Generalized versus partial reflex seizures: A review

Generalized versus partial reflex seizures: A review

G Model YSEIZ-2315; No. of Pages 9 Seizure xxx (2014) xxx–xxx Contents lists available at ScienceDirect Seizure journal homepage:

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G Model

YSEIZ-2315; No. of Pages 9 Seizure xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Seizure journal homepage:


Generalized versus partial reflex seizures: A review Domenico Italiano a,1, Edoardo Ferlazzo b,c,1,*, Sara Gasparini b, Edoardo Spina a, Stefania Mondello d, Angelo Labate b, Antonio Gambardella b,e, Umberto Aguglia b,c a

Department of Clinical and Experimental Medicine, University of Messina, Italy Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy c Regional Epilepsy Centre, Bianchi-Melacrino-Morelli Hospital, Reggio Calabria, Italy d Department of Neuroscience, University of Messina, Italy e National Research Council, Piano Lago di Mangone, Cosenza, Italy b



Article history: Received 27 January 2014 Accepted 24 March 2014

In this review we assess our currently available knowledge about reflex seizures with special emphasis on the difference between ‘‘generalized’’ reflex seizures induced by visual stimuli, thinking, praxis and language tasks, and ‘‘focal’’ seizures induced by startle, eating, music, hot water, somatosensory stimuli and orgasm. We discuss in particular evidence from animal, clinical, neurophysiological and neuroimaging studies supporting the concept that ‘‘generalized’’ reflex seizures, usually occurring in the setting of IGE, should be considered as focal seizures with quick secondary generalization. We also review recent advances in genetic and therapeutic approach of reflex seizures. ß 2014 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Keywords: Photosensitivity Musicogenic Startle Treatment Genetic Prognosis

1. Introduction Reflex seizures are epileptic events triggered by specific motor, sensory or cognitive stimulation. Reflex epilepsies are classified as a specific syndrome ‘‘in which all epileptic seizures are precipitated by sensory stimuli’’ and include Idiopathic Photosensitive Occipital Lobe Epilepsy (IPOE), Primary Reading Epilepsy (PRE), Startle Epilepsy (SE) and other Visual Sensitive Epilepsies.1 Reflex seizures occurring in association with spontaneous seizures are considered as ‘‘seizure types’’ precipitated by visual, somatosensory/proprioceptive stimuli, thinking, music, eating, praxis, reading, hot water and startle.1 Reflex seizures have traditionally been classified into ‘‘generalized’’ and ‘‘focal’’.2,3 ‘‘Generalized’’ reflex seizures, such as myoclonic, absence or generalized tonic–clonic fits, may occur in patients with idiopathic generalized epilepsy (IGE)3–6 following visual stimuli, thinking, praxis or language tasks (reading, talking and writing). Different kind of ‘‘focal’’ reflex seizures may occur in patients with symptomatic or cryptogenic epilepsy4–6 following startle, eating, music, hot water, orgasm or somatosensory stimuli.

In this review we remark the lack of evidences supporting the distinction between ‘‘generalized’’ and ‘‘focal’’ reflex seizures. In addition, we discuss recent advances in genetic and therapeutic approach of these reflex seizures. 2. Review of the literature Medical publications concerning reflex seizures and epilepsies were reviewed. References were identified by searches of PubMed until December 2013 with the terms ‘‘reflex seizures’’ and ‘‘reflex epilepsies’’, alone or in combination with ‘‘photosensitivity’’, ‘‘intermittent photic stimulations’’, ‘‘thinking’’, ‘‘calculation’’, ‘‘praxis’’, ‘‘reading’’, ‘‘language’’, ‘‘startle’’, ‘‘music’’, ‘‘eating, ‘‘orgasm’’, ‘‘somatosensory’’, ‘‘hot water’’. Articles were also identified through searches of the authors’ own files. Selection criteria were newness, importance, originality, quality, opportunities for further references, relevance to the scope of this Review. Table 1 summarizes the main epidemiological, clinical, EEG, genetic, therapeutic and prognostic features of reflex seizures. 2.1. Seizures induced by visual stimuli

* Corresponding author at: Regional Epilepsy Centre, ‘‘Bianchi-MelacrinoMorelli’’ Hospital, Reggio Calabria, Italy. Tel.: +39 0965397972; fax: +39 0965397973. E-mail address: [email protected] (E. Ferlazzo). 1 These authors share the same contribution.

Reflex seizures and epilepsies sensitive to visual stimulation, especially flashing lights, are the commonest and longest know. Clinical photosensitivity may occur in 2% of epileptic patients but its prevalence increases up to 10% if only patients aged 7–19 years 1059-1311/ß 2014 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Italiano D, et al. Generalized versus partial reflex seizures: A review. Seizure: Eur J Epilepsy (2014),

Seizure type

Epileptic syndromes or associated conditions

Genetic background




1/4000 (2–10% of epileptic patients), female preponderance (60%)

- Generalized myoclonic jerks, absences. GTCS - Partial (mainly occipital)

- IGE (especially JME) - IPOE - PME - DS Rarely brain acquired lesions

No major gene identified Inheritance: likely autosomal dominant with reduced penetrance, independent from seizures disorder

Preventive measures (stimulus avoidance, lens, etc.) Drug: VPA first choice LTG and LEV second choice

May remit in 25% of patients following 30 years of age Usually well responding to treatment

Fixation-off sensitivity

Unknown, probably underestimated

Mainly occipital


VPA (first line), CLN or LTG

Excellent in IPOE Variable in other conditions

Eye closure sensitivity

Unknown, female preponderance

Eyelid myoclonia with or without absences

Cryptogenic or symptomatic OLE. Idiopathic or cryptogenic generalized epilepsies Jeavons syndrome IGE (JME, JAE) OLE



Seizures induced by non-verbal cognitive stimuli Reading-induced seizures

Usually overlapping with JME

Generalized myoclonic jerks, absences GTCS Jaw jerks that may progress to GTCS if reading continues Rare: partial seizures, with alexia and variable degree of dysphasia


Unknown Rate of family history 30–40% May overlap with photosensitivity but usually independent Usually overlapping with IGE

Same drugs as IGE

Usually good (as JME)

Considered a variety of IGE; described in patients with JME

Autosomal dominant inheritance with incomplete penetrance

Stimulus avoidance (Interruption of reading) VPA first choice LEV and CLN as second choice

Benign, well responding to treatment


Overlapping with JME

Myoclonias of perioral muscles, sometimes with interruption of reading and speaking

Overlapping with seizure disorder (usually IGE)

The same as reading

Benign, well responding to treatment

Startle induced seizures

Low prevalence, both sexes are equally affected.

Brief axial tonic or hemitonic Atonic

Usually none or overlapping with disease

1:10.000.000 subjects, no gender predominance

Usually temporal lobe seizures

Eating seizures

1/1000 –2000 epileptic patients, male/female ratio 3:1

CP or SP seizures

Seizures induced by proprioceptive stimuli (movement induced) Seizures induced by somatosensory stimuli

Rare, unknown

Myoclonic or somatomotor or somatosensorial seizures Possible secondary generalization. Sensory aura followed by a sensory jacksonian seizure with tonic motor manifestations. Secondary generalization may occur CP seizures

CLB 1st choice Other drug for partial epilepsy Surgery Stimulus avoidance Drug for focal seizures Surgery Stimulus modification, Drug for partial epilepsy CLB before meal Surgery Drugs for focal seizures

Typically intractable

Musicogenic seizures

Typical of Primary Reading Epilepsy, but they may be observed in different epileptic syndromes (JME) Early acquired cerebral lesions Brain malformation Metabolic diseases Chromosomal disorders Localization related epilepsies Reported in patients with ADTLE Usually localization-related epilepsy

Rare, male/female ratio: 1.8/1

Rare, unknown

Hot water seizures

Rare (may reach 5% of all epilepsies in India), male predominance (70%)

Orgasm induced seizures

Very uncommon, female predominance

Partial seizures

Usually none Reported in patients with ADTLE Unknown Familial cluster in Sri Lanka

Variable, usually refractory


Acquired brain lesions Non-ketotic hyperglycemia Acute diffuse encephalopathies

Usually none


Patients with post-rolandic cortical lesions; Malformations of cortical development


As for other symptomatic or cryptogenic focal epilepsies



Two loci at chromosome 10q21.3-q22.3 and 4q24-q28

Relatively benign, age- and situation-related disorder similar to febrile seizures

Usually in localization related epilepsy


Stimulus avoidance/ modification (lowering the temperature of the bath). BZD as needed Antiepileptic drug or surgery


ADTLE: autosomal dominant temporal lobe epilepsy; BZD: benzodiazepines; CLB: clobazam; CLN: clonazepam; CP: complex partial; DS: Dravet Syndrome; GTCS: generalized tonic–clonic seizures; IGE: idiopathic generalized epilepsies; IPOE: Idiopathic Photosentitive Occipital Lobe Epilepsy; JAE: Juvenile Absence Epilepsy; JME: juvenile myoclonic epilepsy; LEV: levetiracetam; LTG: lamotrigine; OLE: occipital lobe epilepsy; PME: progressive myoclonus epilepsies; SP: simple partial; VPA: valproic acid.

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Table 1 Summary of the main epidemiological, clinical, EEG, genetic, therapeutic and prognostic features of reflex seizures.

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are considered.7 Photosensitivity is more frequent in women and has an important genetic component, likely autosomal dominant inheritance with reduced penetrance, although no major photosensitivity gene has been identified.8,9 A recent mega-analysis study denied the existence of an unique locus responsible for photoparoxysmal response (PPR) trait.10 Multiple loci probably underlie the trait, possibly with subtle differences in phenotypic expression; complex inheritance with interaction of several susceptibility genes and environmental factors cannot be ruled out.10 In some families, PPR seems to segregate independently of the epilepsy phenotype, indicating that it is not the consequence of epilepsy.11 Taylor et al. investigated the electro-clinical features of photosensitivity in families with idiopathic epilepsy.12 Those authors postulated a continuum phenotypic spectrum, ranging from the IGE to IPOE, and hypothesized that common genetic determinants between these two entities could contribute to the complex inheritance pattern of photosensitivity.12 Photosensitivity can occur in several epilepsy syndromes, the most frequent association being with IGE, especially with juvenile myoclonic epilepsy (JME) in which it is reported in 40–90% of patients.13 Photosensitivity is also common in some symptomatic epilepsies such as Dravet Syndrome, Unverricht–Lundborg disease, Lafora disease and neuronal ceroid lipofuscinoses.14 Photosensitive patients present seizures when exposed to environmental flicker such as sun shining through trees and discotheque lights, or with apparently more complex stimuli such as television and videogames. Seizures are commonly apparently generalized and include subtle eyelid myoclonus with or without impairment of consciousness, symmetric or asymmetric myoclonic jerks of the arms or involving the whole body, absences, negative myoclonus.15,16 With sustained exposure to the stimulus, these can evolve into generalized convulsions, which can also occur without premonitory events.15 However, focal occipital hyperexcitability is central in the pathophysiology of photosensitivity. Indeed, visual stimuli can also induce focal (mainly occipital or temporal) seizures15 in both idiopathic17,18 and symptomatic19 epilepsies. Other animal and human studies suggest the central role of occipital lobe in photosensitivity. It has been long known that bioccipital resection eliminates the epileptic discharges in the naturally photosensitive baboon Papio-Papio.20 However, evoked potential studies suggest that photosensitivity may result not only from occipital cortex hyperexcitability but also from diffuse or multifocal hyperexcitability involving cortico-cortical pathways.21–23 Takahashi proved that flickering patterns activate both striate and parastriate cortex before transmitting to the nonspecific diffuse system.24 Wilkins argued that pattern-sensitive seizures are triggered in the occipital lobe, but require activation of a critical amount of cortex and depend on synchronization of neuronal activity to induce a seizure.25 Both fMRI26 and magnetoencephalography (MEG)27,28 studies also suggested that photosensitivity in patients with IGE requires regional occipital cortical hyperexcitability, regional activations and abnormal neuronal synchronization. An overall explanation about the mechanisms of photosensitivity with respect to activation of generalized seizures has been proposed by Binnie et al.29 When appropriate stimuli reach the striate and parastriate areas activating a sufficient and critical amount of cortical tissue and inducing synchronization of neuronal activity, an initial local epileptic discharge is produced; subsequently, the discharge would rapidly involve the cortico-reticular or corticocortical pathways with propagation from the parieto-occipital areas eventually leading to a generalized epileptic discharge.29 Treatment of photosensitivity involves a combination of preventive and pharmacological measures.9 Avoidance of the stimulus by looking away or covering one eye, watching television from a distance of at least 2 m and using a remote control to change


channels are often effective precautions. Wearing a particular type of blue lens, named Z1, is highly effective in controlling PPR in most of photosensitive patients.30 Viewing a 100 Hz television or better an LCD/plasma screen is strongly suggested. Indeed flicker frequency is the most important factor in photosensitive epilepsies, with the lower-frequency television sets (50 Hz) more liable to provoke seizures as compared to 100 Hz monitors. Computer screens use a refresh rate of 70–80 Hz to minimize flickering. The new generation television sets such as the LCD/plasma screens use a transistor for each pixel allowing the pixel to keep its state with no flickering. Discotheques should also be avoided, not only because of the stroboscope light but also because alcohol or energy drinks intake, emotional stress and sleep deprivation may contribute to lower seizure threshold.31 If these precautions are ineffective or impractical, drug treatment is necessary. Valproate (VPA) is the drug of choice, with most patients becoming seizurefree.32 Newer antiepileptic drugs such as lamotrigine (LTG),33 levetiracetam (LEV)34 and brivaracetam35 have reduced PPR in acute studies and may be useful in clinical practice. Clobazam, ethosuximide and topiramate also have been recommended as second-choice therapies36 whereas phenytoin or carbamazepine have successfully been used to reduce PPR in animal models.37 Photosensitivity tends to decrease into the third decade and disappears thereafter in 25–30% of patients. The spontaneous reduction of photosensitivity may also occur in some generalized symptomatic epilepsy.38 However, some patients may remain photosensitive even longer and serial EEG evaluation especially with sleep deprivation and IPS is recommended. Pattern sensitivity is characterized by seizures provoked by viewing environmental patterns such as escalator steps, striped wallpaper or clothing. Almost all these patients show a PPR to IPS. The most epileptogenic pattern consists of stripes in sharp contrast to the background, arranged geometrically.39 Clinically, pattern sensitivity is much less common, reported in only 6% of subjects by Kasteleijn-Nolst Trenite´.4 Seizures induced by television and by videogames are closely linked to sensitivity to IPS and to pattern and were brought to attention after the notorious ‘Pokemon’ incident of 1997.40 Although videogame sensitivity is usually not distinct from photosensitivity, Ferrie et al.41 found that 30% of patients with IGE sensitive to videogames were not sensitive to IPS. Videogame play involves factors not applicable to passive television viewing, and non photosensitive patients may have seizures induced by non-specific factors such as prolonged play and sleep deprivation, or by specific but non-visual triggers such as thinking and praxis (see below).3 Wilkins, evaluating several lines of evidence, concluded that pattern-sensitive seizures are triggered in the occipital lobe.25 Treatment is substantially the same as for photosensitivity. Eye-closure sensitivity is a specific type of visual sensitive seizures in which brief, mainly generalized epileptiform changes, usually associated to eyelid myoclonic jerks with or without absences, appear in EEG within 2–4 s following closing of the eyes.42 It is more common in females and may overlap with photosensitivity. It may be seen in different epilepsy syndromes including IGE such as JME, Childhood Absence Epilepsy (CAE), Juvenile Absence Epilepsy (JAE) as well as in a not yet syndrome recognized by ILAE, named Eyelid Myoclonic with Absences or Jeavons Syndrome.42 Status epilepticus following eye-closure has also been reported.43,44 Also in Jeavons syndrome, a focal (occipital) generator has been postulated on the basis of interictal and ictal findings of 12 patients.45 Prognosis is variable and eyeclosure sensitivity may be life-long as in Jeavons syndrome.42 First line drugs are usually represented by VPA and LEV.3,4 The term fixation-off sensitivity (FOS) indicates seizures or EEG abnormalities elicited by elimination on central vision and fixation.46 Visual fixation is the phenomenon that brings the

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image of a bright object of interest on to foveae and maintains it there. FOS should be distinguished from scotosensitivity, the latter referring to seizures or EEG alterations elicited by the removal of retinal stimulation by light. Pure scotosensitivity is actually rare, indeed most of the reported cases should be classified as FOS.46,47 FOS is usually found in idiopathic focal epilepsies with occipital paroxysms but may also be observed in idiopathic or cryptogenic generalized epilepsies as well as focal symptomatic epilepsies.47 Most patients have only interictal epileptic activity induced by FOS, but some may also experience clearly focal occipital seizures.47 Hyperexcitability of occipital regions is clearly present in patients with FOS. Notably, in such patients IPS is usually ineffective.48 The existence of different visual pathways may explain why some patients are sensitive to IPS or patterns (main involvement of magnocellular system) and other to the elimination of central vision (greater involvement of parvocellular system).49 The inhibition on occipital paroxysms by fixation could be explained by the interference of the activity of neural networks involved during visual stimuli on the spread of epileptic discharge (competitive recruitment).49 For patients with FOS-induced clinical seizures, VPA is the drug of choice, clonazepam (CLN) or LTG may also be effective.46 Other drugs for partial seizures may be attempted.46 Drug resistance is not unusual.47 2.2. Seizures induced by non-verbal cognitive stimuli Seizures induced by thinking may occur during calculation or playing chess and similar games. They usually begin during adolescence.50 Patients usually experience generalized tonic– clonic (96%), myoclonic (76%) or absence (60%) seizures. Rare spontaneous seizures may occur in 76% of patients. EEG shows generalized epileptic discharges in 68% of patients. Focal abnormalities, when present, usually involve right hemisphere over the frontal or parietal regions.50 PPR is present in 32% of patients. Activation by mathematics or spatial tasks is found in 72%. Inheritance as well as clinical pattern is in keeping with IGE, especially JME or JAE.50 The role of motor component in seizure provocation was emphasized by Inoue et al.51 who introduced the term ‘praxis-induced epilepsy’ for patients whose seizures were provoked by ‘contemplating complicated spatial task in a sequential fashion, making a decision and practically responding by using part of the body’. This was also stressed by Matsuoka et al.52 who found that cognitive tasks requiring the use of the hands, such as writing, written calculation or spatial construction, were more epileptogenic than higher mental activities not requiring hand movement, such as mental calculation, although some patients had EEG abnormalities activated by purely cognitive stimuli without any motor component. The importance of the spatial components of the task to provoke epileptic abnormalities was evidenced by Wilkins et al.53 who showed that complex multiplication and division were epileptogenic while addition, subtraction and simple multiplication and division, thought to involve fewer spatial components, were not. Indeed, it is known that exact calculation is language-dependent and recruits networks involving the dominant inferior frontal lobe and angular gyrus, while approximate or complex calculation relies on nonverbal visuo-spatial networks of both parietal lobes.54 Probably, unilateral fronto-parietal activation is not enough to recruit a ‘critical mass’ of cerebral cortex, and bilateral parietal activation is required to induce seizures. Therefore, praxis induction would activate hyperexcitable cortical pathways beyond parietal cortices (usually activated during thinking tasks) and beyond the network subsuming spatial thought alone, i.e. the sensorimotor areas, which are also preferentially involved in JME.6,55 Thus, as for sensitivity to visual stimuli, these reflex seizures should be

considered as focal with quick secondarily generalization. Unlike photosensitive patients, avoiding the triggering stimuli in this condition is not always possible, and the majority of these patients have seizures usually controlled by VPA or other drugs commonly used in JME.56 2.3. Seizures induced by reading. Seizures induced by reading typically occur in Primary Reading Epilepsy (PRE), a rare reflex epilepsy whose typical attacks are characterized by jaw jerks (‘‘clicking sensation’’ or ‘‘stammering’’), that may evolve into generalized tonic–clonic seizures if reading continues.57,58 Interictal EEG is normal in 80% of patients, spontaneous spike and wave discharges are present in 11% and temporal paroxysmal discharges in 5%.57 IPS evokes a PPR in 9%, in keeping with an IGE syndrome.6,57 Epileptiform discharges may be bilateral and symmetrical (32%), bilateral but asymmetrical (38%) or unilateral or focal (30%).57 A distinct but rarer pattern of reading-induced seizures was recognized by Koutroumanidis et al.,58 consisting in prolonged alexia with varying degrees of dysphasia, associated with unilateral and strictly focal EEG abnormalities. MRI is usually normal.58 A strong genetic component characterizes this syndrome. In Wolf’s series, 41% had a family history of seizures and, of 20 first-degree family members with sufficient information, 11 also had PRE.59 Autosomal dominant inheritance with incomplete penetrance overlapping with a genetic background for IGE was proposed for some families.60,61 The mechanism by which reading precipitates seizures is not entirely clear.6 The only common factor seems to be the transformation of the linguistic material from graphemes into language.59 Reading aloud is usually more activating than silent reading. Emotional involvement from the story was also suggested by some authors, but this seems not to be crucial since even material difficult to understand or decipher (foreign language, non sense words) can provoke seizures.6,60 Language-related tasks other than reading can induce seizures.60,62,63 Argumentative talking and writing were also effective in eight patients described by Radhakrishnan et al.63 and in 14 patients described by Koutroumanidis et al.58 In Wolf’s series, talking was also effective in 27% of patients while writing in 11%; thinking (difficult calculations) and praxis (playing chess or cards) could provoke seizures in some patients.59 Language processing, and reading in particular, requires the integrated activation of multiple cortical areas. Probably, patients with reading epilepsy present different areas of hyperexcitability involving cortical regions normally activated during language tasks, especially reading and less often writing and talking.6,59 This hyperexcitability could be due to a genetic predisposition or to an acquired lesion.63 A combined EEG/ fMRI study showed that reading-induced seizures involve the activation of left motor and premotor areas, left striatum and mesiotemporal/limbic areas.64 In particular, the main involvement of the left posterior dorsolateral prefrontal cortex has been demonstrated by the activation of this area during a spiketriggered fMRI study on patients with PRE.65 This is further supported by a case of reading epilepsy reported after the removal of this area due to an arteriovenous malformation.66 Also in this condition, a focal or multifocal seizure origin with quick secondary generalization may be postulated.6 Most patients with PRE or language-induced seizures are well controlled by valproate or clonazepam.59 A striking response to LEV was found in a family with language-induced epilepsy and ictal stuttering.61 Mayer et al. reported a peculiar but often-unobserved seizure type provoked by language-related tasks, namely perioral reflex myoclonias (PORM).67 They consist of myoclonias around the mouth, sometimes with interruption of reading and speaking. PORM can be bilateral, but in most cases jerks are strongly asymmetrical

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and do not change the side in individual patients. They can be observed in different epileptic syndromes, especially JME.67 PORM remain often undiagnosed because patients are not aware that they are an epileptic symptom and fail to report them. A focal origin of these seizures has been postulated, since clinical symptoms of PORMs share the characteristics of cortical reflex myoclonus, typically involving only a few adjacent muscles related to a small area of the sensorimotor cortex. Treatment is the same as for JME.56 2.4. Startle-induced seizures These seizures are triggered by unexpected sensory stimuli, usually auditory. Seizures are typically partial, last <30 s and consist of a startle response followed by mostly axial tonic or hemitonic posture, often with autonomic phenomena.68 If seizures occur in patients who are standing, fall is common. Habituation is usual: the stimulus becomes temporarily ineffective if it is repeatedly presented over several minutes. Patients with SE usually have large brain lesions (in particular perinatal hypoxic injury with congenital hemiparesis, cortical dysplasias, schizencephaly), involving sensorimotor and premotor cortex; SE may also occur in the setting of metabolic diseases69 or chromosomal abnormalities such as trisomy 21.70 Patients with normal neurological and neuroradiological studies have been reported.71 Ictal EEG usually shows an initial vertex discharge followed by diffuse relative flattening or low-voltage rhythm at about 10 Hz. Depth electrodes studies demonstrated an initial high-amplitude evoked response over motor areas corresponding to the vertex scalp activity, followed by ictal EEG discharge, starting from motor or premotor cortex and spreading to ipsilateral mesial frontal and parietal regions as well as to contralateral frontal regions.72 A combined video-EEG and MEG study showed that the cingulate gyrus, along with the supplementary motor area, is involved in the genesis of startle-induced seizures.73 Seizures resemble supplementary motor seizures. Indeed, localized injuries and seizure onset often involve that area or its surroundings.74 Although mechanisms of SE are not completely understood, it is believed that the seizures originate in the motor and premotor cortex including the supplementary motor area.75 An exaggerated startle response, possibly due to abnormal activity in the nucleus reticularis pontis caudalis, would lead to an increase of proprioceptive feedback to the hyperexcitable motor cortex, evoking a seizure.72,75 Differential diagnosis includes other types of non epileptic startle disorders, as hyperekplexia and excessive startle response (for review see76). Startle-induced seizures are usually refractory to medical treatment. Clobazam (CLB),77 LTG,78 and LEV79 may be useful. Some patients may benefit from surgical treatment, in particular lesionectomy, callosotomy, multiple subpial transections.80,81 2.5. Musicogenic seizures Seizures induced by music are very rare (1:10.000.000 subjects) but probably underestimated.82 However, only 13% of patients have seizures exclusively provoked by hearing music, while most of them have both spontaneous and seizures induced by music, with the latter beginning usually over a year after the onset of the spontaneous attacks.83 Seizures are usually simple or complex partial, arising from temporal lobes, rarely with secondary generalization. Interictal and ictal EEG shows epileptiform activity from either temporal region, usually the right.83 Seizures have also been reported while the subject is exposed to the musical trigger during sleep or while thinking about it. Listening to music for several seconds or minutes is usually needed to trigger seizures. The effective stimulus is usually stereotyped for each patient. It can


be limited to a single musical track, but there is no clear common pattern among patients. Patients with LG1 mutations and seizures provoked by speech or answering the telephone have been reported.84,85 The pathophysiology of musicogenic seizures is not fully elucidated. Primary auditory cortex consists of multiple tonotopically organized areas and is especially sensitive to pure tones. Surrounding regions are more sensitive to complex stimuli.86 PET studies confirmed the major involvement of right hemisphere structures in pathways involved in processing musical information, exceeding the borders of conventional auditory cortex.87 Zifkin and Zatorre also evidenced that more complex musical processing tasks stimulate cortical and subcortical territory bilaterally but with right hemisphere predominance.88 An emotional content of the stimulus is often reported. An EEG/ fMRI study in a man with musicogenic seizures showed that listening to emotionally charged music provoke widespread activation over the right fronto-temporo-occipital lesions before seizure onset, while listening to neutral music only activated right acoustic area without provoking seizures.89 Moreover, other EEG/ fMRI studies revealed that regional cerebral blood flow recorded during musicogenic seizures is increased in putative epileptogenic foci, as well as in other brain regions not directly related to seizure activity. In particular, an increased cerebral blood flow was found in the nucleus accumbens, orbitofrontal and cingulate cortex, part of the right insula and occipital regions. This activation probably reflects several concomitant conditions such as the possible expectation of the seizure or the personal aesthetic and semantic assessment of the melody.90 Conversely, it was shown that listening to music, in particular Mozart sonata K.448, once a day for 6 months, may reduce both seizure frequency91 and epileptiform discharges92 in epileptic children, although the mechanism remains obscure. Musicogenic seizures can be treated by stimulus avoidance or modification in many cases, especially if there is a useful latency before seizure onset, or if the stimulus is very specific. In alternative, drugs for focal seizures are indicated. Surgical treatment with removal of epileptogenic zones may be considered in drug resistant patients.93,94 2.6. Eating-induced seizures Seizures triggered by eating are rare and are reported to occur in nearly 1/1000–1/2000 of all epileptic patients.95 The triggers are usually stereotyped for each patient, but may differ from a patient to another. Seizures are simple or complex partial, occur shortly after beginning to eat and do not recur during the same meal.96 Such reflex seizures almost invariably occur in the setting of a localization-related symptomatic epilepsy and patients usually experience unprovoked seizures. Seizures usually arise in temporolimbic or extratemporal perisylvian regions and may become secondarily generalized.97 Eating may also induce periodic spams in patients with focal symptomatic epilepsy98 as well as infantile epileptic encephalopathy99 or MECP2 duplication syndrome100, probably by activating the fronto-opercular region that evokes the activity of the brainstem or the cortical motor strip considered to be the areas responsible for spasm initiation.101–103 A high incidence of eating epilepsy, with familial clusters in most cases, has been reported in Sri Lanka, and the role of specific habits such as eating bulky meals rich in carbohydrates has been proposed as possible triggering factors.101 Physiopathological mechanisms are complex.102 Emotional or autonomic components of eating, along with gastric distension or stimulation of the mouth or pharynx, also may play an important role in inducing seizures.97 Overall, participation of autonomic, somatosensory or proprioceptive afferents is probably needed. Seizures provoked by eating can be prevented by modifying the

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trigger, i.e. patients more sensitive to either somatosensory or proprioceptive stimuli during eating are often able to prevent their seizures by altering the sensory characteristics of food (to drink through a straw rather than from a cup, to bite into a whole fruit or cutting it into small pieces). Stimuli modification can reduce seizure frequency in what may otherwise be an intractable or socially disabling condition. Some patients self-induce seizures to benefit of the following refractory period and to avoid having seizure later in a more embarrassing setting. CLB intake before meals was demonstrated to be effective in prevent eating related seizures.101,102 Medically intractable patients can be assessed for surgical treatment. 2.7. Seizures induced by proprioceptive stimuli (movement induced) These reflex seizures are rare and most commonly occur as a transient phenomenon with non-ketotic hyperglycemia.103,104 In these reflex seizures, originally described as movement-induced,105 later experiments showed the determinant role of proprioceptive afferents.106 Thus, these type of seizures are now more precisely described as ‘‘proprioceptive-induced.’’ Seizures are typically partial, and the involvement of the sensorimotor area of the hemisphere contralateral to the clinical seizure onset is constant. New-onset proprioceptive-induced seizures need quick medical and neurologic evaluation to identify patients with nonketotic hyperglycemia. 2.8. Seizures induced by somatosensory stimuli Seizures induced by somatosensory stimulation are typically elicited by particular stimulations such as skin friction (rubbing epilepsy), touching or tapping, tooth brushing (tooth-brushing epilepsy), or stimulation of external ear conduct (auricular epilepsy). In most cases the effective stimulus is limited to a specific cutaneous trigger zone, particularly the head and back. The seizures are usually partial and begin with a sensory aura followed by a sensory jacksonian seizure with tonic motor manifestations suggesting a supplementary motor area seizure. Consciousness is usually preserved, but secondary generalization may occur. Ictal pain and autonomic disturbances have also been described.107 Touch-induced seizures may be induced by compulsive cutaneous self-stimulation in children with severe developmental delay.108 Associated post-rolandic cortical lesions are common but malformations of cortical development have also been described.109 Differential diagnosis with benign reflex myoclonic epilepsy of infancy (for review see6) is needed. Treatment is the same as for focal epilepsies. 2.9. Hot water induced seizures Hot water epilepsy (HWE) is characterized by seizures induced by immersion in or contact with hot water. Descriptions are common in southern India, where ritual bathing involves repeatedly pouring hot water over the head from a jug.109,110 The pouring of the water over the head and the temperature of the water are believed to be the most common triggering factors. HWE has been thought to be a relatively benign age- and situationrelated disorder similar to febrile seizures. Seizures are usually complex partial, they begin in the first year and are always triggered by immersion in hot bath water with a temperature around 37.5 8C.110–112 In infantile HWE, the neurologic and developmental examinations are always normal. Interictal EEG can be normal, but abnormalities over temporal areas have been recorded in most of the patients.109–111 MRI is usually normal although focal cortical malformations have been reported.113 Linkage analysis of families with autosomal dominant inherited

HWE led to the identification of two genetic loci for HWE at chromosome 10q21.3-q22.3 and 4q24-q28.114,115 The exact pathophysiological mechanism of HWE is not clear. Complex tactile and temperature-dependent stimuli have been suggested as the probable inducing factors in HWE. Experimental studies on animal models showed that the repeated exposure to hot water on rats is comparable to ‘kindling’ by repeated sub-threshold electrical stimulation. Thus a similar phenomenon of ‘hyperthermic kindling’, could be responsible for the development of HWE.116 The correspondence with the human epilepsy led to the hypothesis that, in the susceptible subjects, a similar form of induced hyperthermia could be responsible for HWE. So an aberrant, genetically determined, thermoregulatory system, which is sensitive to a rapid rise in temperature, could account for HWE.109 Differential diagnosis includes non-epileptic events such as startle and vasovagal syncope, and SE. Treatment consists in lowering the temperature of the bath. Use of intermittent CLB prior to hot water bath may be considered in some cases. Continuous use of antiepileptic drugs is restricted to patients with additional spontaneous seizures110,117 2.10. Orgasm-induced seizures Very rarely, orgasm may precipitate seizures that usually begin with a certain delay (minutes or hours) following climax.118 Most patients are female and have both spontaneous and reflex partial seizures in the context of a localization-related epilepsy. Right hemisphere involvement is common. The key role of the right hemisphere regarding the sexual function has been well investigated.118 Seizures with sexual phenomena may arise from superior post-central gyrus, parietal parasagittal region, and frontal and mediobasal temporal lobes.119 It was hypothesized that reaching sexual climax may trigger already sensitized neurons within the network localized throughout different responsible centres of the brain.118,119 The predominance of female patients with orgasm epilepsy suggests that the influence of sexual hormones is crucial for such phenomena to occur. A functional and possibly anatomic sexual dimorphism, involving the limbic temporal region has been postulated.120 The role of hyperventilation seems not to be crucial since some of these patients have seizures hours following orgasm. Moreover, hyperventilation did not elicit epileptiform abnormalities during EEG. Because sexual related seizures are embarrassing for patients, they tend to hide these symptoms. Thus prevalence of orgasm epilepsy might be underestimated by the physicians or hidden by the patients unless they are questioned directly. Obviously, couple sexual dysfunction is common, since both the woman and their partners are afraid to reach orgasm and induce seizure, with a progressive avoidance of sexual intercourse. Treatment is the same as for focal seizure disorder in the context of which orgasms seizures occur. Surgical treatment was effective in some patients.121 3. Conclusions Evidences from animal, clinical, neurophysiological and neuroimaging studies clarified the pathophysiology of reflex seizures. ‘‘Generalized’’ reflex seizures, usually occurring in the setting of IGEs, should be considered as focal seizures with quick secondary generalization through cortico-reticular or cortico-cortical pathways (Fig. 1). Indeed, IGE-patients with ‘‘generalized’’ reflex seizures have focal (i.e. occipital lobe in photosensitivity) or multifocal (i.e. parietal lobes in thinking-induces seizures) areas of hyperexcitability that, when appropriately stimulated, give rise to an epileptic activity that quickly generalizes. The lack of such a quick generalization accounts for ‘‘focal’’ reflex seizures occurring

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Fig. 1. Example of ‘‘generalized’’ reflex seizures. Photic stimulation induces an initial occipital lobe epileptic discharge in a patient with JME. Diffuse or multifocal hyperexcitable areas accounts for quick secondary generalization through cortico-thalamic or cortico-cortical pathways, with the final appearance of a generalized epileptic discharge. Th = thalami.

Fig. 2. Example of ‘‘focal’’ reflex seizures. Hearing to music provokes a left temporal discharge in a patient with cryptogenic temporal lobe epilepsy. Hyperecxitable area is well localized with no tendency of the discharge to quick generalize.

in the context of focal epilepsies (Fig. 2). Patients with ‘‘generalized’’ reflex seizures usually benefit from antiepileptic drugs typically used for IGE such as VPA, LTG or LEV. The effectiveness of specific drug for focal seizures such as carbamazepine and phenytoin remain to be elucidated in human. Pharmacological or surgical treatment should be considered in most patients with focal reflex seizures. The use of non-pharmacological measures (i.e. stimulus avoidance, use of lens) not associated with antiepileptic drugs is effective in a few patients only. The prognosis of reflex seizures is extremely variable due to wide clinical heterogeneity and mostly depending on the seizure disorder on which reflex seizures occur. The genetic background of reflex seizures is extremely heterogeneous and mostly unknown with no major gene identified. Indeed, reflex seizures and epilepsies have most of the features that make genetic research difficult such as clinical heterogeneity, heterogeneous aetiology, genetic heterogeneity, often complex mode of inheritance and possible gene-environment interactions. Finally, reflex seizures remain a fascinating field of research to explain physiopathology of epilepsies.

Ethical approval This article does not contain any studies with human or animal subjects performed by any authors.

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G Model

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Please cite this article in press as: Italiano D, et al. Generalized versus partial reflex seizures: A review. Seizure: Eur J Epilepsy (2014),