Reflex seizures, traits, and epilepsies: from physiology to pathology

Review

Reflex seizures, traits, and epilepsies: from physiology to pathology Matthias J Koepp, Lorenzo Caciagli, Ronit M Pressler, Klaus Lehnertz, Sándor Beniczky

Epileptic seizures are generally unpredictable and arise spontaneously. Patients often report non-specific triggers such as stress or sleep deprivation, but only rarely do seizures occur as a reflex event, in which they are objectively and consistently modulated, precipitated, or inhibited by external sensory stimuli or specific cognitive processes. The seizures triggered by such stimuli and processes in susceptible individuals can have different latencies. Once seizure-suppressing mechanisms fail and a critical mass (the so-called tipping point) of cortical activation is reached, reflex seizures stereotypically manifest with common motor features independent of the physiological network involved. The complexity of stimuli increases from simple sensory to complex cognitive-emotional with increasing age of onset. The topography of physiological networks involved follows the posterior-to-anterior trajectory of brain development, reflecting age-related changes in brain excitability. Reflex seizures and traits probably represent the extremes of a continuum, and understanding of their underlying mechanisms might help to elucidate the transition of normal physiological function to paroxysmal epileptic activity.

Introduction Epileptic seizures are referred to as reactive if they occur in association with a transient systemic perturbation such as intercurrent illness, sleep loss, or emotional stress, or as reflex if they are objectively and consistently evoked by a specific afferent stimulus.1 The cause is unequivocal if a specific stimulus results almost immediately in a seizure, and the type of reflex epilepsy is named according to the specific stimulus that precipitates seizures—for example, reading epilepsy or hot-water epilepsy.2 Reflex epilepsies are deemed to be focal in origin and are often acquired or the result of developmental structural brain abnormalities. These disorders typically involve the lateral sensorimotor cortex, which can lead, for example, to activation of the visual cortex by flashing lights or activation of large-scale brain networks through reading.3 The International League Against Epilepsy’s syndrome classification, which was published in 1989,4 listed only one reflex epilepsy syndrome—primary reading epilepsy—but a further three have been introduced since then: photosensitive occipital lobe epilepsy, other visual-sensitive epilepsies, and startle epilepsy.5,6 Complex stimuli and activities, in combination with cognitive processes, can increase the probability of a generalised seizure.7 These stimuli and activities may or may not lead to seizures with different latencies, which makes it difficult to establish a causal relation. Such reflex traits are predominantly seen in patients with genetic epilepsies and stereotyped seizure semiology (ie, the characteristics of seizures) of myoclonic or absence seizures despite rather diverse precipitating stimuli involving various cognitive, motor, or sensory systems.8 Reflex seizures and reflex traits are probably extremes of a continuum.9,10 Advances in neuroimaging, neurobiological concepts derived from the theory of non-linear dynamical systems, conceptual discussions,10 and a recent proposal for a new classification,6 which lists reflex epilepsies under syndromes “with less specific age relationship” mean that

it is timely to review the features of reflex seizures and epilepsies. In this Review, we focus on extrinsic and intrinsic seizure triggers in the most common reflex epilepsies, providing examples of simple and complex stimuli (visual stimulation and reading, respectively). We discuss the concepts of reflex seizures, reflex epilepsies, and reflex traits within interlinked physiological and epileptic networks, and describe common mechanisms that precipitate and inhibit seizures, which we postulate are learned responses within different physiological systems linked to maturational changes in brain development. The features of the most common reflex epilepsies are provided in the table.

Visual stimulation as a precipitating factor Photosensitivity refers to a condition in which epileptiform activity is induced by flickering lights, such as sun shining through tree branches, stroboscopic disco lights, and (coloured) flashes or backgrounds on television or produced by video games on computer screens. Photosensitivity as an EEG trait is characterised by the occurrence of a photoparoxysmal response during intermittent photic stimulation.21 Only a generalised response that consists of multiple spikes or spike-andwave discharges at a wide range of flicker frequencies is thought to be of clinical importance,21 although localised paroxysms can be the only finding in patients with photosensitive occipital lobe epilepsies.18 Photosensitivity is reported in about 10% of patients with epilepsy compared with less than 0·5% in otherwise healthy individuals,22 and is twice as frequent in female as in male individuals.23 In photosensitive patients, photic-induced ictal phenomenology included visual symptoms, such as colourful hallucinations, eyelid myoclonia with or without impaired consciousness, myoclonic jerks of the head, limbs and trunk, and absence seizures. Generalised tonic-clonic seizures can occasionally occur in cases of sustained exposure (5–10 s) to a stimulus.21 Photosensitivity is the distinctive hallmark

www.thelancet.com/neurology Published online November 25, 2015 http://dx.doi.org/10.1016/S1474-4422(15)00219-7

Lancet Neurol 2015 Published Online November 25, 2015 http://dx.doi.org/10.1016/ S1474-4422(15)00219-7 Department of Clinical and Experimental Epilepsy, University College London (UCL) Institute of Neurology, London, UK (Prof M J Koepp PhD, L Caciagli MD); National Hospital for Neurology and Neurosurgery, Queen Square, UK (Prof M J Koepp, L Caciagli); Department of Clinical Neurophysiology, Great Ormond Street Hospital, London, UK (R M Pressler PhD); Clinical Neuroscience, UCL Institute of Child Health, London, UK (R M Pressler); Department of Epileptology, University Hospital of Bonn, Bonn, Germany (Prof K Lehnertz PhD); Department of Clinical Neurophysiology, Danish Epilepsy Centre, Dianalund, Denmark (S Beniczky PhD); and Department of Clinical Neurophysiology, Aarhus University, Aarhus, Denmark (S Beniczky) Correspondence to: Prof Matthias J Koepp, UCL Institute of Neurology, 33 Queen Square, London WC1N 3BG, UK [email protected]

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Review

Age of onset

Cause

Trigger or reflex trait

Reflex seizures or other seizures

EEG features

Key references

Dravet syndrome (severe myoclonic epilepsy of infancy)

2–12 months

Genetic (mutation of SCN1A, rarely missense SCN2A mutation)

Photosensitivity common (40–60% of patients), pattern sensitivity or eye-closure also reported

Reflex myoclonus, initial febrile seizures and then complex partial seizures, atypical absences

Initially normal, fast generalised spike or multiple spike waves, focal abnormalities

Dravet et al (2012)11 and Bureau et al (2011)12

Myoclonic epilepsy in infancy

3–36 months

Presumed genetic, with positive family history for febrile seizures or epilepsy for about 30% of patients

Unexpected auditory or tactile stimuli

Spontaneous myoclonic seizures, a third of patients also have reflex myoclonus involving upper part of body

Ictal: generalised discharge of polyspikes, polyspikes and waves, or spikes and waves Interictal: usually normal

Guerrini et al (2012)13

Reflex myoclonic epilepsy in infancy

3–24 months

Presumed genetic, with positive family history for febrile seizures or epilepsy for about 50% of patients

Unexpected auditory or tactile stimuli

Reflex myoclonus, rare spontaneous myoclonic seizures

Ictal: generalised discharge of Verrotti et al (2013)14 polyspikes, polyspikes-andwaves, or spikes-and-waves Interictal: usually normal, brief generalised discharges in sleep

Startle epilepsy

1–16 years

Variety of localised or diffuse static brain pathology

Unexpected auditory more common than somatosensory, in turn more common than visual stimuli

Reflex tonic-myoclonic seizures, rarely complex seizures (at older age)

Interictal: heterogeneous Ictal: generalised electro-decremental response or rhythmic ictal activity (a or b frequency; appendix)

Yang et al (2010)15

Hot-water epilepsy

1–28 years

Presumed genetic, with Bathing in water with temperature >37·5°C, complex positive family history for up to 25% of patients exteroceptive somatosensory seizures

Complex partial or dyscognitive seizures (children older than 6 years), occasionally generalised tonic-clonic seizures

Interictal: temporal lobe abnormalities

Satishchandra (2003)16

Epilepsy with eyelid myoclonia (Jeavons syndrome)

2–14 years

Genetic, with positive family history in >50% of patients

100% of patients are photosensitive, with eye-closure sensitivity in the presence of light and fixation-off sensitivity (self-induced)

Eyelid myoclonia with or without absence seizures, eye-closure induced seizures, generalised tonicclonic seizures

High-amplitude 3–6 Hz generalised spike-and-wave discharges of mainly polyspikes (appendix)

Panayiotopoulos (2010)17

Photosensitive occipital lobe epilepsy

4–12 years

Presumed genetic

Focal (blurring of vision, Environmental light stimulation (video games more visual hallucinations, blindness, head and eye often than television) version, ictal vomiting)

Normal background, unilateral Guerrini et al (1995)18 or bilateral occipital spikes or spike-and-wave complexes, occasional ictal spread to temporal regions

Juvenile myoclonic epilepsy

12–18 years

Genetic heterogeneity

Photosensitivity, induction by praxis, language induction

Reflex myoclonus or myoclonic seizures, absences, generalised tonic-clonic seizures

Thomas et al (2012)19 Bilateral, synchronous paroxysms of 3–4 Hz spike or polyspike and slow-wave complexes (figure 3; appendix)

Reading epilepsy

12–20 years

Presumed genetic, with concordance in twins and first-degree relatives

Reading (aloud more than silent), language-related activities

Reflex myoclonus, predominantly orofacial, alexia, generalised tonicclonic seizures

Sharp waves, bilateral with left Koutroumanidis (1998)20 side preponderance, temporoparietal (figures 2, 3, appendix)

Table: Clinical and electrographic features of common reflex epilepsies

of photosensitive occipital lobe epilepsy, which is a focal reflex epilepsy syndrome,18 and Jeavons syndrome,24 which is characterised by eyelid myoclonia with or without impaired consciousness after eye closure. Photosensitivity is also frequently reported as a reflex trait in patients with genetic generalised epilepsies (formerly known as idiopathic generalised epilepsies), particularly juvenile myoclonic epilepsy, for which the incidence of photosensitivity ranges from 30%23 to 90%25 of patients. The incidence of photosensitivity in childhood absence epilepsy varies between 18% and 40%.23,26 These discrepancies could be owing to population differences in antiepileptic drug treatment, sleep deprivation, intermittent photic stimulation, and the classification of photoparoxysmal response.25,27 2

The high heritability of photosensitivity is widely recognised. Linkage to various susceptibility loci28,29 was not substantiated by a genetic meta-analysis,30 which suggests that it is a condition with pronounced genetic heterogeneity. However, evidence points to CHD2 as a novel gene implicated in photosensitive epilepsy, with patients exhibiting a higher prevalence of unique CHD2 variants than a control cohort representative of the general population. This gene encodes a DNA-binding protein involved in transcriptional regulation, but how its aberrant function might result in photosensitivity is unclear.31 Additionally, evidence from studies of clinical genetics has led to questions about the biological meaning of a rigid distinction between focal and generalised photosensitive epilepsies. Analyses of several

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Review

families with photosensitive epilepsy documented the coexistence of patients with idiopathic generalised epilepsies and photosensitive occipital lobe epilepsy in the same family, and also reported cases with electroclinical features that suggest overlap between idiopathic generalised epilepsies and photosensitive occipital lobe epilepsy.32 Pattern sensitivity is another form of visually induced epileptiform activity. Pattern-sensitive individuals exhibit epileptiform discharges and can have myoclonic seizures, absences, or generalised tonic-clonic seizures when exposed to patterns of stripes or lines alternating in sharp contrast to a background.33 Pattern sensitivity is closely related to photosensitivity and is very rare as an isolated disorder. Most patients with documented pattern sensitivity also show a photoparoxysmal response during intermittent photic stimulation, whereas up to two-thirds of individuals with photosensitivity are also pattern sensitive.34 Some patients have an unusual disorder in which they can self-induce seizures, and this ability is occasionally reported for patients who are photosensitive and pattern sensitive.35,36 Self-induction habits are often described as compulsive behaviours and include light seeking or gazing at patterns, which can be accompanied by eye fluttering, repeated hand waving, or head rocking. Magnetic-like attraction to light sources has also been reported.37 Whether these manoeuvres represent deliberate attempts to induce seizures or should be interpreted as part of seizure semiology, which suggests involvement of the cingulate gyrus, is debated.37

Ictogenic mechanisms in photic-induced seizures Precipitation of seizures in photosensitive patients inevitably depends on the activation of a critical neuronal mass in the occipital cortex.38 The distinguishing feature of photosensitive individuals seems to lie in intrinsic hyperexcitability of the visual cortex, which can predispose to large-scale neuronal synchronisation. Studies of visual evoked potentials in patients with photosensitive idiopathic generalised epilepsy39 and those with photosensitive occipital lobe epilepsy identified an abnormal excitability profile of the visual cortex, which coexisted with defective contrast gaincontrol mechanisms.40 Transcranial magnetic stimulation showed reduced phosphene thresholds in photosensitive individuals who were non-epileptic41 or who had idiopathic generalised epilepsies.42 Enhanced phase synchrony in the gamma band, seen using magnetoencephalography, is a characteristic finding in photic stimulation trials evolving in photoparoxysmal responses, suggesting the presence of defective gating mechanisms for high-frequency oscillatory processes.43 Gamma oscillation frequency was shown to correlate with concentrations of GABA in the visual cortex at rest.44 Cases of seizures induced by television or video games, such as the Pokémon incident,45 has highlighted the role

of coloured stimuli, especially those in the deep red band46 (wavelength of 680–700 nm). This information has led to identification of two distinct photosensitivity mechanisms: a quantity-of-light mechanism that depends purely on changes in luminance, and a wavelength-dependent mechanism that might contribute synergistically to evoke a photoparoxysmal response.47–49 Stimuli in the deep red band possibly owe their maximally provocative effect to a predominant stimulation of red cones, without concomitant recruitment of counteracting antagonist cones.46 In exceptional cases, ictal involvement of the visual cortex may not be a feature of light-induced seizures. Isnard and colleagues50 described a patient with mesiotemporal seizures provoked by sudden changes in light conditions with no early occipital ictal involvement and no photoparoxysmal response. However, subcontinuous occipital interictal spikes were detected, which suggests aberrant baseline activity of the visual cortex. Whether enhanced functional or structural connectivity between occipital and mesiotemporal lobes underlies seizure generation remains speculative. Although hyperexcitability of the visual cortex explains most ictal and EEG findings in patients with focal reflex epilepsies, such as photosensitive occipital lobe epilepsy, it does not entirely elucidate the range of photosensitivity-associated EEG and clinical correlates. First, photoparoxysmal responses are often generalised, and photic stimulation ultimately can elicit seizures with motor components, which are a particularly frequent reflex trait in patients with idiopathic generalised epilepsies.21 Second, studies using transcranial magnetic stimulation have documented abnormal response patterns of the motor cortex during photic stimulation in patients with idiopathic generalised epilepsies,51,52 but also in healthy participants with a photoparoxysmal response.41 Third, EEG has identified abnormally enhanced functional connectivity in the frontocentral cortical regions during photic stimulation.53 Fourth, white matter microstructural abnormalities are reported in frontoparietal areas.54 And finally, EEG-correlated functional MRI (fMRI) studies have detected photoparoxysmal response-related activations in the parietal and premotor cortices, and supplementary motor area.55,56

Networks involved in photic-induced seizures A purely localised paroxysmal activity underlies occipital photic-induced seizures, and evidence of contextual involvement of visual and frontoparietal cortices during generalised photoparoxysmal responses is compelling. However, the morphological and functional substrates of posterior-to-anterior ictal propagation during photoparoxysmal responses and photic-induced seizures with motor components are more uncertain. Electrophysiology studies in photosensitive baboons showed that the motor cortex is recruited shortly after activation

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of the occipital cortex, possibly via corticocortical or corticosubcortical pathways, and produces generalised myoclonic jerks via sustained hyperactivity of corticosubcortical loops involving the reticular formation and the thalamus.57 Further insights can be derived from the so-called photomyoclonic response,58 also known as the photic cortical reflex myoclonus.59 This condition, which affects healthy people and patients with various neurological disorders, including some epilepsy syndromes, is characterised by the occurrence of muscle jerks during photic stimulation—first involving periorbital muscles, with possible extension to muscles of the face, arms, and legs.58 It is thought to be the visual counterpart of the stimulus-sensitive myoclonus evoked by somatosensory afferents.59 Artieda and Obeso60 reported that photic stimuli in this disorder elicit a normal response in the visual cortex, with subsequent intrahemispheric and transcallosal propagation to the premotor areas, where aberrant activity patterns are evoked, ultimately leading to myoclonic jerks. This finding is in keeping with studies of photosensitive primates and supports a pivotal role for corticocortical connections in triggering motor responses during photic stimulation. Unfortunately, such detailed evidence for the spread of epileptic activity in humans is scarce. EEG–fMRI acquired during an inadvertently photoparoxysmal responsePanel: Case study—a patient with reading epilepsy A 19-year-old man was seen in the clinic having started to have seizures at the age of 16 years. The first seizure occurred in the classroom when he was reading aloud a text in French, a foreign language for the patient. The patient had facial jerks (myoclonus), which led to amusement among his classmates, and the teacher asked him whether he had consumed alcohol. The teacher offered him the option to stop reading; however, the patient insisted that he was fine and continued to read. A couple of minutes later, he had a generalised tonic-clonic seizure and he was admitted to the local hospital. Because of the triggering event, the episode was judged to be stress induced or psychogenic, and the patient was discharged without any further investigations. A second seizure occurred when the patient was studying at home, as he was silently reading a mathematical text that involved many formulas. His parents insisted that they wanted a second opinion, and the patient was referred to a specialist centre. Aside from these two seizure events, the history of the patient was unremarkable. His birth had been uncomplicated and his development normal through childhood and adolescence, and he had no family history of epilepsy. His neurological status was unrevealing and his cognitive status was normal. In view of the clear-cut events that triggered his seizures, a video-EEG recording was made with a special provocation method—reading aloud a difficult text in a foreign language (Hungarian). 6 min after starting the task, the patient had perioral myocloni with an EEG correlate (spike-and-slow-wave complexes). The reading was stopped. The patient was diagnosed with primary reading epilepsy. Antiepileptic drugs were not started, but the patient was instructed to take breaks while reading, to avoid reading aloud, and to stop reading as soon as he felt jerks or any discomfort. During the past year, the patient has had two minor episodes with short-lasting facial jerks but no further generalised tonic-clonic seizures.

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evoked generalised tonic-clonic seizure emphasises the importance of thalamic activation,61 while an EEG–fMRI study in patients with juvenile myoclonic epilepsy suggests that the putamen might act as a mediator between the visual and motor areas during generalised photoparoxysmal responses.56 Vollmar and colleagues62 used diffusion-tensor tractography and detected increased structural connectivity between the occipital cortex and supplementary motor area in patients with juvenile myoclonic epilepsy, which was more pronounced in photosensitive patients. In an electrical source imaging analysis, corticocortical propagation from the occipital to the premotor cortex via the intraparietal sulcus was shown to underlie photoparoxysmal responses, whereas evolution of such responses into a generalised tonic-clonic seizure preferentially implicated relays from the occipital cortex to the thalamus and from the thalamus to the frontoparietal areas.63 It is therefore tempting to speculate that corticocortical and corticosubcortical visuomotor pathways might coexist in humans and can be recruited differentially: bursts of generalised photoparoxysmal responses with no motor output might preferentially imply a corticocortical transmission, while a seizurespecific combination of corticocortical and corticosubcortical connections might underlie the occurrence of seizures with myoclonic or tonic-clonic components. Little is known about the mechanistic underpinnings of photic-induced absence seizures, which are especially prominent in pattern-sensitive patients.64 However, the presence of a corticosubcortical interplay could be postulated in view of the well described patterns of cortical and thalamic activity during typical absences.65–67

Reading epilepsy as the prototypical reflex epilepsy Reading is a complex cognitive process that includes visual analysis, memory functions, and grapheme-tophoneme conversion, followed by articulation and acoustic monitoring. Debate continues as to precisely which cognitive step or component of the reading process is epileptogenic, but there is substantial variability between patients, with eye movements, comprehension, emotional content, production of speech, and proprioceptive feedback all reported as effective triggers (panel).68 Different linguistic tasks—ie, reading, speaking, and writing—can lead to the same seizure type of involuntary jaw jerks, sometimes followed by staring. Whether this condition represents a separate syndrome, also called language-induced epilepsy,69 or part of a range of language-related epilepsies, is unclear, as these other linguistic modalities are also effective in some patients with a diagnosis of reading epilepsy.70,71

Ictogenic mechanisms in reading-induced seizures Recruitment of a critical mass of language-related areas, with synchronisation and subsequent spreading of excitation in response to the epileptogenic stimulus,

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might precipitate a clinical seizure. Increasing the complexity of epileptogenic stimuli might enable such recruitment. Increasing the difficulty, complexity, emotional content, or duration of tasks can enhance the chances of electrographic or clinical activation in patients with reading epilepsy, which suggests that maximal neuronal interaction is at least a facilitating factor.72 Such recruitment might involve the participation and interaction of several cortical and subcortical structures activated by reading or by the emotional content of the reading material (involving the mesiotemporal lobe, amygdala, and limbic structures). It might rely on existing and reorganised functional links between brain regions and need not be confined to physically contiguous brain sites or established neuronal links. This multi-site mechanism of recruitment would be consistent with the concept of variable hyperexcitability at many cortical and subcortical levels, potentially allowing any combination of asymmetrical or symmetrical, generalised, regional, and focal discharges.73 The concept is also consistent with the heterogeneity of clinical phenomena encountered in patients with reading epilepsy and the variable efficacy of various, particularly emotionally charged, linguistic stimuli as triggers of seizures.20,74

Networks involved in reading epilepsy Structural neuroimaging is usually normal in patients with reading epilepsy; however, Archer and colleagues75 reported a local structural abnormality in two of three patients with reading epilepsy: an unusual gyrus branching anteriorly off the left central sulcus, which colocalised with the brain regions activated by the working memory component of the reading task and with increased spike-related activity on EEG-correlated fMRI. In nine patients with reading epilepsy, Salek-Haddadi and colleagues70 reported ictal fMRI activations within a cortical area (the right medial frontal gyrus) and a subcortical area (the left putamen) during readinginduced seizures. Although no gross abnormalities in cognitive or motor organisation were seen, most of the cortical areas were close to or directly overlapping with the areas activated by cognitive and motor functions (figure 1). These subcortical areas might be linked closely to areas of hyperexcitable cortex within the normal reading network or to physiological motor function. Analyses of data from spike-triggered EEG-fMRI and magnetoencephalography show substantial activation in the left precentral gyrus, near or directly in Brodmann area 6, and bilaterally in the central sulcus and globus pallidus (figure 2, panel). Brodmann area 6 seems to be the area that relates the particular cognitive activation (grapheme-to-phoneme transition) to seizure activity. This area of maximum blood oxygenation level-dependent response was also functionally connected to a network of cortical and subcortical regions. Effective connectivity analysis during

reading-provoked seizures suggested that the neuronal states of the left piriform cortex and left Brodmann area 6 were driving the activity within the thalamus, claustrum, and right inferior frontal gyrus.76 This analysis supports the important role of deep cortical structures, particularly the frontal piriform cortex (or the primary olfactory cortex), as key regions that enable the occurrence of seizures. These regions are involved in the propagation and modulation of seizure activity, as previously shown in animals77 and humans.78

Reflex seizures and traits in different epilepsy syndromes Infancy and childhood Reflex seizures have been described in about 30% of patients with myoclonic epilepsy in infancy (formerly known as benign myoclonic epilepsy in infancy), an epilepsy syndrome first described by Dravet and Bureau79 that is characterised by the onset of myoclonic seizures before the age of 3 years in otherwise healthy children, with excellent response to treatment and remission of seizures.13,14,80,81 This clinical syndrome, referred to as reflex myoclonic epilepsy in infancy, has been proposed as a separate nosographic entity, with myoclonic seizures triggered by sudden and unexpected acoustic or tactile stimuli.14,82 Surprise is fundamental in triggering these attacks: children do not have a reflex seizure if they expect the stimulus. Photic stimulation can provoke seizures in a small proportion of patients, but photosensitivity as a pure EEG event is very rare.80 The threshold for reflex seizures increases with ambient levels of noise and the child’s level of attention, and decreases with drowsiness. The interictal EEG is normal, and the ictal EEG is characterised by generalised bursts of polyspikes, polyspikes-and-waves, or spikes-andwaves, similar to those seen in myoclonic epilepsy in

Figure 1: Functional imaging in a patient with reading epilepsy Functional MRI blood oxygenation level (BOLD)-dependent activation in a patient with reading-induced orofacial reflex myocloni, indicating maximum BOLD response at Brodmann area 6 (green), co-registered with languagerelated activations (blue) and motor jaw movements (red).

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infancy. Family history is often positive, and a complex polygenetic inheritance mechanism is suspected. Outlook with respect to long-term freedom from seizures is good, with sodium valproate the most effective drug. Seizure outcomes are excellent, but cognitive outcomes are much less certain, with cognitive difficulties in onethird of affected children.81 A sudden and unexpected acoustic noise is also the most frequent triggering stimulus for startle seizures, although they can also be provoked by somatosensory or visual stimuli. As in reflex myoclonic epilepsy in infancy, the surprise is thought to represent the internal condition that sets off the seizure. Startle seizures occur across a wide age range, with onset nearly always in the first decade of life. These seizures are invariably associated with a structural brain abnormality, typically prenatal and perinatal lesions. Startle seizures are brief, symmetrical, and often include axial tonic posturing that results in falls, but they can also be partial, atonic, tonic-clonic, or myoclonic.15 Widespread frontotemporal or frontoparietal

A FP2–F4 F4–C4 C4–P4 P4-O2 Fp1-F2 F2-C2 C2-P2 P2-O1 Fp2-F8 F8-T4 T4-T8 T8-O2 Fp1-F7 F7-T2 T2-T5 ECG

C

Figure 2: EEG, functional MRI, and magnetoencephalography in a patient with reading epilepsy EEG recorded inside the MRI scanner (A) shows bifrontal discharges (arrows) during reading-elicited orofacial reflex myoclonus. Statistical parametric maps of functional MRI blood oxygenation level-dependent response (B) show significant subcortical activation (p<0·05, corrected for multiple comparisons) associated with reading-induced seizures on covert reading. Magnetoencephalography (C) recorded in the same patient at a different time shows predominantly frontal activity during orofacial reflex myocloni extending pre-centrally into Brodmann area 6. ECG=electrocardiogram.

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Adolescence and adulthood Reflex epileptic traits have been described in patients with progressive myoclonic epilepsies. Distinguishing between progressive myoclonic epilepsies and idiopathic generalised epilepsies can be difficult in the initial stage, when EEG background activity is still normal and cognitive or neurological deterioration has not yet manifested. Lafora disease can resemble juvenile myoclonic epilepsy, and neuronal ceroid lipofuscinosis can mimic myoclonic-astatic epilepsy.87 Up to 93% of patients with juvenile myoclonic epilepsy report seizures precipitated by external factors.88,89 Apart from photosensitivity, three other reflex epileptic traits are common in patients with juvenile myoclonic epilepsy.90 First, eye-closure sensitivity usually manifests with eyelid myocloni or epileptiform EEG discharges that appear within 2 s after intended eye closure but are not elicited by physiological blink, which suggests involvement of the supplementary motor area.91 Second, language activities (such as speaking and reading) and counting can trigger epileptiform EEG discharges and induce myocloni in up to 30% of patients with juvenile myoclonic epilepsy (figure 3).90,92–94 And third, induction by praxis, in which seizures are precipitated by complex tasks of visuomotor coordination and decision making (such as writing, drawing, and playing chess, card, or computer games), is reported in about 20% of patients with juvenile myoclonic epilepsy, with a male preponderance.89,95–97

Networks involved in reflex traits

T5-O1

B

networks have been described during startle seizures,83 with prominent involvement of the motor cortex, in addition to the premotor cortex84 and supplementary motor area.85 Distinctive EEG and electromyographic findings allow differentiation between startle epilepsy and non-epileptic startle syndromes.86

Reflex seizures in patients with epilepsy syndromes occur after several minutes of cognitive activity, which suggests that a critical amount of neuronal activity has to be reached in the physiologically involved networks for ictogenesis to take place. Myocloni are generally thought to occur in the muscles involved in the precipitating activity,95 such as orofacial myocloni for induction by language, and hand or upper limb myocloni for induction by praxis—“it is the active hand that jerks”.97 However, a video-EEG study did not substantiate this relation.90 Seizures can also be induced by thinking activities without an obvious motor component, although this phenomenon should be regarded as a variant of induction by praxis, as the index tasks also involved spatial thinking, which makes the difference from conventional praxis less significant.95 Vollmar and colleagues98 examined induction by praxis in patients with juvenile myoclonic epilepsy using an fMRI paradigm of visuomotor coordination and working

www.thelancet.com/neurology Published online November 25, 2015 http://dx.doi.org/10.1016/S1474-4422(15)00219-7

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memory. They reported increasing co-activation of the primary motor cortex and supplementary motor area with increasing cognitive demand, and increased functional connectivity between the motor system and frontoparietal cognitive networks.98 The concomitant physiological deactivation of the default mode network during the cognitive tasks was not only impaired in patients with juvenile myoclonic epilepsy, as a similar trait was seen in unaffected siblings.99 The supplementary motor area might have a specific role as a relay for abnormal functional connectivity between the cognitive system and motor system in patients with juvenile myoclonic epilepsy. The reported changes in microstructural connectivity of the mesial frontal region might represent the anatomical basis for cognitive triggering of motor seizures in patients with juvenile myoclonic epilepsy and provide an explanatory framework for several of the reflex traits in patients with juvenile myoclonic epilepsy, linking seizure signs, neurophysiology, neuropsychology, and imaging findings.62 First, increased connectivity between the prefrontal cortex and the central region enables cognitive activity to elicit epileptiform discharges in the central region and trigger myoclonic jerks.97 Second, reduced connectivity between the pre-supplementary motor area region and the frontopolar cortex might be the anatomical basis for impairment of frontal lobe function in patients with juvenile myoclonic epilepsy.100 And third, increased connectivity between the supplementary motor area and the occipital cortex, which is stronger in photosensitive patients, might explain the effect of photic stimulation in eliciting frontocentral discharges and myocloni.62 Cognitive activation and myoclonic seizures are both likely to be manifestations of widespread cortical hyperexcitability in patients with juvenile myoclonic epilepsy, in line with the concept of system epilepsies.101 Transcranial magnetic stimulation showed increased cortical excitability, particularly in anterior brain regions, after sleep deprivation and during the morning hours.102 This suggests the presence of abnormalities in intracortical inhibitory networks103 and might explain the effectiveness of antiepileptic drugs that modulate GABA-mediated neurotransmission in treating patients with juvenile myoclonic epilepsy. Mechanisms of reflex ictogenesis in progressive myoclonus epilepsies are different from those in juvenile myoclonic epilepsy and can be ascribed to degenerative changes involving many cortical regions, which disrupt whole-brain networks and ultimately result in enhanced excitation and deficient inhibition.104,105 Hyperexcitability of the visual cortex and sensorimotor cortex, as shown by giant evoked potentials and enhanced long-latency reflexes, leads to cortical reflex myoclonus in patients with progressive myoclonus epilepsies.106,107

and neuroimaging findings in presumed focal reflex epilepsies are compared with findings from reflex traits in generalised epilepsies.7 Patients with either focal or generalised reflex seizures have regions of cortical hyperexcitability that overlap or coincide with the development of physiological networks engaged during specific sensorimotor and cognitive activities. After sustained growth in early childhood, brain maturation during late childhood includes thinning of the grey matter, which starts over the primary sensorimotor areas.108,109 This synaptic pruning has a posterior-toanterior progression in the frontal lobes during adolescence, which results in increased functional segregation. Anatomically adjacent but functionally different brain regions become less connected to each other locally but increasingly connected to other hubs of their respective functional network.110 Age-related changes in the semiology and topography of physiological networks involved in triggering reflex seizures at different stages of brain development suggest that reflex seizures and epilepsies are closely linked to this posterior-toanterior trajectory of brain maturation. During early stages of brain maturation, simple auditory, visual, or sensory stimulation results almost exclusively in reflex myoclonic seizures, or tonic or atonic seizures, indicative of the low level of functional segregation at this stage of brain development. At later stages of brain development with greater functional segregation, if stimulation is mainly sensory, the area of hyperexcitability can be

Reflex seizures and epilepsies: beyond the focal-versus-generalised dichotomy

Figure 3: Orofacial reflex myoclonus in a patient with juvenile myoclonic epilepsy EEG and surface electromyography of the left and right orbicularis oris muscle (electromyograms 5 and 6), recorded while the patient was reading a difficult text, show a myoclonus (A). Although the EEG paroxysm is bilateral (generalised), the three-dimensional voltage map (B) at onset of the myoclonus shows a left-sided topographic distribution. The dipole modelling (C) suggests a source at onset corresponding to Broca’s area.

Previous distinctions between focal and generalised reflex epilepsies seem artificial when the electrophysiological

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Figure 4: Patterns of ictogenesis during reflex seizures: a schematic model Intermittent photic stimulation (IPS) elicits localised photoparoxysmal responses and focal reflex seizures because of activation of a critical neuronal mass in a hyperexcitable visual cortex (highlighted green). During generalised photoparoxysmal responses and photic-induced seizures with motor components, ictal activity spreads to the motor cortex (depicted in red), possibly through corticocortical and corticosubcortical pathways (green arrows), and provokes myoclonic jerks via the aberrant entrainment of corticothalamic loops (see areas highlighted in red and red arrows). Seizures induced by reading (yellow) and other cognition-guided tasks (induction by praxis, blue) rely on the abnormal activation of specific subregions within Brodmann area 6 (blue/yellow), from which ictal activity spreads to the primary motor cortex and thalamus (blue and yellow arrows) and causes myoclonus. The sustained hyperactivation of thalamocortical circuits might represent a common endpoint and explains why different precipitating stimuli, when leading to seizures with motor components, ultimately result in rather stereotypical ictal symptomatology.

restricted and activity does not necessarily spread beyond the stimulated region—whether it is the occipital lobe causing visual hallucinations in patients with photosensitive occipital lobe epilepsy18 or the temporoparietal lobe causing temporal lobe seizures in patients with hot-water epilepsy.16,111 During adolescence and adulthood, activation of widespread, well connected networks by complex sensory, motor, or cognitive tasks results in generalised seizures. Examples include activation of the supplementary motor area, prefrontal cortex, and motor cortex through induction by praxis in patients with juvenile myoclonic epilepsy,95,97 activation of the inferior frontal and temporoparieto-occipital cortex, predominantly on the left, in patients with reading epilepsy,73 and activation of the orbitofrontal and lateral and mesial temporal areas, predominantly on the right, in patients with musicogenic seizures.112,113

From cognitive function to seizure activity Methods and concepts derived from the theory of nonlinear dynamical systems and bifurcation theory can help to shed light on the aforementioned findings114–117 and to derive improved mathematical-physical models of generation, spread, and termination of seizures.118–123 Nevertheless, how external or internal stimuli can cause a transient, harmless modification of cortical activity in the healthy brain, but induce massive synchronous discharges in the susceptible brain, leading eventually to a seizure, remains unclear. Epileptic seizures involve paroxysmal bursting of neurons in local circuits,124,125 but the clinical manifestations of seizures result mainly from the spread of activity from local circuits to involve adjacent and remote brain regions. 8

Widespread neuronal populations are also activated in normal cognitive function, but the recruitment of cortical networks and populations during seizure activity occurs in a non-discriminant pathological fashion, reflecting a profound change in the state of the brain’s dynamical system.114,126,127 Evidence that seizures are not merely an increase in synchronisation between neurons and that hypersynchrony is not a necessary precondition for seizure development is increasing.114,128,129 Modelling studies indicate that seizures in general can be triggered by changes in network parameters or by inputs not evident to an observer.130,131 By the same token, seizures might even represent a self-initiated and self-terminated event, the emergence of which is enabled by topological properties of the neuronal networks118,132–134 or by the brain’s bistability or multistability.124,135–137 Seizures might also be enabled by criticality—the balance (or loss of balance) of the epileptic brain at the border between order and disorder.138–140 These theoretical considerations are paralleled by clinical findings that seizures in patients with reflex epilepsies are precipitated by a particular influx of afferent impulses and can be induced by a wide range of external stimuli or internal cognitive processes that are not always apparent to the patients themselves,141 with rhythmic stimulus input to a hyperexcitable cortex ultimately resulting in seizures (figure 4). For juvenile myoclonic epilepsy, we propose a trigger mechanism of cognitive activity, with increasing beta rhythms generated in cognitively activated areas and spreading into the motor system, where resonance effects with intrinsic motor cortex frequencies can ultimately result in polyspikes and myoclonic jerks.97 More demanding tasks recruit larger neuronal networks and are therefore more likely to reach the critical mass for such spreading. The increased provocative effect of combined cognitive and motor tasks could stem from the fact that such tasks elicit activations with similar frequencies in cognitive and motor networks, which in turn increases the likelihood of interferences between them. Whether or not a neuronal population becomes active depends on the particular properties of an input—for example, photoparoxysmal responses are only induced by a specific frequency range. A particular population responds to that input preferentially and becomes persistently activated, while the activity of other populations remains at baseline levels.140 Although the conditions needed to induce seizures can be very different, the electrophysiological signature of reflex seizures is remarkably similar consistent and stereotyped: fast oscillations and spikes and clinical manifestations of predominantly myoclonic jerks. Nearly every brain region in an individual could be driven out of the healthy state to produce reflex seizures depending on the severity and widespread diffusion of the process leading to the seizure. The difference between the median prevalence of lifetime epilepsy (5·8 per 1000 members of the population in developed countries)

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and the prevalence range of single non-febrile seizures (1·5–5 per 100) suggests that to have seizures is inherent to the human brain.142 However, in the healthy brain, normal activities are far from the seizure threshold and need strong external interventions to reach the seizure state, such as an electroconvulsive shock. By contrast, the functional or structural reorganisation of underlying neuronal networks in pathological conditions can move normal activities closer to a lowered seizure threshold, increasing the likelihood of recurrent seizures. Many factors could potentially move the system in such a way, which would explain why network reorganisations are often dependent on brain region, epilepsy model, time of reorganisation, and type of epilepsy.143 Hence, a large number of possible combinations can lead to the same functional outcome: bringing normal brain activities closer to the seizure threshold. Structural changes and specific inputs can play an important part in changing the state from one to another, acting as a switch between normal and pathological activity. This explains the particular susceptibility to focal reflex seizures in the presence of a structural lesion, and is also valid for seizures in general. More permanent changes caused by repetition—ie, learning144—or trauma might bias activity towards the pathological transition to a pathological state.

Seizure precipitation and inhibition: two sides of the same coin The reverse of seizure precipitation is seizure inhibition, the two being exchangeable modes of response, with the common denominator of strong reactivity of the ictogenic system to external factors. In reflex epilepsy, pathological activity is induced by specific stimuli, and the same type of stimulus is capable of terminating seizure activity once initiated or preventing seizures from occurring, depending on the specific dynamics of the seizure. Modelling studies have shown that excitation of multiple neuronal populations by inputs with specific properties could also prevent the transition of the network to a pathological state;145,146 for example, musical stimuli have been shown to excite strongly a widely distributed population of neurons associated with working memory networks.147 Musicogenic seizures can be generated by external stimulation with particular music, which is a precipitating factor in individuals with musicogenic epilepsies; conversely, other music has been reported to prevent or terminate epileptiform activity.112,113,147 Likewise, electrical stimulation during presurgical cortical mappings can produce repetitive excitatory discharges, whereas delivery of a second short stimulus can occasionally stop such discharges. Electrical stimulation might be most effective in treating seizures with this particular type of dynamics.

Relevance of reflex seizures for the treatment of spontaneous seizures Understanding how reflex seizures can be inhibited might open avenues to the control of spontaneous

seizures. Gowers148 wrote about the arrest of spontaneously occurring seizures by sensory, motor, and other stimuli, and the interruption of incipient seizures by olfactory stimulation has been described in detail.149–151 Yanagisawa and colleagues152 reported suppression of interictal spikes by movement in patients with neocortical sensorimotor epilepsy. In patients with juvenile myoclonic epilepsy, the most frequently reported seizure-inhibiting activities were trying to keep calm and practising sport.153 VideoEEG studies of precipitation of epileptiform discharges by neuropsychological tasks suggested an inhibitory effect of such tasks in a surprisingly large proportion of patients (64–90%).92,94,154 In all of these studies, inhibition was arbitrarily defined as a reduction in the frequency of epileptiform discharges of greater than 50%, compared with the average frequency at baseline. A study that took into account spontaneous fluctuation of epileptiform discharges showed that inhibition occurred in 29% of patients and precipitation in 18%.90 However, unlike precipitation, inhibition was not task specific and was related to global cognitive activation or attention. This is also supported by the high incidence of inhibitory effects among patients with other types of epilepsy.92 Both Gowers148 and Efron149 noted the importance of the timing of the stimulus and suggested that the arresting stimulus should not be delivered too late to stop a seizure. The response depends on the state of the stimulated system at the time of stimulation, which is related to the amount of build-up of seizure activity and whether the tipping point has been reached within the individual ictogenic system. Difficulties in estimating the amount of build-up of seizure activity and in defining the tipping point are highlighted by the so-far futile attempts to predict seizures reliably using complex mathematical tools for EEG analysis.155–158 Event-driven stimulation systems thus attempt to terminate spontaneous seizure activity only once it has been initiated—for example, closed-loop responsive cortical stimulation systems and vagal nerve stimulation using a cardiac-based seizure detector.159 Reflex seizures could provide an ideal model to optimise seizure prediction algorithms and validate neuromodulation and neurostimulation technologies. Available treatment approaches for reflex seizures, as for all epilepsies that cannot be treated surgically, rely on reducing hyperexcitability or increasing inhibition using broad-spectrum anticonvulsant treatments; sodium valproate, benzodiazepines, and levetiracetam are deemed particularly effective for reflex seizures irrespective of the underlying epilepsy syndrome, whereas lamotrigine, carbamazepine, oxcarbazepine, gabapentin, pregabalin, and tiagabine are known to exaggerate myoclonic jerks.160 Lifestyle changes and avoidance of seizure precipitants are equally important: non-pharmacological treatments used for photosensitive patients, such as wearing special glasses, often have a beneficial effect. The relative ease with which drugs can be used to control all kinds of seizures in about two-thirds

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Search strategy and selection criteria We searched PubMed from Jan 1, 1990, to July 31, 2015, using the terms (and synonyms) “reflex epilepsy”, “reflex seizure”, “photo-sensitivity”, “praxis-induction”, and “metabolic syndrome”, in combination with the key terms “epilepsy”, “triggers”, “brain MRI”, and “prediction”. We only searched for papers published in English. We also searched reference lists of identified papers and extracted relevant papers from our records. Subsequently, we selected mainly observational studies or systematic reviews reported in core clinical journals during the past 5 years. Our final selection was made on the basis of originality and relevance to topics covered in this Review.

of patients,161 particularly those with idiopathic generalised epilepsies,162 has meant that physicians have not been inclined to ask about triggering factors.

Summary The study of reflex seizures can provide a framework for understanding seizure prodromes and the generation and termination of seizures, and can explain specific triggers that interact with sustained cortical activity. The stimulatory input and areas of hyperexcitability might be different for different seizure types and depend on the stage of brain maturation at the age of onset (table), but the mechanisms are ultimately the same, implying activation of a critical neuronal mass, supported and sustained by corticosubcortical and thalamocortical pathways that eventually result in a seizure. Ictogenesis is initiated once seizure-suppressing mechanisms fail and the tipping point or threshold of slow, reversible changes has been reached.

Conclusions Reflex epilepsies are unique, because the mechanism of excitation within an identifiable neural system is known to the individual, but identifying the tipping point— when normal physiological activities or sensations lead to recurrent extreme events—is still an observational challenge. In some cases, such as in patients with photosensitive epilepsy, changes in the excitability state of the underlying networks can be uncovered before changes in EEG activity are evident, but changes that precede a seizure might be unobservable, resulting in apparently spontaneously occurring seizures. In this context, the distinction between reflex and non-reflex might relate more to observational ability than to objective fundamental difference.9 Bickford, who first described primary reading epilepsy in 1956,163 emphasised the need for careful history taking to identify environmental precipitating factors in patients with seizure disorders:164 “Clinicians (should) be constantly on the alert for precipitating factors in their patients’ seizures. In many instances, these will not be 10

discovered unless specific questions are asked covering the various categories of precipitation…The electroencephalographer will also miss the diagnosis in these cases, unless he is prepared to record the electroencephalogram under varied conditions of stress in contrast to the classical recording condition of relaxation and the more recent recommendation of sedation and sleep.” Bickford’s advice is reflected in the latest guidelines on the methods of photic stimulation.165 Understanding how specific sensory stimuli or cognitive processes can play a part in ictogenesis and how they are connected and related to seizure symptomatology might help us to define the tipping point—from physiology to pathology—and lead to potential therapeutic interventions for prevention of reflex seizures. In the model of reflex epilepsy presented here, pathological activity is induced by specific stimuli, but those specific inputs are also capable of terminating seizure activity once initiated or of preventing the occurrence of seizures, depending on the specific dynamics of the seizure. In the case of terminating seizure activity once initiated, this might have relevance to the mechanisms involved in attempts to control seizures through electrical stimulation of the cortex. Reflex seizures represent an ideal model to study the dynamics of seizure initiation and termination. Future in-depth studies using advances in electrophysiology and imaging data acquisition and analysis techniques will help to elucidate not only in individual patients with reflex seizures the tipping-point from physiological to pathological activity, but also whether a build-up of activity, often described by patients and their relatives, can be measured and objectified in people suffering from spontaneous seizures. Contributors MJK planned the Review, prepared the first draft, and created figures 1 and 2. All authors commented on the first draft and on subsequent versions of the Review. LC focused on visual stimulation and created figure 4. SB provided the paragraphs on reflex epileptic syndromes in adults and the EEGs for figure 3 and the supplementary figures. RMP focused on reflex epilepsy syndromes in children and created the table. KL refined the ideas on epileptic networks and the models of seizure precipitation and inhibition. Declaration of interests RMP has received consultancy fees from UCB, outside the submitted work. MJK has received consultancy fees from UCB, EISAI, Novartis and GE, outside the submitted work. We declare no competing interests. References 1 Blume WT, Lüders HO, Mizrahi E, Tassinari C, van Emde Boas W, Engel J Jr. Glossary of descriptive terminology for ictal semiology: report of the ILAE task force on classification and terminology. Epilepsia 2001; 42: 1212–18. 2 Wolf P, Koepp M. Reflex epilepsies. In: Aminoff MJ, Boller F, Swaab DF, eds. Handbook of clinical neurology. Amsterdam: Elsevier, 2012: 257–76. 3 Striano S, Coppola A, del Gaudio L, Striano P. Reflex seizures and reflex epilepsies: old models for understanding mechanisms of epileptogenesis. Epilepsy Res 2012; 100: 1–11. 4 Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989; 30: 389–99.

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