Clinical manifestations

Presentation and course

Seizures in ADSHE are essentially indistinguishable from sporadic SHE, both of which have been studied in detail.

Sporadic SHE. Patients have a mean age of onset of 14 years, but with a very wide range of onset from 1 to 64 years. A mean of 20 seizures per month is reported, with 1 to 20 seizures occurring per night. Most individuals have no identifiable trigger for their seizures. Approximately one third of patients have occasional daytime seizures, and for a similar proportion, focal seizures evolve to bilateral tonic-clonic seizures, both usually occurring during periods of poor seizure control. A significant number of individuals with SHE also report a personal or family history of events that are clinically consistent with benign parasomnias such as sleepwalking and sleep terrors. Some patients with SHE may complain only of sleep disturbance, and others may be unaware of their events, with the seizures only being reported by relatives. In some cases of “sporadic SHE,” a family history of nocturnal events may be suggestive of a diagnosis of ADSHE if family members are also experiencing focal seizures that may not have been recognized.

Seizures in SHE have been subdivided into 3 major types, based on both their semiology and duration: paroxysmal arousals, lasting 20 seconds or less; paroxysmal nocturnal dystonia, lasting up to 2 minutes; and episodic nocturnal wanderings, lasting up to 3 minutes (42). Patients rarely have only a single type of attack; most have combinations of these different semiologies. Brief paroxysmal arousals are generally considered to be fragments of larger seizures (61). As all event types are thought to be manifestations of the same underlying epileptic process, this terminology is now rarely used, but the concepts are helpful in dissecting the nocturnal events.

Paroxysmal arousals. Paroxysmal arousals begin with an abrupt arousal from sleep with vocalization and highly stereotyped motor activity, often consisting of head movements, frightened expressions, and dystonic posturing of the limbs (60). They occur repetitively and very frequently throughout the night, often with a periodic repetition (61) and are typically under-reported. Some individuals are completely unaware of their attacks and present with excessive daytime somnolence (52).

Nocturnal paroxysmal dystonia. Nocturnal paroxysmal dystonia begins as a paroxysmal arousal, but is subsequently associated with more complex movements including bipedal automatisms, rhythmic twisting movements of the trunk and pelvis, vocalization, and tonic or dystonic posturing (60).

Episodic nocturnal wanderings. Episodic nocturnal wanderings usually begin as a paroxysmal arousal, progressing through the nocturnal paroxysmal dystonia stage, followed by jumping from the bed and ambulation (usually in an agitated fashion), screaming or other vocalization, and sometimes semipurposeful automatisms that may be violent (36; 59). Such episodes are infrequent, with paroxysmal arousals and nocturnal paroxysmal dystonia making up the majority of events in any given individual (60).

Neurologic examination is usually normal, as is neuroradiological examination with MRI or CT. When patients with SHE are studied using video EEG monitoring, by far the most common seizure type recorded is the paroxysmal arousal; paroxysmal nocturnal dystonia is seen less frequently, with episodic nocturnal wanderings recorded infrequently. Most patients have at least 2 of these seizure types identifiable on monitoring, and autonomic features such as tachycardia and irregular respiration are also prominent.

ADSHE. Although the clinical features of ADSHE are largely indistinguishable from sporadic SHE, ADSHE has also been studied in detail as an independent entity. Seizures usually begin in childhood, with a mean age of onset of around 11 years (69; 49). Although about 85% of cases begin before the age of 20 (69), seizure onset has been reported from less than 1 year of age to 52 years of age (69; 49). In the great majority of cases, affected individuals are of normal intellect and have a normal neurologic examination (69; 49), although some families with mental retardation in association with ADSHE have been described (26; 16). Indeed, there is increasing evidence that psychiatric disorders and mental retardation may be more common than has been recognized in this condition, particularly in individuals with more severe epilepsy, and in some cases cognitive decline may occur (35; 16; 58). Moreover, detailed neuropsychological studies have suggested that subtle cognitive deficits are present in many apparently intellectually normal individuals with ADSHE. Impaired cognitive flexibility appears to be the core deficit (85), but more widespread impairments in memory and general intellectual function may also be present (58).

Seizures in ADSHE occur almost exclusively from sleep; however, as with sporadic SHE, up to one third of patients may have infrequent daytime seizures, particularly during periods of poor seizure control (69; 49). Approximately half of subjects have rare evolution to bilateral tonic-clonic seizures. The majority of patients experience seizures soon after sleep onset, but seizures may also occur just before wakening or, less commonly, throughout the night (69). Patients are often woken by a relatively non-specific aura, such as a sensation of “their breath being stuck in their throat,” a shiver, or a feeling in the limbs; such an aura is more common in ADSHE (69) than sporadic SHE (61). The seizure often begins with vocalization, which may be a grunt, a moan, or a single word (69). Prominent motor features are usually seen, including tonic or dystonic posturing, sometimes with superimposed clonic jerking; sitting up or jumping up; bipedal and bimanual automatisms; and sometimes violent behavior (69; 49). Awareness may be preserved in at least a proportion of seizures, with individuals experiencing fear or panic. Some individuals vocalize during this period (49). The seizures are typically stereotyped and brief, often 1 minute or less in duration, and occur in clusters. During clusters, patients usually have 6 or 7 attacks per night, but in some cases between 20 and 70 attacks per night have been recorded (69).

Within families there is a wide variation in the severity of the disorder (49) and the manifestations of the seizures themselves (21). In individual subjects, the disorder tends to be at its most severe in childhood and adolescence. Some family members experience seizures for brief periods of a few months, whereas others have lifelong attacks. Seizures usually become milder and less frequent in adulthood, and appear like remnants of their earlier attacks; they often do not remit (69; 49).

Prognosis and complications

The prognosis of ADSHE is often relatively favorable. Although seizures may be very troublesome in childhood, they tend to improve from early adulthood onwards. A substantial proportion of affected individuals have mild epilepsy that may be limited to a brief period in childhood or adolescence whereas in others, it continues throughout their lives. The majority of individuals have no significant cognitive or intellectual impairment.

However, it is increasingly recognized that in some cases, ADSHE may have a more severe presentation. Some individuals have highly refractory epilepsy throughout their lives, with periods of status epilepticus. They may also have significant psychiatric and cognitive morbidity (35; 16). Moreover, evidence is accumulating that even in relatively mildly affected individuals, neuropsychological abnormalities of frontal lobe function may be identified on formal testing (58; 85). In a cohort of 60 individuals with SHE, 15% had intellectual disability or cognitive deterioration and nearly half had deficits in at least 1 test of cognitive function (31).

As discussed earlier, the clinical features of ADSHE in most families with different mutations are indistinguishable. There is some evidence, however, to suggest that phenotypic features such as severity of epilepsy, and cognitive and psychiatric morbidity, may be influenced by the specific underlying genetic mutation. Steinlein and colleagues analyzed the clinical features of 150 affected individuals from 19 families in 12 countries and found that certain nAChR mutations appeared to confer a higher risk for mental retardation, schizophrenia-like symptoms, and marked cognitive deficits (73). For example, only 2 of 67 identified individuals with the CHRNA4-S248F mutation had major psychiatric or neurologic features, and only minor neuropsychological deficits were found on formal testing. In contrast, 11 of the 19 known individuals with the CHRNA4-S252L mutation had intellectual capacities in the low normal or moderately intellectually disabled range, and most individuals developed epilepsy at a younger age (6 months to 2 years). However, the small numbers involved in such studies, along with multiple other potential confounding factors, make definitive conclusions difficult.

Clinical vignette

A 33-year-old man presented with nocturnal attacks from the age of 10 years. The events were characterized by waking from sleep with a sensation of his breath “locking in his throat,” feeling unable to breathe. The episodes would usually happen soon after he had fallen asleep (within 30 minutes to an hour) and would often occur 5 to 10 times in close succession on the same night over a few hours. He felt he had partial or full recollection of all the events. He remembered sitting forward during the attacks and sometimes shouting “help.” His mother described how he would suddenly sit forward, with a distressed facial expression and apparently hyperventilating. His legs would kick and his arms would be held stiffly out to his sides, and he would shout. Usually the attacks lasted 30 seconds to a minute, but occasionally they would last up to 2 minutes. They occurred exclusively from sleep.

The patient had a strong family history of similar sleep-related events; his father and brother had been fully investigated and diagnosed with nocturnal epilepsy on the basis of video-EEG monitoring. His father had suffered frequent and troublesome nocturnal events, which started in early childhood, and which were diagnosed as night terrors and psychogenic attacks for many years. His grandmother also had a history of troublesome sleepwalking in her early life, which had settled spontaneously soon after the birth of her first child.

Standard investigations, including MRI and EEG (during sleep and wakefulness), were normal. Video-EEG monitoring captured several events consistent with frontal lobe seizures, characterized by sitting forward with dystonic posturing of the upper limbs and hypermotor bipedal automatisms of the legs. EEG during these episodes was significantly marred by movement artefact, but bifrontal rhythmic sharp and slow activity was clearly present during some of the attacks.

He commenced on carbamazepine, which reduced his seizure frequency, but the episodes still occurred during periods of sleep deprivation or stress. However, during his twenties, the episodes became gradually less frequent and eventually stopped without further changes to his medication regimen at 23 years. He remained seizure-free on carbamazepine monotherapy.

Biological basis

Etiology and pathogenesis

ADSHE is inherited in an autosomal dominant fashion, with variable penetrance. Although ADSHE was initially considered a disorder of the neuronal nicotinic acetylcholine receptor (nAChR), new molecular determinants have emerged. Mutations in genes encoding nAChR subunits (CHRNA4, CHRNB2, CHRNA2) are the most common identified causes of ADSHE; however, mutations in a sodium-gated potassium channel gene (KCNT1), mTOR regulatory genes (DEPDC5, NPRL2, NPRL3), and corticotropin-releasing hormone (CRH) have more been found to be causative in some families.

nAChR gene mutations. Mutations in CHRNA4, CHRNB2, and CHRNA2 can cause ADSHE (74; 53; 01) and are estimated to account for 10% to 20% of families in some populations (50). Penetrance is estimated at 70% in these families. Functional studies of the nicotinic receptor mutations associated with ADSHE demonstrate that result is gain-of-function, sometimes with altered response to antiepileptic medications and acetylcholine (10; 24; 25; 73). The importance of cholinergic signaling in SHE has also been emphasized by the finding of homozygous mutation in the gene PRIMA1 (which encodes a protein that anchors acetylcholinesterase to the neuronal membrane) in a family with autosomal recessive SHE (23).

Nevertheless, the mechanism by which mutations in the nAChR subunit genes result in epilepsy is not clear. The nAChRs are important ligand-gated ion channels that are distributed widely throughout the central nervous system, although the function of these receptors is only partially understood. There is good evidence that they are involved in presynaptic modulation of neurotransmitter release in a number of systems, enhancing the release of norepinephrine, dopamine, GABA, serotonin, and acetylcholine (65). In addition, there may be direct nicotinic synaptic neurotransmission in the CNS (although there is relatively little evidence of this), and the nAChR is believed to play a role in the regulation of gene expression and neuronal pathfinding during development (65). Positron emission tomography (PET) studies have suggested that this developmental function may be important in ADSHE, possibly via influences on dopamine receptor expression (19) or through changes in regional nAChR density (57).

KCNT1 mutations. The discovery of missense mutations in the sodium-gated potassium channel gene KCNT1 in families with severe ADSHE (22), and a sporadic case with a de novo mutation, demonstrated that other genetic mechanisms can also cause ADSHE. Mutations in this gene appear to be associated with a fully penetrant, often more severe form of ADSHE associated with behavioral and psychiatric problems and intellectual disability, but with otherwise typical seizure semiology. Psychiatric features include aggression and psychosis; severe developmental regression is also observed (16). Intriguingly, de novo KCNT1 mutations have also been identified in the syndrome of epilepsy of infancy with migrating focal seizures (EIMFS), a severe epileptic encephalopathy associated with migrating focal seizures and profound developmental impairment (04). A family was comprised of 4 children with 2 sets of half-siblings, 2 half-siblings with ADSHE and 2 half-siblings with EIMFS inherited from their mildly affected mother with ADSHE (40). Functional studies of the mutations causing EIMFS are consistent with a gain of function resulting in hyperexcitability (04), though there is a single report of a child with EIMFS and a KCNT1 loss of function mutation with decreased membrane expression (18). KCNT1 mutations causing ADSHE show gain of function but less than that observed in EIMFS (39). The precise function of KCNT1 and how mutations in this gene result in these distinct epilepsy phenotypes is, however, poorly understood.

mTOR pathway gene mutations. In 2013, the gene underlying familial focal epilepsy with variable foci (FFEVF) was discovered to be DEPDC5 (71; 27; 17). FFEVF is characterized by autosomal dominant inheritance of focal epilepsies in which different family members have focal epilepsies emanating from different cortical regions (71). DEPDC5 mutations were identified in 7 of the 8 large families reported (86; 11; 09; 44; 17). When small families with 2 or more individuals with focal epilepsy were studied for DEPDC5 mutations, 12% (10 out of 82) had mutations. Some families only contained individuals with sleep-related hypermotor epilepsy and could, therefore, have been diagnosed with ADSHE. These families effectively represent a subset of FFEVF in which some families only express a SHE phenotype. Many of the DEPDC5 mutations produce truncation of the protein and consequent haploinsufficiency.

DEPDC5 is a subunit of the GATOR1 complex, which exhibits regulatory control over mammalian target of rapamycin (mTOR), a protein complex involved in regulation of cell proliferation, among other functions (05). The other 2 components of GATOR1 are NPRL2 and NPRL3. Mutations of the genes encoding these proteins (NPRL2 and NPRL3) have also been identified in a smaller fraction of families with FFEVF, with individuals having sleep-related hypermotor, temporal lobe seizures, or other focal epilepsies (Ricos et al 2015; 82). Rare ADSHE families have been identified with mutations of GATOR1 genes (17; 28; 64).

An ADSHE family was described with bottom of the sulcus focal cortical dysplasia in 2 individuals and nonlesional sleep-related hypermotor epilepsy in the remainder of the family who were well characterized (70). Exome sequencing identified a truncation mutation of DEPDC5 in this family, highlighting that this gene could cause lesional and nonlesional epilepsy in a family. This observation has subsequently been confirmed in other families with focal cortical dysplasia and GATOR1 mutations (06; 64; 82). The mechanism of action by which mutations in GATOR1 genes result in epilepsy may relate to small, radiologically unidentifiable, focal cortical dysplasias in those with nonlesional epilepsy. In those with overt focal cortical dysplasia, a second hit such as a mutation in a gene within the same pathway may result in a developmental lesion (67). That mutation may be restricted to the lesional region or germline in origin.

In addition to MTOR regulator genes, a mother-daughter pair, both with nonlesional SHE, were identified and found to both carry a possibly pathogenic variant in the MTOR gene itself (41). Further study is necessary to clarify whether MTOR mutations are a significant cause of ADSHE.

CRH mutations. Missense mutations in the promoter and coding regions of CRH, encoding corticotropin-releasing hormone, have also been implicated in ADSHE (13; 66). The phenotype in these cases appears to be relatively mild, with no reports of the intellectual or psychiatric comorbidities. The mechanism by which altered CRH expression or function leads to epilepsy remains unclear; however, animal studies have demonstrated a proconvulsive effect of corticotropin-releasing hormone in the developing brain (03).

ADSHE can be caused by mutations in different genes and likely arises through different etiologic mechanisms, including channelopathies and focal cortical dysplasia. Even within the same family, variable presentations can be seen, demonstrating that ADSHE exhibits both genetic and phenotypic heterogeneity. The term “phenotypic heterogeneity” refers to the phenomenon of a single genetic mutation producing a phenotype of widely differing severity; this variability is usual within families with ADSHE (69). “Genetic heterogeneity,” on the other hand, describes different mutations causing a similar phenotype and takes 2 forms: allelic heterogeneity, referring to different mutations at the same locus, and locus heterogeneity, referring to mutations at different loci. Both forms of genetic heterogeneity are seen in ADSHE.

CABP4. A large family with ADSHE was reported in which all affected individuals had a variant in CABP4, the gene encoding calcium-binding protein 4 (12). The significance of CABP4 in ADSHE is unclear at this time, as the familial variant in this report is also present 19 times in the Genome Aggregation Database, of individuals without severe childhood-onset disease.

Mutations in known genes still only account for approximately 20% to 30% of ADSHE cases; thus, the remainder must occur via other mechanisms. These include as yet unrecognized genes acting in a monogenic fashion, though some cases may occur as a result of complex or polygenic inheritance. Epigenetic phenomena may also play an important role in some families.

Epidemiology

An Italian study estimated prevalence of SHE at 1.8 to 1.9 per 100,000, based on identification of a total of 14 patients (7 women) in the regions of Modena and Bologna (80). None of the patients in that study had a family history of SHE, suggesting ADSHE is rare. SHE may occur more often in men than women, with the ratio estimated at 7 men to 3 women (61), though the limited available data suggest sex prevalence is likely equal in familial cases.

Sudden unexpected death in epilepsy (SUDEP) occurs in SHE, with an estimated incidence of 0.36 per 1000 person-years (46). The incidence of SUDEP in ADSHE is not known, though at least 1 case has been reported, involving a family with a KCNT1 mutation (40), and SUDEP may be associated with DEPDC5 mutations (02).

Prevention

No recognized measures can be taken to prevent the development of epilepsy in ADSHE. However, prompt diagnosis and appropriate management have a key role in minimizing the psychosocial sequelae of this condition. In many individuals, the burden of their epilepsy is compounded by delayed diagnosis, with patients often misdiagnosed for many years with sleep disorders or non-epileptic psychogenic seizures. Appropriate diagnosis, investigation, and management can help to minimize the harm that such misdiagnoses can cause. Appropriate management of seizures results in improved sleep, which can improve on learning and daily function.

Differential diagnosis

The principal differential diagnosis of nocturnal frontal lobe epilepsy is benign sleep disorders, primarily the NREM arousal parasomnias (15). However, a number of sleep disorders can cause potential confusion with SHE, including the following:

• NREM arousal parasomnias (sleepwalking, confusional arousals, sleep terrors) • REM sleep behavior disorder • Rhythmic movement disorder of sleep (jactatio capitis nocturna) • Catathrenia (nocturnal groaning) • Sleep starts • Nocturnal panic attacks • Psychogenic non-epileptic attacks • Sleep-related breathing disorders

Despite the relatively long list of differential diagnoses, by far the biggest practical problem in clinical setting is the distinction of SHE from the NREM arousal parasomnias such as sleep terrors and somnambulism. A careful history, however, will usually be sufficient to distinguish these disorders (14). In the patient with paroxysmal nocturnal events, the most important historical features indicating SHE as opposed to benign parasomnias are the timing of events (in SHE this is often within 30 minutes of sleep onset, whereas parasomnias typically occur between 1 and 2 hours after sleep onset); the number of events per night (in SHE, there are often multiple events in a single night, whereas parasomnias rarely occur more than once or twice per night); the duration of events, which may be brief or prolonged in parasomnias, but in SHE are almost invariably brief (usually less than 1 minute); and the presence of an aura (very common in at least a proportion of seizures in individuals with SHE, but almost never a feature of parasomnias). Extensive wandering is rare (though occasional) in SHE but is common in parasomnias; conversely, lucid recall for events is common in at least a proportion of seizures in some patients with SHE but is very uncommon in parasomnias (although some vague recollection is not uncommon).

Importantly, few individual features are exclusive to either condition, and the diagnosis must be made by taking into account all pertinent aspects of the history. This can be problematic, even for clinicians with considerable experience with these disorders. The diagnostic process may be improved by use of the Frontal Lobe Epilepsy and Parasomnias (FLEP) scale. This is a brief, validated clinical questionnaire that has been shown to generate reliable diagnoses on the basis of the history in most cases in this setting (14).

Although the history is paramount in this setting, in some cases video-EEG monitoring is required to make a diagnosis. However, this is only practical when events are happening on a frequent basis. Moreover, events in SHE are often associated with normal or non-specific EEG features, and in some cases diagnosis may be difficult even if events are successfully recorded. The key to diagnosis is the stereotyped nature of the attacks, which can be identified on video-EEG studies.

Once SHE has been diagnosed, a careful family history is essential to detect ADSHE. As penetrance is 70%, the diagnosis may not be readily apparent, especially as there is great variation in disease severity between individuals in any given family. Many affected individuals may have only very mild events, and adults in a family may have had no events since childhood or adolescence. A superficially taken family history may often miss affected relatives who are not diagnosed as having epilepsy.

Diagnostic workup

The diagnostic workup in ADSHE is the same as for any patient with epilepsy. It is important to appreciate that the history of the events and family history are paramount in arriving at the correct diagnosis, and other investigations may be non-contributory in many cases.

Routine EEG in wakefulness is normal in up to 90% of individuals with ADSHE, but sleep EEG shows frontally dominant epileptiform discharges in up to 50% (49). Neuroimaging with MRI or CT is almost invariably normal in ADSHE.

Video-EEG monitoring may be essential in some patients to make the diagnosis, but diagnostic uncertainty may occasionally remain even after monitoring. Electrographically, seizures tend to occur during NREM sleep, with about 70% occurring in stage 1 or 2. Ictal EEG, however, shows ictal epileptiform activity in only around 30% of seizures. Diffuse or focal attenuation or frontal rhythmic slow activity occurs in over 50% of events.

At present, there is a limited role for diagnostic genetic testing in SHE. The diagnosis is made on the clinical presentation and family history in ADSHE. Where a patient has no known family history and no lesion is found on MRI, mutational analysis may uncover a de novo mutation in some cases with significant genetic counselling implications (54; 22). Multi-gene panels and next-generation sequencing techniques are becoming increasingly popular and affordable modalities; however, the yield in cases of SHE may be low given the relatively low frequency of mutations in known genes. Once a genetic mutation is found, it carries considerable implications in terms of selection of medications, recognition of comorbidities, and genetic counseling.

Management

Seizures in ADSHE are usually responsive to treatment with antiepileptic drugs, with carbamazepine being particularly effective (69; 49; 75; 56; 20). Both acetazolamide and lacosamide have been reported as effective in resistant cases of SHE/ADSHE (79; 32). A case series of 24 individuals with ADSHE treated with topiramate reported seizure freedom, or a 50% reduction of seizures, in almost all cases (87.5%) (48).

An open-label trial of fenofibrate as add-on therapy in 11 adults with SHE, 5 of whom had ADSHE, found that seizure frequency decreased and quality of life was improved (62). In a single patient with a known alpha4 nicotinic acetylcholine receptor subunit gene mutation, nicotine (administered via patch) was found to result in a significant reduction in seizure frequency (84); however, nicotine has not been used in larger trials in ADSHE.

In cases with KCNT1 mutations, the KCNT1 gain of function shows dose-dependent reversibility with quinidine, a broad spectrum potassium channel blocker (39). Although case reports describe some benefit of quinidine in terms of seizure reduction and mild developmental gains in children with EIMFS, a single case of KCNT1 focal epilepsy with regression did not derive any benefit (07; 38). A placebo-controlled randomized trial of quinidine for SHE with KCNT1 mutations also did not show a therapeutic benefit, and several patients developed prolonged PT intervals even at low quinidine doses (47).

There is probably no role for surgical treatment in ADSHE. Lamotrigine has been reported to block the nicotinic acetylcholine receptor in basic science studies (87), but the clinical importance of this finding remains unclear.

Outcomes

Although there are no large scale studies examining seizure control in ADSHE cohorts, the clinical course can be variable. As mentioned previously, seizure frequency is usually highest in childhood and early adulthood, with clinical improvement later in life, with some patients becoming seizure-free off medication.

Intellect is normal in most cases but over half of SHE patients will have some degree of neuropsychological deficit on formal testing (31). Those with gene mutations have greater risk of intellectual disability (31); in particular, individuals with KCNT1 mutations typically have intellectual disability and severe psychiatric and behavioral comorbidities.

Special considerations

Pregnancy

There are no specific reports about the effect of pregnancy on seizures in ADSHE, although some women report exacerbation during pregnancy (69). Women with ADSHE should be treated in the same manner as other women with epilepsy before, during, and after pregnancy.

Anesthesia

There are no specific data about the use of anesthesia in ADSHE.