The Precipitating Stimulus

The stimulus evoking an epileptic seizure is specific for a given patient and may be extrinsic, intrinsic or both.

I. Extrinsic stimuli are:

• simple, such as flashes of light, elimination of visual fixation and tactile stimuli
• complex, such as reading or eating.

The latency from the stimulus onset to the clinical or EEG response is typically short (1–3 s) with simple stimuli and long (usually many minutes) with complex stimuli.

II. Intrinsic stimuli are:

• elementary, such as movements
• elaborate, such as those involving higher brain function, emotions and cognition (thinking, calculating, music, or decision-making).

The Response to the Stimulus

The response to the stimulus consists of clinical and EEG manifestations, alone or in combination. EEG activation may be subclinical only, that is without overt clinical manifestations. Conversely, ictal clinical manifestations may be triggered without conspicuous surface EEG changes.

Reflex seizures may be:

• generalised, such as absences, myoclonic jerks or generalised tonic clonic seizures (GTCS)
• focal, such as visual, motor or sensory.

Reflex generalised seizures occur either independently or within the broad framework of certain epileptic syndromes. The same patient in response to the same specific stimulus may have absences, myoclonic jerks and GTCS alone, or in various combinations. Usually, absences and myoclonic jerks precede the occurrence of GTCS. Patients may have reflex and spontaneous seizures.

Myoclonic jerks are by far the most common, and manifest in the limbs and trunk or regionally, such as in the jaw muscles (reading epilepsy) or the eyelids (eyelid myoclonia with absences).

GTCS may occur ab initio constituting the first clinical response or more commonly they follow a cluster of absences or myoclonic jerks. Secondarily GTCS to focal, simple or complex, seizures are much less common than primarily GTCS. Reflex absence seizures are common constituting the response to a variety of specific stimuli, such as photic, pattern, fixation-off, proprioceptive, cognitive, emotional or linguistic.⁸ It is recognised that absences are also common in self-induction.

Focal seizures are exclusively seen in certain types of reflex focal or lobular epilepsy, such as visual seizures of photosensitive lobe occipital epilepsy or complex focal temporal lobe seizures of musicogenic epilepsy.

The electroclinical events may be strictly limited to the stimulus-related receptive brain region only (such as photically-induced EEG occipital spikes), spread to other cortical areas (such as in photosensitive focal seizures that propagate in extra-occipital areas) or become generalised (e.g. in photoparoxysmal responses of IGE). Further, the electroclinical response to a specific stimulus may correspond to activation of regions other than those of the relevant receptive area, such as in primary reading epilepsy, which manifests with jaw myoclonic jerks. Conversely, reading may elicit electroclinical events strictly confined to the brain regions subserving reading, such as alexia associated with focal ictal EEG paroxysms. There is great variability in the interindividual responses to the same stimulus.

The role of the EEG is fundamental in establishing the precipitating stimulus in reflex epilepsies, because it allows subclinical EEG, or minor clinical ictal events to be reproduced on demand by application of the appropriate stimulus. However, there are cases in which the stimulus–seizure relationship is difficult to document as in video game-induced seizures (VGS; page 455). Only 70% of these patients have EEG confirmation of photosensitivity with photoparoxysmal responses (PPR) on IPS and, in the other 30%, seizures may be due to a single or a variety of other precipitating or facilitating stimuli. Sleep deprivation, mental concentration, fatigue, excitement, borderline threshold to photosensitivity, fixation-off sensitivity (FOS), proprioceptive stimuli (praxis), or more complex visual or auditory stimuli, alone or in combination, are all possibilities that are difficult to document objectively with EEG.^9–11 There are also epileptic syndromes in which EEG ‘epileptogenic activity’ is consistently elicited by a specific stimulus with no apparent clinical relevance. This is exemplified by certain cases of benign focal childhood seizures in which somatosensory (tapping) or visual (elimination of fixation and central vision) stimuli consistently elicit spike activity, though these children appear to have ‘unprovoked’ seizures, which mainly occur during sleep.¹¹

Table 13.1 lists the types of precipitating stimuli, reflex seizures and epileptic syndromes according to the new ILAE diagnostic scheme.³

Table 13.1

Precipitating stimuli and reflex seizures/syndromes listed in the new ILAE classification scheme

Table 13.2 is an analytical list of reflex seizures, related reflex epileptic syndromes and their precipitating stimuli. Some of these, such as photosensitivity, are well known and common, but others are extremely rare in humans, though they may be common in animals, such as audiogenic seizures.

Table 13.2

Reflex seizures, related reflex epilepsies and the precipitating stimuli (for details see refs )

In this chapter, common and principal forms of simple and complex reflex seizures and epilepsies are reviewed with particular emphasis on the syndromes listed in the new ILAE diagnostic scheme.³ Classical references or reviews are cited for the remainder.

Visually induced seizures and epilepsies are the commonest of the reflex epilepsies.^{4–6;12–15} Visual seizures are triggered by the physical characteristics of the visual stimuli and not by their cognitive effects. Photosensitivity and pattern sensitivity are the two main categories (with frequent overlap) of simple reflex epilepsies in which there is a short time interval (typically within seconds) between stimulus and response. These are detailed below.

Photosensitive Seizures and Epileptic Syndromes

Clinical note

Photosensitivity, the propensity to seizures induced by light, is a genetically determined trait that may be asymptomatic throughout life or manifest with epileptic seizures.^{12;15;60–62}

‘Photosensitive epilepsy’ is a broad term comprising all forms of heterogeneous epilepsies in which seizures are triggered by photic stimulation. It is not an epilepsy syndrome. EEG photosensitivity, that is provocation of PPR by IPS (Figure 13.1), may or may not be associated with clinical photosensitivity. Some recognised syndromes of IGE, such as juvenile myoclonic epilepsy, show a high incidence of clinical or EEG photosensitivity. A high prevalence of photosensitivity is also found in certain forms of severe epilepsy, such as Dravet syndrome (70%),⁶³ Unverricht-Lundborg (90%)⁶⁴ and other progressive myoclonic epilepsies.⁶⁴

Figure 13.1

Examples of photoparoxysmal responses. Top: Generalised 3–4 Hz spike/polyspike–waves associated with an absence. The discharge outlasts the duration of the stimulus.

Pathophysiology of Photosensitive Epilepsy

Clinical note

Photosensitivity results from functional abnormalities in the cortical mechanisms that control the response to strong visual stimulation.¹⁰⁷ It is now well documented that the visual cortex is the primary site of epileptogenesis in occipital photosensitivity and pattern seizure sensitivity.^{6;13;62;72;107–110} This is also true for the onset of epileptogenicity in syndromes of IGE and photically-induced generalised seizures, though this has not been elucidated. It is possible that, in other forms of photosensitivity (eyelid myoclonia with absences may be an example), the onset is in the frontal regions, as is the case in the photosensitive baboon Papio papio.¹¹¹

The pathophysiology of human photosensitivity has gone through several stages. Initially, the predominant view was that it is ‘centrencephalic’ (generalised epilepsy) with the non-specific thalamocortical reticular system activated from the lateral geniculate body.^112;113 This view, which dominated the literature at that time, was mainly based on the findings that PPR are usually synchronous and generalised (Figures 13.1, and 13.2).¹¹³ The first clear evidence of the occipital origin of PPR came from our studies of photically-induced occipital spikes often preceding generalised PPR (Figure 13.3).^109;110;114 This has now been confirmed with elaborate documentation of the primary role of the visual cortex in photic and pattern stimulation.

Figure 13.2

Generalised 3-Hz spike or polyspike–wave associated with clinical absence in two patients with self-induced seizures. Left: Absence seizure induced by IPS. This patient had spontaneous, photically induced (more...)

Figure 13.3

Occipital spikes and their relation to the P100 component of the visual evoked response (VER) in photosensitive patients with generalised PPR. Left: Patterned IPS (2 mm × 2 mm graticule superimposed on (more...)

Evidence that occipital spikes are preferentially elicited in photosensitive patients documents the primary or exclusive role of the occipital cortex in the initiation of photically induced seizures.^109;110;114 This may be the only cortical region involved as in occipital photosensitive seizures or the initial trigger zone of generalised photosensitive epilepsy.

The visual stimuli eliciting occipital spikes depend on the number of flashes of light per second (or the number of pattern image changes per second), spatial frequency, orientation, contrast and the line width ratio.¹² All these factors indicate that the visual cortex is involved and this is the earliest site at which integration occurs.¹²

Failure of Inhibitory or Excitatory Mechanisms or Both?

The IPS flash time-locked occipital spikes appear on the descending arm of the P₁₀₀ component of the VER.^109;110;114 This, we postulated, was a failure of postsynaptic inhibition.^109;110;114 However, the findings that “the P₁₀₀ VER component is enhanced in photosensitive patients and that valproate slightly reduces its amplitude, while occipital spikes are unaffected” were interpreted as evidence of “at least normal, if not supranormal post-inhibitory potentials”, which suggests that the occipital spikes represent an excitatory phenomenon, rather than a failure of inhibition.¹² This latter view was challenged in a more recent study. ¹¹⁵.

Neurotransmitters

A selective dopaminergic mechanism in human epileptic photosensitivity has been postulated. ^116;117 Apomorphine, a dopamine receptor agonist, blocked PPR in patients with IGE and this effect was not modified by naloxone, a specific opiate antagonist, thus suggesting that apomorphine acts on cerebral dopaminergic receptors.^116;117 Conversely, apomorphine did not block spontaneous GSWD in patients with non-photosensitive IGE.¹¹⁶

Pathophysiology of Photosensitive Epilepsy in Animals

Photosensitive Papio papio baboons have long been used as an animal model of photosensitive epilepsy.^118–120 They suffer from IPS-induced myoclonus and have a natural predisposition to ‘non-epileptic myoclonus’, which is not accompanied by electrical discharges or seizures. Clinical manifestations do not show any signs of localised origin of the epileptogenic processes, and the PPR are also bilateral and synchronous. However, experimental data document that the origin of PPR and seizures is in the motor cortex.^118–120

Electroencephalography

The resting EEG of patients with idiopathic photosensitive seizures is usually normal or frequently (in 20–30% of cases) shows eye closure-related paroxysms occurring within 1–3 s of closing the eyes. These are usually brief EEG paroxysms that last for 1–4 s and have similar features to those elicited by IPS for each individual patient. They disappear if eye closure occurs in total darkness.

Properly applied IPS during EEG is the most important test for photosensitivity.^{12;15;62;121–123}

Objectives of Intermittent Photic Stimulation

In deciding what is the best method of IPS, the objectives of this activating technique should be determined. My principle is to get as much information as possible for diagnostic and management purposes without endangering the patient to satisfy scientific curiosity. What is the point of continuing photic stimulation after the appearance of abnormal PPR in patients with a clinical history of photosensitive seizures?

A team of experts rightly recommends that:

“the techniques for detection must use procedures that elicit a clearly defined EEG response in the maximum number of patients who have a history of light-induced seizures, while minimising the chances of inducing such a response in other individuals.”¹²²

The practical objective of IPS is to determine whether:

a. seizures (of any type) are aetiologically linked to environmental photic stimuli (television, video games and others). PPR, if they occur, confirm photosensitivity. Whether the particular patient is clinically photosensitive and also has spontaneous seizures relies on taking a good medical history.

b. photoparoxysmal responses are associated with ictal events. This can only be determined by video EEG recording; otherwise minor events, such as eyelid or limb jerks, are likely to escape notice. The presence of these ictal events may have significant implications for the correct syndromic diagnosis and management. This objective by no means indicates the need for prolonged photic stimulation.

Important note

Important note
Prolonged photic stimulation that may induce a major convulsive seizure should be totally discouraged. There is nothing to learn and no benefit to the patient from this practice. There are plenty of examples of subjects having an IPS-induced GTCS during an EEG that was performed for reasons other than epilepsy. Management and advice to these subjects is not going to change after this unfortunate discovery of their low seizure-threshold to photic stimulation. To continue a train of photic stimulation after the appearance of EEG ictal discharges or ictal clinical manifestations is unacceptable.

However, problems and their solutions in medicine are not black or white, and IPS is no exception:

• Some patients may have one, two or more seizures always associated with environmental photic stimuli (video games are the best example), but routine IPS fails to reveal EEG photosensitivity. Are these patients photosensitive? Should more potent means of activation be used with sleep deprivation and long IPS/pattern activation?

A team of experts recommends:

“It is important to include stimulation that is maximally epileptogenic, if patients show no EEG signs of light sensitivity in response to less-provocative stimulation. Failure to do so may result in an underestimation of the contribution of visual stimulation to the seizure problem.”¹²²

But what is ‘maximally epileptogenic’ and what are its limitations?

This again is a matter of clinical assessment. In a child who has two GTCS 2 years apart from one another while playing video games for many hours after sleep deprivation and other seizure precipitating factors, IPS confirmation may not be needed, because the association comes from logical deduction. All these facilitating factors were ‘maximally epileptogenic’ for this particular patient at the particular moment that the seizure occurred. Partial sleep deprivation EEG recording during sleep and awakening is often very informative.

• Some patients have definite epileptic seizures, which appear to occur spontaneously, but EEG demonstrates PPR. Is this relevant to their disease and management? The answer again should be based mainly on the clinical history. For example, patients with juvenile myoclonic epilepsy often have EEG photosensitivity, though they may never have clinical seizures provoked by environmental photic stimulation.

Factors That Influence the Response to Intermittent Photic Stimulation

Clinical note

The epileptogenic properties of flickering lights “depend on the size of the retinal image of the source, its time-averaged luminance, the modulation of the light, the frequency of the modulation, the colour of the light (spectral power distribution) and the part of the retina receiving stimulation.”¹³

The Epileptogenic Properties of Flickering Lights and ITS Spatial and Directional Relation with the Subject's Eyes (Retina)

Intensity, frequency and duration of the IPS are of crucial importance and the most significant determinants of the response. An abnormal PPR is more likely to occur with light of high intensity, frequency of mainly 12–20 Hz and longer trains of IPS. Combining light IPS with appropriate geometric patterns makes it much more potent^109;124 than diffused or white light. Colour may not be an important provocative factor for PPR, though it is often emphasised by some authors¹⁵ and certain patients improve with the appropriate use of tinted glasses;^13;125 this has been critically reviewed by Harding and Jeavons (see ref ¹²).

Binocular is far more effective than monocular stimulation. This is why it is recommended that photosensitive patients cover one eye when in epileptogenic environmental photic conditions such as discotheques.

Stimulating central vision (fixating on the light source) is much more potent than stimulating peripheral vision. This is because photosensitivity is mainly mediated through central vision and fixation.¹²⁶ This is also the reason for the recommendation that, in IPS testing, “a central marker on the diffuser to aid fixation is specified, as photosensitivity is unlikely to be demonstrable in the eyes-open state unless the stimulator is in central vision”.¹²²

Distance and ambient light mainly influence the intensity of the photic stimuli.

Flicker Frequency

The photosensitive range lies between the lowest and highest frequency of IPS that consistently evokes a PPR. Several advantages have been emphasised of defining the photosensitive range, such as that: (a). it defines the degree of photosensitivity in a specific patient; (b). it enables qualitative comparisons over time, as in studies of prognosis or effectiveness of drug therapy in both acute and chronic administration; and (c). it allows identification of the visual stimuli present in the environment that represent a provocative risk (e.g. television viewing).¹² The photosensitive range is, however, often variable.

Internal Factors Altering the Effectiveness of IPS

The effectiveness of IPS in provoking EEG abnormalities depends on a large number of internal and external factors. Alertness, attention, emotion, menstrual cycle, hormones, electrolytes and ingestion of drugs are some of the internal factors that alter the photoconvulsive threshold of the subject.

In patients subjected to identical trains of IPS under constant experimental conditions over a period of several minutes, the EEG responses varied considerably from no detectable abnormality to self-sustained spike–wave discharges of 10-s duration. Cyclical changes were observed when the length of the spike–wave discharge was plotted over the time period.^127–129

Furthermore, in AED trials the antiepileptic effect on PPR may last for several days after the AED has been eliminated.

Important note

Differentiation between eye-closure and eyes-closed state ( Figure 13.4)
EEG abnormalities suggesting photosensitive, scotosensitive and FOS epilepsies are often seen in the resting EEG before any other specific test is carried out. It is important to differentiate between eyes closed (Figure 13.4) and eye closure (Figure 13.4) EEG abnormalities, because of their different properties and their different response to intermittent light, darkness and fixation-off.
Eyes closed is the state that lasts as long as the eyes remain closed. FOS is a typical example of eyes closed-related seizures and EEG abnormalities.
Eye closure is the transient state, which immediately follows closing of the eyes, lasts less than 3 s and does not persist in the remaining period of eyes closed. Eye closure is much more potent than ‘eyes open’ or ‘eyes closed’ in inducing abnormalities during IPS. Jeavons syndrome is a typical example of eye closure-related seizures and EEG abnormalities. In some photosensitive patients, PPR occur only after eye closure.

Figure 13.4

Samples from video EEG to illustrate the differentiation between eye-closure (top) and eyes-closed (bottom) abnormalities. Top: Eye closure-related abnormalities in a patient with Jeavons syndrome. High amplitude generalised discharges (more...)

Eyes Open, Eyes Closed and Eye Closure

The state of the eyes during IPS is probably the most significant internal factor that modifies the response. There is a great confusion about this.

Eye closure (closing of the eyes while IPS continues) is by far the most potent factor in eliciting PPR, regardless of patterned, unpatterned or diffuse IPS.^12;109;132 This should be expected, because many of these patients have GSWD in their resting EEG only immediately after closing of the eyes.^12;109

The effectiveness of IPS when the eyes are opened or closed depends on the physical properties of the light (direct, appropriately patterned or diffuse).

Eyes open is more provocative than eyes closed when patterned IPS is used.

Eyes closed is more provocative than eyes open when direct unpatterned light is used.

When IPS is applied through a diffuser, eyes open become more effective than eyes closed, because of the reduction in light intensity caused by the closed eyelids.¹³³ This may be the first publication to explain the contradictory findings in the literature as to whether IPS is more effective with eyes-open or closed. Reports that IPS is more provocative when the eyes are closed than when they are open are partly due to methodological problems, such as: (a). eyes closed is often equated with eye closure; (b). eyes closed is tested for the same train of IPS after eyes open, thus after longer exposure to IPS; and (c) testing with unpatterned or non-diffused IPS.¹³³ Eyes open is much more photoparoxysmal than eyes closed when ‘appropriately’ patterned IPS is used. I emphasise ‘appropriately’ patterned, because not all patterns are appropriate.

Appropriate patterns: “Quadrilled patterns of thin lines are more effective than similar patterns consisting of thick lines.”^128;129 “An optimally epileptogenic pattern consists of black and white stripes of equal width and sharp contour (a square-wave luminance profile).”³⁶

Inappropriate pattern: The checkerboard pattern used by some authors¹³⁴ is not only a weak stimulus itself, but also greatly reduces the intensity of the light stimulus, because its alternate solid-black squares black out approximately half the lamp.

Intermittent Photic Stimulation Technique

To achieve maximum provocation, IPS has to apply all the potent physical characteristics of the stimulus (intensity, frequency, contrast) and combine flash with linear patterns. The patient should look at the centre of the stroboscope and IPS on eye closure should be tested.^12;121;122 Monocular stimulation is usually ineffective.

There is a great diversity of techniques and photostimulators used for IPS in EEG as detailed in an experts’ consensus on the standardisation of IPS screening methods.¹²² IPS standardisation is unlikely to have universal success unless the manufacturers of stimulators agree to a standard device. Most of the modern photostimulators are unsuitable for proper IPS testing.

The most comprehensible procedure for photic stimulation is that of Jeavons:^12;135

1. The procedure is explained to the patient.
2. The same photostimulator that was used initially is used in all repeat tests.
3. Illumination of the room is standardised by drawing blinds and using artificial light.
4. The lowest intensity light is used initially, increased if there is no abnormality, and standardised in subsequent tests.
5. A pattern of small squares with narrow black lines (0.3 mm), with spacing of 2 mm × 2 mm or a pattern of parallel, 1-mm lines spaced 1.5 mm apart, is placed behind the glass of the lamp (dry print transfers are cheap and easily available).
6. A circle, 3 cm in diameter, is drawn in the centre of the glass and the patient looks at this circle.
7. The lamp is placed 30 cm from the eyes.
8. Testing is carried out with the eyes kept open or kept closed and then, only if no PPR is evoked, the effect of eye closure tested.
9. An initial test frequency of 16 Hz can be used to identify the photosensitive patient. If no PPR is elicited, testing starts at 1 Hz and is increased in increments of 2 Hz up to 25 Hz, followed by 30, 40 and 50 Hz.
10. In the photosensitive patient, the duration of the stimulus should not usually exceed 2 s.
11. In the photosensitive patient, testing starts at 1 Hz and increases in steps of 1 Hz until a PPR is evoked. The upper limit is then established by starting at 60 Hz and reducing in steps of 10 Hz.
12. The sensitivity limit is defined as the lowest or highest flash rate that consistently evokes a PPR. The sensitivity range is obtained by subtracting the lower from the upper limit.

The recent consensus recommendations^121;122 are very similar to those of Jeavons.^12;135

1. For screening purposes, IPS should not be performed during or less than 3 min after hyperventilation.
2. Patients should be positioned at a distance of 30 cm from the photic stimulator (nasion to lamp) with dim surrounding illumination just sufficient to observe the patient.
3. Flashes should be delivered in separate trains of 10 s for each frequency, with minimum intervals of 7 s. During the 10-s stimulation, the eyes should be initially open with the patient gazing directly at the centre of the lamp. After 5-s stimulation, the patient should be asked to close the eyes and should keep them closed until the stimulation ceases. The following frequencies are used: 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18 and 20 Hz, in that order. If generalised epileptiform discharges are evoked, the stimulator should be turned off immediately, and the sequence aborted. Next, a second sequence should be presented, beginning at 60 Hz and decreased as follows: 60, 50, 40, 30, 25 and 20 Hz. Again, the stimulator must be turned off immediately if a generalised response is seen, and the sequence stopped at that point.
4. For clinical purposes, it is important to know whether the response is self-sustaining (i.e. whether it can outlast the stimulus); this may not be established unless the stimulator is switched off as soon as a generalised discharge is seen. The issue is not whether the discharge is self-limiting: a self-sustaining discharge may well cease spontaneously if the stimulator is left on. It should be noted whether clinical signs and symptoms are elicited. The alertness of the patient should be noted both at the beginning of the recording and also, specifically, during IPS. It should be determined whether the patient is, for any reason, in a sleep-deprived state. Medication should also be documented.
5. This procedure lasts a maximum of 6 min. If there is insufficient time to perform this IPS screening procedure, it is advisable to omit photic stimulation altogether, because the results may be misleading.

There are some limited practical reservations about some aspects of these recommendations:

Clinical note

“with dim surrounding illumination just sufficient to observe the patient”¹²¹

This is to increase the relative intensity of IPS that can be achieved through the photostimulators. Most patients feel uncomfortable in dim surroundings. Further, this makes detection of clinical ictal events, particularly if minor, difficult and the video pictures are disturbed.

Clinical note

“For clinical purposes, it is important to know whether the response is self-sustaining (i.e. whether it can outlast the stimulus); this may not be established unless the stimulator is switched off as soon as a generalised discharge is seen.”¹²¹

The clinical significance of this is probably overemphasised. Further, ‘as soon as’ depends on a variety of factors. Even the same EEG technologist, during the same test, can have different reaction times, and thus make a self-sustaining response outlast the stimulus response and vice versa. The fact that the technologist has to observe for clinical ictal symptoms simultaneously makes this even more difficult.

Clinical note

“This procedure lasts a maximum of 6 min. If there is insufficient time to perform this IPS screening procedure, it is advisable to omit photic stimulation altogether, because the results may be misleading.”

The upper and lower limits of photosensitivity may not be of any clinical significance, and may vary considerably in the same patient and even in the same untreated state. For routine purposes, the test can be reliably performed in half the allocated time without the need to define the photosensitive range.

Photoparoxysmal Responses

PPR are broadly categorised as follows:^12;35;72

• Generalised PPR consist of spike/polyspike–waves in various combinations and intra-discharge frequencies. They may be identical with the discharges associated with typical absence seizures or myoclonic jerks. They may be brief or long. They are of higher amplitude in the anterior regions, but their onset, particularly if patterned IPS is employed, is often with occipital spikes. They are highly associated (90%) with clinical photosensitivity, particularly if they outlast the stimulus train (Figure 13.1). Generalised PPR often (60%) associate with clinical events such as jerks, impairment of cognition or subjective sensations, but video EEG may be needed to detect them.⁷²
• Posterior (temporo-parieto-occipital with occipital emphasis) spike/polyspike–waves. This is the mildest form of PPR and does not spread to the anterior regions.¹³⁶ It consists of occipital spikes, polyspikes or slow waves intermixed with small, larval spikes (Figures 13.1, 13.2, and 13.5). Occipital spikes are often time-locked to the flash with a latency of approximately 100 ms, coinciding with the positive P100 of the VER (Figure 13.2). Occipital spikes and other posterior abnormalities induced by IPS are considered of much lower epileptogenic capacity than generalised PPR. Half of the subjects with posterior PPR have epileptic seizures (spontaneous, photically elicited or both).¹²

Figure 13.5

Video EEG samples of spontaneous EEG paroxysms and photically induced posterior or maximum posterior PPR in two children with photically induced occipital seizures. They probably have IPOE. Top is case 12.1 and bottom is (more...)

Occipital spikes precede generalised PPR in 90% of photosensitive patients when IPS is patterned (combined light and pattern; Figure 13.3).^{11;12;108–110;110;136}

Note on the Duration of PPR and Their Relation to the IPS Train

Emphasis is often placed on whether photoparoxysmal discharges outlast the stimulus train or whether they are self-limited, that is they stop before or with the end of the IPS (Figure 13.1).^121;122 The rationale is that PPR that outlast the stimulus train may strengthen their association with epilepsy. This may be artificial, because the duration of the PPR as a rule depends on the duration and strength of the IPS, and the time that this was stopped after the appearance of the PPR.

Ictal clinical manifestations during PPR are the most important factor with respect to the risk of clinical epilepsy, but this has been neither studied adequately nor emphasised in the expert consensus reports.^121;122

Photomyoclonic Responses

Photomyoclonic responses are not cerebral responses. They are spike or polyspike-like muscle activity that appears in the frontal-central EEG electrodes.^137–140 They occur only when the eyes are closed and are inhibited by opening of the eyes. Provocation of photomyoclonic responses requires very high intensity IPS with the stroboscope positioned very close to the eyes. They are unlikely to occur when IPS is applied at recommended levels.

Photomyoclonic responses are a non-specific finding reported in normal people (0.3%), psychiatric patients (17%), epileptic patients (3%) and patients with brain stem lesions.¹³⁷

Clinically, they manifest with predominant jerking of the facial muscles, especially around the eyes (eyelid fluttering) – a phenomenon called photomyoclonus.^138;139 They may end in generalised convulsions if the stimulation is continued and the eyes of the subject are kept closed.¹³⁷

Idiopathic Photosensitive Occipital Lobe Epilepsy

Clinical note

Idiopathic photosensitive occipital lobe epilepsy^3;11;149;150 is a newly recognised syndrome of reflex epilepsy with an age-related onset.³

Occipital seizures precipitated by photic stimuli have been well described by Gowers (1881)¹⁵¹ and Holmes (1927),¹⁵² but have only recently attracted interest. The reason for this is that they were overshadowed by the prevailing view that photosensitive epilepsies are mainly generalised. This is because, with the application of IPS as a provocation method in EEG, it was discovered that the majority of photosensitive patients have generalised discharges.^153;154 Reports of photically induced occipital seizures with or without secondarily generalisation were scarce.^{108–110;127;155–160} The traditional view that photosensitive occipital seizures are rare contrasts with recent findings.^{9;79;161–167} In one report alone, 45 of 95 patients had occipital seizures precipitated by visual stimuli.⁸⁵

Depending on severity, there may be three significant groups of patients with photosensitive occipital seizures:¹¹

1. Patients with low occipital epileptogenic threshold to IPS that manifest with seizures only under extreme exposure to the offending stimulation. These are classified among ‘seizures that do not require a diagnosis of epilepsy’;³ accidental single isolated occipital seizures in normal young persons¹⁶⁶ or patients with migraine¹⁶⁶ during IPS. These people most likely have a low threshold to such events.
2. Patients with idiopathic occipital (lobular) epileptogenicity that may comprise the majority of IPOE. Patients, usually children, have clinical occipital seizures elicited by various sources of environmental light stimulation (video games are far more common than television).
3. Patients, usually children, with idiopathic focal or generalised epilepsies who also have photosensitive occipital seizures. These are often demanding cases in terms of diagnosis and management.

Diagnostic Procedures

All tests apart from the EEG and VER are normal.

Electroencephalography

By definition, all patients are photosensitive. IPS elicits: (a). PPR spikes or polyspikes entirely confined in the occipital regions; or (b) generalised PPR of spikes or polyspikes that predominate in the posterior regions (Figures 13.5, and 13.6).

Figure 13.6

Adult onset IPOE. Top: Sample from an EEG of a man who had his first seizure at the age of 35 years while in a lift cradle at work. His vision became blurred, he felt dizzy and, within 2 min, he had a GTCS. No further seizures (more...)

Spontaneous, mainly posterior spikes often appear in the resting EEG. Centrotemporal spikes may coexist.

Ictal EEGs document an occipital origin with mainly fast spikes in one or both the occipital electrodes. This may end spontaneously or spread to the temporal regions.¹⁴⁹

In my experience, most patients with IPOE also have other type of seizures induced by IPS, such as eyelid flickering and myoclonia, myoclonic jerks of the limbs, body or fingers, and brief absences that are occasionally mild, which may escape detection if video EEG is not employed (Figure 13.5).¹¹

Visual Evoked Responses

VER are always of abnormally high amplitude,¹⁴⁹ as indeed happens in any type of photosensitive epilepsy.^109;114;173

Jeavons Syndrome

Eyelid Myoclonia with Absences

Jeavons syndrome is one of the most distinctive reflex IGE syndromes with well-defined clinico-EEG manifestations.^130;177;178 However, it is not recognised by the ILAE Commission² and not listed in the new ILAE diagnostic scheme,³ although vividly described by Jeavons^179;180 and documented in numerous reports.^{177;181–183} Jeavons syndrome is characterised by the triad of:

1. eyelid myoclonia with and without absences
2. eye closure-induced seizures, EEG paroxysms or both
3. photosensitivity.

Demographic Data

Onset is typically in childhood with a peak at 6–8 years of age (range 2–14 years). There is a twofold preponderance of girls. In our studies all adult patients with EMA were women.^130;178 However, recently I saw a 32-year-old man with eyelid myoclonia from the age of 3 years. He never had any other type of seizure and his disease would have gone unnoticed if he had not been curious to find out about this ‘embarrassing tic’. I also saw another man in his late 20s, who had Jeavons syndrome as a child, but whose symptoms subsided in his late teens. Based on this experience, I am of the reasonable opinion that Jeavons syndrome is not only less frequent, but also less potent in men than women.

The prevalence of Jeavons syndrome is around 3% among adult patients with epileptic disorders and 13% among IGEs with absences.¹³⁰

Clinical Manifestations

Eyelid myoclonia, not the absences, is the hallmark of Jeavons syndrome (Figures 13.7, and 13.8).^130;178

Figure 13.7

Video EEG samples of four women with Jeavons syndrome. Brief generalised discharges of spikes/polyspike–waves in various combinations occur immediately after eye closure in a lit EEG recording room. They are associated (more...)

Figure 13.8

Video EEG samples from two women with Jeavons syndrome. Top: Brief GSWD with similar characteristics are induced by IPS (left) or eye closure (right). They occasionally occur spontaneously (middle). In (more...)

Eyelid myoclonia consists of marked jerking of the eyelids often associated with jerky upward deviation of the eyeballs and retropulsion of the head (eyelid myoclonia without absences). This may be associated with or followed by mild impairment of consciousness (eyelid myoclonia with absences). The seizures are brief (3–6 s), and occur mainly after eye closure and consistently many times per day.

All patients are photosensitive.

Generalised tonic clonic seizures, either induced by lights or spontaneous, are probably inevitable in the long term and are particularly provoked by precipitating factors (sleep deprivation, alcohol) and inappropriate AED modifications. Typically, GTCS are sparse and avoidable.

Considerations on Classification

The new ILAE diagnostic scheme³ has not recognised Jeavons syndrome. Instead, a new seizure type ‘eyelid myoclonia with and without absences’ has been accepted.^3;178 These seizures occur in many epileptic conditions of idiopathic, symptomatic or possibly symptomatic causes.^178;184 They are the defining seizure symptom in Jeavons syndrome, which has unique clinical and EEG features and often genetic clustering.^{130;178;185;186}

In the absence of any ILAE definition, I propose the following:

Jeavons syndrome (eyelid myoclonia with absences) is an idiopathic epileptic syndrome manifested with frequent (pyknoleptic) seizures, consisting of eyelid myoclonia often associated with absences. Onset is usually in early childhood. The seizures are brief (3–6 s) and occur mainly after eye closure. They consist of eyelid myoclonia, which persists throughout the attack with or without absences. Absences without eyelid myoclonia do not occur. The eyelid myoclonia consists of marked, rhythmic and fast jerks of the eyelids, often associated with jerky upward deviation of the eyeballs and retropulsion of the head. There is probably an associated tonic component of the involved muscles. If the seizure is prolonged, impairment of consciousness occurs. The latter is mild or moderately severe without associated automatisms. Milder seizures of eyelid myoclonia without absences are common, particularly in adults and treated patients, and may occur without EEG accompaniments. All patients are highly photosensitive in childhood, but this declines with age. Infrequent GTCS, either induced by lights or spontaneous, are probably inevitable in the long term and are likely to occur after sleep deprivation, fatigue and alcohol indulgence. Myoclonic jerks of the limbs may occur, but are infrequent and random. The eyelid myoclonia of Jeavons syndrome is resistant to treatment and may be lifelong. However, clinical absences may become less frequent with age.

The EEG ictal manifestations consist mainly of generalised polyspike–waves at 3–6 Hz, which are more likely to occur after eye closure in an illuminated room. Total darkness abolishes the abnormalities related to eye closure. PPR are

Myoclonic jerks of the limbs may occur, but are infrequent and random.

Eyelid myoclonic status epilepticus either spontaneous, mainly on awakening, or photically induced occurs in one-fifth of patients. It consists of repetitive and discontinuous episodes of eyelid myoclonia with mild absence, rather than continuous non-convulsive absence status epilepticus (Figure 13.8).

Precipitating Factors

The most potent precipitating factor is eye closure, whether it be voluntary, involuntary or reflex. The majority and, in some patients, all of the seizures are induced immediately after closure of the eyes in the presence of uninterrupted light. Eye closure in total darkness is ineffective.

Contrary to other forms of photosensitive epilepsies that are sensitive only to flickering lights (IPS), patients with Jeavons syndrome are also sensitive to bright, non-flickering lights. This is probably due to the enhancing effect of bright light on eye-closure sensitivity.

Self-Induction in Jeavons Syndrome

Most relevant reports and most epileptologists unquestionably consider the eyelid myoclonia of Jeavons syndrome as a manoeuvre used by patients to self-induce IPS and elicit seizures. Our view, based on numerous video EEG recordings and interviews with 17 patients, is that eyelid myoclonia is an ictal event (15 patients) and that self-induced seizures in Jeavons syndrome are rare (possibly two patients).^35;178 After all, these patients do not need IPS to induce seizures. Closing of the eyes (there is no need for forceful slow eye-closure) in the presence of uninterrupted light may be more powerful than IPS in provoking a seizure. In physiological terms, these clinical manifestations are likely to be similar to an ‘attraction movement’ to light and other manifestations of the ‘optic fixation reflexes’, when volitional movements of the eyes are unattainable or weak.⁹⁹

Patient note

My eyes flicker as a reflex to the light.

Patients consider eyelid myoclonia as a socially embarrassing condition, they are relieved when the seizures improve with AEDs and they show excellent compliance with their treatment.

Of two patients suspected of self-induction, one had frequent slow eye-closure EEG abnormalities, but she never admitted self-induction. She insisted:

Patient note

I do not know when I am doing it.… It gives me no pleasure, and it is a social embarrassment.

The other patient admitted that she occasionally does it voluntarily:

Patient note

Yes, I can do it on purpose like that (she imitates rapid eyelid blinking with upwards deviation of the eyes). But that is because there are times that my eyes start to want to go … because they are strained and sore and they will sting, and so if I just do it, it relaxes them. … That is a rare occasion. But other than that, I do not know. There have been incidences I have walked into a pole, or into a car. I did not do that on purpose.

However, in a study of six children with Jeavons syndrome, five were found to demonstrate various compulsive or tic-like symptoms including premonitory sensations, compulsive, difficult to resist urges and a sense of relief associated with the attacks.¹⁸¹ Separate facial tics not associated with absences were also evident in at least two children.¹⁸¹ Therefore, these patients may not be deliberate ‘self-inducers’, but may suffer from compulsive ‘self-induction’ similar to the phenomenology described in Tourette’s syndrome.¹⁸¹

Aetiology

Jeavons syndrome is a genetically determined homogeneous syndrome.^185;186 In one study of 18 patients with Jeavons syndrome, 14 had a family history of epilepsy and four patients had other family members affected by the same syndrome.¹⁸⁶

Pathophysiology

In Jeavons syndrome, as opposed to other photosensitive epilepsies, eye closure is more potent than photic stimulation as a triggering factor.^35;130;178 However, eye closure requires the presence of light, and it is entirely ineffective in darkness, which may explain that continuous light also triggers seizures in patients with Jeavons syndrome. Another intriguing feature is that some patients may manifest with both features of photosensitivity and FOS, which have opposing characteristics.

Eye-closure mechanisms and photosensitivity may be linked, the one enhances the other, and they often coexist, but they can also occur independently and one may persist without the other. A similar situation may exist between eye closure, which is mainly linked with photosensitivity and eyes-closed mechanisms, which are mainly linked to FOS. It is fascinating that two apparently opposite conditions (photosensitivity and FOS) can have synergistic actions as demonstrated in some patients with Jeavons syndrome.

It is possible that, in patients with Jeavons syndrome, the alpha-rhythm generators malfunction, and that both the magnocellular and parvocellular systems are functionally disturbed.^35;178 We do not know the physiology of the epileptic phenomena and the alterations that may occur in the brain of patients with Jeavons syndrome, under the continuous bombardment from electrical discharges nearly every time that they close their eyes. Age at onset may be significant.

Diagnostic Procedures

All tests apart from the EEG are normal.

Electroencephalography

Video EEG is the single most important procedure for the diagnosis of eyelid myoclonia with or without absences. It shows frequent high amplitude 3–6 Hz GSWD of mainly polyspikes (Figures 13.7, and 13.8). These typically are:

• related to eye closure, that is they occur immediately (within 0.5–2 s) of closing the eyes in an illuminated recording room and they are eliminated in total darkness
• brief (1–6 s, commonly 2–3 s).

GSWD are also enhanced by hyperventilation. Eyelid myoclonia of varying severity often occurs with the GSWD.

PPR are recorded from all untreated young patients, but may be absent in older patients or those on medication. Photosensitivity and FOS may coexist.³⁹

Sleep EEG patterns are normal. GSWD are more likely to increase during sleep, but may also decrease. In sleep, the GSWD are shorter and devoid of discernible clinical manifestations of any type, even in those patients who have numerous seizures during alert states.

The EEG and clinical manifestations deteriorate consistently after awakening.

A normal EEG is rare, even in well-controlled patients.

Differential Diagnosis

The diagnosis of Jeavons syndrome is simple because the characteristic eyelid myoclonia, if seen once, will never be forgotten or confused with other conditions.¹⁸⁷ Furthermore, the EEG with the characteristic eye-closure related discharges and photosensitivity leaves no room for diagnostic error.

As a simple rule of the thumb, eyelid myoclonia is highly suggestive of Jeavons syndrome. This becomes more likely when eyelid myoclonia is combined with photosensitivity, and it is pathognomonic of the syndrome when it also occurs after eye closure.

Nevertheless, eyelid myoclonia is often misdiagnosed as facial tics, sometimes for many years. Also, eyelid myoclonia should not be confused with: (a). the rhythmic or random closing of the eyes, often seen in other forms of IGE with absences; or (b). the eyelid jerking that may occur at the opening or the initial stage of the GSWD in typical absence seizures of childhood absence epilepsy.

Persistent, frequent, nonepileptic paroxysmal eyelid movements that occur in patients with PPR are a source of diagnostic confusion which can be avoided with video-EEG recordings.¹⁸⁸

The main diagnostic problem, which is probably iatrogenic, is self-induction, but this is a diagnosis that should not be made unquestionably because it is often wrong. However, some photosensitive patients may self-induce seizures by repetitive opening and closing of the eyes in front of a bright light source. These patients are simply photosensitive patients imitating Jeavons syndrome.^35;178

The symptom/seizure of eyelid myoclonia alone is not sufficient to characterise Jeavons syndrome, because it may also occur in symptomatic and cryptogenic epilepsies, which are betrayed by developmental delay, learning difficulties, neurological deficits, abnormal MRI and abnormal background EEG.^178;184;189

Prognosis

Jeavons syndrome is a lifelong disorder, even if seizures are well controlled with AEDs. Men have a better prognosis than women. There is a tendency for photosensitivity to disappear in middle age but eyelid myoclonia persists. It is highly resistant to treatment and occurs many times per day, often without apparent absences, and even without demonstrable photosensitivity.¹³⁰

Management

Based on anecdotal evidence, the drugs of choice are those used for other IGEs.¹⁹⁴ Valproate alone or most likely in combination with clonazepam or ethosuximide appears to be the most effective regimen. The choice of the second drug depends on the main seizure type. Clonazepam is highly efficacious in eyelid myoclonia and myoclonic jerks; some patients achieve relatively good control with clonazepam monotherapy.

Of the new AEDs, levetiracetam may be the most effective, because of its antimyoclonic and antiphotosensitive properties). Lamotrigine may exaggerate myoclonic jerks.

Carbamazepine, gabapentin, oxcarbazepine, phenytoin, tiagabine and vigabatrin are contraindicated.

Lifestyle and avoidance of seizure precipitants are important.

Non-pharmacological treatments used for photosensitive patients (such as wearing special glasses) often have a beneficial effect and should also be employed in Jeavons syndrome when photosensitivity persists.¹⁹⁵

Misconceptions

A main misconception in Jeavons syndrome is that eyelid myoclonia (the seizure) is a self-induced attempt to induce seizures. This belief is so strong that, in nearly all relevant publications, the patient described by Radovici et al. (1932)¹⁹⁰ is erroneously cited as the first reported case of self-induced seizures even by hand waving.⁹³ No such evidence or mention of self-induced seizures can be found in the original report.

“AA… age de 20 ans, presente des troubles moteurs sous forme de mouvements involontaires de la tete et des yeux sous l’ influence des rayons solaires.”¹⁹⁰

Why have the seizures of eyelid myoclonia been mistaken as a maneuver for self-induction?

The first reports of photosensitive epilepsy concerned patients who had seizures when in bright sunlight or suddenly exposed to bright light, or after exposure to bright sunlight for a period of time.^{12;101;109;191–193} However, after the introduction of IPS in EEG activation, the predominant view was that fluctuation of the light stimulus appears necessary to induce an epileptic attack, and that any claims of observing seizure induction by continuous light should probably be discounted as due to interruptions of the light by fluttering of the eyelids.¹²⁷ Thus, most epileptologists find it difficult to accept eyelid myoclonia as a seizure elicited by uninterrupted light.

Differential Diagnosis of Jeavons Syndrome

Non-epileptic conditions, such as tics and exaggerated normal eye movements

Self-induced photosensitive epilepsy

Symptomatic or possibly symptomatic generalised epilepsy

IGE with absences

Idiopathic or symptomatic occipital epilepsy

Pattern-Sensitive Epilepsy

Pattern-sensitive epilepsy^{12;13;36;37;88;128;129;154;196} refers to epileptic seizures induced by patterns; it is not a particular epileptic syndrome. Pattern seizure sensitivity is closely related to photosensitivity. Nearly all patients with clinical pattern sensitivity epilepsy show PPR (Figure 13.9). Conversely, 30% of clinically photosensitive patients are also sensitive to stationary and 70% to appropriately vibrating patterns of stripes. Patterns enhance the effect of photic stimulation, whether under test conditions or in real life. “Whether pattern sensitivity ever occurs in subjects who are consistently insensitive to IPS is uncertain.”³⁶ Pattern sensitivity without photosensitivity,¹² sensitivity to non-geometric patterns¹⁹⁷ and self-induced pattern-sensitive epilepsy are rare. ^38;94;198

Figure 13.9

Samples from a video EEG of a child aged 14 years with pure pattern-sensitive epilepsy from the age of 7 years. Left (top and bottom): Only patterned IPS (2 mm × 2 mm graticule superimposed on the glass of the stroboscope) (more...)

Fixation-off Sensitivity

Fixation-off sensitivity (FOS) is a term that I coined to denote the form(s) of epilepsy and/or EEG abnormalities, which are elicited by elimination of central vision and fixation.^39;131 ‘Elimination of central vision and fixation’ is a specific precipitating stimulus, which even in the presence of light, induces high amplitude occipital or generalised paroxysmal discharges.

FOS is suggested in the routine EEG by abnormalities, which consistently occur as long as the eyes are closed, but not when the eyes are opened.

A previous extensive review of all aspects of FOS can be found elsewhere. ³⁹ FOS can be better understood in reviewing the steps followed for their detection and study.

Pathophysiology

The underlying mechanisms of FOS are not known, but they may be related to an abnormality of the alpha-rhythm generators.³⁹

FOS has the opposite characteristics of photosensitive epilepsies (Table 13.3), but conversion from one to the other may rarely occur:³⁹

Table 13.3

Fixation off sensitivity versus photosensitivity

• The resting EEG of photosensitive patients frequently shows abnormalities with eye closure rather than with the eyes closed (Figure 13.7). These are inhibited by total darkness and probably by elimination of central vision and fixation (Figure 13.4 top).
• Photosensitivity is mainly mediated through central vision and fixation. PPR are induced only if the patient ‘looks’ at the centre of the stroboscope.

Patient note

“Sometimes a shift of gaze from the centre of the lamp to the edge (12° or 15°) will inhibit responses, including photic driving”.¹²⁶

• In photosensitive epilepsy, PPR are enhanced when IPS is combined with patterns (Figure 13.3).^109;110;114

FOS has been recently studied with functional MRI.^209;210 In 3 patients with FOS the EEG paroxysmal activity elicited by eliminating central vision correlated significantly with an increased blood oxygen level-dependent signal in the extrastriate cortex (Brodmann areas 19 and 37). ²¹⁰ Activation of parieto-occipital and frontal brain areas during FOS discharges has been documented in another patient with fMRI and 64-channel EEG source analysis. ²⁰⁹

Startle Epilepsy

Complex Reflex Epilepsies ^4,5

Reading Epilepsy

Reading (the stimulus) is a well-documented provocative seizure-inducing stimulus in idiopathic and less often cryptogenic/symptomatic epilepsies (Figure 13.10).^{40–44;223–226}

Figure 13.10

Two types of reading-induced seizures; jaw myoclonus and alexia. Top left: EEG of a woman with jaw jerks (arrow) while reading (case 8 in ref ). She is successfully treated with clonazepam 0.5 mg nocte. Her sister (more...)

Primary (idiopathic) reading epilepsy is a distinctive form of a reflex epilepsy syndrome, which mainly manifests with myoclonic jerks of the masticatory muscles, absences or other type of seizures, and is rare or exceptional.^40;41;44 Conversely, some patients, with mainly symptomatic causes, have prolonged, focal seizures that manifest with alexia and possibly dysphasia.⁴³

The following description refers to the idiopathic form of reading epilepsy.

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