COVID‐19, neuroleptic malignant syndrome and psychosis - Grant - 2021 - Progress in Neurology and Psychiatry - Wiley Online Library - Wiley
Neuroleptic malignant syndrome (NMS) typically arises through an idiosyncratic drug reaction to medications with dopamine receptor antagonist properties, or the rapid withdrawal of dopaminergic medications, which precipitates the dysregulation of various central neurochemical and neuroendocrine systems.1, 2
The DSM-5 criteria for diagnosing NMS include having the three major criteria of exposure to a dopamine antagonist, muscle rigidity and hyperthermia. Additionally, at least two minor criteria must be present, from: tachycardia; tremor; altered level of consciousness; labile blood pressure; diaphoresis; leucocytosis, and elevated creatine kinase (CK). Development of NMS typically occurs within 30 days of commencing an antipsychotic agent; though exceptions have been reported in instances of dosage increases or additional antipsychotic agents being administered.3
Presentation
The patient was a 56-year-old white male who was living alone with support from family. He had a long-standing diagnosis of treatment-resistant schizophrenia for which he was treated with clozapine, on which he had been stable in the community for almost two decades. His medical history included diabetes mellitus type 2, hypercholesterolaemia and iron deficiency anaemia. Medications on admission included aripiprazole 10mg once daily, venlafaxine 150mg twice daily, metformin 1000mg once daily and atorvastatin 40mg once daily.
As the patient was taking clozapine he was engaging with blood monitoring services every four weeks. This service safeguards against the known clozapine side-effect of neutropenia, which can lead to fatal agranulocytosis. One such appointment returned an amber result (results are categorised via a traffic light system) meaning the neutrophil levels were borderline; while the patient could continue taking clozapine the frequency of blood monitoring had to be increased.
Before being able to return to the blood monitoring clinic for the next blood sample the patient developed flu-like symptoms and subsequently tested positive for SARS-CoV-2. He was forced to self-isolate for 10 days, thereby missing the appointment resulting in his well established clozapine treatment being discontinued abruptly. Following a five-day gap in which no antipsychotic was prescribed aripiprazole 10mg was started in the community, with a view to retitrating clozapine after two green results could be returned from monitoring services.
His COVID-19 infection was mild and did not require hospitalisation. When family observed the patient immediately following this isolation period they became extremely concerned regarding his mental state. He was taken to a nearby emergency department accompanied by his brother, who described pressured speech, confusion and the patient expressing paranoid thoughts, some of which were violent.
After being medically cleared by the emergency department he was referred to liaison psychiatry services, which organised transfer to a psychiatric ward as an informal patient. The impression on admission was that of a psychotic relapse, likely due to clozapine being discontinued. The plan was to retitrate clozapine.
Management
After starting the retitration of clozapine with two 12.5mg doses taken 12 hours apart the patient was reported by nursing staff as having difficulty mobilising, being incontinent of urine, and confused. It had been approximately two weeks since the patient tested positive for SARS-CoV-2, and more than one week since completing his isolation period.
On review the patient presented with pressure of speech. No rigidity was found clinically; he was afebrile and tachycardic (145 beats per minute). ECG showed sinus tachycardia with QTc within normal limits. Bloods showed neutrophilia, with elevated CRP, urea and creatinine, as well as the previously documented microcytic anaemia. The patient was unable to cooperate to provide a sample for urinalysis.
The impression was acute kidney injury (AKI) secondary to urinary tract infection (UTI). The confusion was speculated to be due to possible delirium. The patient was transferred to an acute medical ward for treatment. Here the patient's CK was found to be grossly elevated at approximately 32 000IU/L.
Computed tomography pulmonary angiogram (CTPA) ruled out pulmonary embolism (PE). Computed tomography (CT) of the head was unremarkable. He tested positive for SARS-CoV-2, though this was likely residual viral ribonucleic acid (RNA) from his previous infection.
He was treated over the course of several days for NMS, UTI, AKI and COVID-19 with fluids, antibiotics, and supportive therapies. All antipsychotic agents were discontinued.
On being medically cleared several days later the patient returned to the psychiatric ward where his urea and electrolytes returned to within normal limits, though his tachycardia remained. Echocardiogram, 24-hour electrocardiogram, and deep vein thrombosis clinic found no medical explanation for the tachycardia, which was subsequently treated with bisoprolol on the advice of cardiology. Clozapine was then retitrated without further NMS complications.
Discussion
Pathogenic mechanisms in NMS
The pathogenetic mechanisms underlying NMS remain poorly understood. Given both the dysregulation of autonomic nervous system activity and extrapyramidal symptoms (EPS) being induced, NMS likely arises from a reduction in CNS dopaminergic tone; itself due to inhibition of dopamine receptor activity, with the D2 subtype within nigrostriatal pathways being particularly affected.2 These imbalances subsequently lead to progressive damage of muscular tissue and multi-organ failure.2
NMS associated with second generation antipsychotics (SGAs) such as aripiprazole, clozapine, olanzapine and risperidone, is known to have lower incidence, with a milder clinical course and less fatality than with their first-generation counterparts,1, 4 which include chlorpromazine, fluphenazine, and haloperidol. Given that SGAs have limited activity at the D2 receptor yet can bring about NMS it is widely hypothesised that other CNS receptors are likely involved in the pathogenicity of NMS.1
The clinical similarity between NMS and serotonin syndrome presentations leads to speculation that elevated serotonin levels would in part explain some of the symptomatology of NMS.1 While most SGAs are known to antagonise 5-HT2A receptors, aripiprazole and clozapine share agonistic actions at such sites, which may explain fewer presenting clinical signs of NMS, including less pronounced hyperthermia or EPS.5
Clozapine- and aripiprazole-associated NMS
A review of clozapine-associated NMS case reports found presentations were precipitated by rapid dose increases, previous NMS, and high rates of previous treatments with other antipsychotics.1 Autonomic disruption, including tachycardia and early fever, were more frequent and severe than with other SGAs. However, EPS was seen less often, likely due to lower affinity of clozapine for D2 receptors.6
A similar review of aripiprazole-associated NMS case reports found presentations were precipitated by relatively fast titration schedules.1 The presentation clinically was typically evidenced by mental status changes, lower frequency of hyperpyrexia, and presence of rigidity where rhabdomyolysis was found to be associated with lower peaks in CK. Both severity and duration of NMS were generally lower as compared with other SGAs, which may be explained by the peculiar pharmacodynamic profile of aripiprazole, which exerts both a partial agonist activity on the D2 receptor as well as D3, D4 and 5-HT1A receptors.7
Previous cases of NMS occurring in patients on dual aripiprazole and clozapine therapy report consciousness change and only modest elevation of CK, with hyperthermia not typically seen.8
NMS and COVID
Very few cases of NMS during COVID-19 have been reported9, 10 and to the authors' knowledge this is the first case reported in post-COVID-19 infection.
Conclusion
The patient presentation reported here only met one of the three major DSM-5 diagnostic criteria for NMS through exposure to a dopamine antagonist. He met several minor criteria, including altered levels of consciousness, elevated CK, tachycardia and urinary incontinence. Aspects of the case, however, are out of keeping with previously reported NMS findings. Firstly, there was an absence of relatively fast titration schedules or rapid dose increases of antipsychotic agents: the patient had only received two small doses of clozapine, combined with two weeks of aripiprazole. Secondly, while the lack of fever is in keeping with the SGA drug therapy combination, the grossly elevated CK is highly unusual. The AKI secondary to the UTI likely contributed to raised CK levels but is insufficient to explain the degree of elevation. The extent to which prior COVID-19 infection played a role in this case remains unclear.
Declaration of interests
No conflicts of interests were declared.
References
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