Spotlight on Oculogyric Crisis: A Review

Etiology of OGC

Though the exact pathogenesis of OGC is not certain, various factors that contribute to its occurrence have been reported.

OGC is seen with different kinds of movement disorders such as tongue protrusion, lip-smacking, blepharospasm, choreoathetosis, anterocollis, and retrocollis. ¹¹ Various neurological disorders are also found to be associated with OGC, such as Parkinson’s disease, familial Parkinson’s–dementia syndrome, dopa-responsive dystonia, parkinsonism with basal ganglia calcifications (Fahr’s disease), neurosyphilis, multiple sclerosis, ataxia–telangiectasia, Wilson disease, and acute herpetic brain-stem encephalitis. ¹¹

Various genetic, neurometabolic disorders also play a part in the etiology of OGC. Hereditary dopamine transporter deficiency syndrome, in which, due to novel homozygous SLC6A3 gene mutations, there would be orolingual dyskinetic movements and OGC. ¹² As a result of aromatic L-amino acid decarboxylase (AADC) deficiency, a rare autosomal recessive neurometabolic disorder characterized by a deficit of the AADC, which is involved in serotonin and dopamine biosynthesis,^{13, 14} the patient may have developmental delay, autonomic symptoms, hypotonia and movement disorder including OGC, dystonia or hypokinesia. ¹⁵ In GLUT1 deficiency syndrome, which is due to mutation in the SLC2A1 gene on chromosome 1p35-31.3 and often presents with mental retardation, epilepsy, paroxysmal exercise-induced dyskinesia, OGC can occur as an early sign of the disease in most patients. ¹⁶ Brain dopamine–serotonin vesicular transport disease, which occurs due to novel mutation in the monoamine transporter gene SLC18A2 (p.Pro237His), leads to hypotonia, bradykinesia, epilepsy, autonomic dysfunction, and OGC. ¹⁷ 6-pyruvoyl-tetrahydropterin synthase deficiency, which results in hyperphenylalaninemia along with dopamine and serotonin depletion in the central nervous system, usually presents with hypotonia, seizures, OGC, and developmental delay.^{18, 19} PLA2G6 associated neurodegeneration (PLAN), which occurs due to a homozygous mutation of PLA2G6, is a rare cause of OGC. ²⁰

Some neurodegenerative disorders are also found to be associated with the occurrence of OGC, such as mutations in the GRIN1 gene, which affects the function of both N-methyl-D-aspartate and dopamine D1 receptors, leading to oculomotor dystonic reactions;^{21, 22} Neuronal intranuclear hyaline inclusion disease, a multisystem degenerative disorder that involves both central and peripheral nervous systems, causing diffuse muscle spasms, dysarthria, dysphagia, tremors, ataxia, OGC, progressive muscle weakness, and atrophy ²³ ; Rett syndrome, progressive neurodegenerative disorder in females, leads to gait disturbance, bruxism, OGC, parkinsonism, and dystonia ²⁴ and tyrosine hydroxylase (TOH) deficiency, an inborn error of catecholamine biosynthesis causing dystonia along with tremor, hypersensitivity to levodopa therapy, OGC, akinesia, and rigidity.^{25, 26} Other autosomal recessive disorders that rarely present with OGC are Kufor Rakeb, ²⁷ haemophagocytic lymphohistiocytosis, ²⁸ sepiapterin reductase deficiency,^{29, 30} and GTP cyclohydrolase I deficiency. ³¹

Some brain lesions are also associated with OGC, such as lesions in periaqueductal and midbrain tegmentum, ³² brainstem, ³³ or substantia nigra ³⁴ and cystic glioma in the region of the posterior third ventricle. ³⁵

Finally, medications which would increase the risk of developing OGC include various groups such as antipsychotics, antiemetics, anticonvulsants, and antidepressants ( Table 1 ). Acute dystonic reactions are commonly seen with the use of high-potency typical antipsychotics, relatively uncommon with atypical antipsychotics, ³⁶ and rarely reported with clozapine. ³⁷ A few cases of acute dystonic reaction, including OGC, have been associated with anesthetic agents like propofol, sevoflurane, nitrous oxide, and fentanyl administration. ³⁸

OPEN IN VIEWER

Table 1.

Drugs Commonly Implicated in Oculogyric Crisis^{2, 43, 57}

Drugs Classification	Drugs
First-generation antipsychotics (FGA)	Haloperidol Fluphenazine Flupentixol Perphenazine Chlorpromazine Zuclopenthixol
Second-generation antipsychotics (SGA)	Risperidone Amisulpride Aripiprazole Olanzapine Quetiapine Clozapine Ziprasidone Lurasidone
Antidepressants	Imipramine Escitalopram Fluvoxamine
Anticonvulsants	Carbamazepine Lamotrigine Gabapentin

In recent times, most of the literature is associated with varied causes of OGC belonging to either neurometabolic disorders such as AADC deficiency, sepiapterin reductase deficiency, TUBB4A-related leukodystrophy ³⁹ or medications (apart from what mentioned in Table 1 ) like anti-tubercular drugs, ⁴⁰ or clebopride, a non-selective benzamide with antidopaminergic activity. ⁴¹

Mechanism of OGC

The exact mechanism of OGC is not clear. Most of the brain lesions that lead to OGC are found in the nigrostriatal pathway. ² Besides, several hypotheses have been given for drug-induced OGC such as striatal cholinergic hyperactivity, ⁴² striatal dopaminergic hypoactivity (commonly reported), ⁴³ or the rarely reported striatal dopaminergic hyperactivity. ⁴⁴ The majority of the conditions are related to dopaminergic dysfunction, including disorders of dopamine metabolism leading to low dopamine levels, such as TOH deficiency and AADC deficiency.^{13, 25} An imbalance between dopaminergic and cholinergic neurotransmission in the striatum has also been proposed for drug-induced OGC. ⁴⁵

Hypersensitivity of striatal dopamine receptors due to chronic dopamine receptor blockage, neurodegeneration of striatal interneurons, dysfunction of striatal gamma-aminobutyric acid (GABA)-ergic interneurons, or maladaptive synaptic plasticity are reported to be the causes of tardive involuntary movements. ⁴⁶ Antidepressants-induced OGC is explained with hyperstimulation of 5-HT2 receptors, inhibition of dopaminergic activity, and alteration of cholinergic and GABAergic activity. ⁴⁷

Risk Factors of OGC

Certain characteristics of patients would make them more vulnerable for the emergence of OGC, such as younger age,^{48, 49} male sex, ⁴⁸ greater severity of illness, ⁴⁹ greater baseline psychopathology, ⁵⁰ increasing neuroleptic dose, ⁴⁸ parenteral administration of neuroleptics, ⁵¹ high potency of neuroleptic drugs, ⁵² abrupt discontinuation of anticholinergic medication within the first few weeks of initiating neuroleptics, ⁵¹ metabolic conditions (e.g., hypocalcemia, hyperthyroidism, hyperparathyroidism), ⁵¹ recent cocaine use, ⁵¹ and family history of dystonia. ⁴⁴

Diagnosis of OGC

Diagnosis of OGC is clinical, based on typical symptoms such as paroxysmal, conjugate, and typically upward deviation of the eyeball for seconds to hours. Slow et al. ⁴³ has proposed the required and supportive criteria for diagnosing OGC ( Table 2 ). Whenever clinicians encounter an OGC-like phenomenon, they should approach in a manner as suggested in Figure 1 .

OPEN IN VIEWER

Table 2.

Proposed Criteria for the Diagnosis of Oculogyric Crisis ⁴³

Required Criteria	Supportive Criteria
Tonic, conjugate deviation of eyes Minutes to hours in duration Consciousness preserved	Preceded by anxiety, discomfort The patient is aware of and bothered or disabled by the ocular deviations Associated dystonia Associated with a low dopamine state and improved by anticholinergics or dopaminergic medication

OPEN IN VIEWER

Figure 1.

OGC: Oculogyric crisis.

Differential Diagnosis/Mimickers of OGC

Several clinical entities look similar to OGC. Therefore, meticulous history and thorough clinical examination should be done for differentiating other phenomena from OGC ( Table 3 ).

OPEN IN VIEWER

Table 3.

Common Differential Diagnosis for OGC^8–10resulting in sustained unnatural positioning

Differentials	Description
Seizures	Repetitive, clonic, or tonic eye movements It is usually associated with loss of consciousness or impaired responsiveness, with other seizure phenomena such as tongue bite, incontinence, fall, confusion, and EEG changes Seizures are primarily cortical, while the OGC is primarily subcortical-striatal in etiology. Video-EEG monitoring can help in differentiating from OGC. 53
Paroxysmal tonic upgaze	Upward eye deviation lasting seconds to hours Reported in children only
Ocular dyskinesias	Repetitive, upward gaze usually lasting only a few seconds Associated with L-dopa-induced dyskinesias and tardive dyskinesias. Generally, short-lasting, not associated with anxiety, and the patient often remains unaware of the eye movements.
Ocular tics	Brief ocular deviations It is associated with other tics and can be suppressed
Psychogenic	Distractible ocular movements and associated with other functional movements, and other functional findings

OGC: Oculogyric crisis.

Management of OGC

The mainstay of treatment of OGC is based on its etiology. ² In the case of drug-induced OGC (e.g., antipsychotics), generally, the first approach is to taper down the causative drug. On the persistence of OGC on reducing the dose, discontinuation of the offending agent is advised, with shifting to other agents with a lesser propensity to cause dystonic reactions.^{3, 43}

For the management of cases where the mentioned strategy would not cause improvement, other pharmacological management options should be tried. In OGC, primarily anticholinergics such as trihexyphenidyl, benztropine, benzhexol, biperiden, procyclidine, or other centrally acting anticholinergic drugs or antihistaminergic agents (e.g., diphenhydramine, phenhydramine, chlorpheniramine, promethazine) are commonly used. ⁵¹ In most cases of acute dystonic reactions, the intravenous route is the preferred route of choice as it leads to improvement within 10 minutes. Alternatively, intramuscular (if you cannot access intravenous line) or oral (most unreliable, due to extensive gut first-pass metabolism) route can be used. ⁵⁴ Sometimes benzodiazepines ² and rarely dopamine agonists are also used. ³ To avoid recurrence, it is recommended to continue the management of OGC for at least a week but sometimes for longer periods in case of tardive OGC. If the above line of treatment fails, then clozapine remains a promising option ² as it works via the stimulation of M4 muscarinic receptors, which results in inhibition of D1 receptors or the direct blockade of D1 receptors. ⁴³ But rarely, in some cases, OGC has been reported with the use of clozapine. ³⁷ Electro-convulsive therapy can also be given in tardive OGC cases with psychotic disorders. ⁵⁵

Prophylactic use of anticholinergic drugs for 1–2 weeks is indicated in patients with greater vulnerability for OGC with certain antipsychotics, though the available guidelines are inconsistent for the duration of use of such prophylactic agents. ⁴⁹ Levodopa may be useful in Parkinson’s disease with OGC. Anticholinergics are also found to be beneficial in OGC associated with focal brain lesions.

The dystonic reactions are associated with considerable physical and psychosocial consequences such as increased psychiatric comorbidity, ⁵⁶ poor compliance, ⁵⁷ increased fatigue, and sleep disturbances, leading to decrease quality of life. ⁵⁸ OGC and blepharospasm can significantly affect daily living activities such as driving, shaving, combing, or dressing. These effects are more pronounced with tardive dystonia cases and can even lead to social avoidance, isolation, and stigmatization. ⁵⁹ Hence, both non-motor and motor features associated with dystonia should be managed in order to improve the quality of life.