Neuroleptic Malignant Syndrome/Malignant Catatonia in Child Psychiatry: Literature Review and a Case Series

Abstract

Objective:

To describe the presentation of neuroleptic malignant syndrome (NMS) and malignant catatonia (MC) in children and adolescents.

Background:

NMS and MC are life-threatening, neuropsychiatric syndromes, associated with considerable morbidity and mortality. NMS is diagnosed when there is a recent history of treatment with an antipsychotic (AP) medication, while MC is diagnosed when the symptoms resemble NMS but without a history of exposure to an AP agent. Some authorities believe that apart from the history of exposure to an AP medication, the two conditions are identical. The symptoms of NMS/MC include severe agitation, behavior disregulation, motor and speech changes, self-injury and aggression, autonomic instability, and a range of psychiatric symptoms (affective, anxiety, or psychotic symptoms). Patients may be misdiagnosed with another disorder leading to extensive tests and a delay in treatment. Untreated, the condition may be fatal in 10%–20% of patients, with death sometimes occurring within days of disease onset.

Method:

We describe the presentation and management of five children and adolescents with NMS/MC.

Conclusion:

MC and NMS are life-threatening medical emergencies, which if diagnosed promptly, can be successfully treated with known effective treatments (benzodiazepines and/or electroconvulsive therapy).

Introduction

Catatonia is an under recognized disorder characterized by motor abnormalities and behavior disregulation. The condition has been reported in men and women of all ages (Fink and Taylor 2003). Although it is better recognized in association with mood disorders and schizophrenia, it can also occur in persons with developmental disorders, such as autism (Wing and Shah 2000, 2006), Downs syndrome (Jap and Ghaziuddin 2011; Ghaziuddin et al. 2015), learning disability (Wing and Shah 2006), or intellectual disability (ID) (Ghaziuddin et al. 2012).

Additionally, it has been reported following exposure to antipsychotic (AP) (Menard et al. 2014) or other medications (Maccari et al. 1996; Hadad et al. 2003; Duggal and Singh 2005; Huang et al. 2007) and illicit drug use (Khan et al. 2016). General medical disorders associated with catatonia include autoimmune disorders, endocrine disorders (Dahale et al. 2014), B12 deficiency (Bram et al. 2015), idiopathic encephalitis (Ali et al. 2008), anti-N-methyl D-aspartate receptor (NMDAR) encephalitis (Kanbayashi et al. 2014) and infections such as AIDS, Borrelia, and hepatic amoebiasis (Suner-Churlaud et al. 1992; Pfister et al. 1993; Prakash and Bagepally 2012). Irrespective of the underlying medical or psychiatric pathology, the condition responds to benzodiazepines and electroconvulsive therapy (ECT) (Fink and Taylor 2003).

The motor symptoms of catatonia, which are central for making the diagnosis, include over or underactivity (both may coexist); unusual movements such as freezing, staring, posturing, grimacing, and stereotypies (purposeless or semi-purposeful movements that are markedly repetitive), mitgehen, (an exaggerated response to touch); waxy flexibility (described as the feel of a soft candle); and ambitendency (the inability to complete a motor act using a smooth and a continuous movement). In addition to the motor symptoms, other common symptoms include speech disturbance such as reduced speech or mutism, verbal stereotypies (a senseless repetition of sounds or words), perseveration (senseless repetition of a phrase), and verbigeration (incomprehensive speech). Decline in overall function is frequently noted and is usually accompanied by a senseless refusal to follow directions (negativism). The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) (American Psychiatric Association 2013) lists 12 symptoms of catatonia, which may occur in different combinations. Associated psychiatric symptoms such as anxiety, disturbance of mood, obsessions, or increase in rigid ideas or psychosis are invariably present.

In neuroleptic malignant syndrome (NMS) or malignant catatonia (MC) the symptoms of catatonia are accompanied by autonomic and thermoregulatory dysfunction. The onset may be sudden. There may be an exacerbation of preceding catatonic symptoms accompanied by autonomic and thermoregulatory dysfunction such as rapid changes in blood pressure and heart rate; symptoms of a hypermetabolic state including increased temperature and respiratory rate; and abnormal laboratory findings such as increased levels of creatinine phosphokinase enzyme (CPK), liver enzymes, and white blood cell count.

Although MC and NMS are often regarded as overlapping, even synonymous conditions, the latter term is often used when there is a documented exposure to an AP agent. Indeed, both MC and NMS have similar symptoms, laboratory abnormalities, and response to anticatatonic treatments (Fink 1996; Koch et al. 2000; Taylor and Fink 2003; Fink and Taylor 2006; Caroff et al. 2007). There are several other closely resembling diagnoses (namely, lethal catatonia described by Stauder in 1934 and delirious mania) that closely resemble NMS and MC (Fink 1999; Wachtel et al. 2015). In all four conditions (NMS, MC, lethal catatonia, and delirious mania), patients appear to have an acute infectious process resulting in exhaustive evaluations for infectious or other general medical etiologies. Untreated MC is fatal in 10%–20% of cases, with death sometimes ensuing within mere days of disease onset (Caroff 1980; Taylor and Fink 2003). Common causes of death usually include respiratory failure, cardiovascular collapse, renal failure, arrhythmias, and thromboembolism (Smego and Jurack 1982; Weinber and Twersky 1983).

Children and adolescents with NMS/MC may present in a variety of treatment settings including the emergency department, consultation liaison service, Pediatric Intensive Care Unit (PICU), or child psychiatric services. Despite its increased awareness, the literature is limited to case reports and case series, especially in persons with intellectual and developmental disabilities (Woodbury and Woodbury 1992; Ghaziuddin et al. 2002; Lee et al. 2006; Dhossche et al. 2009; Wachtel et al. 2010; Consoli et al. 2011). Here, we describe five adolescents, four among who were diagnosed with developmental delays, who had presented with MC. See Table 1 for demographics and Table 2 for signs and symptoms of NMS/MC.

Table 1.

Demographic Features of Five Cases with Neuroleptic Malignant Syndrome/Malignant Catatonia

Age	Gender	Duration of acute symptoms in weeks	Main presenting symptom	ASD	Intellectual disability	Treatment setting	Exposure/response to antipsychotics
17	F	4	Severe aggression	Yes	Yes	Psychiatry ward	Yes/no
12	M	2	Aggression	Yes	Yes	Intensive care pediatric	Yes/no
			Restlessness
			SIB
15	M	<1	Hyperactivity	No	No	Psychiatry ward	Yes/no
			Later–posturing, echopraxia
15	M	2	Rigidity	No	Yes	Psychiatry ward	Yes/no
			Mutism			Medical unit
			Posturing
15	F	Several months	Aggression	Yes	Yes	Psychiatry ward	Yes/no

ASD, autism spectrum disorder; SIB, self injurious behavior.

Table 2.

Signs and Symptoms in Five Adolescents Diagnosed Neuroleptic Malignant Syndrome/Malignant Catatonia

								Culture studies: CSF
Case	Blood pressure	Heart rate	Fever	White blood count	AST (IU/L)	ALT (IU/L)	TSH (mIU/L)	Blood	CPK ^a (IU/L)	EEG	Brain MRI
1	Elevated	Elevated	Yes	Elevated	195^b	172^b	1.85	Negative	17,787^b	Normal	Normal
								Negative
2	Elevated	Elevated	No	Normal	76^b	48^b	1.63	Not performed	5993^b	Right temporal spikes	Normal
3	Normal	Normal	Yes	Elevated	55^b	32	2.18	NA	4947^b	Not performed	Normal
								Negative
4	Normal	Elevated (mild)	No	Normal	36	18	1.76	NA	6228^b	Normal	Normal
								Negative
5	Elevated	Elevated (99/mt)	No	NA	39	23	2.79		1800^b	Normal	MRI worrisome for vascular malformation, CT showed no evidence of AVM

Highest recorded CPK.

Abnormal laboratory value.

ALT, alanine transaminase; AST, aspartate transaminase; AVM, atrio ventricular malformation; CPK, creatinine phosphokinase enzyme; EEG, electroencephalogram; MRI, magnetic resonance imaging; NA, not available.

Each case received a comprehensive physical examination including the Bush Francis Catatonia Rating Scale (BFCRS) (Bush et al. 1996), and a laboratory workup including complete blood count, comprehensive metabolic panel, urinalysis, urine culture, urine toxicology, thyroid functions, chest X-ray, electrocardiogram, magnetic resonance imaging, CPK (normal range = 38–248 IU/L), and liver function tests. Additional tests included pancreatic enzymes in case 1; hepatitis antibodies, testing for HIV, respiratory culture, and coagulation studies in case 2; blood culture and anti-streptolysin-O (ASO) titer (antibiotics were administered due to a rising titer) in case 3; and regular checks of blood glucose, rapid plasma reagin test, erythrocyte sedimentation test, c-reactive protein, glutamic acid decarboxylase antibodies, and urine porphobilonogen in case 4.

All cases received ECT using bilateral electrode placement, based on the recommendations of the American Academy of Child and Adolescent Psychiatry Practice Parameters for the use of ECT in minors. The recommendations of the Practice Parameters include, among others, consensus among three child and adolescent psychiatrists (the number of psychiatrists vary by state guidelines), parental informed consent (assent of a minor patient is recommended, whenever possible), consultation with anesthesiology, and a comprehensive medical and a psychiatric workup (Ghaziuddin et al. 2004). Devices used for administering ECT were either the Thymatron^® (Somatics, LLC, Lake Bluff, IL) or the MECTA (MECTA Corporation, Tualatin, OR).

Medications administered during the induction of anesthesia for ECT included methohexital (a sedative; recommended dose = 1 mg/kg), succinylcholine (a muscle relaxant; recommended dose = 0.9 mg/kg), glycopyrrolate (anticholinergic and a cardio-protective agent; usual dose = 0.2 mg), and flumazenil (central benzodiazepine antagonist; usual dose = 0.5 mg). The initial electrical charge used among the five cases ranged from 48 to 288 mC. A considerable between-patient variability has been noted in medication dosages (Bryson et al. 2012). Similarly, the total electrical charge is known to vary due to several physiological factors, such as gender and age (Salvador et al. 2016), and due to the development of tolerance. The seizure threshold is known to increase during a treatment course; therefore, the initial charge does not predict the amount of electrical current necessary at future treatments. Seizure duration was monitored visually using the “cuff” method (an inflated blood pressure cuff isolates circulation in one lower extremity, therefore, a motor seizure can be observed) and via electroencephalogram (EEG) recording, which is a standard feature in most modern ECT device. The estimate of the seizure duration, using these two methods, is highly correlated, with the cuff-estimate 10% shorter than the EEG recording (Fink and Johnson 1982). The aim of ECT is to induce an approximate 30 second long seizure, which is generally considered adequate, although, other factors such as stimulus intensity and seizure threshold are also important for eliciting a therapeutic response (Sackeim et al. 1987).

Institutional IRB approval was obtained to publish these data extracted from standard clinical care.

Case Presentations

Case 1

Case 1 is a 17-year-old Caucasian female with autism spectrum disorder (ASD) and ID. She presented with a month-long history of unexplained, episodic aggression, agitation, incessant pacing, and a progressive decline in the ability to do activities of daily living. Symptoms in the week preceding admission had included insomnia, constipation, tachycardia, restlessness and profuse diaphoresis. Medications on admission were risperidone (for the past 4.5 years), lamotrigine, diazepam, citalopram, and metoprolol and several PRN (as needed) doses of haloperidol and ziprasidone. Initially, she was uncooperative, disoriented to person, slow in her movements, and almost mute (retaining only ability to say “no”). Although afebrile, her pulse varied between 140 and 160 beats/min, the highest recorded systolic blood pressure was 170 mm Hg, while the diastolic BP remained in range 70–80 mm Hg. She became progressively restless, mute, and diaphoretic. Laboratory evaluations were remarkable for elevated CPK of 6402 IU/L, with a later reading of 17,787 IU, elevated liver enzymes (alanine transaminase [ALT] = 141 IU/L and aspartate transaminase [AST] = 127 IU/L), positive urine ketones, and blood chemistry consistent with metabolic alkalosis. Based on these symptoms and the absence of a medical etiology, she was diagnosed with NMS/MC and AP medications were discontinued.

Due to continued deterioration, she was transferred to the PICU for intravenous hydration and airway protection. Autonomic system instability improved with lorazepam and hydration; however, there was no significant change in agitation. Bilateral ECT was started due to an inadequate response to benzodiazepines. She received daily ECT for 6 days while in the PICU, followed by a decreasing frequency (based on clinical response and severity of symptoms) by the end of the following 16 weeks, patient appeared to have reached her baseline level of functioning. Her agitation and rigidity decreased, followed by a gradual increase in food intake. Maintenance ECT was continued after discharge for 1 year, administered with decreasing frequency determined by her symptoms. She received a total of 75 ECTs and has remained off ECT without relapse for ∼6 years at the time of this report. Current medications are lorazepam 5 mg/day and oxcarbazepine 600 mg (both administered in divided doses) and trazodone 225 mg at bedtime. She continues to live in her own home with close supervision and support.

Case 2

Case 2 is a 12-year-old African American male with a diagnosis of ASD and ID who presented with a 3-month history of worsening agitation, self injury and aggression, stereotypic behaviors, and sleep disturbance. A progressive decline in his level of functioning in the 2 weeks leading to the admission included decreased oral intake, extreme restlessness, facial grimacing, posturing, tachycardia, hypertension, and rising CPK. Case 2 did not have a history of prior psychiatric admissions but had been evaluated for progressively worsening aggression at multiple locations. Mother reported increasing difficulty taking care of him due to episodes of unprovoked aggression. He had failed to respond to AP agents (risperidone, quetiapine, ziprasidone, and olanzapine) and stimulants. A benzodiazepine trial with lorazepam (duration = 10 days; highest dose = 3 mg/day) was discontinued due to a skin rash and another trial with clonazepam was discontinued due to deterioration after a day.

On examination in the psychiatric Emergency Department, he was restless, easily agitated, and displayed stereotyped behaviors including new-onset repetitive spitting. He was afebrile, but was tachycardic and hypertensive. His pulse rate varied between 92 and 140 beats/min with a systolic blood pressure of about 160 mm Hg. Laboratory tests revealed an elevated CPK (highest recorded level = 5933 IU/L). AP agents were discontinued due to suspected NMS/MC and the patient was admitted to PICU for intravenous hydration and lorazepam infusion. Because of his worsening agitation and safety concerns, he was chemically restrained with dexmedetomidine, ketamine, and lorazepam and was intubated for airway protection. ECT was started on day 2 of admission to PICU, with daily treatments for 4 days, and then continued at decreasing frequency over a period of 24 weeks. He was maintained on regular ECT, about once a week, for a period of 3 years after his initial presentation at our hospital.

Two previous attempts to reduce the treatment frequency of ECT to less than once per week had resulted in the return of his symptoms. However, at the time of writing this report, ECT has been temporarily discontinued while managing him on a combination medication regimen (lorazepam 32 mg/day, administered 6 hourly), lamotrigine (200 mg/day), clonidine (0.6 mg/day), and memantine 15 mg/day. His most recent EEG report is significant for right temporal spikes but no clear clinical correlates for a seizure disorder. He resides with his mother and siblings and attends a special education program. The current treatment plan is to identify whether case 2 can be managed on pharmacotherapy and behavior therapy, without having to reintroduce ECT.

Case 3

Case 3 is a 14-year-old African American male who presented with a 4-day history of bizarre behavior, pressured speech, and distractibility. He had a psychiatric admission 1 year previously when he was diagnosed with schizophreniform disorder and treated with risperidone. On the day before his admission, he had walked barefoot for an estimated 5 miles. On examination, at the Emergency Department, he was confused, grandiose, and hyperactive. His vital signs were stable; however, laboratory tests were remarkable for elevated CPK of 3674 IU/L and a slight increase in AST (63 IU/L). Because of concern for NMS, risperidone was held. He was treated with lorazepam and valproic acid. CPK trended down over the following 5 days to 493 IU/L. Because of persistent psychosis, it was decided to start olanzapine, in view of its lower EPS side effect profile. After 2 days of treatment with olanzapine, CPK increased to 984 IU/L. Vital signs remained normal and there were no motoric signs of catatonia. Olanzapine was discontinued and CPK started to trend down over the following 3 days to 610 IU/L. His symptoms continued to worsen despite receiving valproic acid (serum level = 85.2 μg/mL). He continued to be grandiose and labile in his mood, had a pressured speech, was hyperactive, paranoid ideation persisted, and had a decreased need for sleep. Although, he had deteriorated in response to two prior trials of AP agents, a cautious third retrial with chlorpromazine was attempted. However, he did not tolerate this agent and along with clinical worsening (increased psychomotor agitation, staring, posturing, and mutism), his CPK again increased to 1066 IU/L. Vital signs remained normal with the exception of an isolated incident of elevated heart rate of 133/min. Lithium was started (stabilized to 0.85–1.32 mmol/L) in addition to valproic acid and lorazepam (titrated to 12–16 mg/day).

One week later, he developed fever (Tmax 38.9 C), elevated heart rate (120/min), periodic elevations in systolic blood pressure (up to 156 mm Hg), elevated white blood cell count (17.3 K/uL, 60% PMN, 0.2% bands), chills, arm rash, and occasional emesis. Case 3 was treated with amoxicillin for a strep infection (ASO titer = 1240 IU/mL). The following week, he continued to demonstrate increased motor activity, restlessness, sleeplessness, psychosis, and aggression. His BFCRS score was 35, and positive for agitation, combativeness, verbigeration, echolalia, and stereotypies.

Because of worsening clinical picture in response to three different APs and mood stabilizers, bilateral ECT was initiated at three times per week; of note, ECT was started only on day 41 of his hospitalization. CPK increased to 5019 IU/L following the second ECT, but started to trend downward as the treatment progressed. He completed the first 12 treatments of ECT index course while hospitalized. By the end of his 2-month hospital stay, he no longer exhibited paranoia, mood lability, thought disorganization, visual hallucinations, or insomnia. His CPK normalized and his mental status examination was remarkable for only mild inattention and minimal ideas of reference. He was discharged on valproic acid, lorazepam, and a plan to taper down outpatient ECT to twice weekly. Three days following discharge, his mother reported that the patient was “back to himself” and had “pretty much reached his baseline behavior.”

Signs and symptoms of NMS/MC in this case were multiple motor symptoms, an acute onset illness with an abrupt change in mental status, tachycardia, and an elevated CPK. The label of delirious mania was not felt to be appropriate because unlike a manic state during a bipolar illness, there was no response, or possible worsening, when AP agents or mood stabilizers were introduced. He was stable on discharge but was lost to follow-up, as his mother did not think that additional treatment was necessary.

Case 4

Case 4 is a 17-year-old male with a history of cognitive impairment and insulin-dependent diabetes mellitus who developed paranoia, visual hallucinations, and bizarre behavior 2 months before admission. After failing to respond to trials of risperidone, quetiapine, and aripiprazole, he was admitted to the psychiatric inpatient unit where he received several PRN doses of olanzapine and chlorpromazine. However, he continued to deteriorate. At interview, he presented with drooling, staring, posturing, muteness, occasional grimacing, markedly reduced oral intake, and reduced urine output. On examination, he showed waxy flexibility, rigidity in the upper extremities, staring, negativism, mitgehen, gagenhalten, and his grasp reflex was positive. Although his blood pressure was normal, his pulse was 118/min and his CPK (6228 IU/L) and liver enzymes (AST 221 IU/L and ALT 84 IU/L) were elevated. He was diagnosed with NMS/MC based on above findings. All APs were stopped and lorazepam was started. He was transferred to the medical unit for intravenous hydration. With lorazepam titrated to 4 mg QID, his CPK started trending downward, but he continued to display symptoms of catatonia including psychomotor retardation interspersed with brief episodes of excitement, agitation, and aggressive behavior. His BFCRS score was 33. Due to inadequate response to lorazepam alone, bilateral ECT was started on day 12 of his admission. After receiving eight treatments, his mother described him as “80% better,” and after 12 treatments, he was reported to have reached his baseline level of functioning. At the time of discharge, after 5 weeks of being hospitalized, his BFCRS score improved to 7 and his CPK had reduced to 286 IU/L. He was discharged home on lorazepam 3 mg TID with a plan to continue outpatient ECT and taper down the dose of lorazepam. However, the patient did not return for follow-up and mother communicated by phone that she did not believe that additional ECT or follow-up was necessary.

Case 5

Case 5 is a 15-year-old African American female previously diagnosed with ASD, ID, impulse control disorder not otherwise specified (NOS), mood disorder NOS, and a possible seizure disorder (although, seizures were noted only after an abrupt withdrawal of phenytoin). She was admitted due to worsening agitation and aggression accompanied by a general decline in functioning, frequent crying spells, and episodes of intense excitement and agitation, which required physical restraints and intramuscular medications (ziprasidone, chlorpromazine, and lorazepam).

Her past psychiatric history revealed eight psychiatric hospitalizations and exposure to multiple AP agents (namely, olanzapine, ziprasidone, chlorpromazine, quetiapine, aripiprazole, haloperidol, and clozapine) and two different SSRI medications.

On admission, she was continued on her home medications, including lithium, benztropine, lorazepam, guanfacine, and chlorpromazine. Her vital signs were within normal limits. Laboratory workup was unremarkable including a normal EEG (a repeat EEG was also normal at the time of writing this report). Her BFCRS was 10, positive for sitting abnormally still, speaking less than 20 words/5 min, staring, posturing and grimacing, occasional mannerisms, impulsivity, and combativeness. Other signs also noted, included increasing echolalia, staring, and grimacing. On day 4 of hospitalization, she began to exhibit stereotypies (e.g., changing clothes repeatedly, eye blinking, rotation of her trunk) and her CPK was found to be 651 IU/L. Lorazepam was titrated up to 25 mg/day; however, the response was poor. At this point, the patient was referred for ECT, and after a complete pre-ECT workup, based on the recommendations of the AACAP Practice Parameters for ECT in children and adolescents (Ghaziuddin et al. 2004), bilateral ECT was started on day 7 of her admission. Slight improvement was noted after the second ECT, after which, the frequency of ECT was increased to daily for the next four treatments. Subsequently, the patient's speech improved; she began to communicate more clearly, became less agitated, aggression was reduced, and her affect improved. However, she continued to display echolalia, stereotypies, and automatic obedience. After her 11th ECT treatment, staff and family agreed that her agitation and aggression had decreased substantially. There were no further episodes of agitation or aggression after her 13th ECT treatment. Her CPK level also trended downward to 62 IU/L. After receiving 15 ECTs, she was discharged home on the 36th day of admission, on a combination of lorazepam (12 mg/day) and chlorpromazine (chlorpromazine was discontinued soon after discharge, which resulted in additional improvement), and lithium (1.10 IU/L). She was followed for 4 years in the outpatient clinic while receiving 1–2 weekly bilateral ECT, depending on symptom severity.

During the first 3 years after discharge, case 5 remained relatively free of aggression, agitation, or stereotypies and was able to live at home and attended a special education school. Several medications were tried (valproate, topiramate, lamotrigine, phenobarbital, phenytoin sodium, lithium, and clozapine) over this period; however, none resulted in any further improvement or allowed us to extend the time between maintenance ECT intervals beyond 5–7 days.

After remaining stable for 3 years, because of parent's request for an ECT-free period, ECT was discontinued over a 4-week period. This was followed by a recurrence of symptoms and two further hospitalizations at outside hospitals, where a diagnosis of delirious mania was considered. Symptoms during each hospitalization included severe aggression and agitation, mood swings, lack of sleep over several nights, stereotyped eye, mouth-chewing and trunk movements, posturing, increased muscle rigidity, and mutism. Outside records showed that the patient was repeatedly restrained due to violent and uncontrollable agitation (reportedly, required nine staff members to restrain her during one such episode) and had sustained broken ribs and a collapsed lung during these episodes. The highest recorded CPK during these outside hospitalizations was 1800 IU/L. Because of the history, clinical examination and lack of response to mood stabilizers or AP agents, we concluded that case 5 had experienced a second episode of NMS/MC possibly due to the reduction in frequency of ECT. At the time of writing this report, the patient receives weekly ECT at an outside hospital close to the family home.

Discussion

The diagnosis of NMS/MC in each of these cases was based on the criteria for NMS suggested by Gurrera et al. (2011). These criteria assign the highest weighted score of 20 to a positive history of exposure to a dopamine agonist or antagonist. Additional symptoms include hyperthermia, rigidity, mental status alteration, creatinine phosphokinase elevation, sympathetic nervous system lability, diaphoresis, urinary incontinence, hypermetabolic state (increased heart rate and respiration rate), and a negative workup for other causes (infective, toxic, metabolic, or neurologic). A necessary threshold for each sign is specified such as a fourfold increase in CPK level and a 25% increase in blood pressure. However, the authors do not specify whether a certain number of symptoms are necessary for making the diagnosis and also acknowledge “until sufficiently validated by future studies, these criteria can be considered only an aid to clinical diagnosis and should not be used as the sole bases for excluding a diagnosis of NMS.”

All five cases had a history suggestive of catatonia before they developed a full syndrome of NMS/MC. There is no consensus in the literature whether NMS/MC is always preceded by catatonia due to the acute nature of presentation and absence of adequate history. Because the cases described in this report had presented in a state of acute decompensation, we could only rely on the history obtained from caregivers, which suggested that there were, indeed, symptoms of catatonia preceding NMS/MC.

It is important to note that three of the five cases described in this report had received a baseline diagnosis of ASD or ID, which have a known association with catatonia. For instance, a 12%–17% rate of catatonia is reported in ASD (Wing and Shah 2006) and similar rates have been identified in a clinical sample with ID (Ghaziuddin et al. 2012).

All the five cases had a history of treatment with AP agents. In each instance, a marked worsening was noted after the administration of these agents, which are often prescribed for the treatment of irritability in persons with ID/autism (Owen et al. 2009; Shea et al. 2004). The present report highlights the risk of catatonia and underscores the need for caution while prescribing AP agents in this population.

Regarding the differentiation from delirious mania, in cases 3 and 5, in whom the diagnosis was considered, both did not respond to standard antimanic treatments (APs and/or mood stabilizers) but responded to known anticatatonic treatments (benzodiazepine and/or ECT) (Fink 1999; Karmacharya et al. 2008). Although, systematic data are lacking, it has been suggested NMS, MC, and delirious mania are all associated with marked worsening when treated with AP agents (Wachtel et al. 2015).

In terms of long-term outcome, case 5 continues to receive ECT and is currently in year 5 of her treatment. Case 2 had been stable over 3 years while receiving approximately weekly ECT, however, a closely monitored trial without ECT is currently underway to determine whether he could be stabilized with pharmacotherapy and behavior therapy alone. It is noteworthy that case 5 experienced a second episode of NMS/MC when she missed her ECT during a 4-week period, highlighting the importance of not stopping the treatment prematurely. Case 1 continues to do well without ECT, which was discontinued 6 years earlier (index course followed by maintenance ECT over 1 year) while cases 3 and 4 were lost to follow-up after a remarkably positive response immediately following an index course of ECT. Outcomes noted in these cases suggest a wide variability, from no need for prolonged M-ECT in cases 1, 3, and 4, to ongoing need for ECT in case 5 while the need for ongoing ECT for case 2 still pending.

In each case, lorazepam was administered as the preferred drug due to its known rapid response, ease of administration, and a wide margin of safety for cardiovascular and respiratory systems (Daniels 2009; Fink and Taylor 2006). Some case reports, usually involving one or two cases, have described that bromcriptine or dantrolene may be beneficial in these conditions (Granato et al. 1983); however, we decided against using these agents because of the possibility of a more prolonged illness and a greater number of sequelae noted in patients treated with these agents (Rosebush et al. 1991). We should note that none of the cases were tested for anti-NMDAR antibodies. With the exception of case 3, for who a single ASO titer was drawn, cases were also not tested for Pediatric Autoimmune Neuropsychiatric Disorder associated with streptococcal infections (PANDAS). It has been reported that anti-NMDAR encephalitis may present with symptoms that closely resemble NMS/MC, which may also respond to anticatatonic treatments (Dhossche et al. 2011) and/or immunotherapy (Armangue et al. 2012). On the other hand, PANDAS is believed to be a distinct disorder associated with streptococcal infections. The diagnosis of PANDAS is based on a temporal association with group A beta hemolytic streptococcus infection and an abrupt onset of a variety of motor symptoms such as tics and obsessive compulsive behaviors (Swedo et al. 2004). Clearly, further investigation is necessary to identify whether these are truly distinct syndromes.

Conclusion

In conclusion, NMS/MC is a serious medical emergency, which may present to a child and adolescent psychiatrist in a variety of treatment settings. The forme fruste presentation is easily mistaken for a variety of other psychiatric or medical conditions and exacerbated by the use of AP agents. Prompt recognition and treatment is life saving. Findings of this study are important in shedding light on the presentation, illness-course, treatment and follow-up of NMS/MC; however, limitations of the study such as the relatively small number of subjects, retrospective nature of the data collection, and limited information about symptoms preceding the NMS/MC diagnosis should be noted. Any patient referred to a child psychiatrist with either an abrupt change in mental status or a dramatic worsening of existing symptoms, especially in persons with developmental disorders, such as autism, should be systematically screened for NMS/MC.

Clinical Significance

NMS/MC should be included in the differential diagnosis of children and adolescents who present with an acute change in mental status and/or behavior.

Recent exposure to dopaminergic agents such as APs is generally found in this patient group.

This syndrome may be acutely responsive to lorazepam and/or ECT. Accurate diagnosis and appropriate treatment have life saving implications.

Since three of five cases reported here are African Americans, further exploration is essential to identify whether race may be a risk factor for this syndrome, when exposed to APs.

Footnotes

Disclosures

N.G. received royalties from the book, “Use of Electroconvulsive Therapy in Children.” All other authors declare no conflicts of interest.

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