Genetic reflex

Authors: Doctors Gabrielle Rudolf1, Maria Paola Valenti and Professor Edouard Hirsch Creation date: March 2004

Scientific Editor: Professor Jacques Motte

1Département de Neurologie, Hôpitaux Universitaires de Strasbourg, 1 Place de l'Hôpital, 67091 Strasbourg cedex, France. mailto:[email protected]

Abstract Key words Photosensitive Non-verbal and verbal induced epilepsies References

Abstract Reflex epilepsies (RE) are rare epileptic syndromes with induced by specific triggering factors (either by visual, auditory, somato-sensitive or somato-motor stimulation, or by higher cortical function activities). Their frequency depends on the type of epilepsies, and can reach 25% for photosensitive epilepsy. Spontaneous seizures may also occur. “Reflex seizures” can be classified into a simple “pure” reflex epilepsy and a complex group. The former comprises triggered by simple sensory stimuli or by movements (photosensitive epilepsies). The latter are triggered by complex mental and emotional processes (verbal and non-verbal epilepsies). RE may also be classified into epilepsies that are primary or idiopathic (a genetic basis is likely) and epilepsies that are secondary or symptomatic (with an acquired basis). Reflex epilepsies are generally considered as idiopathic. Primary RE frequently have a family history, an age of onset in early life, a benign prognosis and good response to medication (sodium (Dépakine®), lamictal (Lamotrigine®)), and an electroencephalogram (EEG) with a variable presentation but an almost invariable normality of background activity. Electroencephalographic seizures expression may be partial or generalized. Secondary RE occur later, frequently in patients with an associated neurologic and non epileptic impairment. There is sometimes less stereotypy in clinical expression, a poorer response to drugs for focal seizures triggered by specific stimuli (carbamazepine (Tégrétol®), phenytoin (Dihydan®)), and frequently an abnormal interictal EEG background.

Key words Reflex seizures, stimulus-sensitive epilepsy, photosensitive epilepsy, epilepsy, video-game epilepsy, reading epilepsy, eating epilepsy, startle epilepsy, hot-water epilepsy, musicogenic epilepsy, thinking epilepsy, psychogenic epilepsy.

Photosensitive epilepsy tubes, sunlight or by flickering light from behind Disease name and synonyms trees seen from a moving vehicle or reflected • Photosensitive epilepsy from a moving aqueous surface. Pattern- • Television-induced epilepsy sensitive epilepsy, a less commonly documented • Video-game induced epilepsy syndrome, is usually triggered by patterns such as those formed by escalators, window blinds, and patterns displayed on television (Fylan et al, Definition 1997) and video-games (Gastaut et al, 1966; Photosensitive epilepsy, the most common reflex Kasteleijn-Nolst Trenité, 1998). seizure, is induced by flickering light, artificial Visually-induced seizures are frequently seen as lighting such as malfunctioning fluorescent one feature of idiopathic generalized epilepsies

Rudolf G, Valenti MP, Hirsch E. Genetic reflex epilepsies. Orphanet Encyclopedia. March 2004. http://www.orpha.net/data/patho/GB/uk-GeneticReflexEpilepsies.pdf 1 or as the only type of seizures in “pure” Diagnostic methods photosensitive epilepsy. With findings similar to Photosensitive epilepsy diagnosis is based on those of other types of reflex epilepsies (i.e. subjective symptoms and clinical signs, EEG primary reading epilepsy), photosensitive recordings in response to intermittent photic epilepsy can be defined as an idiopathic epilepsy stimulation (IPS) or a combination of these. with age-related onset and a specific mode of Photoparoxysmal responses (PPR), which are precipitation (Commission on Classification and elicited by IPS, are classified into four different Terminology of the International League Against types according to the degree of generalization: Epilepsy, 1989). type 1 - spikes within the occipital background activity; type 2 - parieto-occipital spikes with a Differential diagnosis biphasic slow wave; type 3 - parieto-occipital The electroencephalogram (EEG), usually in the spikes with a biphasic slow wave and spread to context of intensive video-EEG monitoring, the frontal region and type 4 - generalized spikes remains fundamental in the investigation of and wave or polyspikes and waves. Type 4 reflex epilepsy. Intermittent photic stimulation discharges are the most frequent finding (IPS) is standard in the performance of EEG sometimes associated with myoclonic jerks. In recordings. Diagnosis confusion may arise due some patients, the epileptiform discharges can to the difficulty in evaluating epilespies, in be accompanied by slight twitches of the upper general, on the basis of the significance of the extremities, the face or the eyes. Consciousness epileptiform reaction to IPS and, in particular, is rarely affected. Almost, all patients with PPR visually-induced seizures in daily life (Kasteleijn- report sensations, usually for an unpleasant Nolst Trenité et al, 1987). Another important feeling ranging from horror to embarrassed consideration is the overlap in phenotype laughter at being unable to control the jerking between the common juvenile myoclonic movement. Standard IPS procedure reported epilepsy and photosensitivity. About 30% that photosensitive patients are most sensitive patients with juvenile have a when photic stimulation is performed during eye photoparoxysmal response (PPR) (see closure (93%), they are less sensitive with their diagnostic methods) to IPS. Some progressive eye closed (81%), and they are least sensitive epilepsies such as Unverricht- with their eye open (66%) (Kasteleijn-Nolst Lundborg or Baltic myoclonus and ceroid Trenité et al, 1999). Difference in prevalence lipofuscinosis are also characterized by rates can be explained by the different epileptiform reaction to IPS. These syndromes equipment used (difference in flash intensity, have been localized to different chromosomes delivery of flashes, flash duration, or a (Berkovic et al, 1993). combination of these), different stimulation conditions such as distance to the photic Etiology stimulator, continuous stimulation with increasing The etiology of photosensitive epilepsy is frequencies or separate trains of stimulation, one unknown. A family history of epilepsy is reported or more eye conditions (eye closure, eyes in a great majority of patients. This is in closed, or eye open), and ambient light levels. accordance with the common genetic All these influence the outcome of IPS. background observed in idiopathic photosensitivity. Epidemiology

In 1980, a prospective prevalence study was Clinical description performed on 2 342 patients (Kasteleijn-Nolst et In visually sensitive patients, myoclonic or tonic- al, 1989). In an initial screening 5,6% appeared clonic seizures manifest typically at the age of 8- to be photosensitive, whereas 1,8% showed a 10 years; the risk of having visually-induced reaction to IPS that did not meet criteria of a seizures then increases until after puberty, with a classic photoparoxysmal response. Two-thirds of decline after the age of 25 years. Most patients the patients were girls and women between 10 (75%) have tonic-clonic, myoclonic, and absence and 25 years old. More than 90% of the patients seizures, whereas a minority (25%) have a with a PPR outlasting the stimulus train had a history of partial seizures. Photosensitive history of epilepsy, whereas a history of epilepsy patients typically have subtle eyelid myoclonic was found in 84% of control subjects from the movements, jerks of the arms (mostly, same EEG population matched for age, sex, and symmetric), and massive jerks of the whole outpatient referral, without a PPR to IPS. In a body. These signs occur with or without loss of German epileptic patient population of 1 000 consciousness and subjective symptoms. subjects, about 4 000 EEGs were screened for

spontaneous and IPS-induced discharges (Wolf, 1986). Ten percent appeared to be photosensitive.

Rudolf G, Valenti MP, Hirsch E. Genetic reflex epilepsies. Orphanet Encyclopedia. March 2004. http://www.orpha.net/data/patho/GB/uk-GeneticReflexEpilepsies.pdf 2

In summary, an epileptiform reaction to IPS can spontaneous and visually-induced seizures is be found in about 4% of normal children 6 years therefore artificial. Partial seizures can be of age and older and in 0,5% to 5% of normal triggered by simple or complex photic stimuli adults. The prevalence in epileptic patients is with no detectable cerebral lesion (Guerrini et al, about 10% to 20% in children, and 5% to 10% in 1995; 1998). This is another unrecognised adults. Often, epileptic seizures are elicited by phenomenon accounting for 2.5% of all photic- IPS. Females are more susceptible to IPS than induced seizures (Jeavons et al, 1975). The males, with a peak age range of 12 to 18 years. focus here is in the occipital lobe and the presentation can mimic migraine.

Genetics Photosensitivity has been used as a genetic Non-verbal and verbal induced epilepsies marker for epilepsy. Results of many genetic studies of photosensitivity suggest that the EEG Disease name and synonyms response to IPS can be considered as a • Non-verbal induced epilepsy: praxis- phenotypic expression of a genetically induced seizures determined trait (Andermann et al, 1982). One - Thinking epilepsy problem in the investigation of genetic factors in - Emotional epilepsy photosensitive epilepsy is the attenuation or - Reflex decision-making epilepsy even the loss of the reaction to IPS with - Epilepsy arithmetica (mathematica) increasing age. In follow-up studies, the reaction - Writing or graphogenic epilepsy to IPS in the laboratory is much diminished or - Chess or card epilepsy abolished after the age of 25 years. - Eating epilepsy Photosensitivity is a frequent EEG finding in idiopathic (IGE), thus genetic analysis of photosensitivity appear to be • Verbal induced epilepsy: language- an important contribution to the genetics of IGE. induced epilepsy Genetic studies of photosensitive epilepsies give - Reading support for an autosomal dominant mode of - Speaking epilepsy inheritance with age-dependent penetrance - Writing or graphogenic epilepsy (Waltz et al, 2000). Definition Management and treatment Higher mental activities such as reading, The presence of a clear triggering factor should speaking, writing, talking, calculating, lead to restrictions concerning exposure to the concentrating, playing chess, reading music or trigger. The indication of medical treatment with playing piano have been reported as triggering anti-epileptic drugs (AED) should be assessed focal or generalized epileptic seizures, termed on an individual basis according to the “reflex seizures”. Seizures triggered by non- photosensitivity range of each patient. The verbal higher brain activities relating to spatial prognosis in most patients ranges from good to processing and ideation or movements are excellent (Jeavons et al, 1986). Valproic acid considered as “praxis-induced seizures” (Gossens et al, 1990; Inoue et al, 1994) whereas (Depakine®) and a more recently marketed AED those precipitated by verbal processing are such as levetiracetam (Keppra®) suppresses classified as language-induced epilepsy the photosensitivity in the majority of patients, (Geschwind and Sherwin 1967; Bennett et al, and after age 25, withdrawal of the medication is 1971; Lee et al, 1980). This last subgroup often possible. Lamotrigine (Lamictal®) and the includes seizures provoked by reading, either benzodiazepines (Urbanyl®) are AEDs of silently or aloud (Bickford et al, 1956), by second choice (Jeavons et al, 1975). The effect speaking (Marchini et al, 1994) or writing of topiramate (Epitomax®) is not already (Asbury and Prensky 1965; Tomohiro et al, established. 2003). Seizures triggered by thinking or by emotion are more specifically induced by spatial Unresolved questions tasks, chess, playing cards and decision-making Whether the seizures in daily life are related to (Ingvar and Nyman 1962; Wilkins et al, 1982). visual stimuli such as intermittent light Seizures induced by eating may occur at the stimulation (ILS) or pattern is difficult to sight or smell of food, at the beginning of eating establish. Sometimes one cannot determine a meal or postprandially (Nagaraja and Chand, whether a seizure was visually induced or 1984). Non-verbal and verbal-induced epilepsies whether it was spontaneous. The distinction may be divided into epilepsies that are primary between patient with pure photosensitive or idiopathic (with a genetic basis) and epilepsy and those with a combination of epilepsies that are secondary or symptomatic

Rudolf G, Valenti MP, Hirsch E. Genetic reflex epilepsies. Orphanet Encyclopedia. March 2004. http://www.orpha.net/data/patho/GB/uk-GeneticReflexEpilepsies.pdf 3

(with an acquired basis). Primary reflex seizures prolonged exposure to the stimulus to prevent are precipitated by one and only one stimulus GTCS. and occur under no other circumstance. Secondary seizures are induced by several Diagnostic methods triggers and spontaneous seizures occur. Diagnosis is based on clinical and electrophysiological criteria. Video-EEG Differential diagnosis recording is a critical test to elucidate the clinical Clinical pattern, genetic and EEG recordings are and EEG features of the induced seizures and overlapping in several idiopathic epileptic the modalities of their precipitation. Familial and syndromes, particularly those developing and personal history of the patient may report witnessed during adolescence (Reutens and factors, which are likely to provoke jerks, and Berkovic 1995). using these, events can often be elicited and EEG findings and clinical seizures in reflex recorded. In some patients, specific seizures provoked by intellectual activity such as neuropsychological tasks induced EEG praxis or decision-making are often reminiscent abnormalities, correlating with clinical of those observed in idiopathic generalized manifestations. Execution of complicated epilepsies with an age-related onset, such as movements, rather than simple ones, is prone to juvenile myoclonic epilepsy (JME) or benign elicit clinical seizures. Video-polygraphic epilepsy with centro temporal spikes (BECRS). recordings show often-normal resting EEG Age at epilepsy onset, family and personal background activity and sometimes interictal history of seizures do not differ from those of focal or generalized abnormalities. Ictal EEG JME patients who do not have reflex seizures. findings have been found to vary widely, both in If isolated jerks occur without leading to terms of morphology and topography (focal or myoclonic jerks, ictal disturbance of spoken generalized), in spite of the rather uniform language, or a generalized convulsion, the clinical correlates. Surface EMG performed condition may not be recognized as a form of simultaneously during EEG recording allows epilepsy. Isolated jerks may be dismissed as a confirming the concomitant occurrence of meaningless tic and associated ictal language myoclonic jerks and epileptic activity. disturbance may be ascribed to stuttering or to a Despite their obvious variability, ictal EEG movement disorder. recordings are used to as a major criterion as to whether reflex epilepsy is a localization-related or a generalized syndrome (Commission on Etiology Classification and Terminology of the The etiology of non-verbal and verbal-induced International League Against Epilepsy, 1989). seizures is unknown. Such reflex seizures are The recognition of the triggering factors is very rare and are sometimes very difficult to important to provoke reflex seizures and to diagnose. become seizure-free.

Clinical description In predisposed individuals, reflex epilepsies can Epidemiology trigger a generalized epileptic process with both Non-verbal and verbal-induced epilepsies are minor (myoclonus) and major attacks unusual and often may be underdiagnosed. The (generalized tonic-clonic seizure). The clinical incidence and prevalence are unknown. hallmarks of these reflex seizures are abnormal sensations or movements (tonic or myoclonic) of Genetics musculature involved in complex trigger Non-verbal (praxis-induced) or verbal-induced performance. Patients reported episodes of seizures represent an inherited trait of seizures abrupt, involuntary, isolated hemifacial or limbs precipitated by specific modes of activation jerks. Verbal-induced epilepsies are associated occurring mainly within idiopathic focal or with a subjective sensation of clicking, mouth generalized epilepsies (Matsuoka et al, 2000). trembling, stuttering, difficulty in pronouncing Genetically, a distinct predisposition for a words and eventual speech arrest that may specific group of stimuli may be found. A family progress to a generalized tonic-clonic seizure history quite often may be investigated. (GTCS) if the stimulus persists. Concentration of Dominant mode of inheritance is sometimes attention or stress may contribute to the suggested (Daly et Forster, 1975). precipitation of seizures. The latency of seizure occurrence is influenced by many non-specific Management and treatment factors such as sleep deprivation, fatigue, Therapy of reflex seizures involves limiting alcohol intake and menstruation. Patients often exposure to the provoking stimulus, as well as recognize the initial symptoms and avoid antiepileptic drugs. Antiepileptic drugs are

Rudolf G, Valenti MP, Hirsch E. Genetic reflex epilepsies. Orphanet Encyclopedia. March 2004. http://www.orpha.net/data/patho/GB/uk-GeneticReflexEpilepsies.pdf 4 selected on the basis of idiopathic or Guerrini R, Dravet C, Genton P, Bureau M, symptomatic origin of the patient’s seizures. Bonanni P, Ferrari AR, Roger J (1995). Valproate, clonazepam and zonisamide are the Idiopathic photosensitive occipital lobe epilepsy. most effective drugs in idiopathic forms. Epilepsia 36:883-891. Ingvar DM, Nyman GE. Epilepsia arithmetices: a References new psychologic trigger mechanism in a case of Andermann E, Straszak M (1982). Family epilepsy. Neurology 1962;12:282-287. studies of epileptiform EEG abnomalities and Inoue Y, Seino M, Kubota H et al. Epilepsy with photosensitivity in focal epilepsy. In: Seino M, praxis-induced seizures. In: Wolf P, ed. Epileptic Kazamatsuri H, Ward A (eds) Advances in seizures and syndromes. London: John Libbey, Epileptology: 1éth Epilepsy International 1994;81-94. Symposium, New York, Raven Press: 105-112. Jeavons PM, Bishop A, Harding GFA (1986). Asbury AK, Prensky AL. Graphogenic epilepsy. The prognosis of photosensitivity. Epilepsia 27: Transactions of the American Neurological 569-575. Association 1965;88:193-194. Jeavons PM, Harding GFA (1975). Bennett DR, Mavor H, Jarcho LW. Language- Photosensitive epilepsy. In: Clinics in induced epilepsy: report of a case. developmental medicine. Philadelphia: Lippincott Clinical JB. Neurophysiology 1971;30:159. Kasteleijn-Nolst Trenité DGA (1989). Berkovic SF, Cochius J, Andermann E, Photosensitivity in epilepsy. Electrophysiological Andermann F (1993). Progressive myoclonus and clinical correlates. Acta Neurol Scand Suppl epilepsies: clinical and genetic aspects. 80 (Suppl 125):1-149. Epilepsia 34 (Suppl 3): S19-S30. Kasteleijn-Nolst Trenité DGA (1998). Reflex Bickford R, Whelan J, Klass D, Corbin K. seizures induced by intermittent light stimulation. Reading epilepsy: clinical and In: Zifkin BJ, Andermann F, Beaumanoir A, electroencephalographic studies of a new Rowan AJ (eds) Reflex epilepsies and reflex syndrome. Trans Am Neurol Assoc 1956;81:100- seizures. Advances in Neurology, vol. 75, pp. 102. 99-121. Philadelphia: Lippicott-Raven Commission on Classification and Publishers. Terminology of the International League Kasteleijn-Nolst Trenité DGA, Binnie CD, Against Epilepsy (1989). Proposal for revised Harding GFA, Wilkins A (1999). Photic classification of epilepsies and epileptic stimulation: standardization of screening syndromes. Epilepsia 30: 842-849. methods. Epilepsia 40 (Suppl 4):75-79. Daly RF, Forster FM. Inheritance of reading Kasteleijn-Nolst Trenité DGA, Binnie CD, epilepsy. Neurology 1975;25:1051-1054. Meinardi H (1987). Photosensitive patients: Fylan F, Harding gFA (1997). The effect of symptoms and signs during intermittent photic television frame rate on EEG abnormalities in stimulation and their relation to seizures in daily photosensitive and pattern-sensitive epilepsy. life. J Neurol Neurosurg Psychiatry 50:1546- Epilepsia 38: 1124-1131. 1549. Gastaut H, Tassinari CA (1966). Triggering Lee SI, Sutherling WW, Persing JA, Butler AB. mechanisms in epilepsy: the electroclinical point Language-induced seizure: a case of cortical of view. Epilepsia 7, (Suppl 3): 85-138. origin. Arch Neurol 1980;37:433-436. Geschwind N, Sherwin I. Language-induced Marchini C, Romito D, Lucci B, Del Zotto E. Fits epilepsy. Arch Neurology 1967;16:25-31. of weeping as an unusual manifestation of reflex Gossens LAZ, Andermann F, Andermann E, epilepsy induced by speaking: case report. Acta remillard GM. Reflex seizures induced by Neurol Scand 1994;90:218-221. calculation, card or board games and spatial Matsuoka H, Takahashi T, Sakaki M, tasks: a review of 25 patients and delineation of Matsumoto K, Yoshida S, Numachi Y, Saito H, the epileptic syndrome. Neurology 1990; Ueno T, Sato M. Neuropsychological EEG 40:1171-1176. activation in patients with epilepsy. Brain Guerrini R, Bonanni P, Parmeggiani L, Thomas 2000;123:318-330. P, Mattia D, Hravey AS, Duchowny MS. (1998). Nagaraja D, Chand RP. Eating epilepsy. Clin Induction of partial seizures by visual stimulation. Neurol Neurosurgery 1984;86:95-99. Clinical and electroencephalographic features Reutens DC, Berkovic SF. Idiopathic and evoked potential studies. In: Reflex generalized epilepsy of adolescence: are the epilepsies and reflex seizures: Advances in syndromes clinically distinct? Neurology Neurology, vol 75, Zifkin BG, Andermann F, 1995;45:1469-1476. Beaumanoir A, Rowan AJ (eds), Lippincott- Tomohiro O, Kazunori H, Hirosuke M, Shigeru Raven Publishers, Philadelphia: 159-178. S, Kousuke K. Graphogenic epilepsy: a variant of language-induced epilepsy distinguished from

Rudolf G, Valenti MP, Hirsch E. Genetic reflex epilepsies. Orphanet Encyclopedia. March 2004. http://www.orpha.net/data/patho/GB/uk-GeneticReflexEpilepsies.pdf 5 reading- and praxis-induced epilepsy. Seizure 2003;12:56-59. Valenti MP, Tinuper A, Cerullo A, Carcangiu R, Marini C. Reading epilepsy in a patient with previous idiopathic focal epilepsy with centrotemporal spikes. Epileptic Disorders 1999;1:167-172. Waltz S, Stephani U (2000). Inheritance of photosensitivity. Neuropediatrics 31:82-85. Witkins A, Zifkin B, Andermann F, Mc Govern E. Seizures induced by thinking. Ann Neurol 1982;11:608-612. Wolf P, Goosses R 1986. Relation of photosensitivity to epileptic seizures. J Neurol Psychiatry 49: 1386-1391.

Rudolf G, Valenti MP, Hirsch E. Genetic reflex epilepsies. Orphanet Encyclopedia. March 2004. http://www.orpha.net/data/patho/GB/uk-GeneticReflexEpilepsies.pdf 6