Abstract
Psychotic symptoms associated with thyroid disorder are relatively uncommon in children and adolescents but are well documented in adults. As early as 1888, the Committee on Myxoedema of the Clinical Society of London published 109 cases of recorded mental changes in myxoedema. Asher in 1949 stated that myxoedema is a frequently missed cause of psychosis [1].
In our literature search we found two case reports on children with unusual presentation of hypothyroidism. Chalk described the case of a 15-year-old girl who presented with a sudden onset of psychotic illness thought to be related to marked hypothyroidism [2]. She responded well to thyroid replacement. Smith and Beattie reported the case of a 12-year-old boy who presented similarly with sudden onset of a confusional state with psychotic features and grossly abnormal thyroid function test [3]. He too responded well to treatment.
Rapid thyroid replacement has also been implicated as a cause of psychotic symptoms in adults [4], but no report of such phenomena in children and adolescents was found in our literature search.
A 12-year-old girl presented to the child psychiatric ward with a 2–3 month history of alteration in mood and behaviour with increasing aggression. Her parents reported 3 weeks of giggling alone, experiencing rapid mood swings and sleeping poorly, often wandering the house at night. She had also been oppositional towards her parents and had been swearing and lashing out at her mother and her brother. This was described as out of character because she was previously well socialized, had an excellent academic record and participated well in sporting activities. She had no previous history of behavioural problems.
The patient had been diagnosed with hypothyroidism approximately 2 months previously and was commenced on thyroxine 100 μg once daily without gradual upward titration of dosage. She had returned to normal functioning after 4 weeks. After a relatively normal 2 week period she developed the aforementioned symptoms, leading to referral to the psychiatric inpatient unit. Thyroxine was ceased by her family doctor 2 days prior to admission for fear that it was causing the psychotic symptoms.
There was a strong family history of thyroid disease. Both her mother and maternal aunt suffered from autoimmune hypothyroidism. Her maternal grandmother suffered from thyrotoxicosis, diabetes mellitus and ischaemic heart disease. Another history of note is that her paternal grandmother had a history of bipolar affective disorder that was well controlled on lithium for 30 years. The patient had a history of epilepsy in childhood but had been symptom free for 5 years under no treatment.
In the ward she appeared perplexed and disorientated at times. She remained guarded and irritable. She showed poverty of thought and psychomotor retardation. Dialogue was limited and non-spontaneous. She often gave monosyllabic answers with noticeable question–answer latency. Her affect appeared flat. She giggled to herself often but was unable to explain why. She was felt to be guarded and distrustful of people. She was found to be slow to complete tasks and paused mid-task, requiring prompting and redirecting to continue. She was unable to identify reasons for these interruptions.
No abnormality was found on physical examination. She was in stage 4 of puberty. Her blood pressure was 113/65 mmHg, her pulse rate was 88 b.p.m., her temperature was 36.2°C. She weighed 60.2 kg and was 165.5 cm tall.
Full blood count, liver function test, renal function test, electrolytes and metabolic screen were all normal. Her thyroid function test was also found to be normal with thyroid-stimulating hormone (TSH) of 0.7 mU L–1(normal range = 0.3–5 mU L–1) and T4 of 20 pmol L–1 (normal range = 9–23 pmol L–1). Electroencephalogram, computed tomography of the brain and magnetic resonance imaging of the brain were all normal.
An endocrinology consult was sought and thyroid replacement was not re-instituted because the thyroid function test was normal. It was felt that hypothyroidism may not have caused the changes in her behaviour. A neurology opinion was sought and no abnormality was found. On neurological examination she showed no prolonged deep tendon reflexes.
Her presentation improved over the next 2 weeks and the patient was discharged with some persisting social withdrawal and psychomotor retardation. No definitive diagnosis was made at this stage. The patient improved further over a few more weeks.
The patient developed similar symptoms 6 months later. There was a 5 week history of sudden change in behaviour. She became socially withdrawn and there had been a significant decline in academic performance. She exhibited psychosocial agitation, poor sleep and concentration and at times inappropriate smile and laughter. She was also heard to be laughing to herself in the shower and she reported seeing a teacher who was not there. She was referred back to the inpatient child psychiatric unit for further assessment and management.
On admission her presentation was similar to that of the previous hospitalization. She was found to be guarded, exhibited flat affect and was laughing to herself for no apparent reason. She was also noted to be looking at an unseen person or object. She denied any psychotic symptoms when asked. Physical examination was once again insignificant. The patient's thyroid function test on this admission showed mild hypothyroid state with TSH of 92 mU/L (normal range = 0.3–5 mU/L) and free T4 of 8 pmol L–1 (normal range = 9–23 pmol L–1).
A paediatric endocrinology consult was sought and thyroxine was re-instituted as per Melbourne Royal Children's Hospital Paediatric Pharmacopoeia guideline. With a starting dose of 25 μg, the patient's dosage of thyroxine was increased every 2 weeks and she was discharged on a dosage of 75 μg daily.
Due to the severity of her psychotic presentation ris-peridone was initiated and titrated up to 2.5 mg over 2½ weeks. Her symptoms subsided gradually, with some residual symptoms of infrequent giggling to herself on discharge 26 day after admission.
The patient received follow up in the outpatient clinic for a further 7 months. Her psychotic symptoms resolved soon after discharge and risperidone was reduced gradually over 4 months and stopped. Despite the resolution of her symptoms the patient could not recall experiencing auditory or visual hallucinations and could not tell us why she laughed and giggled for no apparent reason while unwell. At 2 years since discharge she is functioning well at school and at home. She is currently euthyroid on a regimen of thyroxine 75 and 100 μg on alternate days and has had no re-emergence of psychotic symptoms.
Psychosis secondary to hypothyroidism is relatively rare in children and adolescents. As far as we know this is the third published case report on myxoedema madness in the child and adolescent age group.
This patient showed little physical signs of hypothy-roidism. She did, however, have a slight decrease in free T4 (8 pmol L–1) and a moderate rise in TSH (92 mU L–1). She had other symptoms suggesting hypothyroid state such as slow mentation, psychomotor retardation, hypothermia, emotional lability, confusion and disorientation [3,5–10].
It is possible to have myxoedema psychosis with a modestly elevated TSH and not many other signs of hypothyroidism [10]. There appears to be no correlation between the degree of thyroid dysfunction and psychiatric symptoms, and that psychosis may be unrelated to the degree of thyroid hormone deficit [5,10]. The current patient's presentation seems to be supported by this hypothesis.
Psychosis can appear in association with thyroid replacement therapy; this was first reported by Ziegler in 1931 [4]. Easson reported in 1966 that psychosis caused by hypothyroidism can occur concomitantly with thyroid replacement [4]. Lidz in 1971 stated that psychosis caused by thyroid replacement can aggravate an existing myxoedema psychosis or as a new event [4]. Josephson and MacKenzie reported in their retrospective study of 18 case reports that psychosis following initiation appears 4–7 days after aggressive initiation of thyroid replacement and usually spontaneously resolves [4].
If thyroid therapy is initiated too rapidly or at too high a dose, an acute confusional state or exacerbation of the psychosis may occur [5]. An hypothesis for the cause of psychosis secondary to rapid thyroid replacement is that hypothyroidism decreases receptor sensitivity to central nervous system catecholamines, resulting in compensatory increase in catechol concentration [11,12]. With rapid replacement therapy, the catechol receptor sensitivity will be augmented abruptly. With the increased cat-echol concentration, a hypercatecholaminergic state ensues, leading to psychotic symptoms [13]. The psychiatric presentation is due to acute alteration of thyroid status rather than thyroxine itself [14].
Jameson and DeGroot described that the thyroid hormone binding sites have differing affinity for thyroid hormones [15]. These sites will influence action in enzymes on the plasma membranes, hormone transporting proteins and nuclear receptors [15]. The distribution of the nuclear receptor isoforms varies within the different brain regions [15]. The psychotic symptoms seen with acute alteration of thyroid status may be due to a combination of the aforementioned factors [14]. That is, the difference in thyroid receptor affinity and the difference in distribution of nuclear receptor isoforms in different brain regions plus the rapid increase in thyroid hormone receptor sensitivity to catecholamines as a result of sudden alteration in thyroid hormone concentration cause a transient psychotic feature.
Family history of hypothyroidism, female sex and personal or family history of psychiatric illness predispose to myxoedema madness and psychotic symptoms secondary to thyroid replacement. We suggest that thyroid replacement therapy in paediatric or adolescent patients particularly with the aforementioned risk factors, should be started at a low dose and gradually incremented. One should also observe for emergence of psychotic symptoms during initiation and augmentation of the replacement therapy. Should psychotic symptoms emerge, replacement therapy should be discontinued temporarily and recommenced once psychotic symptoms have subsided. Starting at a lower dose and increasing at a much slower pace [16]. Should psychotic symptoms persist despite adequate thyroid replacement, the addition of an antipsychotic medication may lead to earlier remission [5]. Use of atypical antipsychotic at a low dose is recommended [5].
This case highlights the need to screen for thyroid disease in suspected psychotic illnesses. It also reminds us of the need for caution in initiating thyroid replacement therapy. There is also a need to continually look for emergence of psychotic symptoms in the first few weeks of treatment even after initial clinical response to thyroid replacement therapy.