CASE HISTORY
Presenting symptoms:
A 30 year old married housewife presented to a general teaching hospital in Sydney with an abnormal mental state. She was admitted under the neurosurgical team in view of a past history of having an intracranial shunt inserted due to complications from a post-natal cerebrovascular accident secondary to a coagulopathy caused by an inborn error of metabolism.
Her husband reported that she had been unable to perform her usual household duties or care for the children over the previous week. He noticed that she was sleeping excessively, confusing family members’ names and laughing for no apparent reason during this time. When questioned at the time of the psychiatric assessment, she acknowledged impaired concentration, poor cognitive stamina, word-finding difficulties, muddled thinking, ataxia, a reversed sleep-wake cycle and labile moods over the previous few weeks. She also described what appeared to be poorly-formed psychotic symptoms. She believed she had had a "religious experience", feeling as if she were "the chosen one". She believed a building opposite her ward was a mosque. She reported seeing a man across the road from the hospital who had the physical appearance of a fictional character from a television series.
Mental state examination:
Staff noticed that the patient walked slowly & aimlessly around the ward when she wasn’t lying in her bed staring blankly at the TV. She appeared inattentive, vague, non-spontaneous and detached in interactions, but passively followed simple commands. She appeared oblivious to her environment. There was difficulty communicating due to inappropriate, fatuous laughter, circumstantiality, poverty of detail and disorganised temporal sequencing. On mental state examination, she was a tall lanky woman who was mildly psychomotor retarded, with increased latency of verbal replies & bradykinesia. She was preoccupied with her inner-thoughts, laughed fatuously and incongruously, grinning excessively & described her mood as "very happy". she appeared mildly elevated & irritable for brief periods Her speech was of low volume, nasal & monophonic. There was a poverty of thought form & mild thought disorder (derailing and unclear associations). She expressed a poorly-formed grandiose delusion & described visual illusions or hallucinations but no disturbance in any other sensory modality. The patient was oriented in person and place, with only mild impairment of time (she knew the month and year, not the days of the week or month). Attention and concentration deficits were evident & confirmed on formal testing (she could not perform serial 7’s, 3’s or spell WORLD backwards). Registration and short term memory were intact on testing, but she seemed to forget or disregard commands very quickly. There was evidence of nominal dysphasia, mild difficulty with three-step commands, concretism and visuo-constructional dyspraxia (she could not copy complex diagrams). No confabulation or remote memory deficits were identified. Her Mini-Mental State Examination (MMSE) score totaled 20/30. She denied being in need of medical assistance & explained her presentation as being due to her husband’s concerns, but did not appear suspicious of possible motives or irritated by her presence in hospital. She denied that she had any cognitive deficits. She denied requiring any medication or dietary modification, but accepted medication offered passively.
Past history:
Seven years previously she developed an occipital headache, vomiting, myalgia, arthralgia, blurred vision and depressed mood following the birth of her second child. Two days later she fell comatose and required the insertion of a ventricular drain & cisterno-peritoneal shunt (similar to a ventriculo-peritoneal shunt) to treat raised intracranial pressure. Neuroimaging indicated a superior sagittal sinus thrombosis with enlarged ventricles and bilateral parietal lobe infarction. Her post-operative course was complicated by deep vein thrombosis and pulmonary emboli for which she required anticoagulation. A coagulopathy (raised INR on blood screen), folate and Factor VII deficiency was discovered. The patient was diagnosed with homocystinuria when further investigations were performed on her blood. She was commenced on pyridoxine, folate supplementation and dietary modification. She had suffered a dense left hemiparesis with secondary cognitive impairment for which she required extensive rehabilitation at a Stroke Unit. By the time of discharge, the residual deficits noted were mild left hemiparesis, ataxic gait, dysphonic speech, and right inferior quadrantinopic visual field defect. She was followed up at the Haematology Outpatient Department. Her compliance was intermittent & she did not adhere to the modified diet. She unilaterally discontinued attendance 2 years previously.
Diagnosis:
The provisional diagnosis was delirium due to cerebral homocystinaemia on a background of mild cognitive disorder due to the previous cerebrovascular accident. Electrolytes, calcium, liver function tests, coagulation studies, thrombosis screen were within normal limits. A cerebral CT showed no new changes. The full blood count/film indicated macrocytosis & hyperchromia consistent with folate deficiency secondary to uncontrolled homocysteinuria. An EEG indicated slow-wave activity, more prominent in the posterior areas, consistent with delirium. The differential diagnosis was delirium due to an alternate general medical condition (GMC), mood disorder (with mixed features) due to a GMC, psychotic disorder due to a GMC, or a functional mood or psychosic disorder. Less likely possibilities were multi-infarct (vascular) dementia & pathological laughing and crying (organic emotionally labile [asthenic] disorder).
Initial management:
The biochemistry team confirmed that the patient had been previously diagnosed with ‘pyridoxine-sensitive’ (responsive) CBS deficiency homocystinuria, but had been lost to follow-up. Pyridoxine & folate was recommenced. She was also prescribed a small dose of haloperidol. A blocked or infected shunt, as well as seizure activity (which can be caused by high homocystine levels in the brain) and cerebral micro-infarcts (due to homocystine-induced arterial thromboses) were excluded with a lumbar puncture, MRI, EEG & shunt infusion studies with intracranial pressure monitoring. Urinary amino acids indicated elevated homocystine levels.
Treatment & progress:
The patient's mental state improved over the week of admission. During this time, she became less euphoric, inattentive, fatuous and displayed less pathological laughter. However, she remained passive, vague, dream-like and insightless regarding the severity of her cognitive impairment. The residual symptoms of delirium were managed as an outpatient. The dose of haloperidol was weaned from 2.5 to 1.5 mg nocte by the time of discharge. At the time of first review 5 days post-discharge, there was less euphoria & pathological laughter. Her insight that she had been mentally ill & required hospitalisation emerged. Her MMSE score rose to 24/30 with the remnant deficits consisting of impaired concentration and constructional dyspraxia. There was persistent initial insomnia. She was commenced on warfarin by a haematologist following outpatient review. She complained of poor cognitive stamina but denied inability to perform mental tasks; she was able to count, retain figures in her head, learn new tasks & her concentration and constructional abilities were less impaired on testing. At review 1 month post-discharge, she described her concentration as "normal" and denied any residual symptoms of delirium or affect dysfunction. Her MMSE score plateaued at 27-29/30 & she appeared to be functioning at her optimal premorbid level.
There were significant complicating psychosocial stressors which also required management but have not been discussed here.
Definition of homocytinuria:
A genetically inborn error of sulphur amino acid metabolism leading to elevated homocystine levels in the urine, discovered in 1962.
Causes:
There are 3 distinct enzyme deficiencies known:
- Reduced activity of cystathionine b -synthase (CBS), which reduces the conversion of homocystine to cystathione. This leads to an accumulation of homocystine and methionine in the plasma and CSF and their overflow into the urine. Vitamin B6 (pyridoxine) is a co-factor of the enzyme and supplementation leads to prompt metabolic normalisation in 50% of the patients (‘pyridoxine-sensitive’ sub-group). It causes CBS Deficiency Homocystinuria.
- Reduced activity of 5-methyl-tetra-hydro-folate methyl-transferase (MTHF-MT). Few of these patients have been described.
- Reduced activity of 5,10-methylene-tetra-hydro-folate reductase (MTHF-R).
Literature review of psychiatric symptoms in homocystinuria:
An international questionnaire survey of 629 patients was conducted by Mudd et al (1985) to better define the natural history of the commonest form of the disorder, CBS deficiency1. Of the 472 patients not ascertained by screening newborns or proband siblings, only 2.8% were investigated for homocystinuria as a result of behavioural or psychiatric disorder, and even in these patients this was a contributory rather than a sole cause for investigation. Most patients were investigated because of more than one clinical feature, being combinations of ectopia lentis (dislocated lens) (65%), mental retardation (52%), developmental retardation (21%), early thromboembolic disorder (15%), marfanoid characteristics (36%), bony abnormality (23%) and seizures (3%).
Abbott et al (1987) obtained psychiatric information from 63 patients with CBS homocystinuria2. Despite early case reports of homocystinuria describing a large number of relatives with schizophrenia, no patients in this study had evidence of delusions or perceptual disturbances in clear consciousness that were not associated with an episodic mood disturbance. This has been identical to the findings of other published reports. However, the 10% patient sample with past or present depressive episodes is not statistically different from the rate of such disorders in the general population, negating a specific association. Similarly, whilst ‘behaviour disorders’ (temper tantrums, destructive behaviour, substance abuse or antisocial personality disorder) were common, particularly among patients with mental retardation (33%), this prevalence is similar to frequencies reported for mentally retarded children living in the community. Obsessive-compulsive disorder (OCD), at 15% of the patient sample, however, represented considerably more than would be expected (2-3%), as did personality disorder (19%). While behaviour disorders and OCD predominated in the low IQ patients, personality disorders were unrelated. The common personality traits which appeared to interfere with social or occupational function were lack of ambition, passivity and a narrow interest spectrum. Psychiatric disorder appeared to increase the likelihood of development of strokes and seizures, and correlated with B6-nonresponsiveness and IQ.
Pyridoxine administration is the most widely used treatment for late-detected B6-responsive patients. In responsive patients, it has been shown to significantly reduce thromboembolic events (with aspirin and dipyridamole anticoagulation used as adjuncts), moderately increase IQ, cause behavioural improvement, reduce progression of osteoporosis, possibly reduce seizures and improve survival rates. Other treatments are dietary methionine restriction and folate supplementation, as accumulated homocystine gets channeled back to methionine, which accelerates folate utilisation and causes deficiency8.
The majority of the articles in the literature relating psychiatric interest to homocystinuria were in terms of schizophrenia. A most interesting finding in this literature was that 40% of chronic schizophrenics develop a psychotic exacerbation when given 20g/day of L-methionine ("the methionine effect")3. As methionine is the main methyl donor in the body and the hallucinogen mescaline is a methylated derivative of dopamine, it has been proposed that a deficient enzymatic system for demethylation may cause an accumulation of endogenous hallucinogens in schizophrenia.
Discussion:
Reports of metabolic and toxic causes of secondary (organic) mania have included metabolic aberrations4. Although controversial, some authors have found a variation in phenomenology dependent on the aetiology of the delirium (Ross, 1991). The mechanism by which homocystine accumulation in the brain might cause delirium is unknown, but several theoretical possibilities exist. In animal models, homocystine has been shown to block neuronal GABA receptors and lead to reduced adenosine and raised nitrogen (as occurs in hepatic encephalopathy). GABA receptor blockage may lead to cerebral excitation. This is of interest in light of the patient's hypomanic features.
Brenner quotes studies suggesting that "the EEG may be helpful in detecting secondary manias, i.e. those due to organic impairment" by excluding "mood disorders which may be mistaken for an organic delirium". In fact, The "non-specific slow-wave activity" & dominant posterior rhythm on the Case History's patient's EEG are worthy of note, as these features are 83% sensitive/78% specific and 72% sensitive/82% specific, respectively, for the diagnosis of delirium (using clinical diagnosis as the gold standard)5. They assist to differentiate the patient's diagnosis from dementia, secondary mania or so-called ‘functional’ psychiatric disorders, which are less likely to have diffuse slowing or the degree of magnitude of slowing as that seen in the confused patient with an ‘organic’ disorder6, as well as excluding a seizure disorder.
The pathological laughter prominent in this patient represents a form of disordered emotional expression, originally described by Kinnier Wilson as "a sequel to and consequence of a recognisable cerebral lesion… in which attacks of involuntary, irresistible laughing or crying or both" occur. The main abnormality in organic emotional lability is seen to be one of magnitude of response7. The patient informed at the time of initial psychiatric contact that she had experienced "swinging moods" over the previous few weeks - euphoria associated with laughing and dysphoria with tearfulness. This had progressed to isolated pathological laughter alone by the time of admission. Whilst pathological crying appears to be commoner than laughter, cases of mixed crying and progression from one to the other have been reported7.
The pattern of cognitive dysfunction found in the study by Abbott et al resembled subcortical dementia, with a disproportionate decrease in attention (measured by low scores in arithmetic, digit span and symbol) compared with language2. They also identified a clinical report of a patient who had episodes of both depression and mania. Unfortunately, they did not breakdown their cases of affective disorder to quantify the cases of bipolar disorder. No mention was made of acute brain syndromes.
Macrocytosis in this patient's blood film suggested she may have been folate deficient. Of interest is another case history, described by Bracken et al (1985) of a patient with homocystinuria whose mental disorder resembled "a combination of delirium and schizophreniform psychosis" and whose mental state improved gradually after administration of folic acid alone3.
References:
- Abbott et al, Psychiatric Manifestations of Homocystinuria due to Cystathionine b -Synthase Deficiency: Prevalence, Natural History, and Relationship to Neurologic Impairment and Vitamin B6-Responsiveness, American Journal of Medical Genetics, 26:959-69, 1987
- Bracken et al, Homocystinuria and Schizophrenia: Literature Review and Case Report, Journal of Nervous and Mental Disease, 173(1):51-55, 1985
- Cummings J, Organic Delusions: Phenomenology, Anatomical Correlations, and Review, British Journal of Psychiatry, 146:184-97, 1985
- Brenner R, Utility of EEG in Delirium: Past Views and Current Practice, International Psychogeriatrics, 3:2:211-230, 1991
- Strub and Black, The Mental Status Examination in Neurology, FA Davis, 1985
- Dark et al, Pathological laughing and crying, Australian and New Zealand Journal of Psychiatry, 30(4):472-79, Aug 1996
- Mudd et al, The Natural History of Homocystinuria Due to Cystathionine b -Synthase Deficiency, Americal Journal of Human Genetics, 37: 1-31, 1985
