Oculogyric Crisis (OGC) is a rare, acute dystonic reaction involving the extraocular muscles. OGC is most commonly described as the involuntary upward deviation of both eyes due to spasms and increased tone in the extraocular muscles. Episodes typically last minutes and may occur in conjunction with other dystonic symptoms.
Neuroleptic drugs are the most common cause, though there are many other reported etiologies. In addition, OGC is associated with several diseases, but without clear risk factors that can accurately predict which patients will suffer from an OGC. Furthermore, as most of the associated diseases are psychiatric, OGC can be easily mistaken as an exaggeration of the underlying psychiatric illness rather than a dystonic reaction. This article describes clinical features, differential diagnoses and approaches to management of oculogyric crisis.
Oculogyric crises were first described in association with post-encephalitic Parkinsonism (PEP) following the European epidemic of encephalitis lethargica (EL) from 1910-1930. The dystonic reaction was later identified as a side effect of certain drugs. Today, OGC is also known to be associated with many neurometabolic and neurodegenerative disorders.
There are multiple theories regarding the pathophysiology of OG including inhibition of dopamine receptors and disruption of dopamine metabolism. Overall, the pathophysiology remains ill-defined but suggests an underlying hypodopaminergic state of the brain.
1. Drug-induced OGC: The pharmacodynamics of neuroleptics involve disruption in the pathway of dopamine neurotransmitters. The theory of hypodopaminergic state is further supported by the association of OGC and antiemetics which are dopaminergic inhibitors. However, drugs such as anticonvulsants and antidepressants that are also identified as possible triggers do not operate on the dopamine axis directly.
2. Neurodegenerative disorders: These are also thought to operate on the dopamine pathway via mutated synthesis or transmission of dopamine signals. For example, Rett Syndrome is a neurodegenerative disease that can result in improper formation of the basal ganglia which is involved in dopamine signaling of the motor cortex. Furthermore, neurometabolic disorders associated with OGC are known to cause low dopamine states in patients. This can be tested via cerebrospinal fluid (CSF) homovanillic acid (HVA) concentrations. HVA is a by-product in the breakdown of dopamine and is therefore representative of dopamine levels. As a result, OGC from neurodegenerative and neurometabolic disorders support the hypothesis of disrupted dopamine pathways. In contrast, Parkinson’s disease, though a disease of dopamine deficiency, is not associated with OGC. Possible reasons for this include the slow development of Parkinson disease and the relatively less severe dopamine deficiency compared to other diseases.
3. Focal brain lesions: Lesions that damage the basal ganglia and the brainstem directly disrupt the nigrostriatal pathway on an anatomical level. This pathway is the main dopaminergic pathway connecting the midbrain and the forebrain.
A second hypothesis points at an altered ratio of cholinergic to dopaminergic stimulation. This is supported by the successful use of anticholinergic drugs in treating OGC. Therefore, an increase in cholinergic input relative to dopamine input may be the triggering factor. Ultimately, the pathophysiology remains unclear.
There are three main etiologies described in literature: drugs, neurometabolic and neurodegenerative disorders, and focal brain lesions. Sixty-eight percent of cases have been attributed to neuroleptic drugs. The most commonly described causative drugs are neuroleptics such as haloperidol, flupentixol, fluphenazine and perphenazine. Atypical neuroleptics (e.g. quetiapine) are also reported to cause OGC. However, there is evidence that antiemetics, antidepressants, anticonvulsants and other agents (e.g. cetirizine, levodopa, nifedipine) may also be potential triggers.
OGC has been identified as occurring most often in diseases of dopamine synthesis and signaling. This includes the monoamine neurotransmitter disorders, a group of neurometabolic disorders that affect dopamine synthesis and metabolism. These disorders are characterized by dopamine deficiency, early onset in infancy, and typically have autosomal recessive inheritance pattern. The dopamine deficiency is the suggested link between the resulting parkinsonism and dystonic features. In addition, there are reported cases of OGC as a result of rare neurodegenerative disorders. Examples include Neuronal Intranuclear Inclusion Disorder (NIID), Kufor-Rakeb disease, Perry syndrome, Chediak Higashi syndrome, and Rett syndrome. However, the occurrence of OGC in Rett Syndrome has been disputed. Focal brain lesions of the brainstem, dorsal midbrain, substantia nigra, posterior third ventricle and basal ganglia have also been identified as triggers of OGC. Other diseases associated with OGC include Wilson disease, acute herpetic brainstem encephalitis, vascular parkinsonism, and paraneoplastic syndrome.
The most common characteristic of oculogyric crisis is the bilateral conjugate upward deviation of the eyes, from tonic spasms of the extraocular muscles. However, lateral and downward deviations are also possible. Other features include ocular pain, blepharospasm, periorbital twitches, and protracted staring. Associated symptoms include retrocollis, open jaw, tongue protrusion, and contracted frontalis muscles, which are caused by tonic spasms of other muscles. Dystonic episodes typically last a few minutes, though they can range from seconds to hours. Some autonomic features can be associated, including perspiration, dilated pupils, increased heart rate and blood pressure, as well as psychiatric symptoms, including hallucinations, distorted body schema, and catatonic symptoms.
In the case of drug-induced OGC, the first episode usually occurs within 4 days of starting (or changing the dosage of) the causative drug. However, there are reported cases in which the first episode has occurred up to two months after the change in medication. These reports of tardive drug-induced OGC are accountable for the uncertainty in the pathophysiology of this disease. According to Slow et al., tardive reactions are so uncommon that it is likely that reports of tardive drug-induced OGC are misdiagnosed.
Diagnostic criteria suggested for OGC
The differential diagnosis of OGC includes movement disorders associated with meningitis, encephalitis, head injury, conversion reaction, epileptic seizures, L-dopa-induced ocular dyskinesias, ocular tics, reverse ocular dipping from viral encephalitis or metabolic encephalopathy, and paroxysmal tonic upgaze syndrome. Careful history, observation, and physical examination, and a trial of pharmacotherapy should help the clinician differentiate between many of these pathologies.
For example, while paroxysmal tonic upgaze syndrome like OGC is characterized by attacks of upward deviation of the eyes that last seconds to hours, the syndrome presents with a unique neck flexion to compensate for the involuntary upward gaze. L-dopa-induced ocular dyskinesias typically involve shorter and less tonic episodes.
Management of OGC depends on the etiology. In the case of drug-induced OGC, administration of anticholinergic or antihistamine medication is suggested. Reports of positive responses to treatment include 4-7 days of benztropine or diphenhydramine administration. The causative medication should be discontinued or reduced in dosage (if discontinuation is not possible due to underlying illness). There are some reports of non-response to anticholinergic or antihistamine drugs. In these cases, long-term clozapine therapy was successful, though this must be carefully considered as clozapine is also known to cause OGC.
Focal brain lesions can also be treated with anticholinergics and antihistamines. In comparison, neurometabolic disorders of low dopamine may require dopamine replacement. Dopamine agonists are suggested for vesicular monoamine transporter-2 (VMAT2) deficiency and aromatic L-amino acid decarboxylase (AADC) deficiency. L-dopa supplementation is suggested for tyrosine hydroxylase (TH) and sepiapterin reductase (SR) deficiency, Kufor-Rakeb disease, and Perry syndrome.
While an OGC may be distressing to the patient and family, the disease is not life threatening. In most cases of acute drug-induced OGC, the episodes disappeared after 24-48 hours of management. In tardive cases of drug-induced OGC, symptoms persisted for much longer and/or did not respond as well to treatment. However, there are reports of no re-occurrence following treatment.
There is evidence that dopamine replacement for neurometabolic disorders can completely relieve symptoms. In addition, there are reports of patients going into spontaneous remission.
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