Reflex Epilepsy 

Reflex epilepsy is a condition in which seizures can be provoked habitually by an external stimulus or, less commonly, internal mental processes. Individuals with reflex epilepsy may have seizures exclusively in response to specific stimuli and not suffer spontaneous seizures; alternatively, reflex seizures may coexist with spontaneously occurring seizures.

Reflex seizures may clinically manifest as partial or generalized seizures, and can be associated with either focal or generalized ictal epileptic discharges at onset. Subclinical interictal epileptic discharges can also be provoked by particular stimuli in people with reflex epilepsies.

Photosensitive epilepsy is the most common type of reflex epilepsy. Clinical photoconvulsive seizures or subclinical photoparoxysmal responses occur when an individual is exposed to visual stimuli, usually flashes of light of a particular frequency. In other reflex epilepsies, seizures may be provoked by auditory, autonomic, somatosensory, olfactory, or vestibular stimuli.

Reflex seizures also may occur in response to more elaborate stimuli or mental processes. Examples of these include reading, hearing music, or praxis.

Some epilepsy syndromes are associated with seizures triggered by different stimuli. Ictal or interictal epileptic discharges can be elicited by visual stimuli, praxis, or reading in people with juvenile myoclonic epilepsy.^[1]

Go to Epilepsy and Seizures for an overview of this topic.

With epilepsy in general, the immediate factors that provoke any given seizure vary, and the occurrence of seizures is rarely predictable. Some factors associated with a general tendency for an increase in the likelihood of seizures are known (eg, sleep deprivation, fever or systemic illness, epileptogenic drugs), but usually no immediate trigger is recognized. In contrast, reflex seizures represent a reproducible and time-dependent response to a specific stimulus.

Production of interictal epileptic discharges or clinical seizures in response to repetitive light stimulation (photic stimulation) is termed photosensitivity; it is seen in approximately 25% of patients with primary generalized epilepsy. Photic stimulation is administered as part of routine electroencephalographic (EEG) recording, to determine whether these characteristic EEG patterns can be elicited.

Reflex seizures are induced by the activation of primary sensory cortices, such as the primary auditory, visual, or somatosensory cortices, as well as of parietal lobe association cortices. It is not clear whether the stimulus generates an abnormal response in the sensory or association cortices that subsequently spreads to functionally connected motor cortices or cortical-subcortical networks, or a physiological response that induces abnormal excitation or inhibition in functionally connected motor cortices or cortical-subcortical networks.

Acquired reflex epilepsy

Reflex seizures may be the result of acquired cerebral lesions. Photosensitivity may be induced after production of focal cortical or subcortical lesions in experimental animals. In addition, focal structural or EEG abnormalities have been described in humans with reflex epilepsy.^[2]

A child with seizures induced by bathing in hot water was found to have a left parietal malformation on brain magnetic resonance imaging as well as epileptiform EEG discharges in that region.^[3] EEG and cerebral single-photon emission computed tomography (SPECT) in a patient with musicogenic epilepsy demonstrated a right temporal focus.^[4]

Inherited reflex epilepsy

Animal models of genetic reflex epilepsy have been described. These include the baboon, Papio hamadryas subspecies, in which generalized myoclonic, tonic-clonic, and absence seizures can be induced by visual stimulation.^{[5, 6]} Audiogenic seizures characterize genetic reflex epilepsies in predisposed strains of mice, rats, and birds.^[7]

In recent years, investigators have defined some of the genetic aspects of reflex epilepsies in humans.^{[8, 9, 10]} Photosensitivity is known to be influenced by familial factors, and linkage analyses have identified potential loci for genes causing this susceptibility. In addition, children with chromosomal abnormalities have been shown to have a possibly increased tendency to photosensitivity.

The genetics underlying several forms of reflex epilepsy are being investigated. Photosensitivity was linked to bands 7q32 and 16p13 by one group^{[11, 12]} and was linked to 6p21 and 13q31 by another.^[13] 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^[14] and to band 10q21-q22 in 6 families.^[15]

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.^[16]

Seizures resulting from photosensitivity are more common in females. The sex predilection of less common reflex epilepsies is uncertain.

Photosensitivity generally manifests in late childhood, adolescence, or young adulthood. Other less common reflex seizures also tend to be described in these age groups.

Triggers of reflex seizures include the following:

• Visual inducement
• Somatosensory stimulation
• Auditory stimulation
• Movement
• Complex actions and mental processes

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.^[17]

Seizures occurring in photosensitive epilepsies are the most common type of visually induced seizures. In susceptible patients, seizures or interictal epileptic or epileptiform discharges may be triggered by photic stimulation during EEG recording. Seizures may also be provoked by flickering or flashing lights in the environment. Features of visual stimuli related to their epileptogenicity include flash frequency, luminance, and color of the stimulus.

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. These triggers may consist of circles, stripes, or other patterns, usually of high contrast. Oscillating or moving patterns are more highly epileptogenic. 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.^[18] Mass occurrence of seizures were reported as a result of viewing an animated cartoon program in Japan.^[19]

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.^[20] European television has a lower flicker frequency than North American television (50 vs 60 cycles/second) and is therefore more epileptogenic.

Photosensitivity is a causative factor for the epileptogenicity of electronic games in susceptible individuals. However, the cognitive processes involved in playing these games may also contribute to the provoked seizures.^[18] Many patients who experience their first seizure while playing electronic screen games are found to be photosensitive.

Somatosensory stimulation

Somatosensory stimuli, including light touch, tapping, or immersion in hot water, have been reported to be associated with reflex seizures.

Touch- or tap-evoked generalized seizures may occur in neurologically normal infants younger than 1 year. Seizures evoked by touch may occur as part of another condition of infancy or childhood, referred to as startle epilepsy or reflex myoclonic epilepsy. These also are primary generalized seizures. Less commonly, partial-onset seizures evoked by touch may occur, referable to a seizure focus in the sensorimotor cortex.

Hot water epilepsy was first described in 1945 and is more common in India than in Europe, Japan, or North America.^{[21, 22, 23]} 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 than primary generalized tonic-clonic seizures.

Hot water epilepsy typically begins 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.

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 models of genetically determined epilepsy.

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.^[24]

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. These partial seizures resolve with normalization of the metabolic disturbance. Postanoxic myoclonus may also represent a movement-induced seizure in the medical patient population.

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:

• Reading^{[25, 26, 27, 28, 29]}
• Thinking
• Eating^[30]
• Micturition^[31]
• Toothbrushing^[32]
• Walking^[33]
• Answering the telephone^[34]

In individuals with primary reading epilepsy, reading induces seizures.^[35] Jaw jerks typically occur, associated with focal or generalized epileptic discharges. Episodes may progress to generalized tonic-clonic seizures. Spontaneous seizures may occur, and the likelihood of seizure occurrence may increase with duration of reading or with complexity of the material being read. Processing of language within the cortex is likely to be the physiologic basis for seizure generation.

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.^[36] Mental calculations can also inhibit interictal epileptic discharges in people with juvenile myoclonic epilepsy.^[37]

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.

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.

An electroencephalogram (EEG) is a critical test in the evaluation of patients with presumed reflex epilepsy. Performance of neuroimaging and selection of imaging modalities should be guided by the EEG and clinical features of the seizures.

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 EEG-video 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 15-18 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.

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.

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 can be useful identifying the etiology and potential structural abnormalities underlying the epilepsy. Functional neuroimaging with positron emission tomography (PET) scanning or functional MRI with analysis of blood oxygenation level-dependent (BOLD) signal changes^[38] have been successfully used to evaluate the brain regions and networks underlying reflex seizures.

Therapy of reflex seizures involves limiting exposure to the provoking stimulus and using standard antiepilepsy drugs (AEDs). Treatment with specialized lenses has shown promise for limiting seizures in some patients with photosensitive epilepsy.^[39] Reflex seizures are usually controlled with AEDs. 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, and topiramate have been recommended as second-choice therapies.^[40]