Myoclonus epilepsy with ragged-red fibers
Jun. 10, 2021
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This article includes discussion of reflex seizures, stimulus-sensitive epileptic seizures, triggered-evoked epileptic seizures, and sensory-evoked epileptic seizures. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Reflex epileptic seizures are seizures that are elicited by specific extrinsic (light, tactile, acoustic) or intrinsic (thinking, reading, emotional) stimuli. They affect patients of all ages and have a 4% to 7% prevalence among patients with epilepsies. Reflex epileptic seizures are determined by the specific precipitating stimulus and the clinical/EEG response. Seizures may be generalized (absences, myoclonic jerks, or generalized tonic-clonic seizures) or focal (visual, sensorimotor, or limbic). The electroclinical events may be strictly limited to the stimulus-related receptive brain region only, spread to other cortical areas, or become generalized. Flickering lights are the commoner triggering stimuli, and this is particularly relevant to modern life, with ever increasing numbers of television- and video game–induced seizures. The flickering lights in nightclubs and discotheques are particularly potent. The etiology is diverse, from just a mild genetically determined propensity for reflex seizures in otherwise normal people to severe forms of focal or generalized epilepsies. The role of EEG is fundamental in establishing the precipitating stimulus in reflex epilepsies because it allows subclinical EEG reflex abnormalities, or minor clinical ictal events, to be reproduced on demand by application of the appropriate stimulus. Identification of the offending stimuli has significant clinical implication in the management of patients because some of them may not need anything other than avoidance or modification of the precipitating factors.
• Reflex seizures are provoked by heterogeneous extrinsic and intrinsic stimuli.
• They affect patients of all ages; prevalence is 4% to 7% amongst all epilepsies.
• Visually induced seizures (television, video games, nightclubs) are the commonest types of reflex seizures.
• Although uncommon, reflex seizures elicited by reading, thinking, music, eating, hot water, emotions or movement are of particular interest.
• Clinically, reflex seizures are focal or generalized (absences, myoclonic jerks, generalized tonic-clonic seizures).
• Patients may have reflex seizures alone or together with spontaneous ones.
• Certain epileptic syndromes (juvenile myoclonic epilepsy, Dravet syndrome, progressive myoclonic epilepsies) commonly manifest with reflex epileptic seizures.
• The role of EEG is fundamental in the identification of the offending stimuli, with significant clinical and pathophysiological implications.
• Avoidance, prevention, or modification of the provocative stimulus is the key point of management, and this may be sufficient for patients with reflex seizures only.
• Appropriate antiepileptic medication is needed for those with continuing reflex and spontaneous seizures.
Reflex seizures of different types have been known for centuries (08). Recognition of seizures induced by flashing light predates the invention of EEG and the stroboscope and reaches to classical antiquity (114; 78; 59).
The first reference to reflex epilepsy is attributed to Apuleius Lucius (150 A.D.), a Roman philosopher, in his Apologia and Florida. However, Apuleius does not refer to flickering lights.
Nay, even supposing I had thought it a great achievement to cast an epileptic into a fit, why should I use charms when, as I am told by writers on natural history, the burning of the stone named gagates is an equally sure and easy proof of the disease? For its scent is commonly used as a test of the soundness or infirmity of slaves even in the slave-market. Again, the spinning of a potter's wheel will easily infect a man suffering from this disease with its own giddiness. For the sight of its rotations weakens his already feeble mind, and the potter is far more effective than the magician for casting epileptics into convulsions.
“Gagates” is an old name for the stone “jet” or “black amber,” a carbon fossil that is compact and very light. Jet was known in ancient Egypt, where it was used for making mirrors; in Greece and Rome it was used for cutting amulets, bracelets, and rings. In Medieval times, jet was popular as a talisman and a medicine for migraines, toothache, stomach pains, and epilepsy, and it reached the height of its popularity during the Victorian period. Also, the potter’s wheel in that time was solid, not spoked, which would be needed to produce intermittent light.
The oldest clear reference to photosensitive epilepsy is by Soranus of Ephesus (2nd century A.D.), a Greek gynecologist, obstetrician, and pediatrician who wrote On Acute and Chronic Diseases, which contains an excellent chapter on nervous disorders.
The use of flame, or very bright light obtained from flame has an agitating effect. In fact when a case of epilepsy is in its quiescent stage, the ultimate use of light with its sharp penetrating action may cause the recurrence of an attack.
Reflex epilepsy was first documented in animals by the Italian school of neurophysiologists in the 1920s and 1930s (159). In his pioneering studies of “epilepsy from afferent stimuli,” Amantea found that clonus induced by application of a small disc of blotting paper soaked with strychnine to the sensorimotor cortex of dogs was enhanced by the stimulation of the peripheral area somatotopically related to excited cortex (02; 03). Moreover, when stimulation of the skin persisted, clonus progressed to a generalized tonic-clonic seizure in approximately 25% of animals. Later, strychninization of the visual cortex was used by Clementi, the first to describe experimental light-induced epilepsy in studies of photic stimulation in dogs after strychnine application to the visual cortex (20).
The first medical evidence of photosensitive epilepsy by Gowers (57), and later by Holmes (66), refers to occipital seizures induced by light.
In very rare instances the influence of light seems to excite a fit. I have met with two examples of this. One was a girl of seventeen whose first attack occurred on going into bright sunshine for the first time, after an attack of typhoid fever. The immediate warning of an attack was giddiness and rotation to the left. At any time an attack could be produced by going out suddenly into bright sunshine. If there was no sunshine an attack did not occur.
The other case was that of a man, the warning of whose fits was the appearance before the eyes of “bright blue lights, like stars — always the same”. The warning, and a fit, could be brought on at any time by looking at a bright light, even a bright fire. The relation is, in this case, intelligible, since the discharge apparently commenced in the visual centre (57).
Some men subject to epileptiform attacks commencing with visual phenomena owing to gunshot wounds of the occipital region, have told me that bright lights, cinema exhibitions and other strong retinal stimuli tend to bring on attacks (66).
Holmes attributed this reflex epilepsy to an enhanced excitability of the visual cortex (66).
In 1932, Radovici and associates reported the first case of eyelid myoclonia (often erroneously cited as self-induced epilepsy) with experimental provocation of seizures documented with cine film (124).
AA...age de 20 ans, presente des troubles moteurs sous forme de mouvements involontaires de la tete et des yeux sous l' influence des rayons solaires.
In 1936, Goodkind also detailed various methods used to experimentally induce “myoclonic and epileptic attacks precipitated by bright light” in a photosensitive woman (55).
The patient was placed on a bed in a darkened room in such a position that when the black window shade was raised her face only, was directed towards the early afternoon sunlight, which came through an ordinary wire Window screen. On such exposure of the eyes to the sun, she responded within a few seconds with marked, diffuse, and apparently uncontrollable clonic jactitatory movements. The movements ceased the moment a blindfold was applied, or the black window shade was lowered. She reacted definitely also when either eye was uncovered separately… The patient was also exposed to ultra violet radiation from a quartz mercury vapour lamp, and to bright pocket flash light had little or no effect. A small beam from a carbon arc lamp produced several rapid myoclonic jerks.
With the advent of EEG by Berger in 1929, a new era started for the study of reflex and photosensitive epilepsies (see article on visual-sensitive epilepsies).
“Reflex” or “stimulus-sensitive,” or “triggered” or “sensory-evoked,” epileptic seizures are synonyms denoting epileptic seizures that are consistently elicited by a specific stimulus. “Reflex” is the preferred name in the ILAE Task Force on Classification and Terminology diagnostic scheme (34) and report (35).
There are 3 excellent books exclusively devoted to nearly all aspects of reflex seizures and related epileptic syndromes (Beaumanoir et al 1985; 174; 170).
ILAE definitions and classification. The 1981 ILAE classification of seizures included reflex as follows (21):
Repeated epileptic seizures occur under a variety of circumstances:
(1) as fortuitous attacks, coming unexpectedly and without any apparent provocation;
(2) as cyclic attacks, at more or less regular intervals (eg, in relation to the menstrual cycle, or the sleep-waking cycle);
(3) as attacks provoked by: (a) nonsensory factors (fatigue, alcohol, emotion, etc.), or (b) sensory factors, sometimes referred to as ‘reflex seizures’.
The 1985 ILAE classification of syndromes classified “epilepsies characterized by specific modes of seizure precipitation (reflex epilepsies)” under special syndromes and commended as follows (22):
In simple forms, seizures are precipitated by simple sensory stimuli (eg, light flashes). The intensity of the stimuli is decisive, the latency of the response short (seconds or less), and mental anticipation of stimulus without effect. In complex forms, the triggering mechanisms are elaborate (eg, sight of one’s own hand, listening to a certain piece of music). The specific pattern of the stimulus, not the intensity, is the decisive factor. Latency of response is longer (in the range of minutes), and mental anticipation of stimulus, even in dreams, may be effective.
These properties were first systematically described in the pioneering work of Forster (43).
The 1989 ILAE classification defined precipitating seizures and precipitating factors of “syndromes characterized by seizures with specific modes of precipitation” in Appendix II as follows (23):
Precipitated seizures are those in which environmental or internal factors consistently precede the attacks and are differentiated from spontaneous epileptic attacks in which precipitating factors cannot be identified. Certain nonspecific factors (eg, sleeplessness, alcohol or drug withdrawal, or hyperventilation) are common precipitators and are not specific modes of seizure precipitation. In certain epileptic syndromes, the seizures clearly may be somewhat more susceptible to nonspecific factors, but this is only occasionally useful in classifying epileptic syndromes. An epilepsy characterized by specific modes of seizure precipitation, however, is one in which a consistent relationship can be recognized between the occurrence of one or more definable nonictal events and subsequent occurrence of a specific stereotyped seizure. Some epilepsies have seizures precipitated by specific sensation or perception (the reflex epilepsies) in which seizures occur in response to discrete or specific stimuli. These stimuli are usually limited in individual patients to a single specific stimulus or a limited number of closely related stimuli. Although the epilepsies which result are usually generalized and of idiopathic nature, certain partial seizures may also occur following acquired lesions, usually involving tactile or proprioceptive stimuli.
Epileptic seizures may also be precipitated by sudden arousal (startle epilepsy); the stimulus is unexpected in nature. The seizures are usually generalized tonic but may be partial and are usually symptomatic.
Seizures precipitated by integration of higher cerebral function such as memory or pattern recognition are most often associated with complex partial epilepsies, but are occasionally observed in generalized epilepsies (such as reading epilepsy). Seizures also occur spontaneously in most such patients.
Primary reading epilepsy: All or almost all seizures in this syndrome are precipitated by reading (especially aloud) and are independent of the content of the text. They are simple partial motor-involving masticatory muscles, or visual, and if the stimulus is not interrupted, GTCS may occur. The syndrome may be inherited. Onset is typically in late puberty and the course is benign with little tendency to spontaneous seizures. Physical examination and imaging studies are normal but EEG shows spikes or spike-waves in the dominant parieto-temporal region. Generalized spike and wave may also occur.
According to the ILAE Glossary (14), reflex seizures are
objectively and consistently demonstrated to be evoked by a specific afferent stimulus or by activity of the patient. Afferent stimuli can be: elementary, i.e. unstructured (light flashes, startle, a monotone) or elaborate, i.e. structured. Activity may be elementary, eg, motor (a movement); or elaborate, eg, cognitive function (reading, chess playing), or both (reading aloud).
According to the ILAE Task Force on Classification and Terminology (34; 35), reflex epilepsy syndrome is
a syndrome in which all epileptic seizures are precipitated by sensory stimuli. Reflex seizures that occur in focal and generalized epilepsy syndromes that are also associated with spontaneous seizures are listed as seizure types. Isolated reflex seizures can also occur in situations that do not necessarily require a diagnosis of epilepsy. Seizures precipitated by other special circumstances, such as fever or alcohol withdrawal, are not reflex seizures”.
Reflex epilepsies: Although idiopathic photosensitive occipital lobe epilepsy, primary reading epilepsy and hot water epilepsy in infants are syndromes, it is unclear whether other reflex epilepsies constitute unique syndromes” (35).
The ILAE Commission on Classification provides a list of precipitating factors and classifies reflex epilepsies under an unspecified category of “special epilepsy conditions” (34; 35). The list of special epilepsy conditions includes the following:
• symptomatic focal epilepsies not otherwise specified
Precipitating stimuli for reflex seizures
• Flickering light – color to be specified when possible
Reflex seizures in generalized epilepsy syndromes
Idiopathic photosensitive occipital lobe epilepsy (2)
Conditions with epileptic seizures that do not require a diagnosis of epilepsy
*Numbers in parentheses indicate rating of confidence regarding the certainty with which the ILAE Core Group believed each syndrome represented a unique diagnostic entity (3 being the most clearly and reproducibly defined).
† The ILAE report rightly no longer considered startle epilepsy to be an epilepsy syndrome.
‡Hot water epilepsy in infants has been newly considered an epileptic syndrome by the ILAE.
Modified with permission from (34) and (35).
In current ILAE reports, reflex epilepsies are classified as electroclinical syndromes “with less specific age relationship,” and the newest practical clinical definition of epilepsy considers that “the condition of recurrent reflex seizures, for instance in response to photic stimuli, represents provoked seizures that are defined as epilepsy (10). Even though the seizures are provoked, the tendency to respond repeatedly to such stimuli with seizures meets the conceptual definition of epilepsy, in that reflex epilepsies are associated with an enduring abnormal predisposition to have such seizures” (41). There is no consideration of reflex seizures and/or reflex epilepsies in the recent position papers of the ILAE Commission for Classification and Terminology (42; 133).
A systematic review of definitions employed in the research literature for reflex and nonreflex precipitated seizures has been published (70). Koepp and colleagues provide a comprehensive review on reflex seizures, traits, and epilepsies, focusing on physiology to pathology (85).
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