Sleep-Related Hypermotor Epilepsy: Etiology, Electro-Clinical Features, and Therapeutic Strategies

Figures & data

Figure 1 Historical background of sleep-related hypermotor epilepsy.

Abbreviations: HPD, hypnogenic paroxysmal dystonia; NPD, nocturnal paroxysmal dystonia; NFLE, nocturnal frontal lobe epilepsy; SHE, sleep-related hypermotor epilepsy.

Table 1 Pathogenic and Likely Pathogenic Variants in SHE-Associated Genes

Gene	c.DNA Nucleotidic Change	Protein Aminoacidic Change	Mutation Type	Inheritance	Frequency of Pathogenic Variants	Function Effects
CHRNA4^Citation16,Citation17	c.851C>T	p.Ser284Leu	Missense	Autosomal dominant (ADSHE)	2.9%	Increased sensitivity to ACh
	c.851C>G	p.Ser284Trp	Missense
	c.920G>T	p.Gly307Val	Missense
CHRNB2^Citation18^–^Citation20	-	V287L	Missense		Rare
	-	V287M
CHRNA2^Citation21		Ile279Asn	Non-synonymous substitution		Rare
	c.754T>C	p.Tyr252His	Missense
KCNT1^Citation16,Citation23,Citation26	c.2800G>A	p.Ala934Thr	Missense	De novo	1%	Domain allosterically regulate channel opening and potassium ion permeation
	c.1193G>A	p.Arg398Gln
	c.2386T>C;	p.Tyr796His
	c.2782C>T;	p.Arg928Cys
	c.2688G>A;	p.Met896Ile
	c.862G>A	p.Gly288Ser
DEPDC5^Citation16,Citation33,Citation34	c.1165dupC	p.Arg389Profs*2	Frameshift	Unknown	3.9% the highest	Loss of inhibition of the mTOR pathway, resulting in overproliferation. Warning of FCDs
	c.1264C>T	p.Arg422*	Nonsense	Paternal
	c.193+1G>A	p.(?)	Canonical splice- site variant	Maternal
	c.1225delA	p.Thr409Hisfs*15	Frameshift	Unknown
NPRL2^Citation35	c.314T>C	p.Leu105Pro	Missense	Maternal	1%	Changing the GATOR1 protein complex, thus affecting the mTOR-signaling pathway
	c.100 C>T	p.Arg34*
NPRL3^Citation35	c.835_836insT	p.Ser279Phe fs*52	Frameshift	Unknown	-
CRH^Citation37^–^Citation39	c. 89C>G	p.Pro30Arg	Missense	Unknown		Alter the ability of the cell to promptly produce, process and secrete the mature hormone
PRIMA1^Citation10,Citation40	c.93+2T>C	knockout of PRIMA1.	Splice site	Autosomal recessive (ARSHE)	–	Enhanced cholinergic responses
STX1B^Citation42	C.106–2A>G	–	Aberrant splicing/mRNA decay		–
CABP4^Citation41	c.464G>A	p.G155D	Missense	Unknown	–	Decreases ion channel activation, leading to reduced Ca2+ concentrations
PPT1^Citation42	c.433G>C	p.G145R	–	Autosomal recessive (ARSHE)	–	Neuronal ceroid lipofuscinosis
Tsc1^Citation43	c.843del	p.Ser282Glnfs*36	Unknown	Unknown		(mTOR) cascade dysfunction

Notes: Modyfied with permission from Licchetta L, Pippucci T, Baldassari S, et al. Sleep-related hypermo-tor epilepsy (SHE): contribution of known genes in 103 patients. Seizure. 2020;74:60–64. Copyright 2020, with permission from Elsevier.¹⁶

Abbreviations: SHE, sleep-related hypermotor epilepsy; ADSHE, autosomal dominant sleep-related hypermotor epilepsy; ARSHE, autosomal recessive sleep-related hypermotor epilepsy; Ach, acetylcholine; DEPDC5, pleckstrin domain-containing protein 5; NPRL, nitrogen permease regulator-like; GATOR1, gap activity toward rags 1; mTOR, mammalian target of rapamycin; FCD, focal cortical dysplasia; CRH, corticotropin-releasing hormone.

Figure 2 Schematic representation of the seizure semiology patterns of SHE derived from anatomical-electrical-clinical data.

Notes: The seizure semiology patterns were grouped in three categories (HMS type 1 and 2 and mixed type of HMS) and depicted by three different colors (red, light red, and yellow). Although there were no strict boundaries among the color-coded groups, the specific HMS type contributed to the prediction of the EZ .

Abbreviation: HMS, hypermotor seizures.

Table 2 Diagnostic Criteria of SHE

Diagnostic Elements
Seizure features (essential elements)	Sudden onset and offset, brief (less than 2 min), stereotyped motor patterns within individuals
	Motor patterns: vigorous hypermotor movements or asymmetric dystonic/tonic posturing
	Abrupt arousal or aura at the beginning of the seizure (Awareness of episodes are not an exclusion criterion)
	Seizure frequency: every or almost every night, usually many times per night (Clustering is characteristic but not obligatory for diagnosis)
Age	Occur at any age, predominance in childhood and adolescence (Seizures can also originate in adulthood)
Distribution of sleep/awake seizures	Mainly during sleep, mostly during NREM sleep, rarely during REM sleep, and occasionally during wakefulness (No clearly defined standards of distribution of sleep/awake seizures)
Intelligence	Usually have average intelligence, intellectual impairments have been reported (Intellectual impairments are not an exclusion criterion)
Scalp EEG	Definite epileptic discharges or interictal epileptiform abnormalities (Normal interictal or ictal scalp EEG are not an exclusion criterion)
Diagnostic Levels
Witnessed/possible SHE	A typical clinical history (obvious and violent hypermotor events) provided by witnesses are sufficient
Video-documented/clinical SHE	At least one but preferably two complete events (confirmed by the witness as typical) in the video records are sufficient (A minor motor event or paroxysmal arousal by video records are not sufficient)
Video EEG-documented/confirmed SHE	Hypermotor seizures associated with definite epileptic discharges or interictal epileptiform abnormalities recorded during sleep, with the use of a VEEG at least 19 channels, an electrocardiogram, electrooculography, and chin electromyogram Documentation should include daytime sleep recordings after sleep deprivation or nighttime sleep recordings

Note: Data from references ⁴ and ¹⁵¹.

Abbreviations: NREM, non-rapid eye movement sleep; REM, rapid eye movement sleep; EEG, electroencephalography; VEEG, video- electroencephalography; SHE, sleep-related hypermotor epilepsy.

Table 3 Differential Diagnosis of SHE

Clinical Features	SHE	DOA	RBD
Time of night	No pattern	Usually within 90 minutes of sleep onset	At least 90 minutes after sleep onset, more common in the second half of the night
Sleep staging	NREM I or II	NREM III	REM
Episode pattern	Stereotyped and purposeless	Non-stereotyped variable but often complex	Complex and rough
Episode frequency	Every or almost every night, usually many times per night	Few per week	Variable, can be every night
Duration of episodes	Brief, often less than 2 min	1–30 minutes	Fewer than 10 minutes
Dream mentation	No	Uncommon	Yes
Eyes during episode	Open	Open	Mostly closed
Age of onset	Variable, predominance in childhood and adolescence	Childhood	Older than 50 years in idiopathic cases
Family history	Common	Common	Rare
Episodes during daytime	Sometimes	No	No

Notes: These clinical features are more prominent in one class than in the other; however, these divisions are not always absolute. Data from references.^{111,113,121,149,150}

Abbreviations: SHE, sleep-related hypermotor epilepsy; DOA, disorders of arousal; REM, rapid eye movement; RBD, rapid eye movement sleep behavior disorder; NREM, non-rapid eye movement.

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