, it is important to consider the perinatal story and the general clinical conditions of the newborn. Laboratory studies, including glycemia, electrolytes, urine drug, thyroid and metabolic screening, septic workup, and also neuroimaging, are recommended [1,3]. The presence of perinatal complications in a jittery newborn is related to an adverse neurodevelopmental outcome, needing a careful follow-up [1]. Tremors are often confused with clonic activity but the flexion and extension phases are equal in amplitude in tremor and different in clonic seizures [17]. Furthermore, neonatal seizures present some features that can be helpful in the differential diagnosis with tremor. Indeed, neonatal seizures are unpredictable events, usually not induced by stimuli and they are frequently associated with ocular phenomena and autonomic signs, unlike tremors. Moreover, they are not stopped by passive flexion and repositioning of the affected body part, as opposed to physiological tremors [14,17]. Myoclonus Myoclonus may originate from any part of the central nervous system: cerebral cortex, subcortical structures, brainstem, spinal cord, or peripheral nerve [5,6]. A polygraphy including EEG and electromyogram (EMG) can prove the cortical origin of myoclonus, showing a focal cortical event that precedes myoclonus with a fixed delay [6]. Furthermore, the jerk-locked back averaging technique is used to reveal a premyoclonic spike [6]. EEG abnormal activity could also be found with brainstem myoclonus but, if present, it is not timelocked to the EMG event [5,6]. Focal myoclonus is the primary seizure type in early myoclonic encephalopathy (EME) [9]. Non-epileptic pathological myoclonus may be present in newborns affected by hypoxic–ischemic encephalopathy, intraventricular hemorrhage, glycine encephalopathy [8] and also, as a withdrawal symptom, in preterms treated with endovenous benzodiazepines [1,2] or in maternal use of opiates [7]. A brainstem release phenomenon is probably involved in the pathogenesis of the myoclonus in case of a diffuse brain injury [1]. Hyperekplexia It is a genetically inherited or sporadic neurological disorder characterized by an exaggerated startle reflex that may appear in response to different types of stimuli (tactile, auditive, and visual) [1,10,12]. The exclusive presence of an excessive startle response, sometimes leading to generalized tonic spasms, is the typical hallmark of the minor form. The association with transient general muscular rigidity that usually improves after the first year of life, and with nocturnal myoclonus defines the major form [1,10,12]. A mutation in the alpha-1 subunit of the glycine receptor gene (GLRA1) is involved in major form cases, with autosomal dominant inheritance [11]. The other genes in which mutation is causative are SLC6A5, GLRB, GPHN, and ARHGEF9 [28].
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The differential diagnosis in newborns is represented by neonatal seizures, in particular, startle epilepsy and myoclonic seizures, neonatal tetany, stiff-man syndrome, phenotiazine toxicity, and cerebral palsy [11]. When nose tapping is able to provoke a startle response without habituation, the clinical diagnosis is made [11,12]. EEG background is generally normal for the age [17]. The pathogenesis of the disease is probably related to an increased excitability of the bulbopontine reticular neurons involved in the startle reflex [12]. The newborn with hyperekplexia is probably at increased risk of obstructive and central apneas, responsible for sudden infant death syndrome [11,12]. Therefore, an apnea home monitoring is suggested [12]. The treatment of the exaggerated startle response is clonazepam and, in the case of severe hypertonia causing apnea and bradycardia, the maneuvre of forced flexion of head and legs is often effective [11]. Neonatal dystonia Dystonia is often misidentified with seizures [17]. It may be caused by acute or chronic pathological conditions involving the basal ganglia, such as a severe asphyxia, an inherited metabolic disease (e.g. glutaric aciduria) or an acute bilirubin encephalopathy [13,17,19]. Another possible cause of dystonia is related to neocortical malformations or damages determining a dishinibition of subcortical motor pathways [17]. Dystonic movements and posturing are also described in association with intrauterine cocaine exposure or with gastroesophageal reflux, identifying a Sandifer’s syndrome [2,13]. Ocular movement disorders Paroxysmal tonic upgaze and paroxysmal tonic downgaze may be the clinical signs of neurologic and oculomotor problems [2,13]. Neonatal opsoclonus has been described in association with hypoxic–ischemic encephalopathy, visual loss, and herpes simplex encephalitis [2,13]. Hiccups The association of hiccups with compromised neurological conditions and with neonatal seizures, leading to a burstsuppression EEG pattern, is suggestive for non-ketotic hyperglycinemia. This is an autosomal recessive disorder causing an accumulation of glycine in plasma and cerebrospinal fluid, with variable outcome, unfavorable in the classical form [29]. Tongue fasciculations Tongue fasciculations may be a clinical sign of hypoxic– ischemic encephalopathy, Mo¨bius syndrome and spinal muscular atrophy [13,18]. Motor automatisms Newborns, especially preterms, may display isolated paroxysmal movements not associated with epileptic changes in the EEG, such as chewing, swallowing, sucking, repetitive tongue movements, eye deviation, cycling, boxing, pedaling, and swimming. The origin of these stereotypical phenomena is not clear. They could be the expression of brainstem release phenomena, due to the immaturity of the inhibitory control
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mediated by the corticospinal tract or to neocortical injuries, or they could represent subcortical seizures, not detectable by surface EEG recording [17].
Neonatal seizures Seizures are the most common symptom of an underlying neurological disease in newborns [14]. The incidence rate of neonatal seizures (NS) is reported to be 0.95–5 per 1000 live births [30]. The first cause of NS is hypoxic–ischemic encephalopathy (40–60%), affecting mainly full-term newborns [14], followed by intraventricular hemorrhage (7–18%), that is typical of the preterm population [30]. Less frequently NS are provoked by cerebral strokes (6–17%), cerebral malformations (3–14%), CNS infections (5–10%), acute metabolic disorders (3–5%), inborn metabolic diseases (1– 4%), and epileptic syndromes with neonatal onset, including benign familial neonatal seizures, early myoclonic encephalopathy, and early infantile epileptic encephalopathy (1%) [20]. Clinically, NS are defined according to Volpe’s classification modified by Lombroso as focal clonic, multifocal clonic, generalized tonic, myoclonic, and subtle [14]. Clonic seizures consist of repetitive, rhythmic (1–4 jerks per second) twitching of facial, limb or axial muscles, involving circumscribed muscle groups (focal) or shifting from a muscle group to another one in a random manner (multifocal) [14,15]. Generalized tonic seizures can present with hyperextension of the upper and lower extremities or hyperextension of the legs and flexion of the arms and sometimes with axial hyperextension [14,15]. Myoclonic seizures are characterized by single or slow serial, non-rhythmic, jerking of extremities, or axial musculature. The myoclonic jerks may be generalized, focal, or fragmentary [14,15]. Subtle seizures include tonic horizontal or vertical eye deviation, with or without nystagmus, eyelid blinking or fluttering, oral–buccal– lingual movements (chewing, swallowing, sucking, and repetitive tongue movements), ‘‘cycling’’, ‘‘boxing’’, ‘‘pedaling’’, ‘‘swimming’’ movements, apneic spells, hyperpnea, vasomotor phenomena, and tonic postures of a single limb or portion of a limb [14,15]. Mixed clinical seizures are combinations of more than one type of clinical seizures [15]. An ‘‘electroclinical seizure’’ is defined by the match between the clinical event and the EEG seizure activity. Ictal electroencephalographic discharges consist of a repetitive sequence of waveforms with a clear onset and termination, a duration more than 10 s and an evolution in frequency and morphology [17,31]. A close association to EEG seizure discharges has been confirmed for focal clonic seizures, some forms of myoclonic seizures with generalized or focal jerks, and focal tonic seizures [15]. On the contrary, it has been brought out that generalized tonic seizures, most subtle seizures, and some myoclonic seizures are only inconsistently or are not related to EEG seizure discharges, suggesting that these clinical manifestations may not be epileptic [15]. However, these last ones, together with multifocal clonic movements, are signs of encephalopathy [21]. Although the prognosis is most closely tied to underlying etiologies, it has been demonstrated that newborns with confirmed electroclinical seizures present a high risk of developing neurological sequelae, such as cerebral palsy,
Are stimulus sensitive, they occur commonly when newborns are crying or stressed [3].
It may be evoked by sensory, visual or auditory stimuli [2,5,6].
It is evoked by different types of stimuli, especially auditive. The physiological startle reflex shows a prompt habituation to stimuli [10].
Myoclonus
Startle reflex
Response to external stimuli
Tremor and jitteriness
Paroxysmal motor phenomena
BNSM may be triggered by the rocking maneuver of the newborn in head-to-toe direction and may be worsened by the restraint of the involved body parts [2,7]. Clinical maneuvers do not modify epileptic myoclonus [1,2].
In patients with hyperekplexia the nose tapping may provoke a startle response without habituation. The attacks of hypertonia and apnea in hyperekplexia can be stopped by a passive flexion of the limbs and head towards the trunk [11,12].
–
–
–
Physiological tremors are stopped with a gentle passive flexion and restraint of the affected limb or by suckling stimulation test [2,22].
Are more frequent during sleep or active wakeful than during quiet wakeful [2].
BNSM occurs only during sleep, mainly in quiet sleep [7].
Response to clinical maneuvres
Presentation time
Dependent on cause. BNSM resolves spontaneously within the sixth months of age [1,2]. EME has a very poor outcome: up to half of patients die before two years of age and the others present severe psychomotor impairments [9].
Patients with hyperekplexia are at risk of early motor developmental delay due to the stiffness that, however, decreases after the first year of age and resolves by the third year. Sudden infant death syndrome could be due to central or obstructive apnea. The exaggerated startle reaction remains, causing frequent falls and disability [2,11,12].
EEG is normal in BNSM [1,2]. Epileptic myoclonus is associated with an EEG correlate (an EEG spike preceding the myoclonus by a short interval). The jerk-locked back averaging technique reveals the pre-myoclonic spike [6]. EME is characterized by a suppression-burst pattern, not continuous and more distinct during sleep [9]. It can evolve in an atypical pattern of hypsarrhythmia at 3–5 months of age, returning to burst-suppression after some months [9]. The simultaneous recording of EEG and EMG allows distinguishing between cortical myoclonus (a very short EMG discharge, usually less than 50 ms, immediately preceded by an EEG spike) and subcortical myoclonus (the cortical EEG abnormality, if present, is not time-locked to the EMG event [5,6]. In patients with hyperekplexia the EEG may show fast spikes of myogenic origin during the tonic spasm, followed by slowing and flattening of the background activity during the subsequent apnea, bradicardia and cianosis [10]. The EMG in hyperekplexia may show an almost continuous muscular activities alternated with brief period of electrical quietness [10].
(continued )
Dependent on cause. Physiological tremors stop with increasing post-conceptional age [3,17].
Prognosis
Tremors are not associated with EEG discharges [15]. EMG is useful to assess the frequency of a tremor. A fine tremor is characterized by a high frequency (greater than 6 Hz) and a low amplitude (lower than 3 cm) while a coarse tremor by a low frequency (lower than 6 Hz) and a high amplitude (greater than 3 cm) [1,2,5].
Electrophysiological studies: electroencephalogram (EEG) and electromyography (EMG)
Table 2. Clinical and electrophysiological features useful in the differential diagnosis between neonatal paroxysmal motor phenomena and their prognosis.
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Paroxysmal motor phenomena in newborns 5
–
– –
Tonic seizures
Clonic seizures
Complex motor automatisms
–
–
–
–
Dystonic movements and posturing in Sandifer’s syndrome are related to feeding [2].
–
–
Presentation time
–
–
–
–
–
–
Response to clinical maneuvres
Clonic seizures present a timesynchronized relationship to EEG seizure activity [15]. Not associated with EEG discharges [15].
Focal tonic seizures are usually associated with EEG discharges while clinical generalized tonic seizures are inconsistently associated [15].
Not associated with EEG seizure activity.
Usually are not associated to EEG seizure activity except for regular, rhythmic tongue twitching occurring commonly with other clonic jerks of the face or extremities [15]. EMG could suggest a motor neuron disease in case of tongue fasciculations [33].
In non-ketotic hyperglycinemia EEG could reveal a burst-suppression pattern [2].
Sustained eye deviation with nystagmus, usually after sudden eye opening, can be associated with EEG discharges arising from the occipital regions [15]. Other ocular signs are inconsistently associated with EEG discharges [15].
Electrophysiological studies: electroencephalogram (EEG) and electromyography (EMG)
Dependent on cause.
Most closely tied to underlying etiologies. Newborns with confirmed electroclinical seizures present a high risk of developing neurological sequelae, such as cerebral palsy, developmental delay and epilepsy [31].
Dependent on cause. In Sandifer’s syndrome the treatment of the gastro-esophageal reflux alleviates the movement disorder [13].
Dependent on cause. Patients affected by spinal muscular atrophy type 1 do not acquire the ability to sit unsupported and, if no intervention is provided, generally do not survive beyond the first 2 years [33].
The classical form of nonketotic hyperglycinemia has a poor prognosis with death occurring in the first months of age while the atypical forms of the disease are characterized by a milder clinical presentation and variable neurological outcome [2].
Dependent on cause. Transient opsoclonus has been described in otherwise healthy neonates [13]. Paroxysmal tonic upgaze generally improves or resolves by 2.5 years of age but other neurologic and oculomotor problems can be seen on long-term follow-up [13].
Prognosis
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BNSM, benign neonatal sleep myoclonus; EME, early myoclonic encephalopathy.
–
–
Paroxysmal tonic upgaze and downgaze may be induced by stimuli, such as sudden visual stimuli, water flowing over the upper face, movements, feeding [2,13].
Response to external stimuli
Paroxysmal dystonia
Oral–buccal–lingual repetitive movements
Hiccups
Ocular movement disorders
Paroxysmal motor phenomena
Table 2. Continued
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developmental delay, and epilepsy [31]. Epilepsy affects 18–25% of the patients with a history of NS, involving mainly the full-term newborns and is frequently associated with other neurological impairments [31].
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Differential diagnosis between epileptic seizures and paroxysmal non-epileptic motor phenomena in newborns The differential diagnosis between neonatal seizures and paroxysmal non-epileptic motor phenomena is often hard to make on a clinical basis only. Indeed, there are some conditions that mimic seizures and that could be misinterpreted [17]. An observational study has shown an objective difficulty of health care professionals in distinguishing clinically a neonatal paroxysmal movement as epileptic or non-epileptic [32]. This unreliability can lead to an inappropriate management, with the negative effects related to undertreatment of seizures or, on the contrary, to overtreatment of non-epileptic events [32]. However, there are few clinical features that should be considered because they could help the diagnosis, suggesting a non-epileptic origin (Table 2). In most cases, for a correct differential diagnosis, a continuous synchronized video–EEG–recording, interpreted by an expert in neonatal neurology, is required [2,17] (Table 2). This technique represents the gold standard to prove the cortical origin of a paroxysmal motor phenomenon and it allows also the identification of only electrical seizures, electroclinical dissociation, or electroclinical uncoupling, that are possible in newborns. However, seizures originated in subcortical brain regions and not propagated to the cortical surface are not detected by surface EEG electrodes, remaining an open issue for the clinicians [17].
Conclusions Newborns frequently display paroxysmal motor phenomena that should be carefully considered by the clinicians, in order to identify possible underlying diseases. Some of these events are due to an immaturity in the inhibitory control on the motor system and are self-limited [2]. Both epileptic and nonepileptic paroxysmal motor phenomena are included in the pathological group. Because neonatal seizures, the most common symptom of a neurological injury in newborns [14], are quite often indicative of an unfavorable outcome, a correct diagnosis of any abnormal paroxysmal movement in newborns is mandatory to timely exclude an epileptic origin. Some clinical features have to be accurately taken into account, being more typical for an epileptic or a non-epileptic condition, but in most cases, a polygraphic video-EEG recording is required. A prompt differential diagnosis of such clinical phenomena is essential to guide subsequent management and treatment and to provide appropriate prognostic information.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
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Epileptic and non-epileptic paroxysmal motor phenomena in newborns Carlotta Facini, Carlotta Spagnoli & Francesco Pisani To cite this article: Carlotta Facini, Carlotta Spagnoli & Francesco Pisani (2016): Epileptic and non-epileptic paroxysmal motor phenomena in newborns, The Journal of Maternal-Fetal & Neonatal Medicine, DOI: 10.3109/14767058.2016.1140735 To link to this article: http://dx.doi.org/10.3109/14767058.2016.1140735
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http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, Early Online: 1–8 ! 2016 Taylor & Francis. DOI: 10.3109/14767058.2016.1140735
REVIEW ARTICLE
Epileptic and non-epileptic paroxysmal motor phenomena in newborns Carlotta Facini, Carlotta Spagnoli, and Francesco Pisani
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Child Neuropsychiatry Unit, Neuroscience Department, University of Parma, Parma, Italy
Abstract
Keywords
Objective: The aim of this study is to provide an extensive overview of the clinical features of neonatal paroxysmal motor phenomena, both self-limited, related to the immaturity of the central nervous system, and pathological (epileptic and non-epileptic), in order to help the diagnostic approach. Methods: We reviewed the scientific literature about epileptic and non-epileptic paroxysmal motor phenomena in newborns. Results: Paroxysmal motor phenomena in newborns represent a challenge for the clinicians due to the different underlying pathophysiological mechanisms. A proper differential diagnosis is required. Conclusions: There are some clinical features that may help clinicians with the differentiation among physiological and pathological, epileptic, and non-epileptic events. However, further investigations are often needed to identify the cause. A continuous synchronized video– electroencephalogram (EEG)–recording, interpreted by an expert in neonatal neurology, remains the gold standard to prove the epileptic origin of a paroxysmal motor phenomenon.
Newborns, neonatal paroxysmal motor phenomena, seizures
Introduction Newborns display lots of sudden, mostly short-lasting involuntary movements and alterations of muscle tone, involving various parts of the body (Table 1). These paroxysmal motor phenomena could be due to the immaturity of the central nervous system (CNS) or they could be pathological, epileptic or non-epileptic in origin (Table 1). The knowledge of all these conditions is important for the clinicians in order to make a proper differential diagnosis. In this review, we will give a complete overview of the clinical features of neonatal paroxysmal motor phenomena, focusing on the differential diagnosis among physiological and pathological, epileptic, and non-epileptic events, to help the clinical diagnostic approach.
Self-limited paroxysmal motor phenomena in newborn During the neonatal period, there is still an incomplete maturation of the corticospinal tract, explaining the reduced effectiveness in the inhibitory control on the motor system and the consequent tendency of the newborns, particularly if preterms, to exhibit paroxysmal movements which are agerelated and self-limited [2]. The overview of these Address for correspondence: Carlotta Facini, Unita` Operativa di Neuropsichiatria Infantile, Dipartimento Materno-Infantile, Azienda Ospedaliero-Universitaria di Parma, Via Gramsci 14, 43126 Parma (PR), Italy. Tel: +39 521 702205. Fax: +39 521 704708. E-mail: [email protected]
History Received 22 June 2015 Revised 5 January 2016 Accepted 7 January 2016 Published online 12 February 2016
phenomena is possible after a careful exclusion of pathological diagnoses. Tremor During the first days of life, tremors are reported in 2/3 of healthy infants as an isolated sign and they gradually improve with increasing post-conceptional age [3,17]. Physiological tremors are fine and they are stopped with a gentle passive flexion and restraint of the affected limb or by suckling stimulation test [2,22]. The underlying mechanisms could be an exaggerated muscle stretch reflex, due to immaturity of spinal inhibitory pathways or the adaptative presence of elevated norepinephrine level [23,24]. Benign neonatal sleep myoclonus (BNSM) It is a benign and quite common condition, affecting 0.8–3/1000 full-term and near-term newborns and can be mistaken for epilepsy and even for status epilepticus if prolonged [1,2,7,25]. Therefore, it is important to know the distinctive features of this clinical form. BNSM may be present in neurologically normal, healthy infants [7,17] and it is characterized by myoclonic jerks involving the limbs, most frequently generalized and symmetric but sometimes affecting only one limb or a side [7]. These paroxysmal movements only occur during sleep, mainly in quiet sleep, and they stop with arousal [7]. The onset is during the first 2 weeks of life and the resolution occurs spontaneously within the sixth month of age [1,2]. Rocking or repetitive sound stimuli may
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Table 1. Clinical presentation and etiology of neonatal paroxysmal motor phenomena.
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Paroxysmal motor phenomena
Clinical presentation
Etiology
Tremor and jitteriness
Tremor: an involuntary, rhythmic oscillatory movement of equal amplitude around a fixed axis. Jitteriness: recurrent tremors [1,2].
Myoclonus
Positive myoclonus: brief, shock-like, irregular and arrhythmic muscle jerk, with higher amplitude than tremor. Negative myoclonus: brief lapse of muscle contraction. It may be focal, segmental, multifocal, or generalized. It may occur at rest or during muscular activity [2,5,6].
Startle reflex
Rapid sequence of movements: grimacing and blinking, flexion of neck, trunk, hips and knees, arms adduction and fists clenching, in response to unexpected stimuli [10,11]. Paroxysmal tonic upgaze: episodes of sustained upward deviation of the eyes, often associated with incomplete downward eye movements on attempted downgaze. Paroxysmal tonic downgaze: prolonged downward eye deviation [2,13]. The tonic eye deviation can be also along the horizontal axis [14,15]. Opsoclonus is an irregular and chaotic oscillation of the eyes in any direction [2,13]. A sudden and uncontrolled contraction of the diaphragm, causing the breath to be quickly drawn and then immediately cut off by a closing of the throat.
– Physiological. – Pathological non-epileptic (hypoxic–ischemic encephalopathy, intracranial hemorrhage, hypoglicemia, hypocalcemia, sepsis, hypothermia, hyperthyroidism, drug withdrawal, familial trembling of the chin [1–4]). – Physiological: benign neonatal sleep myoclonus – Pathological, non-epileptic (hypoxic–ischemic encephalopathy, intraventricular hemorrhage, glycine encephalopathy, benzodiazepines or opiates withdrawal symptom [1,2,7,8]. – Epileptic (e.g. early myoclonic encephalopathy, EME, presents with focal myoclonus as the primary seizure type) [2,9]. – Physiological. – Pathological non-epileptic when excessive (genetically inherited or sporadic hyperekplexia) [1,10,12]. – Benign (few cases of brief episodes of paroxysmal tonic upgaze or downgaze, both in response to stimuli and of transient opsoclonus have been described in healthy children [13]. Pathological non-epileptic (e.g. opsoclonus can be a sign of visual loss, hypoxic–ischemic encephalopathy and herpes simplex encephalitis) [13]. – Epileptic [15]. Usually physiological. It could be a sign of non-ketotic hyperglycinemia when it is associated with neurological symptoms such as lethargy, poor feeding, hypotonia, and seizures [2]. – Physiological [16]. – Expression of brainstem release phenomena, due to the immaturity of the inhibitory control pathways or to neocortical injuries; they could represent subcortical seizures [17]. – Epileptic when associated with clonic movements of other body parts [15]. Tongue fasciculations are a sign of hypoxic–ischemic encephalopathy, Mo¨bius syndrome and spinal muscular atrophy [13,18]. – Pathological non-epileptic (a severe asphyxia, an inherited metabolic disease or an acute bilirubin encephalopathy involving the basal ganglia [13,17,19]; neocortical malformations or damages determining a disinhibition of subcortical motor pathways [17]; intrauterine cocaine exposure or gastro-esophageal reflux, identifying a Sandifer’s syndrome [2,13]. – Epileptic (hypoxic–ischemic encephalopathy, intraventricular hemorrhage, cerebral strokes, cerebral malformations, central nervous system infections, acute metabolic disorders, inborn metabolic diseases and epileptic syndromes with neonatal onset, including benign familial neonatal seizures, early myoclonic encephalopathy and early infantile epileptic encephalopathy [20]. – Bilateral tonic stiffening and multifocal clonic movements often do not correlate with EEG discharges, but are associated with encephalopathy [21].
Ocular movement disorders
Hiccups
Oral–buccal–lingual repetitive movements
Repetitive movements of chewing, swallowing, sucking. Fasciculations (small, local, involuntary muscular contraction visible under the skin) of the tongue [13]. Regular, rhythmic tongue twitching.
Paroxysmal dystonia
Episodes of sustained muscle contractions causing twisting and repetitive movements or abnormal postures.
Tonic seizures
Focal tonic seizures present with sustained asymmetric posturing of the limb or trunk or sustained deviation of the eyes. Generalized bilateral tonic seizures consist in hyperextension or, less commonly, flexion of the upper and lower extremities or hyperextension of the legs and flexion of the arms, sometimes associated with axial hyperextension [14,15].
Clonic seizures
Repetitive, rhythmic (1–4 jerks per second) twitching of facial, limb or axial musculature, involving circumscribed muscle groups (focal) or shifting from a muscle group to another one in a random manner (multifocal) [14,15]. Movements of ‘‘cycling’’, ‘‘boxing’’, ‘‘pedaling’’, ‘‘swimming’’.
Complex motor automatisms
They could be the expression of brainstem release phenomena, due to the immaturity of the inhibitory control pathways or to neocortical injuries, or they could represent subcortical seizures, not detectable by surface EEG recording [17].
Paroxysmal motor phenomena in newborns
DOI: 10.3109/14767058.2016.1140735
provoke the motor phenomenon that, moreover, could be exacerbated by holding the affected limbs or administering benzodiazepines [2,7]. To explain the origin of this phenomenon, both an immaturity in the network involved in the motor control during sleep and a genetic component, due to the existence of familial cases, have been proposed [1,2,25]. The electroencephalogram (EEG) and the psychomotor development of the affected newborns are both normal [1,25].
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Startle reflex Healthy newborns are prone to present startle reflex, with prompt habituation, in response to a sudden, more often auditive, stimulus [10]. It is a brainstem reflex that originates in the bulbopontine reticular formation and that gradually undergoes the inhibitory control of the corticospinal motor pathways [11]. It has probably the meaning of a basic alerting reaction [10]. The onset of the startle reflex is contemporary to the Moro reflex and it becomes more noticeable by the time of its disappearance [10]. Upgaze and downgaze movements They may be present in healthy newborns. Hahn has described brief upgaze movements, lasting a few seconds, after the sudden appearance of a visual stimulus into the visual field or during baths with water poured on the face [13]. These cases could represent an uncoupling of the normal Bell’s phenomenon with the eyelid closure [13]. A fast downward eye deviation in response to various stimuli or during feeding is possible, with spontaneous remission [26]. Opsoclonus A few cases of isolated, transient opsoclonus in healthy newborns have been described [13]. Hiccups Newborns show a tendency to hiccup as part of a physiological mechanism, starting in utero, involved in the maturation of the inspiratory muscles [2,27]. Repetitive sucking movements Sucking reflex is a brainstem-mediated reflex that develops around the 25th week of gestation, taking an essential part in competent oral feeding and in coordinating effective breathing and swallowing [16]. It consists of automatic stereotypic movements that sometimes could be particularly repetitive and prolonged, resembling motor automatisms of pathological origin or subtle seizures.
Pathological non-epileptic paroxysmal motor phenomena in newborn Tremor and jitteriness Tremors and jitteriness can be clinical manifestations of pathological neonatal conditions such as hypoxic–ischemic encephalopathy, intracranial hemorrhage, hypoglicemia, hypocalcemia, sepsis, hypothermia, hyperthyroidism, and drug withdrawal (opiates, serotonin reuptake inhibitors, marijuana, cocaine, inhaled volatile substances) [1,2,3].
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There is also an autosomal dominant form of tremor, called familial trembling of the chin, that involves the perioral muscles, particularly during crying [1,4]. Pathological tremors, especially in the context of a mild asphyxia or of an intracranial hemorrhage, are usually coarse [1,3]. In the suspect of an underlying condition causing the tremor, it is important to consider the perinatal story and the general clinical conditions of the newborn. Laboratory studies, including glycemia, electrolytes, urine drug, thyroid and metabolic screening, septic workup, and also neuroimaging, are recommended [1,3]. The presence of perinatal complications in a jittery newborn is related to an adverse neurodevelopmental outcome, needing a careful follow-up [1]. Tremors are often confused with clonic activity but the flexion and extension phases are equal in amplitude in tremor and different in clonic seizures [17]. Furthermore, neonatal seizures present some features that can be helpful in the differential diagnosis with tremor. Indeed, neonatal seizures are unpredictable events, usually not induced by stimuli and they are frequently associated with ocular phenomena and autonomic signs, unlike tremors. Moreover, they are not stopped by passive flexion and repositioning of the affected body part, as opposed to physiological tremors [14,17]. Myoclonus Myoclonus may originate from any part of the central nervous system: cerebral cortex, subcortical structures, brainstem, spinal cord, or peripheral nerve [5,6]. A polygraphy including EEG and electromyogram (EMG) can prove the cortical origin of myoclonus, showing a focal cortical event that precedes myoclonus with a fixed delay [6]. Furthermore, the jerk-locked back averaging technique is used to reveal a premyoclonic spike [6]. EEG abnormal activity could also be found with brainstem myoclonus but, if present, it is not timelocked to the EMG event [5,6]. Focal myoclonus is the primary seizure type in early myoclonic encephalopathy (EME) [9]. Non-epileptic pathological myoclonus may be present in newborns affected by hypoxic–ischemic encephalopathy, intraventricular hemorrhage, glycine encephalopathy [8] and also, as a withdrawal symptom, in preterms treated with endovenous benzodiazepines [1,2] or in maternal use of opiates [7]. A brainstem release phenomenon is probably involved in the pathogenesis of the myoclonus in case of a diffuse brain injury [1]. Hyperekplexia It is a genetically inherited or sporadic neurological disorder characterized by an exaggerated startle reflex that may appear in response to different types of stimuli (tactile, auditive, and visual) [1,10,12]. The exclusive presence of an excessive startle response, sometimes leading to generalized tonic spasms, is the typical hallmark of the minor form. The association with transient general muscular rigidity that usually improves after the first year of life, and with nocturnal myoclonus defines the major form [1,10,12]. A mutation in the alpha-1 subunit of the glycine receptor gene (GLRA1) is involved in major form cases, with autosomal dominant inheritance [11]. The other genes in which mutation is causative are SLC6A5, GLRB, GPHN, and ARHGEF9 [28].
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The differential diagnosis in newborns is represented by neonatal seizures, in particular, startle epilepsy and myoclonic seizures, neonatal tetany, stiff-man syndrome, phenotiazine toxicity, and cerebral palsy [11]. When nose tapping is able to provoke a startle response without habituation, the clinical diagnosis is made [11,12]. EEG background is generally normal for the age [17]. The pathogenesis of the disease is probably related to an increased excitability of the bulbopontine reticular neurons involved in the startle reflex [12]. The newborn with hyperekplexia is probably at increased risk of obstructive and central apneas, responsible for sudden infant death syndrome [11,12]. Therefore, an apnea home monitoring is suggested [12]. The treatment of the exaggerated startle response is clonazepam and, in the case of severe hypertonia causing apnea and bradycardia, the maneuvre of forced flexion of head and legs is often effective [11]. Neonatal dystonia Dystonia is often misidentified with seizures [17]. It may be caused by acute or chronic pathological conditions involving the basal ganglia, such as a severe asphyxia, an inherited metabolic disease (e.g. glutaric aciduria) or an acute bilirubin encephalopathy [13,17,19]. Another possible cause of dystonia is related to neocortical malformations or damages determining a dishinibition of subcortical motor pathways [17]. Dystonic movements and posturing are also described in association with intrauterine cocaine exposure or with gastroesophageal reflux, identifying a Sandifer’s syndrome [2,13]. Ocular movement disorders Paroxysmal tonic upgaze and paroxysmal tonic downgaze may be the clinical signs of neurologic and oculomotor problems [2,13]. Neonatal opsoclonus has been described in association with hypoxic–ischemic encephalopathy, visual loss, and herpes simplex encephalitis [2,13]. Hiccups The association of hiccups with compromised neurological conditions and with neonatal seizures, leading to a burstsuppression EEG pattern, is suggestive for non-ketotic hyperglycinemia. This is an autosomal recessive disorder causing an accumulation of glycine in plasma and cerebrospinal fluid, with variable outcome, unfavorable in the classical form [29]. Tongue fasciculations Tongue fasciculations may be a clinical sign of hypoxic– ischemic encephalopathy, Mo¨bius syndrome and spinal muscular atrophy [13,18]. Motor automatisms Newborns, especially preterms, may display isolated paroxysmal movements not associated with epileptic changes in the EEG, such as chewing, swallowing, sucking, repetitive tongue movements, eye deviation, cycling, boxing, pedaling, and swimming. The origin of these stereotypical phenomena is not clear. They could be the expression of brainstem release phenomena, due to the immaturity of the inhibitory control
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mediated by the corticospinal tract or to neocortical injuries, or they could represent subcortical seizures, not detectable by surface EEG recording [17].
Neonatal seizures Seizures are the most common symptom of an underlying neurological disease in newborns [14]. The incidence rate of neonatal seizures (NS) is reported to be 0.95–5 per 1000 live births [30]. The first cause of NS is hypoxic–ischemic encephalopathy (40–60%), affecting mainly full-term newborns [14], followed by intraventricular hemorrhage (7–18%), that is typical of the preterm population [30]. Less frequently NS are provoked by cerebral strokes (6–17%), cerebral malformations (3–14%), CNS infections (5–10%), acute metabolic disorders (3–5%), inborn metabolic diseases (1– 4%), and epileptic syndromes with neonatal onset, including benign familial neonatal seizures, early myoclonic encephalopathy, and early infantile epileptic encephalopathy (1%) [20]. Clinically, NS are defined according to Volpe’s classification modified by Lombroso as focal clonic, multifocal clonic, generalized tonic, myoclonic, and subtle [14]. Clonic seizures consist of repetitive, rhythmic (1–4 jerks per second) twitching of facial, limb or axial muscles, involving circumscribed muscle groups (focal) or shifting from a muscle group to another one in a random manner (multifocal) [14,15]. Generalized tonic seizures can present with hyperextension of the upper and lower extremities or hyperextension of the legs and flexion of the arms and sometimes with axial hyperextension [14,15]. Myoclonic seizures are characterized by single or slow serial, non-rhythmic, jerking of extremities, or axial musculature. The myoclonic jerks may be generalized, focal, or fragmentary [14,15]. Subtle seizures include tonic horizontal or vertical eye deviation, with or without nystagmus, eyelid blinking or fluttering, oral–buccal– lingual movements (chewing, swallowing, sucking, and repetitive tongue movements), ‘‘cycling’’, ‘‘boxing’’, ‘‘pedaling’’, ‘‘swimming’’ movements, apneic spells, hyperpnea, vasomotor phenomena, and tonic postures of a single limb or portion of a limb [14,15]. Mixed clinical seizures are combinations of more than one type of clinical seizures [15]. An ‘‘electroclinical seizure’’ is defined by the match between the clinical event and the EEG seizure activity. Ictal electroencephalographic discharges consist of a repetitive sequence of waveforms with a clear onset and termination, a duration more than 10 s and an evolution in frequency and morphology [17,31]. A close association to EEG seizure discharges has been confirmed for focal clonic seizures, some forms of myoclonic seizures with generalized or focal jerks, and focal tonic seizures [15]. On the contrary, it has been brought out that generalized tonic seizures, most subtle seizures, and some myoclonic seizures are only inconsistently or are not related to EEG seizure discharges, suggesting that these clinical manifestations may not be epileptic [15]. However, these last ones, together with multifocal clonic movements, are signs of encephalopathy [21]. Although the prognosis is most closely tied to underlying etiologies, it has been demonstrated that newborns with confirmed electroclinical seizures present a high risk of developing neurological sequelae, such as cerebral palsy,
Are stimulus sensitive, they occur commonly when newborns are crying or stressed [3].
It may be evoked by sensory, visual or auditory stimuli [2,5,6].
It is evoked by different types of stimuli, especially auditive. The physiological startle reflex shows a prompt habituation to stimuli [10].
Myoclonus
Startle reflex
Response to external stimuli
Tremor and jitteriness
Paroxysmal motor phenomena
BNSM may be triggered by the rocking maneuver of the newborn in head-to-toe direction and may be worsened by the restraint of the involved body parts [2,7]. Clinical maneuvers do not modify epileptic myoclonus [1,2].
In patients with hyperekplexia the nose tapping may provoke a startle response without habituation. The attacks of hypertonia and apnea in hyperekplexia can be stopped by a passive flexion of the limbs and head towards the trunk [11,12].
–
–
–
Physiological tremors are stopped with a gentle passive flexion and restraint of the affected limb or by suckling stimulation test [2,22].
Are more frequent during sleep or active wakeful than during quiet wakeful [2].
BNSM occurs only during sleep, mainly in quiet sleep [7].
Response to clinical maneuvres
Presentation time
Dependent on cause. BNSM resolves spontaneously within the sixth months of age [1,2]. EME has a very poor outcome: up to half of patients die before two years of age and the others present severe psychomotor impairments [9].
Patients with hyperekplexia are at risk of early motor developmental delay due to the stiffness that, however, decreases after the first year of age and resolves by the third year. Sudden infant death syndrome could be due to central or obstructive apnea. The exaggerated startle reaction remains, causing frequent falls and disability [2,11,12].
EEG is normal in BNSM [1,2]. Epileptic myoclonus is associated with an EEG correlate (an EEG spike preceding the myoclonus by a short interval). The jerk-locked back averaging technique reveals the pre-myoclonic spike [6]. EME is characterized by a suppression-burst pattern, not continuous and more distinct during sleep [9]. It can evolve in an atypical pattern of hypsarrhythmia at 3–5 months of age, returning to burst-suppression after some months [9]. The simultaneous recording of EEG and EMG allows distinguishing between cortical myoclonus (a very short EMG discharge, usually less than 50 ms, immediately preceded by an EEG spike) and subcortical myoclonus (the cortical EEG abnormality, if present, is not time-locked to the EMG event [5,6]. In patients with hyperekplexia the EEG may show fast spikes of myogenic origin during the tonic spasm, followed by slowing and flattening of the background activity during the subsequent apnea, bradicardia and cianosis [10]. The EMG in hyperekplexia may show an almost continuous muscular activities alternated with brief period of electrical quietness [10].
(continued )
Dependent on cause. Physiological tremors stop with increasing post-conceptional age [3,17].
Prognosis
Tremors are not associated with EEG discharges [15]. EMG is useful to assess the frequency of a tremor. A fine tremor is characterized by a high frequency (greater than 6 Hz) and a low amplitude (lower than 3 cm) while a coarse tremor by a low frequency (lower than 6 Hz) and a high amplitude (greater than 3 cm) [1,2,5].
Electrophysiological studies: electroencephalogram (EEG) and electromyography (EMG)
Table 2. Clinical and electrophysiological features useful in the differential diagnosis between neonatal paroxysmal motor phenomena and their prognosis.
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Paroxysmal motor phenomena in newborns 5
–
– –
Tonic seizures
Clonic seizures
Complex motor automatisms
–
–
–
–
Dystonic movements and posturing in Sandifer’s syndrome are related to feeding [2].
–
–
Presentation time
–
–
–
–
–
–
Response to clinical maneuvres
Clonic seizures present a timesynchronized relationship to EEG seizure activity [15]. Not associated with EEG discharges [15].
Focal tonic seizures are usually associated with EEG discharges while clinical generalized tonic seizures are inconsistently associated [15].
Not associated with EEG seizure activity.
Usually are not associated to EEG seizure activity except for regular, rhythmic tongue twitching occurring commonly with other clonic jerks of the face or extremities [15]. EMG could suggest a motor neuron disease in case of tongue fasciculations [33].
In non-ketotic hyperglycinemia EEG could reveal a burst-suppression pattern [2].
Sustained eye deviation with nystagmus, usually after sudden eye opening, can be associated with EEG discharges arising from the occipital regions [15]. Other ocular signs are inconsistently associated with EEG discharges [15].
Electrophysiological studies: electroencephalogram (EEG) and electromyography (EMG)
Dependent on cause.
Most closely tied to underlying etiologies. Newborns with confirmed electroclinical seizures present a high risk of developing neurological sequelae, such as cerebral palsy, developmental delay and epilepsy [31].
Dependent on cause. In Sandifer’s syndrome the treatment of the gastro-esophageal reflux alleviates the movement disorder [13].
Dependent on cause. Patients affected by spinal muscular atrophy type 1 do not acquire the ability to sit unsupported and, if no intervention is provided, generally do not survive beyond the first 2 years [33].
The classical form of nonketotic hyperglycinemia has a poor prognosis with death occurring in the first months of age while the atypical forms of the disease are characterized by a milder clinical presentation and variable neurological outcome [2].
Dependent on cause. Transient opsoclonus has been described in otherwise healthy neonates [13]. Paroxysmal tonic upgaze generally improves or resolves by 2.5 years of age but other neurologic and oculomotor problems can be seen on long-term follow-up [13].
Prognosis
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BNSM, benign neonatal sleep myoclonus; EME, early myoclonic encephalopathy.
–
–
Paroxysmal tonic upgaze and downgaze may be induced by stimuli, such as sudden visual stimuli, water flowing over the upper face, movements, feeding [2,13].
Response to external stimuli
Paroxysmal dystonia
Oral–buccal–lingual repetitive movements
Hiccups
Ocular movement disorders
Paroxysmal motor phenomena
Table 2. Continued
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Paroxysmal motor phenomena in newborns
DOI: 10.3109/14767058.2016.1140735
developmental delay, and epilepsy [31]. Epilepsy affects 18–25% of the patients with a history of NS, involving mainly the full-term newborns and is frequently associated with other neurological impairments [31].
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Differential diagnosis between epileptic seizures and paroxysmal non-epileptic motor phenomena in newborns The differential diagnosis between neonatal seizures and paroxysmal non-epileptic motor phenomena is often hard to make on a clinical basis only. Indeed, there are some conditions that mimic seizures and that could be misinterpreted [17]. An observational study has shown an objective difficulty of health care professionals in distinguishing clinically a neonatal paroxysmal movement as epileptic or non-epileptic [32]. This unreliability can lead to an inappropriate management, with the negative effects related to undertreatment of seizures or, on the contrary, to overtreatment of non-epileptic events [32]. However, there are few clinical features that should be considered because they could help the diagnosis, suggesting a non-epileptic origin (Table 2). In most cases, for a correct differential diagnosis, a continuous synchronized video–EEG–recording, interpreted by an expert in neonatal neurology, is required [2,17] (Table 2). This technique represents the gold standard to prove the cortical origin of a paroxysmal motor phenomenon and it allows also the identification of only electrical seizures, electroclinical dissociation, or electroclinical uncoupling, that are possible in newborns. However, seizures originated in subcortical brain regions and not propagated to the cortical surface are not detected by surface EEG electrodes, remaining an open issue for the clinicians [17].
Conclusions Newborns frequently display paroxysmal motor phenomena that should be carefully considered by the clinicians, in order to identify possible underlying diseases. Some of these events are due to an immaturity in the inhibitory control on the motor system and are self-limited [2]. Both epileptic and nonepileptic paroxysmal motor phenomena are included in the pathological group. Because neonatal seizures, the most common symptom of a neurological injury in newborns [14], are quite often indicative of an unfavorable outcome, a correct diagnosis of any abnormal paroxysmal movement in newborns is mandatory to timely exclude an epileptic origin. Some clinical features have to be accurately taken into account, being more typical for an epileptic or a non-epileptic condition, but in most cases, a polygraphic video-EEG recording is required. A prompt differential diagnosis of such clinical phenomena is essential to guide subsequent management and treatment and to provide appropriate prognostic information.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
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