Ophthalmic Signs of Epilepsy

Key Points at a Glance

Highlights of This Disease

• Epilepsy is a disorder of recurrent seizures due to abnormal excessive synchronous brain activity, accompanied by various ophthalmic signs.
• Occipital lobe seizures cause visual hallucinations (flashes, colors, complex scenes), which become more complex when spreading to the temporal lobe.
• Epileptic nystagmus is a rare finding in focal onset seizures, with the fast phase directed away from the epileptic focus.
• Antiepileptic drugs (AEDs) themselves can cause abnormal eye movements (nystagmus, gaze palsy, etc.).
• Aicardi, MERRF, Jeavons, and sialidosis type I are representative syndromes with characteristic ophthalmic findings.
• Visual hallucinations in epilepsy last only seconds, which helps differentiate them from the scintillating scotoma of migraine (lasting tens of minutes to hours).

1. What are the ophthalmic signs of epilepsy?

Epilepsy is a group of disorders characterized by recurrent unprovoked seizures due to abnormal hypersynchronous brain activity. The 2017 International League Against Epilepsy (ILAE) classification divides seizures into focal, generalized, and unknown onset. Epilepsy types are further classified into focal, generalized, combined, and unknown.

Clinical diagnostic criteria require meeting one of the following:

• Two or more unprovoked seizures occurring more than 24 hours apart.
• A single unprovoked seizure with a future risk of seizures
• Diagnosis of an epilepsy syndrome

Epilepsy presents a broad spectrum with symptoms varying by patient. Ophthalmologically, various signs such as visual hallucinations, illusions, visual field defects, eye deviation, nystagmus, eyelid automatisms, and eyelid myoclonus can occur. These reflect the location of the epileptic focus and the propagation pathways of seizure waves.

2. Main Symptoms and Clinical Findings

Subjective Symptoms

Visual Hallucinations and Illusions

• Visual hallucinations: Occur in occipital lobe seizures. Range from elementary (flashes, colors, strange patterns) to complex (people, animals, scenes). Become more complex with spread to the temporal lobe.
• Perceptive illusions: Macropsia, micropsia, palinopsia, depersonalization, etc. Caused by seizures in visual processing centers.
• Alice in Wonderland syndrome: Includes akinetopsia, complex visual hallucinations, body schema disturbances, teleopsia, depersonalization, and out-of-body experiences.
• Palinopsia: Persistence of visual images after stimulus removal. Associated with posterior temporal lesions.

Aura and photosensitivity

• Aura: Precedes generalized seizures. Common in temporal lobe epilepsy, includes motor, sensory, autonomic, and psychic symptoms.
• Photosensitivity: Occurs in some reflex epilepsies. Light stimulation reduces GABAergic inhibition, triggering seizures.

Q What are the characteristics of visual hallucinations during epileptic seizures?

A

They range from elementary phenomena such as flashes, colors, and strange patterns to complex visual hallucinations of people, animals, or scenes. They occur in occipital lobe seizures, and the content becomes more complex when the seizure wave spreads to the temporal lobe. Duration is short, a few seconds, differing from the scintillating scotoma of migraine.

Clinical Findings (Findings Confirmed by a Physician)

• Homonymous hemianopsia: Visual field defect depending on the side of the lesion. Upper quadrantanopia may go unnoticed by the patient. Prevalence of visual field defects increases with diffuse lesions.
• Tonic eye deviation: Due to overactivation of the contralateral frontal eye field. Spread of the seizure wave precedes generalization.
• Epileptic nystagmus: A rare but important finding that can occur in focal onset seizures. It is unilateral and horizontal, with a fast phase away from the epileptic focus. It is accompanied by gaze deviation. Confirmed by video EEG. ¹⁾
• Eyelid myoclonia: Forced twitching of the eyelids including the eyebrows.
• Eyelid flutter: Repetitive blinking occurs in occipital, temporal, and frontal lobe seizures. Unilateral blinking suggests ipsilateral cortical lesion.
• Automatisms: Including rhythmic blinking, sucking movements, and mouth chewing movements.
• Staring: Lasts 5–20 seconds in absence seizures. Not accompanied by convulsions.

3. Causes and Risk Factors

The etiology of epilepsy is classified into the following six categories by the ILAE. The categories are not mutually exclusive.

Etiological category	Representative causes
Genetic	KCNQ2, SCN1A, CAE, JME, GEFS+
Infectious	Tuberculosis, HIV, cytomegalovirus
Immune	NMDA receptor antibody, LGI1 antibody
Structural, metabolic, unknown	Stroke, head trauma, brain malformation, etc.

Major risk factors include stroke, family history of epilepsy, head trauma, and CNS infection.

The central mechanism of epileptogenesis is abnormal neuronal excitation and hypersynchronization due to an imbalance between GABA and glutamate.

Precautions in daily life

• For photosensitive epilepsy, avoid strong flashing lights (strobe lights, game screens, etc.).
• Do not stop taking medication on your own. It may lead to recurrence of seizures.
• If eye symptoms (visual hallucinations, visual field defects, etc.) change, report them to your doctor.

Q What types of causes are there for epilepsy?

A

The ILAE classifies etiologies into six categories: structural, genetic, infectious, metabolic, immune, and unknown. These are not mutually exclusive, and multiple etiologies may overlap. Examples of genetic causes include KCNQ2 and SCN1A, while immune causes involve NMDA receptor antibodies and LGI1 antibodies.

4. Diagnosis and Testing Methods

Diagnostic Approach

The diagnosis of epilepsy is based on clinical criteria (see Section 1: What are the ocular signs of epilepsy?) and combines the following tests.

• Neurological examination: Detailed history taking and neurological examination are fundamental.
• Electroencephalography (EEG) monitoring: Records abnormal discharges during interictal and ictal periods.
• Neuroimaging (CT/MRI): Used to identify structural lesions.
• Blood tests: Used to screen for metabolic and infectious causes.

Video EEG is essential for diagnosing epileptic nystagmus. Neuroimaging may be necessary to identify structural lesions. EEG-fMRI fusion is being researched as an advanced tool to improve diagnostic accuracy for epileptic nystagmus. ¹⁾

Differential Diagnosis

Q How can you distinguish visual hallucinations in epilepsy from those in migraine?

A

Migraine scintillating scotoma is caused by cortical spreading depression. It lasts for tens of minutes to hours and characteristically expands within the visual field. In contrast, epileptic visual hallucinations last only a few seconds. If headache persists as a prodrome, it suggests migraine.

• Migraine: Accompanied by scintillating scotoma due to cortical spreading depression, lasting tens of minutes to hours. Epileptic visual hallucinations are brief, lasting seconds.
• Transient ischemic attack (TIA): Negative symptoms (numbness, monocular visual loss) are typical. Recurrence occurs over days to weeks. Loss of consciousness and Jacksonian march are rare.
• Occipital lobe ischemia: Causes homonymous visual field defects. Peduncular hallucinosis is also included in the differential diagnosis.

5. Standard Treatment

Antiepileptic Drugs (AEDs)

AEDs are selected according to the classification of the epilepsy syndrome. Representative drugs are shown below.

• Valproic acid: A broad-spectrum drug for generalized epilepsy. Also the first choice for sialidosis type I.
• Carbamazepine/Oxcarbazepine: Used for focal epilepsy.
• Ethosuximide: First choice for absence seizures.
• Levetiracetam/Lamotrigine: Used for various epilepsy types.

Polytherapy is also often employed. For epileptic nystagmus, AEDs such as valproic acid, carbamazepine, and levetiracetam are the mainstay. Combined with EEG monitoring and seizure prevention measures, nystagmus disappears with seizure control. ¹⁾

Alternative and Adjunctive Therapies

• Vagus nerve stimulation (VNS): A device is implanted in the upper chest or neck to stimulate the vagus nerve and suppress seizures. It is a relatively minimally invasive option.
• Responsive focal cortical stimulation: A certain success rate has been reported for refractory epilepsy.
• Cannabidiol (CBD): Has shown efficacy in reducing seizure frequency as an adjunctive treatment for drug-resistant epilepsy.

Ocular side effects of antiepileptic drugs

Antiepileptic drugs can affect the oculomotor system. Be aware of the following side effects.

• Decreased saccadic velocity: Occurs with benzodiazepines, carbamazepine, gabapentin, etc.
• Smooth pursuit abnormalities: Occur with benzodiazepines, phenytoin, carbamazepine, etc.
• Gaze palsy: Caused by phenytoin, carbamazepine, valproic acid, etc.
• Nystagmus (especially downbeat nystagmus): Caused by lithium, pregabalin, and various anticonvulsants.
• Gaze-evoked nystagmus: Can occur with carbamazepine and phenytoin. ¹⁾
• Convergence spasm: Reported with phenytoin.

Q Do antiepileptic drugs have ocular side effects?

A

Several antiepileptic drugs affect the oculomotor system. Gaze palsy, nystagmus, decreased saccadic velocity, and abnormal smooth pursuit have been reported. These are particularly common with phenytoin and carbamazepine. If ocular side effects are suspected, consult the prescribing physician.

6. Pathophysiology and Detailed Mechanisms

Basic Mechanisms of Epileptogenesis

The core pathophysiology of epilepsy is an imbalance between GABA and glutamate. Abnormal neuronal migration, cortical abnormalities causing hyperexcitability, mutated Na⁺/K⁺ channels, and reduced GABA inhibition are involved in combination. Amygdala kindling, temporal hippocampal atrophy, and periventricular dysplasia also contribute to pathogenesis.

Mechanisms of Ophthalmic Signs

• Mechanism of epileptic nystagmus: It results from the spread of seizure discharge from the parieto-occipital cortex to the frontal eye field. Contralateral saccade commands are driven, causing involuntary fast eye movements away from the epileptic focus. ¹⁾
• Mechanism of eye deviation: It is caused by overactivation of the contralateral frontal eye field. The spread of seizure waves precedes generalization.
• Mechanism of photosensitivity: Light stimulation of the occipital cortex activates the epileptogenic occipital cortex when the visual stimulus is sufficiently strong, leading to eyelid myoclonus. Reduced GABAergic inhibition is involved.

Epilepsy syndromes with characteristic ophthalmic findings

Aicardi syndrome

Inheritance: X-linked recessive. Usually affects only females (males are lethal in utero).

Triad: Agenesis of the corpus callosum, chorioretinal lacunae, and infantile spasms.

Ophthalmic findings: Optic nerve coloboma, pigmentation of retinal lesions.

Prognosis: Intellectual disability is present, and the survival rate to age 14 is approximately 40%. The success rate of AEDs is limited.

MERRF syndrome

Etiology: Caused by a mutation at nucleotide 8334 of mitochondrial DNA.

Main symptoms: Myoclonus epilepsy and ragged red fibers.

Ophthalmic findings: Optic atrophy is characteristic. Cataracts, ptosis, and ophthalmoplegia may be present.

Jeavons syndrome

Classification: Idiopathic generalized epilepsy.

Triad: Eyelid myoclonus, eye-closure-induced seizures, and photosensitivity.

Course: Photosensitivity decreases with age, but eyelid myoclonus persists. Often resistant to AEDs.

Sialidosis type I

Etiology: Sialidase deficiency due to autosomal recessive mutation in the NEU1 gene (6p21.3).

Age of onset: Usually in the teenage years.

Ocular findings: Cherry-red spot is specific. Young patients may develop cataracts.

Treatment: First-line drug is valproic acid.

---

7. Latest research and future prospects (reports at research stage)

For patients: Please read this

The following content is currently at the research stage or under clinical trial, and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

EEG-fMRI fusion method

The fusion method combining EEG and functional MRI is attracting attention as an advanced tool that contributes to improving the diagnostic accuracy of epileptic nystagmus. Its strength lies in the ability to simultaneously evaluate the spatial localization of seizure discharges and blood flow changes. ¹⁾

Experimental treatment for sialidosis type I

In studies using mouse models for sialidosis type I, enzyme replacement therapy, bone marrow transplantation, and gene therapy have all shown efficacy. However, enzyme replacement therapy has significant challenges: it does not cross the blood-brain barrier and carries a risk of anaphylaxis. Research continues toward human application.

---

8. References

1. Gurnani B, et al. Nystagmus: A Comprehensive Clinical Review of Etiology, Pathophysiology, Diagnostic Approaches, and Management. Clin Ophthalmol. 2025;19:1617-1650.