PSYCHOTIC SYMPTOMS PRECEDING OCULAR DEVIATION IN A PATIENT WITH TARDIVE OCULOGYRIC CRISES Perminder Sachdev, Wai Mun Tang
This report describes a patient with schizophrenia who developed episodes of ocular dystonia as a delayed side effect of neuroleptic medication. Each episode was preceded and accompanied by marked agitation, stereotypic behaviourand exacerbation of hallucinations. Both the psychoticand dystonic symptoms responded to anticholinergic medication. The theoretical and practical implications of this observation are discussed. Australian and New Zealand Journal of Psychiatry 1992; 26:666-670 Much before the introduction of neuroleptics, the syndrome of oculogyric crisis ( O W ) was described in association with epidemic encephalitis lethargica [ 131. In these reports, considerable attention was given to the associated mood, thought and behavioural disturbances that preceded, accompanied and/or followed the OGC [2-51. In fact, the term “oculogyric crisis’’ to describe these cases could be considered a misnomer for a number of reasons: a “gyric” or rotational component to the eye movement was usually lacking, the episode rarely represented a medical crisis and the eye movements were but one aspect of a multifaceted disturbance of movement, behaviour, thought and emotion. Episodes were described in these patients in which the ocular dystonic component was insignificant or totally absent. This led McCowan and Cook 141 to conclude it may be that the apparently causeless outbursts ofexcitement and grief not uncommonly seen in encephalitics are more often accompanied by ocular crises than is generally suspected” (p290).
OGC is now most commonly seen as an acute side effect of neuroleptic medication [6]. Less commonly, neuroleptic-induced OGC may have a delayed onset and/or a persistent course: the syndrome of tardive OGC [7]. The association of psychiatric symptoms with acute drug-induced dystonia and OGC has been occasionally reported, usually being in the form of anxiety and distress secondary to the dystonia [8,9]. Chiu [ 101reported 3 cases of acute drug-induced OGC which were associated with transient recurrence of auditory hallucinations, but it is unclear whether the psychotic symptoms preceded the dystonia in any of these patients. Leigh el al. [ 1 i ] reported three patients, 2 tardive and 1 post-encephalitic OGC, in whom nonpsychotic thought or behavioural disturbances preceded the onset of ocular dystonia. The following patient is unusual in that his psychotic symptoms increased and he became markedly agitated some time before the onset of each OGC. He was referred from a psychiatric service for the investigation of episodic behavioural disturbance, apparently unaware of the ocular dystonia.
Neuropsychiatric Institute, The Prince Henry Hospital, Little Bay, New South Wales Perminder Sachdev MD, PhD, FRANZCP Wai Mun Tang MBBS
case report
L‘..
A 22-year-old man was referred to the Neuropsychiatric Institute, Sydney, for the investigation of
Downloaded from anp.sagepub.com at MCGILL UNIVERSITY LIBRARY on April 7, 2015
PERMINDER SACHDEV. WAJ MUN TANG
recurrent episodes of bizarre behaviour. He had a history of regular abuse of alcohol and cannabis and occasional abuse of amphetamine, cocaine and LSD, since the age of 15 years. In April 1989, he had an episode of psychosis manifesting as withdrawal, delusions of persecution and disturbing auditory and visual hallucinations. H e was treated with chlorpromazine (250 mg per day) with improvement in symptoms but the auditory hallucinations persisted. He suffered from mild rigidity but had no dystonia or akathisia at this stage. As the hallucinations persisted while he abstained from drugs of abuse over many months, chlorpromazine was gradually increased to 600 mg per day, with only mild relief. He was unable to return to his job as a labourer. A diagnosis of schizophrenic disorder was made. There was no history of perinatal or early developmental abnormality. He had been an average student at school, popular with his friends and a good sportsman. Apart from his father’s alcohol abuse, there was no significant family history. About 8 months after onset, he reported episodic exacerbation of hallucinations associated with marked agitation occurring 2-3 times per week and lasting many hours. In between the episodes, hallucinations were present to a mild degree, along with mild suspiciousness but no other significant psychotic symptoms. He was started on fluphenazine decanoate, gradually increasing to 37.5 mg weekly. The episodes continued. Mild parkinsonian symptoms were treated with benztropine 2 mg/day. In July 1990, his medication was changed to haloperidol 20 mg/day, with an increase in the frequency of the episodes to many times a week. He was admitted again to hospital and an electroencephalogram (EEG) done during one of the episodes was normal. Two episodes were reportedly aborted by an intravenous (iv) injection of 5 mg diazepam, but other episodes were unaffected by this drug. The episodes often continued for many hours until he “slept off from sheer exhaustion”. All neuroleptics were stopped in early August 1990, and the episodes continued to occur at a frequency of about 3 per week. It was at this stage that he was referred to our unit. Our examination revealed a young man who was well except for the report of mild auditory hallucinations. He had not taken any drugs of abuse for over a year. Two episodes were observed by us, both of which were similar. There were no identifiable precipitating factors. The episode started with a sub-
667
jective report of anxiety and distress, followed by an exacerbation of his auditory hallucinations. These consisted of the voices of 3 friends who addressed him directly in an accusatory and derogatory manner. He repeatedly swore at the voices. He became agitated, shrieking loudly, jumping up and down, rubbing his head and face repeatedly, pulling at his clothes and pacing. About 10 minutes after the onset, his eyes deviated conjugately upwards. For the first few seconds he could look down on command, but this was not possible subsequently. The eye deviation was associated with retrocollis, intermittent opisthotonus, tonic contraction of the jaw with mouth opening, drooling of saliva, tremor of hands and stereotyped flexion-extension m o v e m e n t s of the legs. Oculocephalic manoeuvres could not drive his eyes into the lower field, but full horizontal reflex eye movements were present. He was fully alert and conscious during the entire episode, and had detailed memory of it afterwards. After observation for 10 minutes, he was given iv saline as a placebo with no change over the next ten minutes. This was followed by benztropine 2 mg iv. Two minutes after the injection he relaxed, his stereotypic activity reduced and his retrocollis improved. After another 5 minutes, the ocular dystonia terminated. He was still anxious and agitated, but considerably less so than previously, stereotypic activity was minimal, the voices had significantly reduced and he felt tired. An EEG immediately following the episode was normal. The patient was treated with benztropine 6 mg/day with reduction of his episodes to one per week over the next fortnight. The dose was then increased to 10 mg/day, on which he was maintained for 3 months. He had two brief episodes of recurrence of OGC and psychotic symptoms, each lasting for about one-half hour and responding to an additional 2 mg dose of benztropine. The benztropine was gradually tapered over the next 3 months without any further recurrences. At last follow-up 6 months later, he had been free of psychotic symptoms and was not on any medication.
Discussion This case is significant for two reasons: it illustrates the syndrome of tardive OGC of which only a few cases have been described (71, and it describes a striking association between ocular dystonia and psychiatric symptoms reminiscent of the post-en-
Downloaded from anp.sagepub.com at MCGILL UNIVERSITY LIBRARY on April 7, 2015
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cephalitic patients seen earlier in this century. The psychiatric symptoms were in fact the most outstanding feature of the episodes to the extent that the ocular symptoms had been missed by the referring psychiatrist. Given the rarity of similar reports in the published literature [ 111, it raises important theoretical and practical issues. While OGC as an acute side effect of neuroleptic therapy is common and well-recognized, the occurrence of OGC as a delayed or chronic symptom is not generally appreciated. In the 4 cases reported by Fitzgerald and Jankovic [ 7 ] ,OGC had not been recognized until evaluation by the authors. It is possible that the recognition of this syndrome will increase as the awareness spreads. Such recognition may result in the increased observation of associated psychiatric symptomatology. It also remains to be investigated whether some episodic behavioural disturbances in medicated schizophrenics are in fact associated with dystonic or other movement disorders. A brief comment on the primary psychiatric diagnosis in this patient is needed. The symptoms at the time of presentation, and the duration of his illness, qualified him for a DSM-111-R diagnosis of schizophrenia. The role of drug abuse in the precipitation of the disorder remained uncertain, but it was clear that the psychotic symptoms persisted for months in the absence of any further drug abuse. The auditory hallucinations were slow to remit, but eventually all psychotic symptoms remitted. It may well be that the episodic exacerbations contributed to the delay in the remission of the hallucinations. The disorder, therefore, had some atypical features, but we do not think that they significantly impact upon the discussion of the pathophysiology of OGC and its association with psychotic symptoms. The striking co-occurrence of movement disorder and psychotic symptoms permits one to speculate on the common features in the pathophysiology of the two disorders. The aetiological basis for OGC is uncertain. The eyes typically deviate upwards, and sometimes laterally. Downward deviation is rare, and during the episode, individuals have difficulty in looking down except when they combine a downward saccade with a blink [12]. This suggests a defect in the vertical gaze-holding mechanisms, possibly due to a fault in the hypothesized “neural integrator” [ 131. The anatomical basis of the neural integration of vertical gaze is believed to be in the mesencephalon, probably involving the interstitial nucleus of Cajal, with in-
fluences from higher centres [12]. There is also evidence from animal data that the neural mechanisms for upward and downward eye movements may be distinct [ 1 11, e.g. in monkeys, bilateral or midline electrical stimulation of the mesencephalon produces sustained upward movement of the eyes [14], and bilateral lesions in the rostra1 interstitial nucleus of the medial longitudinal fasciculus paralyses downward saccades without affecting upward movements significantly [ 151. Since involuntary gaze deviations have been described in association with movement disorders such as Parkinson’s disease, Gilles de la Tourette Syndrome and Huntington’s disease, abnormalities in the basal ganglia have been imputed in the causation, although the precise mechanisms are unclear. Another model used to explain OGC is that of “efference copy” which suggests that a saccade is programmed by the brain comparing the desired eye position with the estimated current position (efference copy), using the difference to drive the saccade [ 161. If the efference copy is incorrect, a sustained deviation may result. The neurochemical substrate of OGC is poorly understood. The ability of tobacco to produce an upbeating nystagmus suggests the role of nicotinic cholinergic mechanisms for vertical gaze [ 171. Anticholinergic drugs rapidly reverse OGC [6,8], as in our patient. Physostigmine intensifies haloperidol-induced dystonia in baboons [ 181, acute administration of neuroleptic drugs increases striatal ACh release [ 191, and cholinergic agonists may induce dystonia in neuroleptic-primed monkeys [20]. A cholinergic excess can therefore be presumed to play a role in OGC. The role of catecholamines has been extensively speculated upon. The fact that dystonia usually occurs soon after the administration of neuroleptics, even those that are relatively specific dopamine (DA) antagonists, leads one to conclude that it is due to DA receptor blockade. Tardive OGC has similarly been speculated to occur due to a temporarily decreased DA activity in the presence of supersensitive DA receptors [21]. Other investigators [ 181 have argued for the role of excess DA activity in causing dystonic reactions: the administration of L-DOPA to both humans and primates can cause dystonia [22], direct intrastriatal application of dopamine in primates induces dystonia [23], and pre-treatment of baboons with AMPT, an amine synthesis inhibitor, may prevent the emergence of neuroleptic-induced acute dystonia [24]. These observations have resulted in the proposition of a “missmatch” hypothesis [18] according to which the
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increased release of DA in the acute phase of neuroleptic treatment is able to overcome the DA blockade as the neuroleptic levels fall. Some support has emerged from experiments with a rodent model [25]. There is also some evidence that changes in DA receptor sensitivity may contribute to dystonic reactions [21], and this may explain the phenomenon of tardive OGC. Involuntary gaze deviations have been described in Tourette Syndrome which is a putative hyperdopaminergic disorder [27]. One attempt to reconcile some of the disparate observations has been to suggest the classic hypercholinergic-hypodopaminergic state like that in parkinsonism. The evidence for a hyperdopaminergic state is, however, not easy to dismiss. Moreover, anticholinergic drugs may not always prevent OGC [28]. There is also some evidence implicating norepinephrine, serotonin and gamma-aminobutyric acid [ 181 in the aetiology of OGC. The association of OGC with psychotic symptoms, and the prompt response of both to anticholinergic drugs leads to further speculation. The hypothesis that the positive symptoms of schizophrenia, such as the hallucinations and stereotypic behaviour seen in our patient, are due to DA overactivity has survived although with substantial revision since its conception [29]. This sits well with the hyperdopaminergic hypothesis of OGC, except that positive symptoms of schizophrenia are not generally known to respond to anticholinergic drugs. On the other hand, the so-called negative symptoms, not seen in our patient, may well do so [30]. There is, therefore, no one coherent neurochemical explanation for the observed phenomena in this case that our current understanding permits. Finally, given the close structural and functional relationship between limbic and striatal structures [31],it is not surprising that psychiatric symptoms are associated with dystonia. The association of obsessive-compulsive behaviour with involuntary movement disorders is increasingly being recognized [32]. Psychiatric symptoms are an important feature of Parkinson’s disease, just as motor disorder is a characteristic feature of melancholia [33]. A number of motor abnormalities are seen in schizophrenia [34] including disturbances of extraocular movement such as abnormal blink rate, absent glabellar reflex, increase in horizontal eye movements [35] and impaired smooth pursuit eye movements [36]. The association seen in our patient, therefore, supports the trend
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towards a broader view of striatal-limbic interaction and the neuroanatomical and neurochemical basis of neuropsychiatric disorders.
Acknowledgements Dr S Singh referred the patient. The Clive and Vera Ramaciotti Foundation, the Rebecca Cooper Foundation and the Prince Henry Hospital Centenary Fund have provided ongoing financial assistance.
1. Oeckinghaus W. Encephalitis epidemica und Wilsonsrhes
Krankheitshild. Deutsche Zeitschrift fur Nervenheilkunde 1921; 72:294-309. 2. Stern F. Ueher psychische Zwangsvorgaenge und ihre Entstehrtng hei encephalitischen Blirkkraempfen, mit Bermerkungen ueher die Genese der encephalitischen Blickkraempfe. Archives of Psychiatry 1927; 81522-560. 3. Jelliffe SE. Psychological components in postencephalitic oculogyric crises: contributions to a genetic interpretation of compulsive phenomena. Archives of Neurology and Psychiatry 1929; 21 :491-532. 4. McCowan PK, Cook LC. Oculogyric crises in chronic epidemic encephalitis. Brain 1928; 5 1:285-309. 5 . Onuaguluchi G . Crises in post-encephalitic parkinsonism. Brain I961;84:395-414. 6. Dorevitch A. Neuroleptics as causes of oculogyric crises. Archives of Neurology 1984 4 1 :15- 16. 7. Fitzgerald PM, Jankovic J. Tardive oculogyric crises. Neurology 1989; 39:1434-1437. 8. Swett C. Drug-induced dystonia. American Journal of Psychiatry 1975; 132532-534. 9. Dorevitch A. Neuroleptics as causes of oculogyric crises. Archives of Neurology 1984; 41:15-16. 10. Chiu LPW. Transient recurrence of auditory hallucinations during acute dystonia. British Journal of Psychiatry 1989; 115:110-113. 11. Leigh RJ, Foley JM, Remier BF, Civil RH. Oculogyric crisis: A syndrome of thought disorder and ocular deviation. Annals of Neurology 1987; 22: 13-17. 12. Leigh RJ, Zee DS. The neurology of eye movements. Philadelphia: FA Davis, 1991. 13. Robinson DA. Integrating neurons. Annual Review of Neuroscience 1989; 12:33-45. 14. Bender MB, Shanzer A. Oculomotor pathways defined by electrical stimulation and lesions in the brain stem of monkey. In: Bender MB, ed. The oculomotor system. New York: Harper & Row, 1964:81-96. 15. Kompf D, Pasik T, Pasik P, Bender MB. Downward gaze in monkeys: stimulation and lesion studies. Brain 1979; 102527558. 16. Optican L. Saccadic dysmetria. In: Lennerstrand G, Zee DS, Keller EL, eds. Functional basis of ocular motility disorders. Oxford: Pergamon, 1982:441-461. 17. Sibony PA, Evinger C, Manning KA. Tobacco-induced primary position upbeat nystagmus. Annals of Neurology 1987: 21 53-58,
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18. Marsden CD, Jenner P. The pathophysiological basis of extrapyrdmidal movement disorders. Psychological Medicine 1980: 1055-7 I. 19. Sethy VH, Van Woert MH. Modification of striatal acetylcholine concentration by dopamine receptor agonists and antagonists. Research Commuications in Chemical Pathology and Pharmacology 1974; 8: 13-28. 20. Casey DE, Gerlach J, Christensson A. Dopamine, acetylcholine and GABA effects in acute dystonia in primates. Psychopharmacology 1980; 70:83-87. 21. Nasrallah HA, Pappas NH. Crowe RR. Oculogyric dystonia in tardive dyskinesia. American Journal of Psychiatry 1980; 137:850-851. 22. Parkes JD, Bedard P, Marsden CD. Chorea and dystonia in parkinsonism. Lancet 1976; 1:155. 23. Cools AR, Hendriks G, Korten J. The acetylocholine-dopamine blance in the basal ganglia of rhesis monkeys and its role in dynamic, dyskinetic and epileptoid motor activities. Journal of Neural Transmission 1974; 36:91-105. 24. Meldrum BS, Anlezark GM, Marsden CD. Acute dystonia as an idiosyncratic response to neuroleptics in baboons. Brain 1977; lW313-326. 25. Kolbe H, Clow A, Jenner P, Marsden CD. Neuroleptic induced acute dystonia reactions may be due to enhanced dopamine release onto supersensitive post-synaptic receptors. Neurology 1981; 31~434-439. 26. Christensen AV, Fjalland B, Moller Nielsen 1. On the supersensitivity of dopamine receptors induced by neuroleptics. Psychopharmacology 1976; 48: 1-6.
27. Frankel M, Cummings JL. Neuro-ophthalmic abnormalities in Tourette’s syndrome: Functional and anatomic implications. Neurology 1984; 34:359-361. 28. Sramek JJ, Simpson GM, Morrison RL, et al. Anticholinergic agents for prophylaxis of neuroleptic-induced dystonic reactions: A prospective study. Journal of Clinical Psychiatry 1986; 47:305309. 29. Carlsson A. The current status of the dopamine hypothesis of schizophrenia. Neuropsychopharmacology 1988; I :179-186. 30. Tandon R, Greden JF. Cholinergic hyperactivity and negative symptoms. A model of cholinergic/dopaminergic interactions in schizophrenia. Archives of General Psychiatry 1989; 46:745-753. 3 1. Alexander GE, De Long MR, Strick PL. Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annual Review of Neuroscience 1986; 9:357-381. 32. McDaniel KD, Cummings JL, Shain S. The “yips”: A focal dystonia of golfers. Neurology 1989; 39: 192-195. 33. Parker G, Hadzi-Pavlovic D, Boyce P, et a/. Classifying depression by mental state signs. British Journal of Psychiatry 1990 157~55-65. 34. Manschreck TC, Maher BA, Rucklos ME, Vereen DR. Distributed voluntary motor activity in schizophrenic disorder. Psychological Medicine 1982; 12:73-84. 35. Stevens JR. Disturbances of ocular movements and blinking in schizophrenia. Journal of Neurology, Neurosurgery and Psychiatry 1978; 41:1024-1030. 36. Holzman PS, Proctor LR, Hughes DW. Eye tracking patterns in schizophrenia. Science 1973; 181:179-181.
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This report describes a patient with schizophrenia who developed episodes of ocular dystonia as a delayed side effect of neuroleptic medication. Each episode was preceded and accompanied by marked agitation, stereotypic behaviourand exacerbation of hallucinations. Both the psychoticand dystonic symptoms responded to anticholinergic medication. The theoretical and practical implications of this observation are discussed. Australian and New Zealand Journal of Psychiatry 1992; 26:666-670 Much before the introduction of neuroleptics, the syndrome of oculogyric crisis ( O W ) was described in association with epidemic encephalitis lethargica [ 131. In these reports, considerable attention was given to the associated mood, thought and behavioural disturbances that preceded, accompanied and/or followed the OGC [2-51. In fact, the term “oculogyric crisis’’ to describe these cases could be considered a misnomer for a number of reasons: a “gyric” or rotational component to the eye movement was usually lacking, the episode rarely represented a medical crisis and the eye movements were but one aspect of a multifaceted disturbance of movement, behaviour, thought and emotion. Episodes were described in these patients in which the ocular dystonic component was insignificant or totally absent. This led McCowan and Cook 141 to conclude it may be that the apparently causeless outbursts ofexcitement and grief not uncommonly seen in encephalitics are more often accompanied by ocular crises than is generally suspected” (p290).
OGC is now most commonly seen as an acute side effect of neuroleptic medication [6]. Less commonly, neuroleptic-induced OGC may have a delayed onset and/or a persistent course: the syndrome of tardive OGC [7]. The association of psychiatric symptoms with acute drug-induced dystonia and OGC has been occasionally reported, usually being in the form of anxiety and distress secondary to the dystonia [8,9]. Chiu [ 101reported 3 cases of acute drug-induced OGC which were associated with transient recurrence of auditory hallucinations, but it is unclear whether the psychotic symptoms preceded the dystonia in any of these patients. Leigh el al. [ 1 i ] reported three patients, 2 tardive and 1 post-encephalitic OGC, in whom nonpsychotic thought or behavioural disturbances preceded the onset of ocular dystonia. The following patient is unusual in that his psychotic symptoms increased and he became markedly agitated some time before the onset of each OGC. He was referred from a psychiatric service for the investigation of episodic behavioural disturbance, apparently unaware of the ocular dystonia.
Neuropsychiatric Institute, The Prince Henry Hospital, Little Bay, New South Wales Perminder Sachdev MD, PhD, FRANZCP Wai Mun Tang MBBS
case report
L‘..
A 22-year-old man was referred to the Neuropsychiatric Institute, Sydney, for the investigation of
Downloaded from anp.sagepub.com at MCGILL UNIVERSITY LIBRARY on April 7, 2015
PERMINDER SACHDEV. WAJ MUN TANG
recurrent episodes of bizarre behaviour. He had a history of regular abuse of alcohol and cannabis and occasional abuse of amphetamine, cocaine and LSD, since the age of 15 years. In April 1989, he had an episode of psychosis manifesting as withdrawal, delusions of persecution and disturbing auditory and visual hallucinations. H e was treated with chlorpromazine (250 mg per day) with improvement in symptoms but the auditory hallucinations persisted. He suffered from mild rigidity but had no dystonia or akathisia at this stage. As the hallucinations persisted while he abstained from drugs of abuse over many months, chlorpromazine was gradually increased to 600 mg per day, with only mild relief. He was unable to return to his job as a labourer. A diagnosis of schizophrenic disorder was made. There was no history of perinatal or early developmental abnormality. He had been an average student at school, popular with his friends and a good sportsman. Apart from his father’s alcohol abuse, there was no significant family history. About 8 months after onset, he reported episodic exacerbation of hallucinations associated with marked agitation occurring 2-3 times per week and lasting many hours. In between the episodes, hallucinations were present to a mild degree, along with mild suspiciousness but no other significant psychotic symptoms. He was started on fluphenazine decanoate, gradually increasing to 37.5 mg weekly. The episodes continued. Mild parkinsonian symptoms were treated with benztropine 2 mg/day. In July 1990, his medication was changed to haloperidol 20 mg/day, with an increase in the frequency of the episodes to many times a week. He was admitted again to hospital and an electroencephalogram (EEG) done during one of the episodes was normal. Two episodes were reportedly aborted by an intravenous (iv) injection of 5 mg diazepam, but other episodes were unaffected by this drug. The episodes often continued for many hours until he “slept off from sheer exhaustion”. All neuroleptics were stopped in early August 1990, and the episodes continued to occur at a frequency of about 3 per week. It was at this stage that he was referred to our unit. Our examination revealed a young man who was well except for the report of mild auditory hallucinations. He had not taken any drugs of abuse for over a year. Two episodes were observed by us, both of which were similar. There were no identifiable precipitating factors. The episode started with a sub-
667
jective report of anxiety and distress, followed by an exacerbation of his auditory hallucinations. These consisted of the voices of 3 friends who addressed him directly in an accusatory and derogatory manner. He repeatedly swore at the voices. He became agitated, shrieking loudly, jumping up and down, rubbing his head and face repeatedly, pulling at his clothes and pacing. About 10 minutes after the onset, his eyes deviated conjugately upwards. For the first few seconds he could look down on command, but this was not possible subsequently. The eye deviation was associated with retrocollis, intermittent opisthotonus, tonic contraction of the jaw with mouth opening, drooling of saliva, tremor of hands and stereotyped flexion-extension m o v e m e n t s of the legs. Oculocephalic manoeuvres could not drive his eyes into the lower field, but full horizontal reflex eye movements were present. He was fully alert and conscious during the entire episode, and had detailed memory of it afterwards. After observation for 10 minutes, he was given iv saline as a placebo with no change over the next ten minutes. This was followed by benztropine 2 mg iv. Two minutes after the injection he relaxed, his stereotypic activity reduced and his retrocollis improved. After another 5 minutes, the ocular dystonia terminated. He was still anxious and agitated, but considerably less so than previously, stereotypic activity was minimal, the voices had significantly reduced and he felt tired. An EEG immediately following the episode was normal. The patient was treated with benztropine 6 mg/day with reduction of his episodes to one per week over the next fortnight. The dose was then increased to 10 mg/day, on which he was maintained for 3 months. He had two brief episodes of recurrence of OGC and psychotic symptoms, each lasting for about one-half hour and responding to an additional 2 mg dose of benztropine. The benztropine was gradually tapered over the next 3 months without any further recurrences. At last follow-up 6 months later, he had been free of psychotic symptoms and was not on any medication.
Discussion This case is significant for two reasons: it illustrates the syndrome of tardive OGC of which only a few cases have been described (71, and it describes a striking association between ocular dystonia and psychiatric symptoms reminiscent of the post-en-
Downloaded from anp.sagepub.com at MCGILL UNIVERSITY LIBRARY on April 7, 2015
668
PSYCHOTIC SYMPTOMS AND TARDIVE OCUYLOGYRIC CRISES
cephalitic patients seen earlier in this century. The psychiatric symptoms were in fact the most outstanding feature of the episodes to the extent that the ocular symptoms had been missed by the referring psychiatrist. Given the rarity of similar reports in the published literature [ 111, it raises important theoretical and practical issues. While OGC as an acute side effect of neuroleptic therapy is common and well-recognized, the occurrence of OGC as a delayed or chronic symptom is not generally appreciated. In the 4 cases reported by Fitzgerald and Jankovic [ 7 ] ,OGC had not been recognized until evaluation by the authors. It is possible that the recognition of this syndrome will increase as the awareness spreads. Such recognition may result in the increased observation of associated psychiatric symptomatology. It also remains to be investigated whether some episodic behavioural disturbances in medicated schizophrenics are in fact associated with dystonic or other movement disorders. A brief comment on the primary psychiatric diagnosis in this patient is needed. The symptoms at the time of presentation, and the duration of his illness, qualified him for a DSM-111-R diagnosis of schizophrenia. The role of drug abuse in the precipitation of the disorder remained uncertain, but it was clear that the psychotic symptoms persisted for months in the absence of any further drug abuse. The auditory hallucinations were slow to remit, but eventually all psychotic symptoms remitted. It may well be that the episodic exacerbations contributed to the delay in the remission of the hallucinations. The disorder, therefore, had some atypical features, but we do not think that they significantly impact upon the discussion of the pathophysiology of OGC and its association with psychotic symptoms. The striking co-occurrence of movement disorder and psychotic symptoms permits one to speculate on the common features in the pathophysiology of the two disorders. The aetiological basis for OGC is uncertain. The eyes typically deviate upwards, and sometimes laterally. Downward deviation is rare, and during the episode, individuals have difficulty in looking down except when they combine a downward saccade with a blink [12]. This suggests a defect in the vertical gaze-holding mechanisms, possibly due to a fault in the hypothesized “neural integrator” [ 131. The anatomical basis of the neural integration of vertical gaze is believed to be in the mesencephalon, probably involving the interstitial nucleus of Cajal, with in-
fluences from higher centres [12]. There is also evidence from animal data that the neural mechanisms for upward and downward eye movements may be distinct [ 1 11, e.g. in monkeys, bilateral or midline electrical stimulation of the mesencephalon produces sustained upward movement of the eyes [14], and bilateral lesions in the rostra1 interstitial nucleus of the medial longitudinal fasciculus paralyses downward saccades without affecting upward movements significantly [ 151. Since involuntary gaze deviations have been described in association with movement disorders such as Parkinson’s disease, Gilles de la Tourette Syndrome and Huntington’s disease, abnormalities in the basal ganglia have been imputed in the causation, although the precise mechanisms are unclear. Another model used to explain OGC is that of “efference copy” which suggests that a saccade is programmed by the brain comparing the desired eye position with the estimated current position (efference copy), using the difference to drive the saccade [ 161. If the efference copy is incorrect, a sustained deviation may result. The neurochemical substrate of OGC is poorly understood. The ability of tobacco to produce an upbeating nystagmus suggests the role of nicotinic cholinergic mechanisms for vertical gaze [ 171. Anticholinergic drugs rapidly reverse OGC [6,8], as in our patient. Physostigmine intensifies haloperidol-induced dystonia in baboons [ 181, acute administration of neuroleptic drugs increases striatal ACh release [ 191, and cholinergic agonists may induce dystonia in neuroleptic-primed monkeys [20]. A cholinergic excess can therefore be presumed to play a role in OGC. The role of catecholamines has been extensively speculated upon. The fact that dystonia usually occurs soon after the administration of neuroleptics, even those that are relatively specific dopamine (DA) antagonists, leads one to conclude that it is due to DA receptor blockade. Tardive OGC has similarly been speculated to occur due to a temporarily decreased DA activity in the presence of supersensitive DA receptors [21]. Other investigators [ 181 have argued for the role of excess DA activity in causing dystonic reactions: the administration of L-DOPA to both humans and primates can cause dystonia [22], direct intrastriatal application of dopamine in primates induces dystonia [23], and pre-treatment of baboons with AMPT, an amine synthesis inhibitor, may prevent the emergence of neuroleptic-induced acute dystonia [24]. These observations have resulted in the proposition of a “missmatch” hypothesis [18] according to which the
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PERMINDER SACHDEV, WAI MUN TANG
increased release of DA in the acute phase of neuroleptic treatment is able to overcome the DA blockade as the neuroleptic levels fall. Some support has emerged from experiments with a rodent model [25]. There is also some evidence that changes in DA receptor sensitivity may contribute to dystonic reactions [21], and this may explain the phenomenon of tardive OGC. Involuntary gaze deviations have been described in Tourette Syndrome which is a putative hyperdopaminergic disorder [27]. One attempt to reconcile some of the disparate observations has been to suggest the classic hypercholinergic-hypodopaminergic state like that in parkinsonism. The evidence for a hyperdopaminergic state is, however, not easy to dismiss. Moreover, anticholinergic drugs may not always prevent OGC [28]. There is also some evidence implicating norepinephrine, serotonin and gamma-aminobutyric acid [ 181 in the aetiology of OGC. The association of OGC with psychotic symptoms, and the prompt response of both to anticholinergic drugs leads to further speculation. The hypothesis that the positive symptoms of schizophrenia, such as the hallucinations and stereotypic behaviour seen in our patient, are due to DA overactivity has survived although with substantial revision since its conception [29]. This sits well with the hyperdopaminergic hypothesis of OGC, except that positive symptoms of schizophrenia are not generally known to respond to anticholinergic drugs. On the other hand, the so-called negative symptoms, not seen in our patient, may well do so [30]. There is, therefore, no one coherent neurochemical explanation for the observed phenomena in this case that our current understanding permits. Finally, given the close structural and functional relationship between limbic and striatal structures [31],it is not surprising that psychiatric symptoms are associated with dystonia. The association of obsessive-compulsive behaviour with involuntary movement disorders is increasingly being recognized [32]. Psychiatric symptoms are an important feature of Parkinson’s disease, just as motor disorder is a characteristic feature of melancholia [33]. A number of motor abnormalities are seen in schizophrenia [34] including disturbances of extraocular movement such as abnormal blink rate, absent glabellar reflex, increase in horizontal eye movements [35] and impaired smooth pursuit eye movements [36]. The association seen in our patient, therefore, supports the trend
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towards a broader view of striatal-limbic interaction and the neuroanatomical and neurochemical basis of neuropsychiatric disorders.
Acknowledgements Dr S Singh referred the patient. The Clive and Vera Ramaciotti Foundation, the Rebecca Cooper Foundation and the Prince Henry Hospital Centenary Fund have provided ongoing financial assistance.
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