Transient Fever Response After ECT in a Patient with Catatonic Schizophrenia: A Case Report

ABSTRACT

Electroconvulsive therapy (ECT) is an effective and safe treatment method for many psychiatric disorders. In general medical practice, ECT may cause side effects as most other treatment methods do. Headache, myalgia, nausea, vomiting, confusion, anterograde amnesia are common side effects of electroconvulsive therapy. Fever; in addition to general medical conditions such as infection, malignancy, connective tissue diseases, drug treatments, malignant hyperthermia, convulsions, it can also occur due to conditions such as neuroleptic malignant syndrome (NMS), serotonin syndrome, catatonia, malignant catatonia, which are frequently encountered in psychiatry clinics. In the literature, transient fever response due to electroconvulsive therapy application have been described, albeit rarely. Although there are many proposed mechanisms for the emergence of a fever response, regardless of its cause, it is still not understood why some fever responses occur. In this article, we present the differential diagnosis of the fever response, possible causes, and the mechanisms that may reveal the secondary fever response to electroconvulsive therapy in a case with a diagnosis of catatonic schizophrenia, who developed a fever response during electroconvulsive therapy sessions and no fever response was observed at times other than electroconvulsive therapy sessions. In this case, postictal benign fever response associated with electroconvulsive therapy was considered after excluding other medical conditions that may cause a fever response after electroconvulsive therapy.

INTRODUCTION

Electroconvulsive therapy (ECT) is currently used effectively and safely in many psychiatric diseases such as mood disorders, psychotic disorders, and catatonia syndrome (Kellner et al. 2020). The most common and recognized side effects of ECT are headaches, anterograde amnesia, confusion and muscle pain (Andrade et al. 2016). Fever or hyperthermia are not among the commonly reported side effects of ECT. In the literature, a transient fever response after ECT has been reported in only a few case reports (Antosik-Wojcinska et al. 2014, Bation et al. 2012, Bryson et al. 2012, Lau et al. 2015, Majeske et al. 2013).

In this article, it was aimed to discuss possible differential diagnoses for a patient with a transient fever response observed four times during acute ECT sessions.

CASE

A 25-year-old male patient, who was being followed-up with the diagnosis of schizophrenia, applied to the emergency department of our hospital with complaints of not speaking, staring, and aggression. After he had been evaluated in the emergency room, he was admitted to our inpatient service due to the catatonia symptoms such as staring, mutism, catalepsy, waxy flexibility, withdrawal, automatic obedience, mitgehen, ambitendency, and posturing.

His psychiatric complaints started when he was 18 years old, with social withdrawal and paranoid thoughts that there were people trying to poison him. He had auditory hallucinations of voices saying that his mother was not his real mother and he also had aggressive behavior.

He was hospitalized in the psychiatry ward with these complaints twice. Despite the use of olanzapine, risperidone, amisulpiride and clozapine treatments for a sufficient duration and in effective doses, his complaints did not improve. For this reason, eight sessions of bitemporal effective ECT has been administered in addition to the antipsychotic drug treatment. He did not benefit from this treatment either. It was found out that his complaints reduced only with 100 mg once-monthly long-acting injections of paliperidone palmitate in the past, but the patient’s insight into his disease was still weak and his treatment compliance was low. It was found out that his positive psychotic symptoms exacerbated and his catatonic symptoms reappeared after he had interrupted the paliperidone palmitate 100 mg once-monthly maintenance injection treatment.

Complete blood count (CBC), liver function tests (LFT), kidney function tests (KFT), serum electrolyte levels, electrocardiography (ECG), posterior-anterior chest X-ray, complete urinalysis were within normal limits. Brain magnetic resonance imaging (MRI) was performed for the etiology of catatonia. Brain MRI revealed volume loss in the cavum septum pellicidum et vergae, inferior vermian and cerebellar folia, enlargement pointing to arachnoid cysts in the posterior fossa, enlargement in the perirolandic sulci, cerebellopontine and prepontine cisterns. Lorazepam 5 mg/d treatment was started for catatonic symptoms and increased up to 10 mg/d. After lorazepam was increased to 10 mg/d, the patient’s symptoms of catatonia such as refusal to eat, urinary incontinence, catatonic stupor, and catatonic combativeness improved and the Bush-Francis Catatonia Rating Scale (BFCRS) score decreased from 32 to 19. However, immobility, staring, catalepsy, grimace, automatic obedience, mitgehen, ambitendency, withdrawal, waxy flexibility, rigidity, verbigeration persisted. In addition to lorazepam treatment, it was decided to start ECT twice a week. During the ECT sessions, 150 mg of propofol was used as a general anesthetic agent, 50 mcg rocuronium as a muscle relaxant, and 200 mg of sugammadex and 0.2 mg of flumazenil were used. The patient had a fever of 38.6°C six hours after the seventh ECT session. In order to investigate the etiology of fever, CBC, KFT, LFT, serum electrolyte levels, ECG, posterior-anterior chest X-ray, complete urinalysis, urine-blood and stool cultures, sedimentation rate, C-reactive protein (CRP), procalcitonin, serum total creatinine-kinase (total CK) tests were performed. Except for borderline elevation of CK (185 U/L, reference value: <171 U/L) and mild leukocytosis (13,800 /mcL; reference value: 4,300-10,300 /mcL), no abnormal laboratory findings were detected. The Covid-19 PCR test was negative. It was observed that the patient’s fever returned to the normal limits within two hours after 500 mg oral paracetamol was administered, and the leukocyte count and total-CK values also returned within twelve hours after the fever response. The department of infectious diseases was consulted and it was stated that the fever was not due to an infection as a result of the examination, the laboratory tests and the fact that the fever subsided easily with paracetamol within two hours and did not reappear in the following days. The patient’s fever response was not accompanied by autonomic instability, altered consciousness, rigidity, or any other clinical symptoms.

During the follow-up, the patient’s BFCRS score decreased to 10. Signs of waxy flexibility, catalepsy, staring, automatic obedience, and ambitendency persisted. Lorazepam 10 mg/d and two sessions of ECT per week were continued. Although there was no change in the symptoms of catatonia in the follow-up of the patient, it was observed that he was more talkative and communication with the environment being better. 150 mg of paliperidone palmitate monthly injections was added to the treatment of the patient who had persecutory thoughts and auditory hallucinations.

The patient, whose ECT was continued, had fever responses in the range of 38.4-39.1°C in three different sessions, approximately six hours after the completion of the procedure. In order to investigate the etiology of fever, CBC, KFT, LFT, serum electrolyte levels, ECG, posterior-anterior chest X-ray, complete urinalysis, urine, blood and stool cultures, sedimentation rate, C-reactive protein (CRP), procalcitonin, and total creatinine kinase (total CK) level tests were performed at the time of fever. No abnormal findings were detected except neutrophilia, leukocytosis and mild total CK elevation. Mild leukocytosis and total CK elevation spontaneously regressed to normal limits within twelve hours in the follow-up. The patient’s fever decreased within approximately two hours after 500 mg oral paracetamol was administered. On days when ECT was not applied, the patient never had a fever, his vital values were normal, and no leukocytosis or neutrophilia was observed.

After the 21st ECT session, the patient had disorientation and confusion, fever response was not observed in this session, and the patient’s confusion completely resolved after 72 hours. ECT was discontinued because the patient’s catatonic symptoms didn’t improve and BFCRS score did not decrease after the twelfth session. The patient’s treatment was arranged as lorazepam 10 mg/d, paliperidone 150 mg monthly long-acting injection and biperiden 2 mg/d. Clinical and laboratory findings accompanying ECT sessions in which fever response is observed are shown in Table-1.

Table 1.

A Table Showing the Pattern of Fever Response and Other Clinical and Laboratory Findings Accompanying ECT Sessions in Which Fever Response is Observed

ECT Sessions	Application Dates	Fever (max, C)	Total-CK (U/L)	Rigidity Sign	Leukocyte (/mcL)	Control Leukocyte Value Within 24 Hours (/mcL)	Confusion	Autonomous instability	Time to Onset of Fever After ECT (hours)	Duration of Fever Response (hours)	Paliperidone Long-acting Injection Application Dates
7. ECT	16 November 2020	38.6	185	-	13800	6900	-	-	6	2	20 November 2020 (first initiation)
13. ECT	25 December 2020	38.4	225	-	12400	6200	-	-	6.5	1.5	27 December 2020 (first maintenance)
20. ECT	22 January 2021	38.4	200	-	12200	6000	+	-	6	1.5	24 January 2021 (second maintenance)
21. ECT	25 January 2021	39.1	168	Cogwheel	11300	9700	+	-	6.5	2

Not-1: Hacettepe University Hospital Laboratory reference range for Total-CK:<171 U/L. Not-2: Hacettepe University Hospital Laboratory reference range for leukocyte values: 4300-10300/mcL. Not-3: 150 mg of propofol, 50 mcg of rocuronium, 200 mg of sugammadex and 0.2 mg of flumazenil were administered during all sessions, including ECT sessions in which there was no fever response.

DISCUSSION

Infection, malignant catatonia, malignant hyperthermia, neuroleptic malignant syndrome (NMS) could be considered in the differential diagnosis of fever observed after ECT sessions of this patient who was being followed-up for the diagnosis of catatonic schizophrenia and received antipsychotic treatment.

Possibility of infection was excluded by the Department of Infectious Diseases because the patient’s fever response lasted only two hours, there was no growth in cultures, and there were no other accompanying physical examination findings.

Neuroleptic malignant syndrome (NMS), known as an idiosyncratic drug reaction, with four cardinal symptoms such as fever, autonomic instability, altered consciousness, and lead pipe rigidity, should be considered in the differential diagnosis of the patient (Velamoor 2017). Some authors also classify NMS as a severe subtype of catatonia (Mathews and Aderibigbe 1999). It was reported that blood-brain barrier (BBB) permeability increases temporarily after ECT (Bolwig et al. 1977, Zimmermann et al. 2012) and increased penetration of psychotropics into the brain tissue with increased permeability may lead to NMS symptoms (Zimmermann et al. 2012). In this case, the patient was not taking antipsychotic medication during the ECT session, in which the fever response first occurred. Also, considering the time of long-acting antipsychotic injection, no fever response was observed in ECT sessions with the highest levels of paliperidone in the plasma. The occurrence of fever response in ECT sessions when paliperidone is in the lowest levels in the plasma weakens this possibility.

It was stated that the disruption of the integrity of BBB with ECT might lead to a mild cerebral edema, and that some molecules leaching into the brain due to loss of integrity might interrupt the normal functioning of neurons for a short time (Andrade and Bolwig 2014). This mechanism is suggested to cause the associated cognitive adverse effects of ECT, though it has not been verified for certain. (Andrade and Bolwig 2014).

Another disorder that should be excluded in the differential diagnosis is malignant (lethal) catatonia which is a syndrome that progresses with clinical and biochemical changes similar to NMS, occurs on the basis of a neuropsychiatric disorder or a general medical condition, and can result in coma and then death when left untreated. In addition to behavioral disorders and psychotic symptoms, dehydration, blood pressure changes, hyperthermia, rigidity, marked increase in muscle enzymes, leukocytosis, electrolyte imbalances can be seen in malignant catatonia (Oldham et al. 2015, Özkul et al. 2010). The patient’s fever regressed within two hours after paracetamol, CK values increased slightly (176-200 U/L), and CK elevation and leukocyte elevation resolved spontaneously within 24 hours. Beside all these, there is a time-wise relationship between this finding to ECT. The fact that ECT is effective in the treatment of NMS rather than being a factor that will trigger NMS reduces the possibility of the patient having NMS or malignant catatonia.

Neuroleptic malignant syndrome should also be excluded because of the presence of confusion and disorientation after the last ECT despite the absence of fever. The absence of fever, rigidity, and abnormal laboratory findings strengthened the possibility of postictal confusion associated with ECT. The sign of lead pipe rigidity had never been observed in the patient since the first occurrence of catatonic symptoms, including the period before and after lorazepam treatment. Mild cogwheel rigidity was a stable finding during the antipsychotics use, and the severity did not change when fever and leukocytosis occur.

It was reported that the innate immune system members, IL-1beta, IL-6, and the proinflammatory cytokine TNF-alpha which are thought to be responsible for the fever response and increased in serum 3 hours after a single ECT session returned to their basal values within 24 hours after ECT (Fluitman et al. 2011, Guloksuz et al. 2014). It was determined that proinflammatory cytokines eotaxin-2, eotaxin-3, IL-5, IL-1beta, IL-6 decreased after repeated ECT sessions (Guloksuz et al. 2014, Rotter et al. 2013, Yrondi et al. 2018). In this case, fever response was observed after repeated ECT sessions, in contrast to previous findings showing that the inflammatory response gradually decreased.

Fever after ECT is a very rare condition and may be directly related to the seizure or anesthetic agents used in the procedure (Blossom et al. 2009, Yatabe et al. 2015). Propofol used during ECT was not reported to be associated with fever response after ECT until now, but there are some case reports presenting drug reactions related to propofol used in other surgical procedures (Blossom et al. 2009, Yatabe et al. 2015). One of the case reports which suggests fever response after propofol use declares continuous use of it for sedation after the surgical procedure (Yatabe et al. 2015). In another one, fever response has been stated to be present in 74 patients due to propofol used once for sedation (Blossom et al. 2009). The proposed mechanism for the propofol-induced fever response is that propofol is open to environmental microbiological contamination due to its lipid-based content (Blossom et al. 2009, Yatabe et al. 2015). In this case, propofol was administered as a single dose before the procedure, and fever response did not occur in other patients who were administered the same trademarked propofol on the same days.

Drugs used in anesthesia during ECT may cause a malignant hyperthermia reaction (Bation et al. 2012, Lau et al. 2015). Symptoms of malignant hyperthermia are tachycardia, tachypnea, muscle rigidity, rhabdomyolysis, myoglobinuria, arrhythmia, and it may be fatal (Larach et al. 2010). In this presented case, propofol was used for anesthesia induction, rocuronium was used for myorelaxant in all ECT sessions, inhaler drugs or depolarizing myorelaxants that could trigger malignant hyperthermia were not used.

In five cases, it has been reported that the transient fever response after ECT is associated with electrical stimulation (Antosik-Wojcinska et al. 2014, Bation et al. 2012, Bryson et al. 2012, Lau et al. 2015, Majeske et al. 2013). One of the hypotheses put forward to understand the underlying mechanism is that electrical stimulation in the preoptic area, the heat regulation center in the hypothalamus, triggers the transient fever response (Bation et al. 2012). In the literature, it was suggested that the thermoregulatory center of the hypothalamus might be affected in the ictal period after electrical stimulation (Mraovitch and Calando 1999), and febrile reactions might occur after spontaneous seizures (Rossetti et al. 2007). In some studies, it was argued that the production of pyrogens which stimulated the natural immune system might increase (Lau et al. 2015, Turrin and Rivest 2004). It has been stated that ECT might cause neurochemical changes in the thermoregulation center and these changes might trigger the fever response after ECT. However, the underlying mechanism is not yet clearly known. (Lau ve ark. 2015).

We believe that post-ictal benign fever response was the main factor in the etiology of fever in this patient, since possible causes of fever response after ECT could be excluded in this particular case. In this case, unlike the previous ones, fever response occurred at a later period, not after the first ECT session, and was observed intermittently while ECT sessions were in progress. In addition, fever responses could be reduced more rapidly by paracetamol administration than other cases. However, it is not clear why fever occurs after some ECT sessions. It was reported that, side effects of ECT such as anterograde amnesia, headache and fever might occur with cumulative effects of ECT after later sessions and might be observed intermittently (Jo et al. 2021).

In this case report, possible mechanisms of transient fever response, which is a rare side effect that may occur within the first hours after ECT, and possible differential diagnoses are discussed. Since pathologies that may lead to fever after ECT may increase morbidity and mortality, differential diagnosis of post-ictal benign fever response should be made cautiously. Further studies are needed to understand the neurobiological mechanisms of this rare side effect.