Abstract
Delayed neurological sequelae after carbon monoxide poisoning
A 29-year old woman attempted suicide by burning charcoal and inhaling the fumes. She survived after having lost consciousness for 2 days. Sensorineural hearing loss was documented clinically at day 4. Partial improvement in hearing ability was found at day 14.
The patient remained well until week 4, with increasing dullness, disorganized thinking, disorientation, perplexity, psychomotor retardation, parkinsonism, double incontinence, unstable gait, and impairment of basic self-care. Mini-Mental State Examination (MMSE) yielded a score of 13/30. Neuropsychological assessment indicated significant impairment in verbal memory, visual memory and executive function. Computed tomography of the brain showed bilateral globus pallidus infarcts. The patient was prescribed benzhexol for parkinsonism.
The patient started to show clinical improvement at week 7. MMSE at week 13 indicated improvement, with a score of 26/30. Benzhexol was stopped at 3 months without recurrence of parkinsonism. Repeated neuropsychological assessment at 6 months showed improvement in her verbal memory, and at 9 months normal functioning was seen in all domains except for mild impairment in object naming. Normal occupational functioning also resumed.
The patient suffered from delayed neurological sequelae (DNS) 4 weeks after the poisoning, but had recovered almost completely 9 months after the poisoning without specific therapy. DNS occurs in 0.06–40% of carbon monoxide (CO)-poisoned survivors with an onset of 2–40 days after the poisoning episode [1]. Symptoms of DNS include mental deterioration, double incontinence, gait disturbance, impaired memory and parkinsonism [2], [3]. White matter hyperintensities, basal ganglia (globus pallidus, putamen) and fornix atrophy contribute to the cognitive impairment [4]. Cellular theories, such as immunopathological damage and the role of CO as an endogenous neurotransmitter have been proposed as the underlying pathophysiology of DNS [5]. In a series of 16 patients reported by Choi followed up for 1 year, 13 (81.3%) recovered spontaneously within 6 months [2].
Several points were pertinent in the present case. The patient had early neurological sequelae (sensorineural hearing loss). Clinicians should look for any such or similar neurological complication in the early phase of CO poisoning, which may predict the occurrence of DNS. Although the patient had recovered from acute complication, DNS developed after a latent period of 4 weeks. Clinicians should not feel secure if a patient recovers in the early phase and should be aware of the possibility of the delayed complication of CO poisoning. It is essential to follow up and monitor CO-poisoning survivors for neurocognitive function using neuropsychiatric tests to detect DNS, if any.
Amisulpride-induced dystonia
Amisulpride is an atypical antipsychotic with a preferential action on limbic D2/D3 receptors and preferential blockade of presynaptic D2/D3 receptors [1]. In clinical trials it has been reported to cause fewer extrapyramidal side-effects compared to haloperidol, fluphenazine and even risperidone [2–4]. Dystonia has been reported in trials mostly involving higher doses [5]. We report on a schizophrenia patient who developed dystonia on a lower dose of amisulpride (200 mg day−1).
The patient was a 20-year-old single woman, premorbidly well adjusted, with no significant past or family history of mental illness, who presented with a history of insidious onset illness, without any precipitating event, of 2½ years duration. To start with she developed symptoms characterized by delusion of persecution, delusion of presence, hallucinatory behaviour and formal thought disorder. In addition she was found to be fearful, aloof and apathetic towards her surroundings. Gradually the patient lost interest in studies and day-to-day household activities, and had stopped going to school. Her self-care deteriorated. At 6–8 months after onset of illness the patient received antipsychotics (details of which could not be elicited), as prescribed by a private practitioner, on which her positive symptoms improved but the negative symptoms persisted. After approximately 1 year of taking the medication the patient's family stopped the medication because there were no positive symptoms, following which she remained in the same state for the next 5–6 months. After this she again had a full blown relapse of earlier symptoms, this time with increased severity.
The patient was brought to us for the first time, after 4–5 months of relapse, diagnosed as having schizophrenia (as per DSM-IVTR) and was started on amisulpride tablet 50 mg day−1, which was gradually increased to 200 mg day−1 over 2 weeks. After 3 days of taking amisulpride at a dose of 200 mg day−1, the patient suddenly developed spasmodic movement of the neck with her face deviated to the right side. This was not accompanied by loss of consciousness, tongue bite, fall, oculogyric crisis, or protrusion of tongue. The patient was brought to the emergency outpatient department and was given an i.m. injection of promethazine 50 mg, with which she improved. The whole episode lasted for 1 h. Subsequently the dose of amisulpride was reduced to 150 mg day−1 and tablet trihexyphenidyl 2 mg day−1 was added. Over the next 8 weeks her psychotic symptoms, both positive and negative, have improved partially, with no recurrence of dystonia.
Amisulpride, a substituted benzamide derivative, has a therapeutic profile similar to that of other atypical agents such as clozapine [4]. Clinical studies have reported lower treatment-emergent extrapyramidal effects compared to traditional neuroleptics such as haloperidol [2]. It has been suggested to have dose-related extrapyramidal side-effect potential, which is lower than that for first-generation antipsychotics and higher than that for olanzapine and quetiapine [6]. This has been thought to be due to its unique pharmacodynamic profile of blocking presynaptic dopamine autoreceptors that control dopamine synthesis and release at low doses, and blocking post-synaptic D2 receptors at high doses. The latter explains the occurrence of extrapyramidal symptoms at high doses [2].
In the index case, the dystonia fulfilled the criteria of neuroleptic-induced acute dystonia as per DSM-IVTR. The episode of dystonia occurred only 3 days after a dose increase to 200 mg day−1 and responded rapidly to administration of promethazine. There were no other offending agents that could explain the occurrence of dystonia. Rating on the Naranjo causality scale for adverse drug reactions [7] was 5, which indicates a probable adverse drug event.
Although young age has been considered as a risk factor for dystonia [2], the appearance of dystonia with amisulpride in the absence of a past history of extrapyramidal symptoms in the index case showed that in addition to the established mechanism of action, there may be some other pathophysiological mechanisms responsible for development of dystonia, even at low doses, which is yet to be identified. The present case highlights the fact that acute dystonia can occur even on low doses of amisulpride.
Possession states precipitated by nortriptyline
Possession states are a unique category of dissociative disorders, which are characterized by a change in behaviour and apparent replacement of identity by a ghost, demon, animal, or some deceased individual. The unique transient alteration in the identity of the person makes it especially interesting for understanding the makeup of normal personality and consciousness. The aetiology of this disorder remains unknown. To date, psychosocial factors along with psychodynamic aspects of the person have played major roles in its conceptualization. This is supported by multiple observations, which encompass a wide range of factors including presence of psychosocial stressors in such conditions, of cultural influences, as well as clinical observations of projective tests [1] and insignificant improvement by psychotropic agents. But some reports of successful treatment of such disorders using psychotropics, particularly antipsychotics, may point towards a biological underpinning of such disorders [2], [3]. We report a case of precipitation of possession disorder by treatment with nortryptiline, with the understanding of possible contribution to complexity of aetiological factors in such disorders.
The patient, a 27-year-old married woman, presented with a 3 year history of paroxysmal attacks characterized by sudden falls, irregular, jerky movements of the whole body and pelvic thrusting. The attacks were preceded by quarrels with her mother-in-law. On detailed interview it was found that during the attacks she would often respond to environmental changes, but she denied remembering anything about the attacks. There was no post-ictal confusion. The clinical interview indicated a mildly depressed patient with multiple somatic complaints. After detailed investigation and electroencephalogram she was diagnosed as having dissociative epileptic disorder, as per the ICD criteria. Subsequently she was started on tablet nortryptiline 25 mg day−1 with a gradual titration up to 50 mg day−1 after 1 week. At 2 week follow up the patient complained of multiple attacks of possession by the ghost of her maternal aunt-in-law, who had died approximately 10 years previously in a road mishap. She had her first attack on the day after the consultation for pseudoseizure. During a typical attack she would repeatedly identify herself as the deceased person. She would recite events from the life of the deceased person and gave the reasons for returning to her body as identifying and taking revenge on the person who she alleged to have murdered her (the deceased person). A more detailed investigation among the family members found that the patient had had an interest in ghost stories since childhood and that she would ask for details about any such events in her locality, even before her marriage. The cause of death of the deceased person was due to a road mishap but, on being asked about her condition, she reported complete amnesia for the events. The attacks were mostly not preceded by any stressful event, but at times they would occur during a quarrel with her mother-in-law.
During this period she did not have any attack of seizure-like phenomena. Subsequently nortryptiline was stopped and she was started on low-dose olanzapine 5 mg day−1. On follow up after 1 month the patient reportedly did not have any such attacks but her pseudoseizure attacks persisted in a decreased frequency. On further follow up the patient had not had any attacks of being possessed and was well, as compared to her earlier condition, and still had occasional occurrence of pseudoseizure, once every 1–2 months or so. She was repeatedly requested to attend supportive psychotherapy but she refused, giving as the reason the distance of her home from the institution.
Dissociative symptoms are commonly found as comorbidities of non-epileptic seizure disorders [4]. However, conversion of dissociative pseudoseizures into possession states have not been reported so far. In general, the occurrence of possession disorders has been found to be secondary to some psychosocial stressors, but unusual precipitating events have been noted in the literature, including door-to-door sales [5]. The precipitation of possession state by nortryptiline raises several impzortant issues. The foremost is the importance of conceptualization of possession as a dissociative condition. Cases similar to the present one, in which conversion of symptomatology from one dissociative state into other is seen, suggest that both the states could have some common aetiological basis. The next important issue is the neurological basis of such disorders. Although dissociative states have traditionally been considered as anxiety spectrum disorders, anti-anxiety agents have been rarely found to be useful. In this context supportive psychotherapy has been found to be successful [3], but antipsychotics have also been found to be effective in a small group of such patients [2], [3]. This suggests dopaminergic dysfunction in such cases.
The role of antidepressants and anti-anxiety drugs remains controversial. Traditionally they have been used to treat associated anxiety or depressive symptoms and have rarely been effective in resolving dissociative symptoms. Precipitation of possession disorder in a person treated with a benign drug such as nortryptiline could be the result of two probable conditions. First, it could be due to a direct consequence of alteration of neurotransmitters in the brain, which, despite being an unusual event, cannot be ignored given the wide range of actions of nortryptiline and the lack of adequate understanding of the neurobiology of trance and possession. The second possibility could be that nortryptiline interacted with the prevailing patient psychological factors or cultural factors to precipitate the possession states. This would be equally unusual but worth consideration given the complexity of psychodynamics of such states. Whatever the mechanism, it seems reasonable to conclude that dissociative states are highly enigmatic and thus close monitoring of any alteration of symptoms is warranted in the course of illness, particularly so when the patient is on psychotropics.
Olanzapine and delirium: lesson from clinical practice
Although delirium associated with olanzapine overdose is well described in the literature [1], reports of delirium caused by therapeutic doses of olanzapine is less common [2]. We report such a case.
The patient was a 75-year-old man who had been transferred from a general medical unit to the acute inpatient unit of the Aged Mental Health Service for the investigation and management of rapid cognitive decline. Ten days earlier the patient had been admitted to a private hospital with a 2 month history suggestive of psychotic depression. He had been treated with venlafaxine 37.5 mg day−1 and risperidone 1 mg day−1 with little improvement.
In hospital risperidone was ceased and olanzapine 2.5 mg nocte was started. Because the patient was suspicious and distressed he was given an additional dose of 5 mg olanzapine. Over the next 36 h he was given a further total of 5 mg olanzapine. All olanzapine doses were given orally. On day 3 of admission the patient became febrile and developed a tachycardia. He became disorientated, agitated and his speech was incoherent. He was transferred to a general hospital for further investigation and management.
Physical examination, haematological and biochemical screening, chest X-ray and urine culture were all unremarkable. Magnetic resonance imaging demonstrated bilateral hippocampal atrophy. Over 24 h the patient became afebrile, but his level of cognitive impairment and behavioural disturbance persisted. He was then transferred to our care.
On arrival to the Aged Mental Health Service the patient presented as disorientated and distractible. Although speech was largely incoherent, he expressed persecutory beliefs and on one occasion indicated that he could see people climbing trees outside the window. Mini-Mental State Examination (MMSE) score was 0/30.
The initial diagnosis was of delirium. Further investigations including human immune deficiency virus, syphilis and herpes simplex virus (HSV) serology were negative, other than indicating past HSV infection. Electroencephalogram was in keeping with a diffuse encephalopathic process.
Because there was a temporal relationship between exposure to olanzapine and onset of the acute confusional state, olanzapine was ceased and the patient was maintained on oxazepam. Over the next week the patient started to improve. His speech became more coherent and his behaviour less disinhibited. In light of negative investigation results and clinical improvement after the withdrawal of olanzapine a diagnosis of delirium secondary to olanzapine was made.
Two weeks after olanzapine was ceased the patient's rate of improvement plateaued. MMSE score was 11/30. Because the patient continued to express intermittent persecutory beliefs quetiapine was commenced and gradually titrated up to a total of 200 mg day−1. The longitudinal history was carefully reviewed. It became evident that the patient had experienced subtle decline in cognitive function in the 18 months prior to his initial presentation. Positron emission tomography demonstrated marked hypoactivity over the parietal and temporal lobes. A final diagnosis of anti-cholinergic delirium secondary to olanzapine and comorbid dementia–Alzheimer type, was made and donepezil was commenced. Six weeks later MMSE score was 20/30, persecutory beliefs had resolved and there was no significant behavioural disturbance.
Although the final diagnosis was Alzheimer's dementia, a diagnosis of Lewy body dementia was considered because the patient had displayed fluctuation in cognition and experienced visual hallucinations. However, the visual hallucinations had occurred only once, lacked detail and there was no evidence of motor features of parkinsonism. Therefore a diagnosis of probable dementia with Lewy bodies was considered unlikely [3].
The present case demonstrates that therapeutic doses of olanzapine can precipitate an acute confusional state in vulnerable individuals. This observation is of particular importance given the increasing use of olanzapine in the management of behavioural disturbance in delirium and dementia [4]. This case also reinforces the idea that the early cognitive changes in dementia may be concealed by an individual's previous high level of cognitive function and support provided by a familiar environment. Cognitive impairment may then be abruptly unmasked by illness, in the present case delirium precipitated by the anti-cholinergic effects of olanzapine.
Clozapine-induced myocarditis
The risk of agranulocytosis, myocarditis/cardiomyopathy has restricted the use clozapine to the most refractory cases. Clozapine-induced myocarditis clinically ranges from sudden death within hours of commencement on clozapine to mild influenza-like symptoms.
The following case highlights this syndrome. A 34-year-old single woman was followed up at a mental health clinic in Melbourne since June 2005 following involuntary inpatient admission for first paranoid schizophrenic episode (DSM-IV) characterized by a 6 month history of increasing social withdrawal, paranoid delusions regarding parents’ safety, some depressive symptoms, prominent auditory hallucinations and bizarre behaviour.
All the symptoms except for auditory hallucinations (AH) cleared away in a matter of weeks. She was treated with risperidone for 3 months ceased at 7 mg day−1 because of important extrapyramidal symptoms; quetiapine for the next 6 months, at a dose of 1400 mg day−1 on which the patient reported sedation and postural hypotension, and presented hyperprolactinemia; and aripiprazole 60 mg day−1 for 4 months plus cognitive behavioural therapy as an adjunctive treatment. To all these trials the patient reported some improvement in frequency and intensity of the AH, but they continued to be prominent and distressing. Clozapine was introduced. Prior to it, blood tests, electrocardiogram (ECG), and echocardiogram were normal. She was started on 12.5 mg twice a day, with daily increments of 25 mg. On day 7 (125 mg day−1) she reported some dizziness and nausea; clinical examination was normal. Clozapine was increased by 25 mg day−1 every second day, reaching a dose of 200 mg day−1 at week 2, when she reported one incidence of hot/cold sensation the previous night. White cell count (WCC), creatine phosphokinase (CPK) and troponin were normal. QTc interval had increased from 428 baseline to 506. The patient was kept on the same dose (200 mg day−1).
Four days later the patient complained of feeling feverish and nauseous without other symptoms. Laboratory results were as follows: CPK 54 IU L−1 (0 − 70 IU L−1), C-reactive protein (CRP) 117.8 mg L−1 (0–10 mg L−1), WCC 12.1×109, NC 9.6×109, troponin-I 0.243 (<0.05), erythrocyte sedimentation rate 81 mm h−1 (<20 mm h−1); and ECG: tachycardia, QTc 503. Physical examination at the emergency department indicated tachycardia (120 b.p.m.), confirmed by ECG, CRP 98 mg L−1 (0–10 mg L−1), WCC 10.9 × 109 L−1 with slightly raised eosinophils, troponin T 0.04 XX. Echocardiogram was normal.
Clozapine-related myocarditis was suspected, and after cessation of clozapine all clinical pictures remitted; troponin T normalized within 24 h. Subsequent full blood counts were normal, as were ECG and echocardiogram at 7 months follow up.
The patient's age (34 years) and presentation of myocarditis (19 days from commencement) are in line with that of 28 days and a median age of 30 years previously reported [1–3].
The highest incidence of clozapine-induced myocarditis (8.5%) has been reported in Australia [4]. This may represent a true population difference or a higher level of awareness. Its underlying pathophysiology is likely to be an acute hypersensitivity reaction [5]. This is further supported by time to onset, fever, leucocytosis and eosinophils. Individual susceptibility may result from an interrelation of intrinsic (genetic) and extrinsic (gender, age, dose titration, etc.) factors.
In addition to blood tests it is suggested that clinical examination, WCC, troponin, CPK, ECG and echocardiogram be carried out weekly for the first 6 weeks, when most patients develop myocarditis, and thereafter every 6 months or before if clinically deemed.
Use of escitalopram in psychogenic excoriation
Excessive scratching of otherwise healthy skin is known as psychogenic excoriation. Sometimes the presentation may involve lips [1]. It has previously been suggested that selective serotonin re-uptake inhibitors (SSRIs) [1] and olanzapine [2] might be effective in the treatment of this condition. In this report we describe one case of excessive scratching and one case of frequent lip biting.
The first patient was a 63-year-old woman who presented to the dermatology department at Jubilee Mission Hospital, Kerala, India with a 1 month history of itching all over the body and excessive scratching in the context of depressive symptoms meeting DSM-IV-TR criteria for major depressive disorder. Dermatological evaluation indicated multiple excoriations and a few lichenified plaques with signs of secondary infection (Figure 1). There was no evidence of dermatological or systemic cause for itching. She had similar symptoms 5 years previously that resolved with imipramine. After explaining the probable nature of her symptoms she was referred to the psychiatry department. On further evaluation the excoriation was found to be a compulsive but gratifying act in response to itching. It was never ego-dystonic. The patient received treatment with escitalopram at a daily dosage of 10 mg. Imipramine was avoided because of the unfavourable side-effect profile. After 1 week itching and scratching subsided and then disappeared over a period of 2 weeks. Depression remitted gradually over the subsequent 6 weeks.
Psychogenic excoriation with lichenified plaques and signs of secondary infection.
The second patient was a 24-year-old man who presented with a 10 year history of frequent lip biting with a relapsing and remitting pattern, and features of major depressive disorder as per DSM-IV-TR criteria. After the onset of depressive symptoms lip biting became severe. He felt a peculiar sensation in the lower lip associated with mounting tension but without any visible abnormality. He could not control the urge to bite (Figure 2). As in the case of the first patient, biting yielded relief. Movement disorder was excluded. Escitalopram (10 mg day−1) was given. The frequency of lip biting declined as depression improved. Lip biting stopped completely after 2 weeks.
Lip biting with ulceration of lower lip.
These cases are consistent with previous reports showing that psychogenic excoriation is found to be comorbid with psychiatric disorders, that depressive disorders are the most common and that they favour the psychogenic origin of excoriations[1], [3]. Infection following excoriations is not uncommon [3]. Psychogenic excoriation belongs to the spectrum of obsessive–compulsive spectrum disorders. In our patients symptoms are more impulsive in nature. The impulsive nature of psychogenic excoriation is described elsewhere [3].
It is interesting to note that psychogenic excoriation is not included in DSM-IV as a distinct disorder. It is true that many patients, as described here, do really itch while they scratch. Itching is a physical sensation that may or may not be psychogenic in origin. Unless the act of excoriation is proved to be clearly psychological in origin rather than a response to physical sensations the DSM-IV stand is justified. Given that other SSRIs are known to be effective in mucocutaneous syndromes and a temporal relationship is observed between administration of escitalopram and the improvement of both behavioural and dermatological features, it is rational to suggest that this drug is effective in such conditions regardless of physical or psychogenic origin of itching. The effect of escitalopram may be mediated through serotonin rather than peripheral action at skin (imipramine and olanzapine block H1 receptor). Serotonin is implicated in itching [4]. Being a drug that has a superior profile over other SSRIs [5], escitalopram may be considered in the treatment of psychogenic excoriations. This is the first report illustrating the use of escitalopram in the aforesaid situations