Oculogyric crisis (OGC) is a rare acute dystonic reaction involving the extraocular muscles. Due to spasm and hypertonicity of the extraocular muscles, both eyes involuntarily deviate conjugately upward. Episodes typically last several minutes and may be accompanied by other dystonic symptoms (e.g., retrocollis, jaw opening).
OGC was first reported in association with postencephalitic parkinsonism following encephalitis lethargica, which was epidemic in Europe from the 1910s to 1930s. In modern times, drug-induced causes are most common, with 68% of cases attributable to neuroleptic agents.
Epidemiologically important points are shown below.
In prospective studies using second-generation antipsychotics, the incidence of OGC during a treatment period of 3 months to 2 years is reported to be 1.8%1). 68% of all OGC cases are caused by neuroleptics. The incidence varies greatly depending on the type of drug, dose, route of administration, and patient background.
Eye Deviation
Conjugate upward deviation of both eyes is most common. Rarely, variants with lateral or downward deviation are also observed. Downward deviation is extremely rare, presenting as sustained downward gaze fixation lasting 30 minutes to 1 hour and recurring 2–3 times a day, as reported in some cases2).
Duration and Frequency
Episodes last from seconds to hours. A literature review reports a range of 5 minutes to 2 hours3), with a tendency to recur.
Associated dystonia symptoms
Autonomic symptoms
May be accompanied by sweating, pupillary dilation, and increased heart rate and blood pressure.
Accompaniment or exacerbation of psychiatric symptoms
Hallucinations, distortion of body schema, exacerbation of obsessive thoughts, and catatonic symptoms may occur3).
Time course of onset
Drug-induced OGC typically first appears within 4 days of starting (or changing the dose of) the causative drug. However, there are reports of first onset up to 2 months after the change. In a literature review, most of 11 cases developed within 1 month of starting or increasing treatment, and one case in a patient with Down syndrome developed after 9 months3).
The most common cause of OGC is drug-induced, but it can also result from neurometabolic diseases, neurodegenerative diseases, and focal brain lesions.
The list of causative drug categories is shown below.
| Drug category | Representative drugs | Notes |
|---|---|---|
| Typical antipsychotics | Haloperidol, fluphenazine, perphenazine | Most frequently reported |
| Atypical antipsychotics | Aripiprazole, quetiapine, risperidone, olanzapine | EPS rate is low but not negligible1) |
| Third-generation antipsychotics | Cariprazine | Onset within one week after dose increase reported2) |
| Antiemetics | Metoclopramide | EPS incidence 1–10%4) |
| Antiepileptics | Carbamazepine, lamotrigine | |
| Others | Lithium, cefixime, ondansetron, L-dopa |
The characteristic points of each drug are described below.
OGC occurs in diseases related to dopamine synthesis and metabolism.
OGC can also occur due to lesions in the brainstem, dorsal midbrain, substantia nigra, posterior third ventricle, and basal ganglia.
Typical antipsychotics (e.g., haloperidol) are most commonly reported, but atypical antipsychotics (e.g., aripiprazole, cariprazine) can also cause it1, 2, 3). The antiemetic metoclopramide can cause symptoms within 36 hours of administration, so caution is needed4). Carbamazepine, lamotrigine, and lithium may also be causes.
The following diagnostic criteria have been proposed for OGC.
Essential Items
Supportive items
The Naranjo Adverse Drug Reaction Probability Scale is useful for diagnosing drug-induced OGC. It consists of 10 items, with scores of 5–8 considered “probable” and 9 or more “definite.” In the three cases of Basera 2024, scores were 6, 6, and 5 (all “probable”) 2), and in the case of Sivagurunathan 2025, the score was 7 (“probable”) 4).
Treatment of drug-induced OGC proceeds in the following three steps.
This is the most fundamental approach. If discontinuation is not possible due to the underlying disease, consider dose reduction.
During the acute phase, anticholinergic or antihistamine drugs are administered.
Anticholinergic drugs
Benztropine: Administered during the acute phase. Usually continued for 4 to 7 days.
Biperiden: Used to control EPS at a sustained-release dose of 4 mg1). Also reported for use in children3).
Trihexyphenidyl (THP): Oral 2 mg has been reported to begin symptom improvement within 2–3 hours, with complete resolution by the next day 4). Use at 4 mg/day has also been reported 2).
Procyclidine: 5 mg/day has been reported in combination with lorazepam 1 mg/day 3).
Antihistamines
Diphenhydramine: Intravenous administration in the acute phase. Improvement has been reported 30 minutes after IV administration 4). It is pregnancy category B and has relatively high safety in pregnant patients.
It is usually continued for 4–7 days.
Alternative: Amantadine
An alternative option when anticholinergic side effects (dry mouth, constipation, angle-closure glaucoma, urinary retention, etc.) are problematic or anticholinergics are contraindicated 2). As a weak NMDA receptor antagonist, it increases dopamine release in the nigrostriatal pathway. The usual dose is 200–300 mg/day (divided doses) 2). There is a report that EPS disappeared after one month of increasing amantadine from 100 mg to 200 mg (divided into two doses) over three days 2).
If discontinuation of the causative antipsychotic is necessary, switch to a drug with a lower incidence of EPS.
For refractory cases that do not respond to anticholinergic or antihistamine drugs, long-term clozapine therapy has been reported. However, since clozapine itself can also cause OGC, careful consideration is required.
Select replacement therapy according to the disease.
There is no established first-line medication during pregnancy. Selection is based on drug availability and risk-benefit assessment4).
First, discontinue or reduce the dose of the causative drug. In the acute phase, administer anticholinergic drugs (benztropine, biperiden, trihexyphenidyl, etc.) or antihistamines (diphenhydramine) for 4 to 7 days 4). If anticholinergics are contraindicated, amantadine 200–300 mg/day is an alternative 2).
A hypodopaminergic state in the brain is suggested as a prerequisite for the development of OGC. Inhibition of dopamine neurotransmission in the nigrostriatal pathway (the major dopaminergic pathway connecting the midbrain and forebrain) forms the basis of OGC.
The mechanisms for each cause are shown below.
A relative increase in cholinergic input compared to dopaminergic input is considered a trigger for OGC. The effectiveness of anticholinergic drugs in treating OGC supports this hypothesis. D2 receptor blockade by metoclopramide is thought to result in unopposed cholinergic activity4).
In CYP2D6 poor metabolizers, blood levels of metoclopramide are elevated, increasing the risk of dystonic reactions4). Elevated estrogen during pregnancy may modulate dopamine receptor sensitivity, further increasing the risk of dystonic reactions4).
Children may have higher pharmacokinetic and pharmacodynamic sensitivity than adults because dopamine receptor density decreases with age3). OGC should be understood within the framework of dystonic reactions, and it presupposes a sudden change in dopamine regulation in a previously normal system. It is fundamentally different from Parkinson’s disease in that it does not involve presynaptic dopamine degeneration3).
D2 receptor blockade by antipsychotics or antiemetics inhibits dopamine neurotransmission in the nigrostriatal pathway, leading to a relative predominance of cholinergic input. This imbalance in dopamine-cholinergic tone is thought to cause involuntary muscle contractions (dystonia), including in the extraocular muscles. The improvement of OGC with anticholinergic drugs supports this hypothesis.
The EPS risk of cariprazine may be higher than previously thought.
Basera et al. (2024) reported a case series of three patients with cariprazine-induced EPS and OGC 2). In one case (Case 3), an extremely rare OGC variant with sustained downward gaze fixation instead of typical upward deviation was observed. They noted that since the half-life of DDCAR metabolites can be up to three weeks, the mechanism of EPS persisting for weeks after drug discontinuation needs to be elucidated, and post-marketing surveillance in young patients should be strengthened.
Although downward deviation is an extremely rare variant of OGC, awareness of its existence among psychiatrists and ophthalmologists can prevent diagnostic delays 2). It is recommended that OGC be considered when tonic eye deviation with preserved consciousness occurs, without excluding it based on the expectation of typical upward deviation.
Sivagurunathan et al. (2025) reported a case of metoclopramide-induced OGC in a patient at 12 weeks of gestation 4). They pointed out that identifying CYP2D6 poor metabolizers may help predict risk, and that elucidating the interaction with hormonal changes (increased estrogen) during pregnancy is a future challenge.
Bernardo et al. (2022) reported three cases of pediatric aripiprazole-induced OGC and a literature review of 11 cases 3). Some cases showed OGC persisting for months after discontinuation or switching of antipsychotics, and they noted that neurobiological elucidation of the dopamine receptor density hypothesis as a basis for individual susceptibility is necessary.
