Overview
Reflex epilepsy is a condition in which seizures can be provoked habitually by an external stimulus or, less commonly, internal mental processes. [1, 2] Individuals with pure reflex epilepsy have seizures almost exclusively in response to specific stimuli and do not suffer spontaneous seizures; alternatively, reflex seizures may coexist with spontaneously occurring seizures.
Reflex seizures may clinically manifest as partial or generalized seizures. [1] The most common triggers for reflex seizures are visual stimuli, followed by sensory, auditory, somatosensory, olfactory, or proprioceptive stimuli. More complex triggers are less frequent, such as reading, hearing music, or praxis.
Reflex epilepsy can only be diagnosed in people whose seizures occur only in the presence of particular triggers. [1] However, most people with reflex seizures present with spontaneous, unprovoked seizures as well. Interictal epileptic discharges (IEDs) can be provoked by particular stimuli in people with recurrent unprovoked seizures or reflex seizures, but if occurring spontaneously, they reflect susceptibility for unprovoked seizures.
Reflex epilepsies are relatively rare, occurring in only 5% of all epilepsies. [3] Most of these epilepsies are genetic in origin. Photosensitive epilepsy is the most common type of reflex epilepsy. Clinical photoconvulsive seizures or subclinical photoparoxysmal responses occur when an individual is exposed to intermittent light stimulation (ILS), consisting of flashes of light of a particular frequency. Other forms of epilepsy are less frequent, such as hot water epilepsy or reading epilepsy. People with multiple seizure triggers tend to have idiopathic or genetic generalized epilepsy with unprovoked seizures. Ictal or interictal epileptic discharges can be elicited by visual stimuli, praxis, or reading in people with juvenile myoclonic epilepsy. [4] Some authors have described cases of myoclonic seizures as a reflex response to sudden unexpected tactile or acoustic stimuli and this clinical entity has been proposed as a separate nosographic syndrome, referred to as reflex myoclonic epilepsy in infancy (RMEI). [5, 6, 7]
Go to Epilepsy and Seizures for an overview of this topic.
Pathophysiology
In people with epilepsy, the occurrence of seizures is rarely predictable. Factors that provoke seizures may vary from person to person and may include sleep deprivation, systemic illness, or ingestion of particular food products. [3] These factors usually do not provoke seizures in a consistent fashion and probably do so by lowering seizure threshold in people with unprovoked seizures. In contrast, reflex seizures represent a reproducible and time-dependent response to a specific stimulus.
One type of stimulus that more consistently triggers IEDs or clinical seizures in photosensitive individuals is ILS. In people susceptible to ILS, 12- to 18-Hz frequencies are more likely to elicit seizures than others, and the degree of photosensitivity may depend on the time of day, usually being increased early in the morning. [8] Photosensitivity is seen in approximately 25% of patients with genetic or idiopathic generalized epilepsies. ILS is administered as part of routine electroencephalographic (EEG) recording, to determine whether ictal or interictal epileptic discharges can be elicited.
In addition to visually induced seizures, reflex seizures are also triggered by the activation of other primary sensory cortices, such as the primary auditory, or somatosensory cortices, but also by activation of premotor, pericingulate (SMA), and parietal lobe association cortices. It is unclear whether the stimulus generates an abnormal response directly in the sensory or association cortices, with a synchronized discharge spreading functionally connected cortical or subcortical structures or if a physiological response is responsible for the induction of synchronization of larger networks or functionally connected epileptogenic cortex.
Visual stimulation in photosensitive individuals leads to activation of IEDs in the frontoparietal cortices. [9, 10, 11] In the latter study, modeling of effective connectivity during the photoparoxysmal response suggested the frontocentral cortices were already synchronized prior to the appearance of the ictal or interictal discharge.
One study demonstrated decreased inhibition of the motor cortex during ILS, measured by transcranial magnetic stimulation in photosensitive individuals. [12] This decrease appears to represent either synchronization of the frontocentral cortices or the lack of an inhibitory modulation by an intervening cortical region, such as the parietal lobe. Similarly, in people being evaluated for resective surgery, a temporal lobe epileptogenic zone was triggered by ILS without evidence of the seizure being generated occipitally, [13, 14] which again indicates mechanisms other than propagation being essential to the generation of “reflex seizures”.
Animal models have also contributed to our understanding of cortical networks during ILS. [15, 16] Structural equation modeling of the photoparoxysmal response in the epileptic baboon (Papio hamadryas subspecies) demonstrated normal connectivity of the visual cortices, but hyperconnectivity of the frontoparietal cortices in subsequent levels of connections. The superior parietal cortex appeared to play an important role in the synchronization related to the response, as it was the only region involved at every level of connectivity.
There is increasing morphometric and histologic evidence of abnormal cortical development in the baboon, [15, 17] which has also been associated with juvenile myoclonic epilepsy in humans and focal reflex seizures.
Acquired reflex epilepsy
Rarely, reflex seizures may be the result of acquired cerebral lesions. The most common etiologies are strokes, encephalitis, or cortical dysplasia. All of these etiologies tend to affect the brain frontal, temporal or parietal association cortices, in contrast to trauma and meningitis, which tend to affect more the anterior frontal and temporal lobes. Hence, reflex seizures are most likely triggered by sensory or auditory inputs, as well as movements.
Common manifestations of acquired reflex epilepsy are startle seizures, [18] expressed as sudden myoclonic or tonic contraction of the truncal and extremity musculature. Startle seizures can be triggered by somatosensory, auditory, or proprioceptive (movement) stimuli. This is usually associated with a brief electroencephalographic discharge, which can be isolated or followed by evolution of a partial seizure. The perirolandic cortices and mesial frontoparietal networks are commonly implicated in the generation of reflex seizures. [19]
Inherited reflex epilepsy
As mentioned above, animal models of reflex epilepsy have been described, all of which have a genetic etiology. These include the baboon, which demonstrates generalized myoclonic, tonic-clonic, and absence seizures that occur spontaneously or that can be induced by ILS. [20, 21] Audiogenic seizures characterize genetic reflex epilepsies in predisposed strains of mice, rats, and birds. [22, 23, 24]
In recent years, investigators have defined some of the genetic aspects of reflex epilepsies in humans. Photosensitivity is influenced by familial factors, and linkage analyses have identified potential loci for genes causing this susceptibility. Photosensitivity was linked to bands 7q32 and 16p13 by one group [25, 26] and was linked to 6p21 and 13q31 by another. [27] In addition, children with chromosomal abnormalities have been shown to have a possibly increased tendency to photosensitivity. [28]
The genetics underlying several forms of reflex epilepsies are being investigated. Hot water epilepsy (HWE), which was identified to be highly prevalent in a few large Indian family pedigrees, was linked to band 4q24-q28 in one family [29] and to band 10q21-q22 in 6 families. [30] Some people with autosomal dominant temporal lobe epilepsy (a rare, inherited form of localization-related epilepsy) may have seizures provoked by speech or other auditory stimuli. This epilepsy syndrome is associated with mutations close to those described in one study of HWE, namely in the LGI1 gene in chromosome 10q22-q24. [31]
In summary, genetics play an important role in the expression of reflex seizures than acquired lesions. Several genetic factors predispose to reflex epilepsies, some related to channelopathies, other affecting brain development.
Inherited forms of neurodegenerative disorders are also associated with reflex seizures. These diseases begin in childhood, adolescence, or young adulthood and present with myoclonic and generalized tonic-clonic seizures, leading to progressive cognitive and neurological decline. These diseases affect both the cortex and subcortical structures. They are referred to as progressive myoclonic epilepsies, and the embrace a heterogenous group of diseases, including Unverricht-Lundborg disease, Lafora disease, neuronal ceroid lipofuscinosis, and mitochondrial encephalomyopathies (mitochondrial disorders complicated by cognitive decline and progressive weakness). [32, 33] Photosensitivity, particularly to lower ILS frequencies, as well as large amplitude visual or sensory evoked responses, are common to most of these degenerative disorders.
Epidemiology
Seizures resulting from photosensitivity are more common in females. The sex predilection of less common reflex epilepsies is uncertain. [1, 3]
Photosensitivity generally manifests in late childhood, adolescence, or young adulthood. Other less common reflex seizures also tend to be described in these age groups. [1, 3]
Triggers
Visual inducement
Visually induced seizures may result from flickering light, removal of visual fixation or light intensity, complex visual patterns, viewing particular objects, or other visual stimuli. [34, 35]
Seizures occurring in photosensitive epilepsies are the most common type of visually induced seizures. In susceptible patients, seizures or interictal epileptic discharges may be triggered by ILS during EEG recording. [36] Seizures may also be provoked by flickering or flashing lights in the environment (strobe lights, lightning). Features of visual stimuli related to their epileptogenicity include flash frequency, luminance, and color of the stimulus. [8, 37]
When clinical seizures occur, they are most often generalized seizures, either absence or myoclonic seizures that can progress to generalized tonic-clonic seizures. Alternatively, complex partial or other seizure types may occur.
In pattern-sensitive epilepsies, seizures are produced by particular visual patterns. [38, 39] These triggers may consist of circles, stripes, or other patterns, usually of high contrast. Oscillating or moving patterns are more highly epileptogenic. [39] One case evaluated by the author is illustrative: an infant boy experienced myoclonic seizures and associated EEG discharges only when looking at a particular red hound's-tooth–pattern dress worn by his mother. In addition, the pattern needed to be slowly moved from side to side across the visual field. The pattern did not elicit the seizures when held stationary, nor did other patterns, including the same hound's-tooth pattern in black and white.
Seizures may be produced in some individuals by a reduction in light intensity (scotosensitive seizures) or by removal of visual fixation (fixation-off seizures). More complex visual stimuli, such as seeing particular objects, also may be a cause of reflex seizures.
Television and electronic screen games have been well-publicized causes of reflex seizures. [35] Mass occurrence of seizures were reported as a result of viewing an animated cartoon program in Japan. [38] Photosensitivity is a causative factor for the epileptogenicity of electronic games in susceptible individuals. Epileptogenicity of such stimuli may relate to flicker frequency of the screen and distance from the viewing screen, as well as the particular visual images. [39] European television has a lower flicker frequency than North American television (50 vs 60 cycles/second) and is therefore more epileptogenic.
Somatosensory stimulation
Somatosensory stimuli, including light touch, tapping, or immersion in hot water, have been reported to be associated with reflex seizures.
Seizures evoked by touch may occur in infancy or childhood, referred to as startle epilepsy or reflex myoclonic epilepsy. [40] The seizures tend to be generalized in onset; less commonly, partial-onset seizures can be evoked by touch due to the activation of a sensorimotor cortex.
Hot water epilepsy was first described in 1945 and is more common in India than in Europe, Japan, or North America. [41, 42, 43] The seizures associated with this syndrome are commonly triggered during bathing, when hot water is rapidly poured over the head or body. The seizures are more commonly complex partial seizure with or without secondary generalization beginning in adolescence. More than a quarter of patients have a history of febrile seizures in early childhood. More than a quarter of patients with hot water epilepsy eventually develop spontaneous seizures. [44]
Several case reports indicate that the presentation with hot water seizures in childhood can be associated with cortical dysplasias. The cortical malformations tend to affect the temporoparietal association cortices. [45, 46]
Auditory stimulation
Auditory stimuli are less common precipitants of reflex seizures. Sounds may produce seizures in cases of startle epilepsy. Audiogenic seizures have been described in many animal species and occur in commonly employed mouse and rodent models of genetically determined epilepsy. [22, 23]
In humans, musicogenic epilepsy is the term for a condition in which seizures are produced by tones or music. Music-induced seizures are partial rather than generalized. The type of stimuli producing such seizures varies, and spontaneous seizures may occur in these patients. [47]
EEG and cerebral single-photon emission computed tomography (SPECT) in a patient with musicogenic epilepsy demonstrated a right temporal focus. [48]
Movement
Movement-induced reflex seizures of nonketotic hyperglycemia warrant particular mention, since these are the reflex seizures most likely to be seen by general neurologists, internists, or other medical specialists in the hospital setting. [49] These partial seizures resolve with normalization of the metabolic disturbance. Postanoxic myoclonus (Lance-Adams) may also represent a movement-induced seizure in the medical patient population. [50]
Complex actions and mental processes
Some of the most unusual and intriguing disorders in neurology are the reflex epilepsies in which seizures are provoked by complex actions or mental processes. Examples of these triggers include the following:
In individuals with primary reading epilepsy, reading induces seizures in the absence of photosensitivity. [51] Onset of reading epilepsy is usually in early adolescence, and it can often remit spontaneously. Jaw jerks typically occur, associated with focal or generalized epileptic discharges. Episodes may progress to generalized tonic-clonic seizures. The likelihood of seizure occurrence increases with reading aloud, duration, and complexity of the material being read. Processing of language, particularly with the grapheme-to-phoneme transition, is most likely to induce epileptiform discharges. A recent study combining functional MRI and magnetoencephalography demonstrated activation of the epileptic network in the language-dominant hemisphere, in the premotor cortex. [64]
Cognitive processes have been reported to induce seizures in susceptible persons. Initially described during the performance of mathematical calculations, the seizures also may be produced by processing spatial information or by other forms of decision-making. Reflex seizures have been described as a result of playing chess or checkers, likely due to the cognitive processes involved in playing these games. [61] Mental calculations, writing, solving puzzles (Rubik’s Cube), and reading aloud can also inhibit interictal epileptic discharges in people with juvenile myoclonic epilepsy. [62, 63]
Seizures induced by eating do not comprise a specific epilepsy syndrome. Rather, eating-induced seizures occur in individuals with localization-related epilepsies, namely temporal lobe epilepsy. The precise causative stimulus varies. Seizures may occur at the sight or smell of food, oral or pharyngeal stimulation, or gastric distention.
Evaluation
History
If a history of seizures in response to specific stimuli is reported, the physician must elicit as many details as possible about the nature of the provoking stimuli. In addition, a detailed description from the patient and family members of seizure symptoms is important.
Determination of whether the seizure has features suggestive of focal or generalized onset guides subsequent diagnosis and treatment. A thorough family history needs to be elicited and the presence or absence of unprovoked seizures must be ascertained.
Electroencephalography
In patients with presumed reflex epilepsy, the routine EEG should be expanded to encompass potential stimuli that evoke the patient's habitual seizures. Such testing can be performed under continuous video-EEG monitoring if detailed characterization of clinical seizure type is needed or in cases requiring differential diagnosis or presurgical monitoring.
Photic stimulation is standard in the performance of EEG recordings. Stroboscopic light (photic stimulation) at various frequencies is presented to the patient. A photoparoxysmal response is most often elicited at stimulation frequencies of 12-18 cycles/second. Responses to photic stimulation include (1) photic driving, (2) a photoparoxysmal response, or (3) a photoconvulsive response in which clinical seizures are provoked by the light stimulus. [8]
Pattern-sensitive epilepsies can be investigated in the EEG laboratory by presenting a series of visual patterns to the subject. Alternating or oscillating, black and white, and linear patterns are more highly epileptogenic than static patterns. [34]
More individualized testing, often encompassing the use of detailed neuropsychological evaluation under EEG monitoring, can be used to investigate seizures induced by thinking or other complex activities.
Imaging studies
Since some types of reflex seizures can occur in the context of symptomatic, localization-related epilepsy, a brain magnetic resonance imaging (MRI) scan should be obtained to identify the etiology and potential structural abnormalities underlying the epilepsy. Since ictal and interictal epileptic discharges can be elicited in people with reflex epilepsies, functional MRI with analysis of blood oxygenation level-dependent (BOLD) signal changes [10, 51, 61] can be used to evaluate the potential generators and brain networks underlying the reflex seizures. Ictal SPECT scans can also be acquired in patients admitted to the video-EEG monitoring to characterize the seizure types and location of the generator. [48, 57]
Treatment and Management
The treatment of reflex seizures hinges on limiting exposure to the provoking stimulus and using standard antiepileptic drugs (AEDs).
Photosensitivite people should generally avoid discotheques and videogames with high contrast flashing and should keep distance from any screen (3 times the width of the screen) or use smaller screens. [3] Treatment with specialized lenses has shown promise for limiting seizures in some patients with photosensitive epilepsy. [65]
People with hot water epilepsy are also advised to modify bathing practices, using water that is less hot or avoid pouring the water over the head. [66]
Nonetheless, most patients with reflex seizures resort to AED therapy. In patients with hot water epilepsy, a single preventative dose of clobazam can be taken prior to bathing. [66] The choice of a particular AED for reflex seizures is guided by considerations similar to those in other types of epilepsy. Electroclinical seizure type, prior treatment history, patient age, comorbidities, and medication adverse effects are primary considerations. Valproic acid monotherapy has a success rate of 73-86% in patients with photosensitive epilepsies. Levetiracetam appears to be effective; lamotrigine, ethosuximide, andtopiramate have been recommended as second-choice therapies. [67] Other treatments that may be effective include zonisamide or lacosamide. People with partial reflex seizures may benefit from carbamazepine, oxcarbazepine, lamotrigine, or phenytoin.
