Oculogyric crises: etiology, pathophysiology and therapeutic approaches

Ewgenia Barow1 MD; Susanne A. Schneider2 MD, PhD; Kailash P. Bhatia3 MD;

Christos Ganos1,3 MD

1. University Medical Center Hamburg-Eppendorf (UKE), Department of Neurology

2. Department of Neurology, Ludwig-Maximilians-University, Munich, Germany

3. Sobell Department of Motor Neuroscience and Movement Disorders, Queen Square,

UCL

Title character count: 71

Corresponding Author:

Dr. Christos Ganos

University Medical Center Hamburg-Eppendorf (UKE)

Department of Neurology

Martinistraße 52

20251 Hamburg

Germany

[email protected]

Search Terms: Oculogyric crisis; dystonia; acute dystonic reaction; drug-induced

dystonia.

Word count: 3510

Number of tables: 2
Abstract

Oculogyric crisis (OGC) describes the clinical phenomenon of sustained dystonic,

conjugate and typically upward deviation of the eyes lasting from seconds to hours. It

was initially observed in patients with postencephalitic parkinsonism, but since then a

number of conditions have been associated with OGC. These include drug-induced

reactions, hereditary and sporadic movement disorders, and focal brain lesions. Here,

we systematically review the literature and discuss the spectrum of disorders associated

with OGC in order to aid clinicians place this rare but distinctive clinical sign into the

appropriate diagnostic context. We also provide a brief synthesis of putative

pathophysiological mechanisms, as well as therapeutic recommendations based on the

literature and our own experience.

Introduction

Oculogyric crisis (OGC) is a rare neurologic manifestation characterized by sustained

dystonic, conjugate and typically upward deviation of the eyes lasting from seconds to

hours [1]. Oculogyric crises were first described in patients with parkinsonism

following the epidemy of encephalitis lethargica (Economo’s disease) during the 1910-

1930s [2]. Since then, OGCs have been reported in association with numerous

conditions, as for example drug-induced, but also neurometabolic and

neurodegenerative movement disorders, or as a consequence of focal brain lesions [3-

7].

Although commonly reported as acute disorder, OGC may also occur within weeks or

even months after an inciting event [1, 8-10]. Clinical presentation may vary from very

brief and subtle eye deviation as an isolated symptom to more severe and even painful

forms accompanied by neck flexion, jaw opening, blepharospasm, tongue protrusion

and autonomic signs, such as perspiration, pupillary dilation, increases in blood

pressure and heart rate. Episodes generally last minutes, but may range from seconds

to hours. In addition, psychiatric symptoms such as agitation and anxiety, but also

psychotic symptoms including visual, tactile and auditory hallucinatons, distortions of

body schema, catatonic symptoms, mood disorders such as depression or mania and

obsessive-compulsive behaviors may occur [3, 8, 11-14].

Oculogyric crises are not life threatening. However, they often present a source of

distress for patients and their environment. Due to their rarity and variable clinical

severity OGCs may be easily overseen or misinterpreted as functional or as

exacerbation of psychotic illness [11, 13]. Oculogyric crises are non epileptic eye

movements and should, therefore, be distinguished from more commony occurring

tonic eye deviations within the context of epileptic seizures (i.e. thorough history and

clinical observation for features suggestive of an epileptic event and EEG), but also
from oculogyric tics, as part of tics disorders [15, 16]. Oculogyric crises should also be

separated from the paroxysmal tonic upgaze syndrome characterized by infantile-/early

childhood-onset and episodic tonic upward deviation of the eyes, neck flexion

downbeating saccades in attempted downgaze and normal horizontal eye movements

[17]. Indeed, the recognition of OGCs is a useful clinical sign to guide the diagnostic

procedure, leading in turn to appropriate counceling and treatment. To date, there has

been no systematic study to assess the spectrum of conditions reported to occur with

OGCs and to provide a list of relevant diagnoses in such cases.

Methods

This review is based on a systematic search of the literature in PubMed (a service of

the National Library of Medicine’s National Center for Biotechnology Information;

http://www.ncbi.nlm.nih.gov) for all publications up to March 2016 using the key

words oculogyric eye movements, oculogyric crisis/crises, tonic eye deviation, tonic

gaze deviation and all combinations of these. Only articles with publication of original

clinical information and published in English were considered. Pertinent references

cited in relevant articles and their bibliographies were also checked and considered if

fulfilling the criteria for this review. After removal of articles without abstract,

duplicates and opinions/comments about articles, all abstracts and full texts if available

were reviewed. Articles without original, insufficient or inconsistent clinical

information were excluded. All identified articles are referenced in supplement 1.

Results

According to our inclusion and exclusion criteria 147 publications reporting the clinical

characteristics of 394 patients with OGCs were identified. Based on our results, three

main aetiological categories were discerned: 1. Drug-induced OGCs; 2. Oculogyric

crises associated with hereditary and sporadic movement disorders; 3. Oculogyric

crises as a result of focal brain lesions. Following, we present the clinical characteristics

of patients of these three categories according to their reported frequency. Based on

these data we also provide a synthesis of putative pathophysiological mechanisms and

present recommended treatment strategies.

1. Drug-induced OGC

The majority of the reported OGC cases were drug-induced, most commonly as adverse

effects of neuroleptics, antiemetics or other dopamine antagonists (complete list of

drugs inducing OGCs is provided in table 1). Among the 175 reported patients the

median age was 22 years (range: seven months to 54 years), with a 1:1 male/female

ratio. Oculogyric crises usually disappeared within 24 to 48 h upon withdrawal or

reduction of the antidopaminergic/neuroleptic medication.

Neuroleptics

Sixtyeight percent of all reported patients (median age: 24 years; range: five to 47 years)

with drug-induced OGCs we could identify were due to neuroleptics. In this context

OGCs were commonly described as an acute dystonic reaction usually occurring

promptly after the administration, or less often, following long-term exposure to

neuroleptics (i.e. OGC as a tarvide dystonic reaction) [8, 18]. Both typical and atypical

neuroleptics induced OGCs, however the use of typical neuroleptics and OGCs was

more commonly reported (63 patients in 15 articles for typicals versus 32 patients in 21

articles for atypicals; the exact neuroleptic agent was not reported for 24 remaining

cases). Younger age, male sex, dose increase of an existing pharmacological agent or

the introduction of a new agent were reported as associated risk factors [19-22].
Antiemetics

We found nine articles reporting OGCs in ten female patients and one male patient

(median age: 21 years; range: 13 to 55 years) receiving antiemetics. Oculogyric crises

were reported in five patients following intake of metoclopramide [23-27], in three

patients upon administration of phenothiazines [28] used as antiemetics, and also in

single cases associated with intake of clebopride, ondansetron and droperidol [29-31].

Anticonvulsants

Thirteen patients in seven different articles were identified reporting OGCs as a result

of treatment with anticonvulsants. The five male and five female patients (the gender

of the remaining three patients was not reported) had a median age of 26 years (range:

three to 33 years). Carbamazepine (six patients) [32-35], lamotrigine (four patients)

[36], gabapentin (two patients) [37], and oxcarbazepine (one patient) [38] are described.

All patients were treated for epilepsy with or without mental retardation. In most

patients OGCs were terminated by dose reduction suggesting a dose-depending effect

[33, 34, 36].

Antidepressants

Oculogyric crises were also reported in association with antidepressants (four articles,

three female and one male patients; median age: 28 years; range: ten to 44 years). Three

articles reported OGCs following intake of selective serotonine reuptake inhibitors

(SSRIs; fluoxetine and citalopram, fluvoxamine, escitalopram) [39-41]. One article

reported the induction of OGCs by imipramine, one of the first tricyclic antidepressants

acting by inhibiting serotonine and noradrenaline reuptake [42].

Others
Further case reports and case series (13 articles, 24 patients; median age: 15 years;

range: seven months to 54 years) described OGCs after intake of cetirizine (number of

patients; n=9) [43], organophosphate poisoning (n=3) [44], tetrabenazine (n=2) [45, 46],

L-dopa (n=2) [47], lithium (n=1) [48], tensilon (n=1) [49], cefexime (n=1) [50],

pentazocine (n=1) [51], nifedipine (n=1) [52], isotretinoin (n=1) [53], phencyclidine

(n=1) [54] and salicylate intoxication (n=1) [55].

OGC despite withdrawal or following discontinuation of medication

Oculogyric crises usually disappear within 24 to 48 h upon withdrawal or reduction of

the triggering agent; and continuation of OGCs without further exposure is generally

not seen.

Schneider and collegues, however, observed OGCs in three patients in whom episodes

of OGCs, initially triggered by a single dose of haloperidol (in two cases) or a single

dose of metoclopramide (in one case), continued spontaneously despite withdrawal [9].

Oculogyric crises in these cases were successfully treated with anticolinergics.

On the other hand, Mendhekar and Duggal described a female patient with mental

retardation and aggressive behavior who developed OGCs only after abrupt

discontinuation of clozapine. This resolved upon recommencing the medication [56].

Oculogyric crises have also been described during off-periods of L-dopa treatment in

two parkinsonian patients, which improved with increasing the dopaminergic

medication [57, 58].

2. Hereditary and sporadic movement disorders

The second most common association of OGCs was with hereditary and sporadic

movement disorders (complete list of all disorders is provided in table 2). In total 57
articles with 207 patients were identified with a median age of 23 years (two months to

92 years) and 1:1.3 male/female ratio (64 males, 83 females; 60 patients no gender

reported).

Disorders of dopamine metabolism

Disorders of dopamine metabolism are the most common metabolic cause of OGCs,

which may be a clue towards the pathophysiology (see below). The literature review

revealed 103 cases (in 28 reports). This included deficiency of aromatic L-amino acid

decarboxylase (AADC) (n=75 in 17 articles)[59-61], sepiapterin reductase (SR) [62-

65] (n=19; median age: 10 years; range: three to 23 years), tyrosine hydroxylase (TH)

[66-70] (n=7) and guanosine-triphophate cyclohydrolase type I (GTPCH) [71] (n=1) or

moleculary-undefined dopa-responsive dystonia (n=1) [72], all autosomal-recessive

disorders with similar phenotypic features [4]. In more detail, for AADC, reported

patients were mostly infants and children (median age: five years; range: two months

to 33 years) and presented with early (neonatal) hypotonia, developmental delay,

autonomic abnormalities, such as excessive sweating or temperature instability and

OGCs. Associated movement disorders included parkinsonism, dystonia and/or chorea.

Other hereditary movement disorders

Oculogyric crises were reported in 22 female patients with Rett syndrome [73], six

patients (median: nine years; range: three to 16 years) with mutations at the SLC18A2

gene encoding the vesicular monoamine transporter 2 (VMAT2) in the presynaptic

neurons [74, 75] and three cases of Kufor Rakeb disease due to mutations in ATP13A2

[76, 77]. Further, OGCs were described in two cases with neuronal intranuclear

inclusion disease (NIID) [78, 79]. Oculogyric crises have also been associated with

neurodegeneration with brain iron accumulation due to mutations in PLA2G6 [80] and
pantothenate kinase-associated neurodegeneration (PKAN) [81].Interestingly, in the

two cases of PLA2G6 neurodegeneration with brain iron accumulation, OGCs occurred

in the dopaminergic ON state, and this has been suggested as a helpful clinical hint to

differentiate this type of disorder from other brain iron accumulation syndromes[80].

Pathogenic mutations in GRIN I gene, encoding for the GluN1 subunit of the ionotropic

glutamate N-methyl-D-aspartate (NMDA) are associated with an early onset

dysmorphic syndrome, oculomotor abnormalities, epilepsy, spasticity and hyperkinetic

movement disorders, to include chorea and myoclonus [82]. MRI images show

structural abnormalities such as ventriculomegaly, thin corpus callosum and cerebral

atrophy. Oculogyric crises have been described in two such cases [82].

Furthermore, single cases of OGCs were described in hypomyelination with atrophy of

the basal ganglia and cerebellum (H-ABC) syndrome [83], rapid-onset dystonia

parkinsonism due to mutations in the ATP1A3 gene [84], Perry syndrome [85],

Wilson’s disease [5], Chédiak-Higashi syndrome [86] and ataxia-telengiectasia [87].

Also, OGCs were described in a patient with molecularly unclassified juvenile

parkinsonism [88].

Sporadic movement disorders

Oculogyric crises in sporadic movement disorders were identified in 15 articles

describing 59 patients. The majority of the identified articles reported OGCs in

parkinsonian patients (number of patients: n=54; median age: 35 years; range: eight to

92 years), as a result of encephalitis lethargica (EL) (n=48) [14, 89-94], EL-like illness

(n=1) [95] or Japanese Encephalitis (n=1) [96]. Oculogyric crises were further reported

in patients with young-onset (n=1) [97] and juvenile onset parkinsonism (n=2)[88, 98],

and due to subcortical arteriosclerotic encephalopathy (n=1) [99]. Blepharospasm (n=4)

[100] and non-wilsonian hepato-cerebral degeneration (n=1) [101] were also associated

with OGCs. Movements described as OGCs have also been more recently described in

patients with functional movement disorders [102].

3. Focal brain lesions:

Twelve single case reports of OGCs occurring as a result of focal brain lesions were

also identified. They included lesions of the brainstem caused by herpetic encephalitis

[7], the dorsal midbrain area (mesencephalic locomotor region) [103], the substantia

nigra [6], the posterior third ventricle affected by a cystic glioma [104] and the basal

ganglia [105, 106], [107]. Also two patients with either multifocal drug-induced

encephalopathy or posterior leukencephalopathy syndrome were reported to develop

OGCs [108, 109]. However, in both of these cases additional factors may have

contributed to the development of OGCs. Finally, OGCs have also been reported most

likely in association with focal lesions caused by neurosyphilis and multiple sclerosis

[110].

Pathophysiology

The pathophysiology of OGCs remains elusive. However, despite the numerous

conditions associated with OGCs and the diversity of clinical presentations, there

appear to be common pathophysiological changes associated with the manifestation of

OGCs. First, in all reviewed cases where OGCs were clearly a result of focal brain

lesions, damage was reported either to the basal ganglia or the midbrain, and thereby

related to possible anatomical disruption of the nigrostriatal pathway. Second, most

agents related to drug-induced OGCs (e.g. neuroleptics or antiemetics)

characteristically lead to a functional disruption of dopaminergic neurotransmission.

Third, most of the hereditary and sporadic movement disorders associated with OGCs

are also directly related to either neurochemical (e.g. AADC and others [4]) or

anatomical disruption of dopamine synthesis (e.g. through lesions or gliosis as for

example in postencephalitic parkinsonism [111], Wilson’s disease [5] or Perry

syndrome [85]) and typically manifest with parkinsonian and/or dystonic symptoms. It,

thus, appears that dopaminergic neurotransmission is at the pathophysiological

epicentre of OGCs.

Considered within the frame of dystonic reactions (also referred to as “extraocular

muscle dystonia” [100], it has been often proposed that OGCs, as other acute drug-

induced dystonias, could be the result of an imbalance between dopaminerigc and

cholinergic inputs within the striatum. Indeed, striatal dopaminergic input is known to

suppress cholinergic tone [112, 113]. Dopaminergic hypofunction, particularly related

to striatal dopamine D2 receptors of cholinergic interneurons, could lead to a relative

increase of cholinergic neurotransmission within the striatum and alterations in

excitation properties of medium spiny neurons leading to dystonic symptoms, including

OGCs [114]. Clinical knowledge also lends support to this hypothesis, as

anticholinergic drugs often lead to an amelioration of OGCs.

However, an imbalance between dopaminergic and cholinergic neurotransmission may

not be the sole pathophysiological explaination for all OGC cases. For example, the

pathophysiology of tardive OGCs, as of other tardive dystonic syndromes, might be

different and more complex. Hypersensitivity of striatal dopamine receptors due to

chronic dopamine receptor blockage, neurodegeneration of striatal interneurons, as well

as dysfunction of striatal gamma-Aminobutyric acid (GABA)-ergic interneurons and

more recently the hypothesis of maladaptive synaptic plasticity have been proposed to
explain the presence of tardive involuntary movements [115]. However, robust

experimental data, including animal models of OGCs, to support either hypothesis in

humans are lacking. Moreover, it is unclear, whether tardive OGCs share similar

pathophysiological properties with other tardive syndromes, such as tardive dystonia.

Similarly, the pathophysiology of OGCs related to drugs, not directly associated with

dopaminergic function, as for example SSRIs also remains unclear. Several hypotheses

have been put forward, including hyperstimulation of 5-HT2 receptors, inhibition of

dopaminergic and alteration of cholinergic and GABAergic activity [116-118]. Indeed

these hypotheses have been linked to SSRI-induced dystonic reactions. However, most

of these hypotheses are not supported by direct experimental data in humans, nor

specifically address OGCs.

Taken together, although the vast majority of conditions associated with OGCs are

related with dopaminergic dysfunction, in the absence of direct experimental data,

hypotheses regarding the origin of OGCs remain speculative.

Treatment

Treatment strategies are variable and depend on the aetiology of OGCs. In drug-

induced OGCs the first step of management should include removing or, if not possible,

reducing the dose of the offending agent [10, 119]. In acute cases, administration of

anticholinergics, such as benztropine (e.g. 2mg intravenous) and biperiden (e.g. 5mg

intramuscular) or antihistaminics, such as diphenhydramine can lead to symptom

alleviation within minutes. If response is lacking drug administration should be

repeated after 15-30 minutes [119-122]. To avoid re-occurance of symptoms over the
ensuing time frame oral administration of anticholinergics for at least 4-7 days is

recommended [119]. Oral administration of anticholinergics may be the most feasible

approach for cases seen outside the emergency setting. In cases of persistent lack of

response oral treatment with benzodiazepines such as clonazepam (e.g. 0.5-4 mg) might

provide symptom relief [123]. In cases of tardive OGCs the aforementioned agents

might be insufficient and long-term treatment with (atypical) neuroleptics such as

clozapine might be required [124, 125]. However, it should be noted that treatment

effects might be limited in tardive OGCs, as substances such as clozapine themselves

may also cause OGCs [126-128].

Treatment of OGCs with L-dopa may also be successful in patients with parkinsonism

including idiopathic Parkinson’s disease with OGCs related to wearing off [57, 58]; but

also in other conditions such as Kufor Rakeb disease [76], NIID [78] and PKAN-

associated neurodegeneration [81]. Of note, administraton of L-dopa has been reported

to elicit OGCs in patients with parkinsonism as peak-dose phenomenon and hence some

caution is advised[47]. Although L-dopa is benefitial in postencephalitic parkinsonism,

the presence of drug-induced dyskinesias in these patients limits therapeutic success

[14]. Benztropine has also been reported to alleviate symptoms in patients with EL-like

illness [95].

In OGCs associated with focal brain lesions (e.g. striatocapsular infarction [105],

pallidonigral lesion [6], lentiform nuclei [107]) the use of anticholinergics has been

reported beneficial. Single cases have highlighted the use of antihistaminics

(ondansetron-induced encephalopathy [108] and posterior leukencephalopathy

syndrome [109]) and carbamazepin [103] in treatment of OGCs episodes.

Conclusion and future directions

The spectrum of conditions associated with OGCs is wide and encompasses three main

caterogories of disorders: 1. drug-induced disorders, 2. hereditary and sporadic

movement disorders, 3. disorders related to focal brain lesions. The common basis of

these disorders is a metabolic, anatomical or functional disruption of the nigrostriatal

pathway, mainly of dopamine metabolism. Treatment should be causal where possible

(i.e. removal of triggering factors; avoidance of further exposure). In the acute phase

restoration of the imbalanced neurotransmitters using anticholininergics can provide

rapid improvement. In-depth understanding of the pathophsyioligical mechanisms is

lacking.

Indeed, the systematic analysis of the data presented here also revealed several

knowledge gaps pertaining to clinical and pathophysiological aspects of OGCs. There

is large heterogeneity in the clinical presentations of OGCs between patients and

conditions, but this remains largely underexplored and, therefore, poorly understood.

While attempts have been made to delinate differences between associated phenomena,

such as psychiatric and autonomic symptoms in some of the conditions presenting with

OGCs [11], this has been based on retrospective literature reviews and there are no

studies systematically characterizing prospective pharmacogenetic and clinical features.

Hence, to date, no predictors have been identified regarding which patients could be

susceptible to developing OGCs, under which conditions and how severe their clinical

manifestations might be. Also, there are no well-established treatment

recommendations for patients who fail to respond to first-line drugs. Paucity of

systematic clinical data makes it challenging to pinpoint concise pathophysiological

mechanisms of OGCs. Indeed, although our systematic review provides evidence that

both the dopaminergic and cholinergic system are involved in the pathophysiology of
OGCs, the exact mechanisms, including functional neuroanatomic and

neuropharmacologic underpinnings, remain elusive. Animal models, alongside

neuropathologic case studies, as well as in-vivo high-resolution structural and

functional neuroimaging will be helpful to shed further light on these matters. Indeed,

addressing the aforementioned questions will inevitably lead to better patient care.

Importantly, it will also expand our understanding beyond the narrow

pathophysiological framework of OGCs by providing information on the interplay

between dystonic (oculmomotor) symptoms with psychiatric and autonomic

phenomena. The number of different etiological conditions with partially overlapping,

but distinct pathophysiologies we provide here is a first step towards understanding the

pathophysiology behind OGCs and their associations.

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4.
Author roles:
1. (A) Conception and design of the study, (B) acquisition of data, (C) analysis and
interpretation of data
2. (A) Drafting the article, (B) revising it critically for important intellectual content
3. Final approval of the version to be submitted.

E.B.: 1B, 1C, 2A, 3

S.A.S., K.P.B: 1C, 2A, 2B, 3
C.G.: 1A, 1C, 2A, 2B, 3

Funding:
This research did not receive any specific grant from funding agencies in the public,
commercial, or not-for-profit sectors.

Author disclosures:

Ewgenia Barow is funded by the German Parkinson Society.

Susanne Schneider – founded by the Else Kröner-Fresenius-Stiftung. Receives support from

the Eva Luise und Horst Köhler-Stiftung and royalties from Springer.

Kailash P. Bhatia receives royalties from publication of the Oxford Specialist Handbook

Parkinson's Disease and Other Movement Disorders (Oxford University Press, 2008) and of

Marsden's Book of Movement Disorders (Oxford University Press, 2012). He received funding

for travel from GlaxoSmithKline, Orion Corporation, Ipsen and Merz Pharmaceuticals.

Christos Ganos has nothing to disclose.