Neuropharmacology & Neurotherapeutics
Sep. 05, 2021
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Eyelid myoclonia with or without absences is a form of epileptic seizure manifesting with myoclonic jerks of the eyelids, often with brief absences. These seizures are mainly precipitated by closing of the eyes and lights. They occur in symptomatic, possibly symptomatic, and idiopathic generalized epilepsies. Most authors support the view that eyelid myoclonia on eye closure is the defining seizure type of an idiopathic generalized syndrome (Jeavons syndrome) of reflex epilepsy, which is genetically determined, has age-related onset, and affects otherwise normal children, with a female preponderance. Jeavons syndrome is probably lifelong with continuing seizures in adult life. Eyelid myoclonia is often confused with facial tics or self-induction of seizures. In this article, the author details developments in the clinical manifestations, pathophysiology, genetics, and pharmacological treatment of eyelid myoclonia with absences.
• Eyelid myoclonia with absences is a distinct type of epileptic seizure that is often misdiagnosed as facial tics or another nonepileptic paroxysmal event of eyelid jerking.
• The characteristic eyelid myoclonia, if seen once, will never be forgotten or confused with other conditions.
• A main misconception is that eyelid myoclonia with or without absences is an attempt to self-induce seizures.
• Jeavons syndrome is a generalized idiopathic epilepsy characterized by eyelid myoclonia and absences on voluntary or on command eye closure in the light. Eye closure in the dark or passive eye closure does not trigger clinical symptoms or EEG discharges.
• Myoclonic and absence seizures are the predominant seizure type in Jeavons syndrome.
The first documentation of eyelid myoclonia was by Radovici and colleagues (81).
In 1977, Jeavons described “eyelid myoclonia and absences” as follows (48):
Eyelid myoclonia and absences show a marked jerking of the eyelids immediately after eye-closure and there is an associated brief bilateral spike and wave activity. The eyelid movement is like rapid blinking and the eyes deviate upwards, in contrast to the very slight flicker of eyelids which may be seen in a typical absence in which the eyes look straight ahead. Brief absences may occur spontaneously and are accompanied by 3 Hz spike and wave discharges... All patients are photosensitive. The mean age of onset is 6 years.
Eyelid myoclonia with absences has been studied extensively (28; 46; 05; 09; 36; 44; 73; 75; 89; 87; 35; 71; 72; 20; 22; 23; 50; 18; 19; 79; 96; 66). In recognition of Jeavons’s contribution, Duncan and Panayiotopoulos proposed the name “Jeavons syndrome” for eyelid myoclonia with absences in a book devoted to this condition (33); see also (71; 72; 20; 22; 23; 87; 86). However, the ILAE has not, as yet, recognized Jeavons syndrome (eyelid myoclonia and absences) as a separate syndrome.
The latest ILAE position paper of the operational classification of seizure types divides generalized seizures into motor and nonmotor (absence) seizures. Nonmotor (absence) seizures are typical or atypical, or seizures that present prominent myoclonic activity or eyelid myoclonia (40; 39). However, this ILAE operational classification of epileptic seizures has been criticized by a number of experts (94; 59). A comprehensive assessment of absence seizures concluded the following (94): “The classification as “generalized nonfocal and nonmotor (absence) seizure” does not covey the complex semiology of a patient's clinical events.”
This article and other publications present a significant number of video-EEG recordings documenting the fact that eyelid myoclonia is the more obvious clinical manifestation and can also occur alone without impairment of consciousness (15; 71; 20; 47; 14).
Eyelid myoclonia and absences have 2 components. The initial and more prominent of these components is eyelid myoclonia, and the second component is the concomitant conspicuous or inconspicuous absence seizure. These unique clinical features that occur immediately after voluntary or on command eye closure in the light are associated with generalized spike-and-wave discharges and are characteristic of what is called Jeavons syndrome. The electroclinical phenomena vanish on eye opening and are enhanced during drowsiness, hyperventilation, and intermittent photic stimulation. During photic stimulation, myoclonic jerks other than eyelid myoclonia are commonly evoked on eye closure and may precede or follow a brief absence. Absence and myoclonic jerks can also be provoked with the eyes open in some classical cases.
Jeavons syndrome is an idiopathic generalized epilepsy in which myoclonic seizures (eyelid myoclonia and myoclonic jerks other than eyelid), absence seizures, and generalized tonic-clonic seizures contribute to the clinical phenotype to a variable degree (22). In a few cases, a tonic eyelid spasm is recorded on EEG at the end of eye closure as a plateau before the eyelids open and jerk in concordance with a jerk of the upper part of the body and generalized spike-wave discharges.
Since 1977, many publications refer to eyelid myoclonia with absences or without absences. However, the term “eyelid myoclonia and absences,” as initially reported, better expresses the characteristic phenotype of Jeavons syndrome because absence seizures may occur independently of eye closure during hyperventilation and intermittent photic stimulation (21; 22; 23). Myoclonic seizures other than eyelid are reported in 34% to 54.5% of cases (44; 21; 22). Generalized tonic-clonic seizures are seen in 50% of cases and are the usual presenting symptom in mild forms (21; 22).
Eyelid myoclonia. Eyelid myoclonia on eye closure, voluntary or on command, in light of variable intensity represents the hallmark of Jeavons syndrome. An eyelid flutter may be associated with generalized beta, theta, or delta rhythm on EEG as well as a marked eyelid jerking concomitant with an upward deviation of the eyeballs and retropulsive head movement, with generalized polyspike-and-wave or spike-and-wave discharges ranging from 3 to 6 Hz that are often irregular and fragmented.
In some cases, if the eyelid jerking is marked, the person is unable to control their eyes when open; they close again following the person’s urge to close their eyes according to the command ‘‘close your eyes’’ given by the technician. As a result, similar clinical phenomena are reproduced. This repetition of events may continue for a few seconds, and the concomitant EEG discharges appear irregular and fragmented. After a few repeats of clinical and EEG phenomena, the patient manages to control their eyes when open and returns to the normal baseline state with a sigh of relief (22). The eyelid movements are rhythmic, repetitive, slight or marked, and single or multiple, even in the same patient. Phenotypic variability exists not only among individuals, but also within the same individual—a projection of genetic variation and brain maturity level.
Absence seizures. Conspicuous or inconspicuous absence seizures, concomitant with eyelid myoclonia on eye closure, are almost always present and usually very brief, requiring a very meticulous video-EEG assessment. The longer the concomitant generalized spike-wave discharges are, the more obvious the absence. Absence seizures can also be observed during hyperventilation and intermittent photic stimulation, with the eyes opened.
Myoclonic seizures. Myoclonic seizures other than eyelid have been reported to occur in children (34%) (22) and in adults (54.5%) (44). The majority of cases occur either independently or in association with eyelid jerking on eye closure (48; 21; 22; 71). The jerks, subjective or objective, usually involve the upper part of the body. The head may jerk to one side or be drawn to one side like a magnet (nodding, shaking). Myoclonic jerks during voluntary or on command eye closure may be preceded or followed by a brief absence and are commonly induced during photic stimulation (21; 22).
Generalized tonic-clonic seizures. Generalized tonic-clonic seizures are the usual referral symptom in mild or classical types of eyelid myoclonia and absences and occur in about 50% of cases, particularly those receiving no treatment or treated unsuccessfully or inappropriately. Generalized tonic-clonic seizures are usually precipitated by drowsiness, sleep deprivation, fatigue, bright or flashing lights, and alcohol abuse associated with sleep deprivation. In cases that show marked photosensitivity, perpetuating the photic stimulation may lead to a generalized tonic-clonic seizure. An indication that heralds such an event is repetition of generalized spike-and-wave discharges during the same flash frequency.
EEG during intermittent photic stimulation of a 13-year-old girl with a 6-month history of facial grimace-like movements occurring daily, which were considered tics. Two weeks prior to being seen, she had a generalized tonic-cl...
Nonconvulsive status epilepticus in eyelid myoclonia and absences. Exceptionally, Jeavons syndrome may present as nonconvulsive status epilepticus. The main presenting symptoms are prolonged confusion states. Routine electroclinical assessment reveals the typical characteristics of seizures associated with eyelid myoclonia and absences on eye closure. Photosensitivity is usually marked and may lead to a generalized tonic-clonic seizure (23).
Typical form. The characteristic electroclinical phenomena of Jeavons syndrome are easily diagnosed and differentiated from other idiopathic generalized epilepsies appearing early in life. For example, juvenile myoclonic epilepsy, which is officially recognized as a syndrome, may appear in children under the age of 4 years with myoclonic seizures with or without absences, but the diagnosis as a syndrome is made in childhood after treatment is discontinued and relapses occur. In eyelid myoclonia and absences, the frequent and brief (1 to 3 seconds) absence seizures with upward deviation of the eyes, which are triggered by eye closure in the light or photic stimuli, are characteristic and not seen in typical absence seizures of early onset. EEG demonstrates 3- to 5-Hz spike-and-slow-wave activity on eye closure and intermittent photic stimulation but also spontaneously.
Atypical form. The presentation of the atypical form is with frequent generalized tonic-clonic seizures in the first year of life. Sodium-channel blockers provoke absence and myoclonic seizures and eyelid jerking; other myoclonic jerks usually become apparent during infancy. EEG shows frequent brief and irregular generalized 2- to 3-Hz spike-waves and polyspike and slow-wave discharges, particularly on eye closure with concomitant eyelid jerking and occasional jerks of the upper limbs. Photosensitivity is usually marked. Focal spike or spike-and-slow-wave complexes are also seen. MRI is normal. The children show moderate intellectual disability.
Mild form eyelid myoclonia and absences. It may be months or years before a person with eyelid fluttering after eye closure seeks medical advice for an occasional generalized tonic-clonic seizure. EEG shows abnormalities on eye closure and positive response to intermittent photic stimulation. Some milder cases with 1, or even 2, generalized tonic-clonic seizures in their lifetime never seek treatment.
Case presentation. The patient presented at the age of 12.5 years, after a generalized tonic-clonic seizure provoked by drowsiness. She recalled having rare myoclonic jerks since the age of 12, particularly during the summer, when she was looking at the sun’s reflection on seawater. She also remembered some unilateral jerks involving the upper limbs. Her sleep-awake video-EEG showed polyspike-wave complexes in the frontal regions and single or up to 3-second-long generalized spike-and-wave discharges, which were maximal over the frontal regions during sleep. Hyperventilation increased the generalized 3- to 5-Hz spike-and-wave discharges of 1- to 3-second duration, which were almost always after eye closure and associated with eyelid flutter and some jerks of the head or arms. The photosensitivity range on eye closure was 1 to 60 Hz; with the eyes open, it was 7 to 30 Hz. Most of the discharges were typical, with concomitant eyelid flutter and spontaneous eye opening and staring. Some frequencies evoked myoclonic jerks. She was put on levetiracetam.
Her mother, aged 33, was noticed to have eyelid flutter on eye closure. On direct questioning, she remembered that her father and his sister also had eyelid fluttering or jerking on eye closure. On waking, the mother’s EEG showed brief discharges of fast activity or irregular generalized spike-and-wave discharges on eye closure with eyelid flutter during the hyperventilation. She had never asked for medical advice and had never had any generalized tonic-clonic seizures.
Classical eyelid myoclonia and absences. In classical eyelid myoclonia and absences, there is marked jerking of the eyelids, often with upward deviation of the eyes and retropulsive movements of the head, immediately after eye closure that are associated with generalized spike-wave discharges on EEG. In all cases, eyelid myoclonia is associated with absences, and the positive response to intermittent photic stimulation and pattern is usually marked.
Video-EEG images of an 8.5-year-old girl who was referred by a child psychologist following an assessment for educational problems. At the age of 6, she started having eyelid jerks, but her parents believed she was having tics....
When asked about their feelings during the events, people with eyelid myoclonia and absences are often unable to explain the feeling, but admit it is rather relieving or pleasant.
Jeavons syndrome and juvenile myoclonic epilepsy. In some cases, the presenting symptom is myoclonic jerks of the arms on awakening, suggesting juvenile myoclonic epilepsy. During the sleep-awake video-polygraphic EEG following sleep deprivation, typical eyelid myoclonia associated with myoclonic jerks and generalized spike-wave discharges are observed on eye closure. All cases are photosensitive, and hyperventilation and intermittent photic stimulation provoke clinical and generalized EEG discharges. Generalized tonic-clonic seizures may occur.
Headache and eyelid myoclonia. Ictal headache has been associated with eyelid myoclonia in only 1 report (34).
Precipitating factors of eyelid myoclonia and absences. The most potent precipitating factor is eye closure, voluntary or on command, in the light. Other precipitating factors are sleep deprivation, bright light or flashing lights, drowsiness, fatigue, alcohol abuse associated with sleep deprivation, and drug-resistant or inappropriate treatment or noncompliance (21). Photosensitivity declines with age, whereas eye closure is likely to remain a lifelong precipitating factor (44) or even continue, in some cases, as a habit after the self-limitation of the epileptic events in adulthood (21; 22).
Eyelid myoclonia is highly resistant to treatment, occurring many times per day, often without apparent absences, and even without demonstrable photosensitivity. Generalized tonic-clonic seizures and absence status may be unavoidable in adult life, either as the result of accumulating precipitating factors, or more often, due to inappropriate medication (71; 72). In Jeavons syndrome, neuropsychological evaluations of patients showed that performance was below average on measures of global IQ, processing speed and rote, verbal learning coupled with average nonverbal reasoning, and sustained attention (41). There was also evidence of impaired higher-level verbal reasoning. Although global IQ ranged from low average to borderline impaired, no participant could be accurately described as impaired or having intellectual disability given the consistently average performance noted on some higher-order tasks, including nonverbal reasoning.
Eyelid myoclonia with absences is a generalized epileptic seizure with generalized multiple spike-and-slow-wave discharges that may be of higher amplitude in the anterior or posterior regions.
Eyelid myoclonia (the seizure) may occur in various conditions. Jeavons syndrome, a separate entity, is a genetically determined condition that may be different from most other idiopathic generalized epilepsy syndromes. Bianchi and colleagues reported that the familial preponderance and concordance in families of probands with eyelid myoclonia with absences is high (09). Parker and colleagues reported that of 18 patients with eyelid myoclonia with absences, 14 had a family history of epilepsies (78). Four patients had other family members affected by a similar type of epileptic condition. Eyelid myoclonia with absences in monozygotic twins has been reported (01). Rarely, benign myoclonic epilepsy of infancy (65) or cryptogenic myoclonic epilepsy of early childhood (67) may evolve into eyelid myoclonia with absences. In a 2005 study based on 50 cases, it was reported that the family history of eyelid myoclonia and absences induced by eye closure in the light was 28%, and among them, there were 9 families of probands with Jeavons syndrome and first-degree relatives with eyelid myoclonia and absences or idiopathic generalized epilepsy (21). The concordance rate was 78%, indicating a dominant mode of inheritance. In another study, the family history for epilepsy was 39.5%, the majority with idiopathic generalized epilepsy, and the family history for febrile seizures was 9.5% (19). Familial cases have been reported in other studies (30; 01; 83) and in monozygotic male twins of Chinese origin, associated with absence status (107). In another report, 6 out of 108 children with childhood absence epilepsy later developed eyelid myoclonia with absences after treatment withdrawal (43).
Rudolf and colleagues performed whole-exome sequencing in a family with eyelid myoclonia with absences (82). They identified an inherited nonsense variant in the RORB (retinoid-related nuclear receptor) gene, which encodes the retinoid-related nuclear receptor ROR-beta, as a new candidate gene for neurodevelopmental disorders, including epilepsy and especially in generalized epilepsies with predominant absence seizures. A KCNB1 mutation was reported in 6 patients with early-onset generalized and focal epilepsies, including a case diagnosed as Jeavons syndrome (60). Furthermore, evidence has suggested mutations in the CHD2 gene in Jeavons syndrome amongst a number of epilepsy syndromes (42). This further supports the hypothesis that Jeavons syndrome is a separate syndrome entity.
(A), (B), and (C) A 4.5-year-old girl was referred for a routine EEG by her pediatrician for immaturity and was discovered to have eyelid myoclonia. She was noted to have tonic eyelid contraction at eye closure each time she cl...
Three factors are important in order for eyelid myoclonia and absences (Jeavons syndrome) to manifest clinically: (1) genetic predisposition, (2) voluntary or on command slow eye closure, and (3) light input.
In order for the genetic predisposition to be expressed with electroclinical phenomena, it needs to be provoked by voluntary or on command slow eye closure in bright light. The cortical area representing eye closure lies in the precentral gyrus adjacent to the hand area (57), which is involved in self-induced epilepsy. The “cortical factor” involved in voluntary or on command eye closure seems to be important, as passive slow eye closure in the presence of light does not induce discharges or eyelid myoclonia in a predisposed person. Similar phenomena are observed in self-induced epilepsy whereby the cortical hand area is involved, and electroclinical events are induced by voluntary or on command hand waving in the presence of light. Passive hand waving, waving the nonpreferred hand, or waving the examiner’s hand in front of the patient’s eye(s) in the presence of light does not induce discharges and clinical phenomena in a predisposed person.
The frontal eye field area, occipital cortex, and subcortical circuits involving the thalamus play an important role in the genesis and spread of electroclinical paroxysms in bright light in Jeavons syndrome (23). The frontal eye field area plays a critical role in voluntary eye closure (95), triggering the occipital cortex and subcortical circuit and involving thalamocortical pathways in generating and spreading the EEG paroxysms. A study found abnormal occipital and frontal cortex activities that seemed to be related to visual sensitivity and eyelid myoclonia in patients with Jeavons syndrome (45). A similar pathway is probably involved in self-induced epilepsy whereby the patient, waving his preferred hand with fingers apart in front of his eyes, triggers the occipital cortex via the hand area to generate discharges as well as a subcortical circuit involving the thalamus to spread them. These systems are not triggered when, in bright light, the examiner passively closes the patient’s eyes in eyelid myoclonia and absences or waves his hand in front of the patient’s eyes in self-induced epilepsy, but the occipital lobe can be triggered directly by flashing lights (23). The background of genetic variation, which is unique to each individual’s genome, contributes to the clinical variation (61). In contrast to eye closure, the cerebral cortex is not involved in its generation during photic blink (a brainstem reflex), as experimental ablation of the occipital cortex does not influence the response (103). Some authors believe there is a malfunction of the alpha-rhythm generator or of the magnocellular and parvocellular system in eyelid myoclonia and absences (104; 73; 75). However, alpha rhythm is produced on passive eye closure. Another intriguing feature is that some cases may manifest with features of photosensitivity and fixation-off sensitivity, which have opposing characteristics (70; 72; 54; 13).
Liu and colleagues studied the ictal and interictal epileptic activity in 4 patients with eyelid myoclonia with absences using EEG-fMRI (58). The main regions of activation included the thalamus, mesial frontal cortex, middle parietal lobe, temporal lobe, insula, midline structures, and cerebellum. The activation in the thalamus and cortex may be associated with generalized spike-waves in eyelid myoclonia with absences, whereas deactivation in the anterior frontal regions, parietal lobe, and cingulate gyrus might suspend the default state induced by spike-wave and slow-wave complexes. The combination of consistent patterns of deactivation and varied patterns of activation in patients with eyelid myoclonia and absences may prognosticate different types of states of consciousness in response to ictal and interictal epileptic discharges.
Vaudano and associates investigated the functional and structural brain correlates of eyelid myoclonia and absences (Jeavons syndrome) triggered by eye closure (96). Fifteen patients with Jeavons syndrome, 14 cases with idiopathic generalized epilepsies without eyelid myoclonus, and 16 healthy controls underwent an EEG-correlated fMRI and voxel-based morphometry protocol. The functional study consisted of 30-second epochs of eyes-open and eyes-closed conditions. The following EEG events were marked, and the relative fMRI maps obtained (1) eye closure times, (2) spontaneous blinking, and (3) spontaneous and eye closure-triggered spike-and-wave discharges. Within-group and between-group comparisons were performed for fMRI and voxel-based morphometry data, as appropriate. Compared to the other 2 groups, the eyelid myoclonia with absences group had a higher blood oxygenation level-dependent signal related to eye closure over the visual cortex, posterior thalamus, and network implicated in the motor control of eye closure, saccades, and eye pursuit movements. Additionally, increments were observed in gray matter concentration at the visual cortex and thalamic pulvinar, whereas decrements were observed at the bilateral frontal eye field area. No blood oxygenation level-dependent differences were detected when comparing the spike-wave discharges in eyelid myoclonus and absences triggered by eye closure and idiopathic generalized epilepsy. Thus, these results demonstrated altered anatomo-functional properties of the visual system in eyelid myoclonia and absence seizures (Jeavons syndrome). These abnormalities involve a circuit encompassing the occipital cortex and the cortical and subcortical systems physiologically involved in the motor control of eye closure and eye movements (96). These findings are consistent with a study of the possible contribution of brainstem structures in the pathophysiology of eyelid myoclonus (03).
The prevalence of Jeavons syndrome among idiopathic generalized epilepsies has been reported to vary from 7.3% to 12.9% and 2.5% to 2.7% among all patients with epileptic disorders (24; 44; 21; 22; 23). The age of onset, as in childhood absence epilepsy, varies from 2 to 14 years (mean 6.5 ± 2.5 years) (22), and the female-to-male ratio varies from 1.25:1 to 3.2:1 to 4.1:1 (24; 05; 19; 22; 88; 18). Jeavons syndrome is as common as juvenile myoclonic epilepsy but is underdiagnosed, and the mild forms are underreported.
The only way to prevent visually provoked seizures is to avoid exposure to all possible triggers, which is increasingly difficult in today’s technology-rich environment (25). Mitigating triggering factors as much as possible, reducing underlying causes, assuring compliance, and avoiding sodium-channel blocker antiepileptic drugs will help prevent seizures from happening. Early correct diagnosis using appropriate antiseizure medication at an optimum daily dose, taking into consideration the risk-benefit ratio, will contribute to better outcome. Dark lenses, particularly blue or dark cobalt blue lenses (Z1), will protect against the light trigger. Early diagnosis and treatment of comorbidities will also contribute to a better quality of life.
Misdiagnosis and underdiagnosis is common among the general population and among physicians. Patients with eyelid myoclonia and those who make grimaces to avoid eye closure phenomena are usually referred to psychologists or psychiatrics for tics or mannerisms.
Video-EEG images of an 8.5-year-old girl who was referred by a child psychologist following an assessment for educational problems and facial grimaces. At the age of 6 years, she started having eyelid jerks, but her parents bel...
In children, and in some adults, eyelid trembling or fluttering is often seen on eye closure and should be differentiated from mild forms of eyelid myoclonia and absences by EEG findings. Transient or chronic tics are common in childhood, particularly in males. There is a genetic and clinical heterogeneity. Motor manifestations are stereotypical, involuntary, sudden, inappropriate, nonprepositional, absurd, irresistible, and of variable intensity (21).
If seen once, the characteristic eyelid myoclonia and absences occurring immediately after eye closure will never be forgotten or confused with other conditions.
Structural, metabolic, and genetic epilepsies. Eyelid myoclonia with or without absences may be a seizure symptom in structural, metabolic, and genetic epilepsies, including Dravet syndrome, ring chromosome 20 syndrome, l-2 hydroxyglutaric aciduria, SYNGAP1-associated intellectual disability and epilepsy, KCNB1 gene mutation, and KIAA2022-related disorders (33; 63; 93; 66; 64; 97; 11; 60; 99; 100; 84). Diagnostic confusion between the patients who exhibit ictal eyelid myoclonia and those suffering from eyelid myoclonia and absences (Jeavons syndrome) is rarely a problem based on the unique and pathognomonic electroclinical characteristics of the syndrome. Focal EEG abnormalities are common in eyelid myoclonia and absences, as in any other idiopathic generalized epilepsy, but they are likely to indicate an underlying structural abnormality when severe or persistent. In structural, metabolic, and genetic cases, eyelid myoclonia may be an inconstant ictal feature and may be associated with seizures, both of variable duration and of different types, such as atypical absences and tonic, atonic, or partial seizures. Seizure activation caused by eye closure in structural, metabolic, and genetic epilepsy cases may be rarer than in eyelid myoclonia with absences (37; 36), particularly in voluntary or on command eye closure combined with the electroclinical characteristics seen during hyperventilation and photic stimulation.
In a retrospective study, Capovilla and colleagues described 18 patients with eyelid myoclonia who also had impairment of intellectual functions and fast generalized polyspikes and polyspike and waves on EEG (18). All patients were photosensitive, highly pharmacoresistant, and had generalized tonic-clonic seizures that were mostly nocturnal.
Idiopathic generalized epilepsies with absences. Sensitivity to eye closure is also seen in juvenile absence epilepsy, juvenile myoclonic epilepsy, generalized epilepsy with tonic-clonic seizures, and idiopathic occipital lobe epilepsy. In idiopathic generalized epilepsies with absences, eyelid myoclonia should be differentiated from eyelid myoclonia and absences, which is triggered on voluntary or on command eye closure, as seen in Jeavons syndrome. A defining feature of photosensitivity in Jeavons syndrome that distinguishes it from other idiopathic generalized epilepsy syndromes is that patients are sensitive to both flickering and nonflickering bright light (98). In a study of 90 cases with idiopathic generalized epilepsy with typical absence seizures either alone or with myoclonic jerks, generalized tonic-clonic seizures, or both, 39 (43.3%) had eyelid or eye-related ictal clinical manifestations. Only 5 of the cases (5.6%) had ictal manifestations similar to those occurring in eyelid myoclonia with absences (73). In addition, only 1 of those 5 was photosensitive, and another one experienced absences provoked by eye closure. Conversely, 20 patients (22.2%) had clinical or video-EEG-documented photosensitivity, but only 5 of them had eyelid and eye-related ictal clinical manifestations during the absences. Two patients had random eyelid blinking, which is strikingly different from eyelid myoclonia. Two patients had fast rhythmic eyelid fluttering. One patient had eyelid myoclonia with absence-like manifestations. Symptoms often overlapped in the same patient and even for the same seizure.
In certain myoclonic epilepsies, the eyes may open and stare, or the eyelids may even blink, but they do not retract and jerk as in eyelid myoclonia and absences (21). An overlap between Jeavons syndrome and juvenile myoclonic epilepsy exists whereby myoclonic jerks appear as the presenting symptom; during a video-EEG recording, jerks are recorded immediately after eye closure and simultaneously with eyelid myoclonia, particularly during intermittent photic stimulation (21; 22). The coexistence of the 2 syndromes in the same patient has also been reported in other studies (19).
In a cohort of 50 children with Jeavons syndrome, myoclonic jerks were recorded in 34% of cases, and massive myoclonias were mainly recorded during intermittent photic stimulation (21; 22). In rare cases, persistent photic stimulation may lead to a generalized tonic-clonic seizure. In a study by Kim and colleagues, even massive myoclonias were recorded among cases with eyelid myoclonia and absences having sporadic generalized tonic-clonic seizures (52). In another study, myoclonic jerks were considered an exclusion criterion (89). In an adult cohort, myoclonic jerks were recorded in 54.5% (44).
The eye closure sensitivity seen in Jeavons syndrome should be differentiated from the fixation-off sensitivity characterized by posterior or generalized paroxysms that occur after closing the eyes, which last for as long as the eyes are closed (13). Few focal abnormalities, frontal or occipital, were reported in a study (66). In another study, frontal predominance was seen in males, and occipital in females, with Jeavons syndrome (102).
Jeavons syndrome is an eye closure, and not a closed eye, phenomenon. The eye closure period starts immediately after closing the eyes and lasts only up to 3 seconds, whereas the closed eye period lasts longer than 3 seconds and persists as long as the eyes remain closed (107). As with early-onset absence epilepsies (20), early-onset Jeavons syndrome (21; 22; 19) has a worse prognosis regarding response to treatment and cognitive performance.
Eyelid flickering or fluttering has been reported in other types of idiopathic generalized epilepsies with absences (76; 36), symptomatic absence epilepsy (74), fixation-off sensitive epilepsy (70), and even benign myoclonic epilepsy of infancy (32). In idiopathic childhood absence epilepsy, the absence seizures are not an eye closure phenomenon and usually last longer.
Forced eyelid closure and eyelid blinking is also an ictal clinical symptom in focal seizures described in both symptomatic and idiopathic occipital epilepsy. In idiopathic occipital epilepsies, some forced eyelid closure or blinking may occur as an ictal event or herald a secondary generalized seizure (106; 69). In these cases, slow spike-wave complexes appear on eye closure in the posterior regions and continue in long runs for as long as the eyes remain closed. Eyelid flutter may be observed, but never eyelid contraction and jerking, and a partial or complete attenuation of the discharges is observed on eye opening. Generalized polyspike-wave discharges do not characterize occipital epilepsies, and the spike of the spike-wave component is smoother, as it is in all forms of benign focal epilepsies (21). Eyelid myoclonia alone can also be observed in certain symptomatic and cryptogenic epilepsies. However, the characteristic electroclinical events of Jeavons syndrome do not exist, and the associated developmental delay, neurologic deficit, abnormal MRI, and slow background EEG can easily differentiate them (36). In Jeavons syndrome, the characteristic eyelid myoclonia and EEG-related discharges following eye closure, combined with photosensitivity, leave no room for diagnostic error (71; 72). Jeavons syndrome also appears to be homogeneous in people of different races and ethnicities (108).
Nonepileptic paroxysmal eyelid movements consisting of eyelid closure, upturning of the eyes, and rapid eyelid flutter have been described in patients with generalized photosensitive epilepsy and eyelid myoclonia (16; 14).
Blinking, which is a brainstem reflex, does not induce electroclinical events in patients with Jeavons syndrome (21; 22).
Habitual self-induction of ictal eyelid myoclonia and absences is a rare phenomenon observed in some untreated or incorrectly treated cases, or those with borderline IQ, as well as in some early-onset cases in which the genetic predisposition is “marked.”
Self-induced epilepsy (Sunflower syndrome). Self-induced epilepsy (Sunflower syndrome) is a rare reflex photosensitive epilepsy. Typically, the patient looks at the sun or a bright light source and rapidly waves one hand, with fingers apart, across their eyes (04). The hand waving episodes are associated with generalized spike-and-wave discharges and +/− polyspike-and-waves ranging from 3 to 4 Hz on EEG. Generalized discharges are also elicited during hyperventilation and intermittent photic stimulation (07). Seizures include eyelid flutter with or without absence seizures. Eye closure, particularly during intermittent photic stimulation, may be followed by eye opening, staring, and head jerking. The myoclonic jerks invariably involve the waving hand and head, which jerk in a similar fashion. Involvement of the lower extremities in self-induced epilepsy is more frequent than in eyelid myoclonia and absences (21). Generalized tonic-clonic seizures are rare in self-induced epilepsy but are more frequent in cases of lower IQ through the extensive use of trigger factors during long periods of boredom.
Video-EEG images of a boy with average IQ and self-induced seizures in the light. Waving his preferred left hand with outstretched fingers in front of his left eye in bright light triggered electroclinical phenomena. Waving the...
In a study of 24 cases (18 females), all patients presented with hand-waving episodes (06). The average age of onset was 6 years old, and the most prevalent symptom was an attraction to light and possible absence seizures. A 15-year-old girl was reported to have had a generalized tonic-clonic seizure following rapid hand movements in front of her eyes while staring at the sun (68). The patient had a history of multiple admissions to the emergency department due to similar events since the age of 8. Most occurrences were associated with episodes of frustration. Sunflower syndrome appears to be pharmacoresistant for the majority of patients (26; 56). In Sunflower syndrome, as in other idiopathic generalized epilepsies, some genetic and phenotypic variability exists.
If untreated or drug resistant, patients with Jeavons syndrome close their eyes in bright light in order to avoid light disturbance, thereby falling into the trap of inducing discharges and clinical phenomena. This habitual behavior may be repeated in situations of boredom and anxiety. The majority of patients with only educational difficulties or discrete cognitive impairment refer to their eyelid jerking as a nuisance or a disturbing and embarrassing phenomenon that they are unable to control under certain circumstances. They are relieved when therapy is successful and show good compliance (21).
There are some similarities and differences between eyelid myoclonia and absences on voluntary or on command eye closure and self-induced epilepsy triggered by waving outstretched fingers in front of the eyes in the presence of lights (Table 1).
• Both syndromes are hereditary photosensitive epilepsies.
• Clinical heterogeneity and variability in intelligence exist in both syndromes.
• In order to manifest, both syndromes need the coexistence of 3 factors:
-- genetic predisposition
-- voluntary or on command eye closure or hand waving
-- the presence of light; bright sunlight triggers more pronounced symptoms.
• In both syndromes, no symptoms are triggered in total darkness.
• In eyelid myoclonia and absences, passive eye closure or closing 1 eye in bright light triggers no symptoms. In self-induced epilepsy, hand waving or waving the nonpreferred hand, or even the examiner’s hand, in front of the eyes in bright light triggers no symptoms.
• Females predominate in eyelid myoclonia and absences, and males predominate in self-induced epilepsy.
• The eye closure and hand waving brain areas are adjacent.
• If untreated, mistreated, drug resistant, misdiagnosed, or borderline low IQ, self-induced cases invariably provoke seizures; however, only a few cases with eyelid myoclonia and absences do.
The cortical area representing eye closure lies in the precentral area adjacent to the hand area (57), and the topography of physiological networks involved follows the posterior-to-anterior trajectory of brain development, reflecting age-related changes in brain excitability (53). Light is needed to unbalance the genetically predisposed occipital cortex triggered either by voluntary or on command eye closure in eyelid myoclonia or the preferred hand waving in front of the patient’s eyes in self-induced epilepsy. The cortical factor involved in voluntary or on command eye closure or hand waving seems important as passive eye closure or hand waving in the presence of light does not induce electroclinical phenomena in the predisposed person. Further, voluntary or on command closing of 1 eye while looking at a light source does not trigger electroclinical symptoms.
In addition to the appropriate antiepileptic drugs, modifying bright light, the main triggering factor, by wearing dark lenses is advisable in patients with self-induced seizures. Blue or filtered lenses, eg, a dark blue lens named “Z1,” are effective (25).
In view of reports implicating slow eye closure in self-induction (29; 10), Panayiotopoulos and colleagues (75) extensively interviewed and studied video-EEG of 17 adult patients with eyelid myoclonia with absences. None of the 15 patients who were admitted were suspected of self-induced seizures. On the contrary, they considered eyelid myoclonia as a socially embarrassing condition. They were relieved when the seizures improved with medication, and they showed excellent compliance. Although other types of seizures were controlled in most of the patients, the eyelid myoclonia continued; however, it was less severe and frequent than before appropriate treatment began. This is contrary to self-induction, in which eyelid myoclonia should be more forceful after treatment if its purpose was to induce seizures. The remaining 2 patients were suspected of self-induction. One of the patients had frequent slow eye closure EEG abnormalities, but she never admitted self-induction. She insisted “I do not know when I am doing it…It gives me no pleasure, and it is a social embarrassment.” The other patient admitted that she was occasionally doing it voluntarily but only in rare circumstances to relax her eyes when they were strained, sore, and stung. There have been incidences “I had walked into a pole, or into a car and I did not do that on purpose.”
Eyelid manifestations in normal people. With the possible exception of violent myoclonic jerks in eyelid myoclonia, all other eyelid symptoms during absence seizures are manifested by normal people in their everyday life. The eyes and the eyelids are the most sensitive and expressive parts of our body.
Some authors reached the following conclusions on observing the behavior of a few people during TV interviews, round table discussions, and debates (73). Repetitive spontaneous blinks similar to those described in self-induced photosensitive epilepsy increased significantly during moments of tension, either at the beginning of an utterance (like a breath before starting a sentence) or at the end (like a relief). Slow and sustained eye closure was rarely manifested, and, less frequently, eyes were wide open with a cessation of spontaneous blinks. Thus, we have a simple movement that is under voluntary, automatic, reflex, emotional, and autonomic control (80).
da Conceicao and colleagues analyzed the characteristics of blinking and eye closure in 20 patients with eyelid myoclonia by video-EEG (27). Eyelid myoclonia occurred spontaneously while awake in 18 patients, on eye closure in 10 patients, and during intermittent photic stimulation in 1 patient. Eyelid myoclonia assumed the form of flicker, flutter, or jerk and was accompanied by generalized discharges, spiky posterior alpha rhythm, theta rhythm, or the absence of any EEG abnormality. Analysis of the characteristics of blinking had no statistical differences between patients and healthy subjects. The rate of blinks and eyelid myoclonia increased during speech and decreased during reading. Eyelid myoclonia never occurred during blinking or in the dark.
Eyelid myoclonia are myoclonic jerks of the eyelids and upward deviation of the eyes, often precipitated by closing the eyes or by light. Eyelid myoclonia can be associated with absences but can also be motor seizures without a corresponding absence, making them difficult to categorize. The 2017 classification groups them with nonmotor (absence) seizures, which may seem counterintuitive, but the myoclonia in this instance is meant to link with absence rather than with nonmotor (40; 39).
Eyelid myoclonia and absences induced by voluntary or on command eye closure in the presence of light, concomitant generalized spike-and-wave discharges of 3 to 6 Hz, and photosensitivity constitute the characteristic triad of Jeavons syndrome, a well-defined idiopathic generalized epilepsy syndrome, or a spectrum of photosensitive conditions (21; 22; 23; 87). The fact that generalized spike-and-wave discharges that follow eye closure disappear when the eyes open and remain open, and are enhanced or evoked even with the eyes open during intermittent photic stimulation and hyperventilation, constitute the most characteristic EEG finding of Jeavons syndrome (21; 22; 23).
In an extensive review of 17 adults and 3 children with eyelid myoclonia with absences, the authors concluded that (1) eyelid myoclonia with absences is the most typical type of seizure in Jeavons syndrome; (2) eyelid myoclonia is often associated with jerks of the eyeballs, head, or other muscles and may terminate without discernible absence; and (3) milder ictal eyelid manifestations consist of either abortive eyelid myoclonia with eyelid tremor-like jerks or fast eyelid fluttering (36; 44; 73; 75; 78; 71; 72). The eyes remain closed while the upper eyelids exhibit small-range, fast fluttering that would be difficult to appreciate without close-up video-EEG recordings.
Eyelid myoclonia can only rarely be seen in typical absence seizures of idiopathic generalized epilepsy other than Jeavons syndrome. In a study of 60 such patients with video-EEG recorded absence seizures, only 5 had eyelid myoclonia (73). Of these 5 patients, only 1 was also photosensitive, and only 1 experienced seizures precipitated by eye closure.
Absence status epilepticus with eyelid myoclonia. Continuous clusters of prolonged seizures of eyelid myoclonia with absences may occur as the result of accumulating precipitating factors, discontinuation, or inappropriate treatment. They are more likely to occur on awakening (85; 02; 101; 08; 71; 72; 55).
Eyelid myoclonia with absences in unknown (cryptogenic) or symptomatic generalized epilepsies. Eyelid phenomena are commonly seen during nonconvulsive seizures in children with unknown (cryptogenic) and symptomatic generalized epilepsies. These include eyelid blinking and flutter. True eyelid myoclonia is less common (36; 70).
In a report, 2 female pediatric patients with probable genetic cryptogenic epilepsy presented with eyelid myoclonia with prominent myoclonic seizures, atonic components on video-EEG, and cognitive impairment (31).
The diagnosis is easy based on the history; observation of the patient; and detailed sleep-awake video-EEG, with correct technique and assessment during photic stimulation (49; 21; 51). Video-EEG is the single most important procedure to diagnose and elucidate the unique electroclinical characteristics of Jeavons syndrome. During drowsiness, hyperventilation, and intermittent photic stimulation, an exacerbation of clinical and EEG events is seen (22).
Interictal EEG. EEG is dominated with high-amplitude discharges of spike-and-slow waves at 3 to 6 Hz. These are brief (1 to 5 seconds) and are commonly associated with clinical manifestations of eyelid myoclonia of varying severity. They occasionally appear simultaneously with impairment of cognition. They often occur immediately (within 0.5 to 2 seconds) after voluntary or on command eye closure in an illuminated recording room. They are eliminated in total darkness. Photoparoxysmal responses are recorded from all untreated young patients and may be absent in older patients on medication. Photosensitivity and fixation-off sensitivity may occur together (70).
A study emphasized a high incidence of (1) focal interictal epileptiform discharges from the posterior head region and (2) predominant focal posterior ictal epileptiform discharges preceding generalized epileptiform discharges (98). Focal frontal spikes may sometimes precede the generalized discharges (90). According to a report from China, a predominantly male group had frontal predominant epileptiform discharges, eyelid myoclonia, and eyes rolling up, and a predominantly female group had occipital predominant epileptiform discharges with eyelid myoclonia alone (102).
Sleep EEG may be normal or may show generalized spike-wave discharges, focal spikes, or spike-and-wave complexes in the frontal regions. The generalized discharge of polyspike-slow waves during sleep tends to be of longer duration and fragmented. In a few cases, a slight tremor of the eyelids or an opening and closing of the eyes is observed during the discharge. The discharges are shorter and devoid of discernible clinical manifestations of any type, even in patients who have numerous seizures during the alert state. Sleep EEG patterns are normal. EEG and clinical manifestations deteriorate consistently after awakening.
Ictal EEG. Ictal EEG accompaniments of eyelid myoclonia with absences are generalized discharges of mainly polyspikes and polyspike-slow waves at a frequency of 3 to 6 Hz (usually more than 4 Hz) and a duration of 3 to 6 seconds (typically around 3 seconds and seldom more than 5 seconds).
Eyelid myoclonia and absences (Jeavons syndrome) is a lifelong disorder, and its prognosis is similar to that of juvenile myoclonic epilepsy with photosensitivity. For the classical types of eyelid myoclonia and absences, appropriate treatment usually results in significant reduction of seizures and prevention of eyelid myoclonia status epilepticus, as well as generalized tonic-clonic seizures.
Lifelong treatment with medication may be necessary for patients with eyelid myoclonia with or without absences. In the absence of controlled therapeutic trials, it is not possible to draw scientifically valued conclusions about the most effective approach to the drug treatment of eyelid myoclonia with or without absences.
Based on anecdotal evidence, the drugs of choice are those also used for other idiopathic generalized epilepsies with absences and myoclonia (71; 72; 86). Eyelid myoclonia and absences (Jeavons syndrome) is difficult to treat but responds best to sodium valproate. In 1982, Covanis and colleagues reported that monotherapy with sodium valproate was successful in 53% to 76% of idiopathic generalized epilepsies. The worst results were seen in eyelid myoclonia and absence seizures and the best in pure photosensitive epilepsy. The response about 20 years later was reported to be 74% to 86% (26). The increase in response of eyelid myoclonia and absences from 53% to 74%, based on 50 cases, was attributed to early diagnosis and treatment. In addition, giving sodium valproate chrono once daily appeared to improve compliance. Covanis and colleagues noted that although 75% of patients with Jeavons syndrome respond to valproate monotherapy, only 40% of patients with self-induced seizures respond to this treatment. Valproate remains the most effective treatment for photosensitive epilepsies (26; 53) and should be considered early. For nonresponders to monotherapy with sodium valproate, a combination of sodium valproate and ethosuximide is considered to be the most effective regimen. However, clonazepam, which is highly effective in myoclonic jerks, may be a valid option. Small doses of lamotrigine added to sodium valproate may result in dramatic improvement because of their possible pharmacodynamic interaction (38). Lamotrigine alone may exaggerate myoclonic jerks.
Levetiracetam may be effective because of its anti-myoclonic and anti-photosensitive properties (88; 72; 77). However, the exact antiepileptic mechanism of action of levetiracetam is unknown. Several theories have been proposed: (1) it inhibits voltage-dependent calcium channels, (2) it binds to synaptic proteins that control neurotransmitter release, and (3) it facilitates GABA-like inhibitory transmission. In a prospective clinical trial, it was found that levetiracetam was most effective if given at a dose of 50 to 60 mg/kg/day (88; 77).
Perampanel has also demonstrated efficacy and safety in generalized tonic-clonic seizures among patients with idiopathic generalized epilepsy and does not seem to exacerbate absence seizures (12).
Carbamazepine, oxcarbazepine (62), gabapentin, phenytoin, pregabalin, tiagabine, and vigabatrin are contraindicated (71; 72).
Patients who deliberately use visual stimulation to induce either overt seizures or ‘‘subclinical’’ epileptiform EEG discharges are very resistant to valproate and to any combination of antiepileptic drugs, even if they are compliant (22).
Nonpharmacological treatments used for photosensitive patients should be employed in Jeavons syndrome when photosensitivity persists (105; 26). Wearing special tinted glasses (105; 26) or the commercially available blue Z1 lenses may be beneficial (17; 25). Self-induced seizures might be modifiable by psychiatric treatment.
In general, by choosing the correct antiepileptic medications at an appropriate daily dose taking into consideration the risk-benefit ratio and recognizing comorbidities for early intervention contributes to better management. Sodium valproate has proven to be successful for this type of seizure, either as monotherapy or combined with other appropriate antiepileptic drugs. Taking into consideration dose-related teratogenicity, it should be avoided as a first choice in adolescent females. Special care should be given to females on valproate who intend to become pregnant or are pregnant; the daily dose of sodium valproate should be based on a careful risk-benefit decision (92). There is an urgent need for the development of up-to-date, globally applicable recommendations (91).
Appropriate treatment usually results in a significant reduction of seizures and prevention of eyelid myoclonia status epilepticus, as well as generalized tonic-clonic seizures.
Photosensitivity tends to disappear in middle age. In some cases, a mild eyelid flutter in association, or not, with theta-beta discharges on eye closure persists. Eyelid movements that are not associated with EEG discharges on eye closure constitute a habitual tick-like behavior and are observed in patients who never received treatment or did not show complete response to treatment. This behavior may continue for a few years after eyelid myoclonia and absences have completely vanished (22).
Cases that start under the age of 3 years are, as a rule, drug resistant and have moderate to severe educational problems requiring remedial teaching. Electroclinical features of early-onset cases, including photosensitivity, gradually disappear before puberty, and the child starts showing signs of educational improvement. In addition, cases that are misdiagnosed or are inappropriately treated for many years, or those that show noncompliance, and associated comorbidities that are not diagnosed or treated early have a worse prognosis.
Thanos Covanis MD DCH PhD
Dr. Covanis of Childrens’ Hospital Agia Sophia in Athens, Greece has no relevant financial relationship to disclose.See Profile
Solomon L Moshé MD
Dr. Moshé of Albert Einstein College of Medicine has no relevant financial relationships to disclose.See Profile
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