Clinical manifestations

Presentation and course

Hyperkinetic seizures are characterized by bizarre and complex motor patterns. They can be associated with dystonia or affective symptoms, such as fear, and vocalizations are common. Consciousness might or might not be preserved. These attacks often occur in clusters of many seizures per day (25; 11).

Hyperkinetic seizures often occur during sleep, especially during non-rapid eye movement (NREM) sleep phases 1 and 2 (41). A clinical series observed 40% of patients with exclusively nocturnal occurrence of hyperkinetic seizures (28).

Hyperkinetic seizures occurring during sleep can be part of a spectrum of different, but closely related, seizure semiology, which also includes short-lasting (5 to 10 seconds) simple stereotyped motor phenomena that resemble a sudden arousal (paroxysmal arousals) and prolonged episodes that mimic sleepwalking (nocturnal wandering) (41). This spectrum of seizure semiology often coexists in the same patient.

In patients with hyperkinetic seizures occurring during sleep, personal (up to one third) and family history of parasomnias is frequent, including night terrors, sleepwalking, bruxism, and enuresis (41).

Family history of epilepsy is observed in up to 25% of patients with sleep‐related hypermotor epilepsy, and autosomal dominant inheritance characterizing the autosomal dominant sleep-related hypermotor epilepsy (ADSHE), previously termed (autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), should be suspected (38; 41; 39; 33). Familial and sporadic sleep‐related hypermotor epilepsy have similar clinical features (51).

Overall, patients with hyperkinetic seizures have normal neurologic and neurophysiological exams (41).

Prognosis and complications

The prognosis of seizure control in patients with hyperkinetic seizures is associated with the underlying etiology of the epilepsy. Overall, 60% to 70% of patients with hyperkinetic seizures will achieve seizure control with antiseizure meditation (41). In NFLE and ADNFLE, the morbidity of the seizures is usually lower than in other types of focal epilepsies due to its occurrence exclusively during sleep. A long-term study of patients with NFLE/sleep-related hypermotor epilepsy showed a cumulative 5-year remission rate of 28.4% after 30 years of follow-up. The study also confirmed that the outcome is primarily related to the underlying etiology (20).

In cases of pharmacoresistant hyperkinetic seizures, the outcome for seizure control is usually good in patients who undergo surgical resection of the epileptogenic zone, with up to two-thirds of patients becoming seizure-free (34). Around 6% of sleep-related hyperkinetic seizures were observed in a population of pharmacoresistant epilepsies (27).

In NFLE, the incidence of sudden unexplained death in epilepsy (SUDEP) is 0.36 per 1000 person-years, similar to other epilepsy populations (29).

Clinical vignette

A 38-year-old male patient was referred to a tertiary epilepsy center for the evaluation of pharmacoresistant epilepsy. His seizures started by the age of 11. Seizures were characterized by recurrent attacks during sleep with no warning sensation and sudden arousal with abrupt flexion of the legs, followed by rocking movements of the trunk, ballistic or kicking movements of the legs, and partial extension of the arms. The seizures usually lasted 30 seconds and recurred 10 to 15 times per night, with intervals of 5 to 10 minutes. He had no past medical history and no family history of epilepsy.

His interictal EEG revealed rare low-amplitude epileptiform discharges in the right frontocentral region. However, during the ictal events, his EEGs were unremarkable. His brain MRI revealed a small hypointensity in T1-weighted images in the right medial frontal region, and FDG-PET showed hypometabolism in a concordant area.

This patient demonstrates the most common presentation of hyperkinetic seizures. The attacks are characterized by bizarre motor components that predominantly occur during sleep and recur many times per night. The seizures have a presumed frontal lobe epileptogenic zone as verified by scalp EEG and corroborated by the presence of a possible epileptogenic structural lesion in a concordant area.

Biological basis

Localization

Hyperkinetic seizures are typically a symptom of frontal lobe epilepsy. They commonly originate in deep structures of the frontal lobes and, therefore, scalp EEGs constantly fail to reveal ictal or interictal abnormalities (41; 01). Intracranial EEG studies have confirmed, however, that hyperkinetic seizures can originate from other brain areas, more commonly the temporal lobe or insula, but also the parietal and occipital lobes (27; 40; 01).

Neuroimaging and intracranial electroencephalography (EEG) studies and postsurgical series point to an epileptogenic zone most often localized in the mesial frontal region (41; 01). Hyperkinetic seizures may also originate from other frontal lobe areas such as the orbitofrontal cortex and frontal pole (28). Irrespective of seizure onset, a combined neuroimaging and neurophysiology study suggests that hyperkinetic seizures are associated with an abnormal network involving mainly the insula, mesial premotor cortex, and middle cingulate cortex is recruited (54; 55).

Kheder and colleagues defined three distinct ictal SPECT hyperperfusion patterns in patients with hyperkinetic seizures: (1) hyperperfusion in the anterior insula orbitofrontal cortex, anterior cingulate, and anterior perisylvian region spreading to basal ganglia and rostral midbrain; (2) hyperperfusion in the anterior cingulate, frontal pole, and orbitofrontal cortex and involving basal ganglia and contralateral cerebellum; and, (3) hyperperfusion in the temporal pole and anterior perisylvian region (19).

One study evaluated patients with hyperkinetic seizures who underwent intracranial EEG evaluation and were seizure-free after a minimum period of 24 months (43). The authors proposed that two types of hyperkinetic seizures could be distinguished. The first type consisted of marked agitation, body rocking, kicking or boxing, and a facial expression of fear, and the onset was localized on the ventromesial frontal cortex. The second type was characterized by mild agitation, with horizontal movements or rotation of the trunk on the bed, and associated with tonic or dystonic posturing; the onset was localized on the mesial premotor cortex.

Using stereo EEG analysis, Bonini and colleagues identified anatomic organization of different semiologic subgroups of frontal lobe seizures, including hyperkinetic seizures (06). The authors used the term "gestural motor behavior" to describe what they consider as a heterogenous group of complex motor behavior (including stereotypes and hyperkinetic movements). They further subdivided these gestural motor behaviors according to a "natural" or "unnatural" pattern as integrated gestures (for example, reaching, pedaling, kicking) or nonintegrated gestures (anarchic movements), respectively. They observed that the seizure activity of nonintegrated gestural motor behavior involved the premotor and prefrontal regions; integrated gestural motor behavior with distal stereotypies involved anterior lateral and medial prefrontal regions; and seizures with fearful behavior involved the ventromedial prefrontal cortex with or without anterior temporal structures (06).

Another study described three clusters of hyperkinetic seizures and its relationship with the seizure onset zone: (i) asymmetric hyperkinetic seizures associated with marked dystonia in parietal onset seizures, (ii) symmetrical hyperkinetic seizures without dystonia in dorsolateral prefrontal or temporal lobe onset seizures, and (iii) symmetrical hyperkinetic seizures with emotional expression and vocalization in temporal lobe or ventromesial prefrontal onset seizures (11).

In surgical series, a temporal lobe onset origin can be found in up to 28% of patients with drug-resistant hyperkinetic seizures (27). One surgical series reported that 6% of patients with temporal lobe epilepsy had hyperkinetic seizures (47). In these patients with hyperkinetic seizures and temporal lobe epilepsy, the striking motor component, short duration of the event, and prevalence during sleep resembled frontal origin; however, additional characteristics of their attacks were more suggestive of temporal lobe origin, such as a warning sensation or dystonic posture contralateral to the epileptiform discharge (27). Auditory aura was also suggested as a feature associated with extra-frontal origin, more often the left temporal lobe (12). In addition, interictal EEG usually demonstrated clear abnormalities in temporal lobe epilepsy patients, whereas it was often normal in frontal lobe epilepsy. Poor quality of sleep and excessive daytime sleepiness were more often observed in patients with frontal lobe origin. Intracranial EEG studies in patients with hyperkinetic seizures of temporal lobe origin suggested that the hypermotor component starts when the ictal discharge extends and includes the frontal lobe or the cingulate gyrus. Other series have suggested that the temporal pole and its connections with mediobasal prefrontal cortex are the main regions involved in the brain network responsible for the hyperkinetic semiology observed in patients with temporal lobe epilepsy (52).

Hyperkinetic seizures of frontal lobe origin had emotional facial expressions with fear, laughing, or anger; bilateral forceful elbow flexion; bilateral forceful grasping; facial flushing; and bilateral facial contraction more frequently than those with temporal lobe onset, whereas oroalimentary automatisms, seizures during wakefulness, salivation, and bilateral drop of the corners of the mouth were more frequent in temporal lobe onset hyperkinetic seizures (32).

Pathophysiology

There are similar aspects of hyperkinetic seizures that occur during sleep in sleep‐related hypermotor epilepsy and other physiological events of light sleep. This suggests similar mechanisms are involved in the organization of the microstructure of sleep and seizures in sleep‐related hypermotor epilepsy (41; 33).

Tassinari and colleagues suggest that the hyperkinetic behaviors in these seizures are the expression of genetically determined motor patterns related to central pattern generators localized in the brainstem, and similar mechanisms are involved in the parasomnias (50). These central pattern generators participate in the innate motor behaviors essential for survival and could be activated by the epileptiform discharges.

Electrical stimulation of the anterior cingulated cortex can elicit complex bilateral movements, and ictal hyperperfusion as well as interictal functional abnormalities of the cingulate gyrus has been demonstrated in patients with hyperkinetic seizures (53; 31).

In patients with sleep‐related hypermotor epilepsy, autosomal dominant inheritance (ADSHE) is observed in up to 25% of patients (41; 48; 04). In patients with ADSHE, a mutation occurs in one of the subunits of the neuronal nicotinic acetylcholine receptor (nAChR) (41; 39; 48; 33). The association of nocturnal seizures, arousal, and abnormal nAChR has led to an investigation of the role of cholinergic systems in the pathophysiology of ADNFLE and hyperkinetic seizures. It has been demonstrated that nAChR is involved in the control of arousals (57). Furthermore, the increased density of nAChR density in the mesencephalon observed in PET studies of patients with ADSHE corroborates the hypothesis of the role of brainstem ascending cholinergic systems in the pathophysiology of this syndrome (39). Therefore, the abnormalities in nAChR in ADSHE could favor the instability of sleep and facilitate seizure origin in these patients.

A resting state functional MRI study showed that patients with sleep‐related hypermotor epilepsy had a significantly higher functional connectivity in sensorimotor and thalamic regions and suggested that it supports the hypothesis of a hyperexcitability of the motor cortex during thalamic K-complexes in this condition (10).

Differential diagnosis

Confusing conditions

Because of its bizarre motor components and the predominance of its occurrence during sleep, the most important differential diagnoses of hyperkinetic seizures are sleep disorders and psychogenic nonepileptic seizures.

Hyperkinetic seizures during sleep can easily be mistaken with parasomnias. The absence of clear ictal epileptiform abnormalities in scalp EEG of a significant number of patients with frontal lobe epilepsy and hyperkinetic seizures also contributes to the difficulty in establishing the epileptic nature of the events (41; 30). A high frequency of recurrence of the attacks in the same night and between nights, the stereotyped characteristics of the fits, and the response to antiseizure medications are suggestive of the diagnosis of epileptic events (53).

However, one must have in mind that approximately 30% of patients with hyperkinetic seizures will not respond to antiseizure medications (41). Other features suggestive of an epilepsy diagnosis are the short duration of the episodes (less than 2 minutes), unstructured vocalization, an aura preceding the motor attack, and the history of tonic-clonic seizures during sleep (41).

The intense motor behavior during the attacks can also be a challenge for differentiation from psychogenic nonepileptic seizures or behavioral aberrations in children. The lack of alteration of consciousness, the fact that some actions can resemble normal movements, and the often-normal ictal scalp EEG contributes to the difficulty in diagnosis (56).

Associated and underlying disorders

Sleep-related hypermotor epilepsy (SHE), previously named nocturnal frontal lobe epilepsy (NFLE). NFLE is a syndrome of heterogeneous etiology characterized by the occurrence of hyperkinetic seizures exclusively during sleep (51). It has predominance in males. The age of onset varies, but the majority starts during infancy and adolescence (41). It may have a genetic or structural etiology.

Autosomal dominant sleep-related hypermotor epilepsy (ADSHE), previously named autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). ADNFLE has autosomal dominant inheritance and is clinically characterized by exclusively nocturnal hyperkinetic seizures of frontal lobe origin (46; 21; 07). Linkage sites were reported in the chromosomes 20q13.1-13.3 (ADNFLE type 1), 15q24 (ADNFLE type 2), and chromosome 1 (37; 38; 09). The mutations are observed in genes encoding α4 (CHRNA4) or β2 (CHRNB2) subunits of the neuronal nicotine acetylcholine receptor (49; 09). Another locus was identified on chromosome 8p21.2-8q12, and a mutation was described in the α2 (CHRNA2) subunit of the neuronal nicotine acetylcholine receptor in an Italian family with ictal fear and nocturnal wanderings (02) and in a family with paroxysmal epileptic arousal (08). Two other loci were found in chromosomes 3p22-p24 and 8q11.2-q21.1, and one gene involved in the corticotropin-releasing hormone is suspected to be associated with the ADSHE phenotype (45). These patients and their relatives also have a high frequency of parasomnias (41).

Other genetic epilepsies. Sleep-related hyperkinetic seizures were demonstrated in patients with a CDKL5 mutation (18). Hyperkinetic seizures were also described in families with drug-resistant epilepsy, frequent status epilepticus, intellectual disabilities, psychiatric comorbidities, and KCNT1 mutation (16). A recessive pattern of NFLE was described in two siblings with a mutation in PRIMA1 gene, which is associated with reduction of acetylcholinesterase and accumulation of acetylcholine at the synapse level in animal models (17).

Structural/metabolic epilepsies. Hyperkinetic seizures can occur in epilepsies secondary to different types of structural lesions. In surgical series of pharmacoresistant sleep-related hyperkinetic seizures, focal cortical dysplasia type II is the most frequent finding (27; 40). Co-occurrence of mild malformation of cortical development (mMCD) and mutation in the sodium-activated potassium channel gene KCNT1 was described in four patients with sleep‐related hypermotor epilepsy (44).

Diagnostic workup

The diagnostic workup of patients with hyperkinetic seizures can be divided into two steps: (1) diagnosis of epilepsy and epileptic syndrome and (2) localization of seizure origin in patients with pharmacoresistant seizures.

The diagnosis of hyperkinetic epileptic seizures can be achieved by a detailed clinical history. However, due to the clinical similarities of these events with sleep disorders and psychogenic nonepileptic seizures, a further workup is usually necessary.

Routine scalp EEG often fails to reveal ictal or interictal discharges in hyperkinetic seizures if the origin is in deep brain structures (41). Interictal scalp EEG, however, can be helpful in demonstrating epileptiform discharges in temporal lobe epilepsy patients with hyperkinetic seizures (27). Ictal events recorded during prolonged video-EEG can be necessary to differentiate epileptic events from parasomnias and psychogenic nonepileptic seizures.

A specific diagnostic criterion based on level of certainty has been developed for sleep‐related hypermotor epilepsy. In this criterion, it can be diagnosed as witnessed (possible), video-documented (clinical), and video-EEG-documented (confirmed) (51).

Although scalp video-EEG can often confirm the epileptic nature of the hyperkinetic attacks, it is sometimes unable to localize the seizure origin due to its origin in deep brain structures or the diffuse electromyography artifacts during the spells (56). Therefore, the accurate localization of seizure origin in patients with pharmacoresistant hyperkinetic seizures aiming the appropriate surgical resection of the epileptogenic zone demands thorough investigation with structural (brain MRI) and functional (ictal SPECT, PET) neuroimaging, or intracranial EEG, or both (34).

Management

There is no evidence of a specific antiseizure medication for the treatment of hyperkinetic seizures, and choice of therapy must follow the same principles as that of other focal seizures (41). Carbamazepine is still considered the first treatment choice for patients with sleep‐related hypermotor epilepsy, and many patients will respond to small doses (03). Studies report seizure control with carbamazepine in approximately 20% of the patients with hyperkinetic seizures and significant reduction of the seizures in about 50% of patients (41; 22). Other antiseizure medications, including topiramate (36), oxcarbazepine (42), and perampanel (22) should be considered in mono or polytherapy in those who do not respond or do not tolerate carbamazepine.

There have been preliminary reports suggesting that nicotine patch can be an effective therapy in ADSHE patients with mutations involving the neuronal nicotinic acetylcholine receptor (nAChR) subunits (CHRNA4, CHRNB2, and CHRNA2) who did not respond to antiseizure medications (24; 14; 35). However, randomized placebo-controlled trials in sleep‐related hypermotor epilepsy patients are lacking.

For patients with pharmacoresistant hyperkinetic seizures, surgical treatment might benefit those with a defined epileptogenic zone in noneloquent areas. To this purpose, a detailed presurgical workup is necessary. In selected patients, seizure freedom can be expected in more than two-thirds of patients submitted to surgical resection of the epileptogenic zone. However, the surgical prognosis is associated with the underlying pathology (34).

Outcomes

The prognosis of seizure control in patients with hyperkinetic seizures is associated with the underlying etiology of the epilepsy. Overall, 60% to 70% of patients with hyperkinetic seizures will achieve seizure control with antiseizure medication treatment (41; 22). In sleep‐related hypermotor epilepsy and ADSHE, the morbidity of the seizures is usually lower than in other types of focal epilepsies due to its occurrence exclusively during sleep. However, seizures in sleep‐related hypermotor epilepsy usually do not remit, and prolonged use of antiseizure medications are needed (41). The identification and treatment of possible associated specific sleep disorders is important for the management and outcome of patients with sleep‐related hypermotor epilepsy (33).

In cases of pharmacoresistant hyperkinetic seizures, the outcome for seizure control is usually good in patients who undergo surgical resection of the epileptogenic zone, with up to two-thirds of patients becoming seizure-free (34). Around 6% of sleep-related hyperkinetic seizures were observed in a population of pharmacoresistant epilepsies (27).