Case ReportDiagnostic, Treatment, and System Challenges in theManagement of Recurrent Neuroleptic Malignant Syndrome ona General Medical Service

Karan Verma ,1,2 Vivek Jayadeva,2,3 Raymond Serrano,2 and Karthik Sivashanker1,2,4

1Department of Psychiatry, Boston University School of Medicine, Boston Medical Center, Boston, MA, USA2VA Boston Healthcare System, Boston, MA, USA3VA Boston Healthcare System, Brockton Division, Harvard South Shore Psychiatry Residency, Brockton, MA, USA4Brigham and Women’s Hospital, Boston, MA, USA

Correspondence should be addressed to Karan Verma; karan.verma@bmc.org

Received 10 March 2018; Accepted 19 April 2018; Published 11 June 2018

Academic Editor: Toshiya Inada

Copyright © 2018 Karan Verma et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Neuroleptic malignant syndrome (NMS), an iatrogenic form of malignant catatonia, carries high morbidity and mortality ratesespecially in the context of delayed recognition and standard intervention protocol of lorazepam trial. However, there is limitedguidance available through literature for further management if benzodiazepine treatment is ineffective and electroconvulsivetherapy (ECT) is not readily accessible.This case report describes a multimodal approach to address the diagnostic, treatment, andlogistical system challenges in an acutemedical hospital through the case of a 69-year-oldmanwith schizophrenia who representedfrom a psychiatric ward with neuroleptic malignant syndrome. We educated our inpatient colleagues for timely recognition ofhyperexcited subtype of catatonia to avoid iatrogenic progression to neuroleptic malignant syndrome and our medical colleagueson the clinical course of catatonic symptoms to avoid any further disagreements and delays in treatment. We advocated for timelyelectroconvulsive therapy in the setting of limited access and utilized creative pharmacologic strategies such as N-methyl-D-aspartate (NMDA) receptor antagonists and longer acting benzodiazepines while managing medical complications.

1. Introduction

Neuroleptic malignant syndrome (NMS) has been conceptu-alized as an iatrogenic form ofmalignant catatonia secondaryto antipsychotic use (see Table 1) [1]. It is characterized bya clinical tetrad of fever, lead-pipe rigidity, autonomic insta-bility, and altered mental status [1–6]. Other extrapyramidalsigns (EPS) such as cogwheeling, coarse tremors, akinesia,or dystonia may occur before autonomic symptoms. Theevolution of symptoms over one to three days may be accom-panied by elevated creatine kinase (typically more than 1000IU/L), leukocytosis (10,000 to 40,000 cells/mm3 with a leftshift), impaired liver functioning, electrolyte derangements,and renal impairment secondary to myoglobinuria [4, 5].If not recognized and managed promptly, this syndromecarries a high potential for morbidity and mortality [1, 3, 7–12]. Discontinuation of the offending agent and support-ive care remain the first-line interventions [10–14]. Due

to shared pathomechanisms of motor abnormalities withcatatonia, intravenous lorazepam is gold standard treatment.In lorazepam nonresponders or severe cases requiring rapidintervention, electroconvulsive therapy (ECT) is the definiteintervention, with a reported response rate of 85% [15]. Theliterature provides limited guidance to clinicians regardingfurther management, when standard interventions fail orare unavailable. We describe a case of neuroleptic malignantsyndrome with refractory catatonia complicated by delirium,provider disagreement regarding the diagnosis, and a delay intimely electroconvulsive therapy (ECT) that required creativesolutions to achieve clinical improvement.

2. Case Presentation

A 69-year-old Caucasian man with schizophrenia repre-sented to our emergency department (ED) from a psychiatrichospital with catatonia, notable for agitation and altered

HindawiCase Reports in PsychiatryVolume 2018, Article ID 4016087, 5 pageshttps://doi.org/10.1155/2018/4016087

2 Case Reports in Psychiatry

Table 1: Differential diagnosis.

NMS Malignant Catatonia Neuroleptic-inducedParkinsonism Delirium

Key features

Autonomic Instability,Delirium, Fever,

Rigidity; Precipitated byuse of an antipsychotic

AutonomicInstability,

Delirium, Fever, Rigidity

Postural and restingtremors, Rigidity

(Cogwheel), Oral-buccaldyskinesias(concurrent)

Waxing and waningconsciousness,

Inattention, Perceptualdeficits, Behavioraldisorganization

Notable Lab Values

Elevated serum CK,leukocytosis, electrolyteabnormalities, low serum

iron

Typically normal Typically normal Dependent on etiology

Treatment

Dantrolene,Bromocriptine,

Benzodiazepines, NMDAantagonists, ECT

Benzodiazepines,ECT, NMDA antagonists

Stopping the offendingagent; if

not, Anticholinergics,Amantadine

Typically antipsychotics;benzodiazepines for

GABAergicwithdrawal or status

epilepticus

mental status requiring physical restraints. Limited physicalexamwas revealing for increased tone and rigidity in bilaterallower extremities while the patient self-dialogued and yelledat times. Per outside records, he was observed to be persis-tently agitated, engaging in self-injurious behaviors such ashitting himself, banging his head, and refusing to eat or drinkfor a week.

Three weeks prior, he was admitted to the medicineservice with early signs of NMS that resolved over thecourse of a few days with discontinuation of neuroleptics andtreatment with parenteral lorazepam. He was subsequentlytransferred back to the outside hospital psychiatric unit forfurther stabilization and optimization of his psychotropicregimen, with a recommendation to avoid high-potencyneuroleptics. There, he was started on fluphenazine, a high-potency first generation antipsychotic, after a washout periodof one week. His religious delusions with disorganizedthought process showed minimal improvement. He wassubsequently switched to haloperidol, which was rapidlyincreased to 35 mg per day. Clonazepam 1.5 mg per day andlorazepam 1 mg per day were also utilized over this timeframe. The patient, however, became increasingly agitated,with self-injurious behavior and some posturing that wasattributed to “refractory psychosis.” This prompted furtherantipsychotic dose escalation. He had stopped eating ordrinking by this timewith associatedworsening of behavioraldysregulation. 75 mg of chlorpromazine was given the sameday after 35 mg of haloperidol showed minimal benefit.While chlorpromazine temporarily decreased his behavioraldysregulation, his agitation continued unabated the followingmorning. He was given additional chlorpromazine 25 mgwith fluid resuscitation in urgent care before his transfer toour facility for a delirium work-up.

On arrival, standard treatment was implemented, includ-ing antipsychotic discontinuation, supportive care, and initi-ation of parenteral benzodiazepines consisting of lorazepam2 mg intravenously (IV) every 8 hours. His complete bloodcount, electrolytes, vitamin B12, thyroid function, and liverfunction tests were within normal limits, except for a CKof 1090 IU/L, mildly elevated 10,680 white blood cells per

mcL, low iron level of 26 ug/dL, and creatinine value of1.26 mg/dL thought to be prerenal in nature secondary todehydration. He tested negative for syphilis on the rapidplasma reagin test. Urinalysis did not reveal an infection.Urine drug toxicology was positive for benzodiazepinesonly, which the patient had been receiving on the inpatientunit. A head CT revealed no acute intracranial pathology.An electroencephalogram performed on day 4 of admis-sion was notable only for increased beta waves, reflectingthe high-dose benzodiazepines he was receiving at thetime.

The patient’s hospital course was notable for continuedfluctuating motor symptoms with episodes of severe rigidityin both upper and lower extremities, intermittent droningvocalizations, waxy flexibility, posturing, negativism, auto-matic obedience, and presence of mitgehen. Such periodswere accompanied by diaphoresis and autonomic hyperac-tivity. On the fifth day, lorazepam was increased to 4 mgIV every 4 hours and amantadine 100 mg (by mouth) POtwice a day was started the following day. The doses wereheld past midnight due to planned ECT on the seventhday of admission. Lorazepam was resumed post-ECT butamantadine was held until after the third session. Priorto each subsequent ECT treatment, benzodiazepines wereheld to prevent increasing the patient’s seizure threshold.He received a total of three ECT sessions, each three daysapart. In between the second and the third ECT sessions, thepatient became overtly delirious secondary to a urinary tractinfection, whichwas treatedwith antibiotics. After the secondECT session, lorazepam was decreased to 2 mg IV every 6hours and then switched to a longer acting diazepam 20 mgIV every 6 hours after the third ECT session. Amantadinewasrestarted at the same dose and was increased to 100 mg POthree times a day, four days after the last ECT session. Aftera three-week washout period, Clozapine 12.5 mg PO twice aday was introduced for underlying psychotic symptoms andtitrated to 25 mg twice a day without recurrence of NMS orcatatonia.With gradual lysing of catatonia and normalizationof lab values, the patient was discharged back to the inpatientpsychiatric unit after a month-long hospitalization.

Case Reports in Psychiatry 3

3. Discussion

NMSmay be difficult to distinguish from a variety of medicaland psychiatric conditions. Medically, NMS may appear likenonconvulsive status epilepticus, severe Parkinson’s disease,locked-in syndrome, or akinetic mutism from brain injury[13]. Psychiatrically, NMS may be mistaken for extrapyrami-dal symptom, such as antipsychotic-induced Parkinsonism.NMS is associated with both first- and second-generationantipsychotic use (SGAs), though SGAs are associated withlower incidence and clinical severity [7, 16].

Most commonly, NMS can be indistinguishable frommalignant catatonia (the most severe form of catatonia),except for the precipitating factor of antipsychotic treatmentas noted in Table 1. Malignant catatonia and NMS are oftenconceptualized on the same spectrum and some have evenproposed them as “two variants of the same disorder” dueto dysfunctional central dopaminergic systems that accountfor motor symptoms [4, 9, 12]. In addition to history, thereare certain clinical features that may assist with the diag-nostic process. Positive motoric findings, such as dystonicposturing, waxy flexibility, and stereotyped movements, areseen more commonly in malignant catatonia than NMS [16].As with our patient, a prominent behavioral or affectiveprodrome marked by agitation or catatonic excitement isalso more common in malignant catatonia than NMS [16].In this case, this catatonic prodrome was misattributed to“refractory psychosis,” prompting escalating antipsychoticuse, which further exacerbated catatonic symptoms andultimately resulted in NMS. More timely recognition of thecatatonic prodromemay have avoided further clinical deteri-oration to a less treatment responsive state. Of note, nosologicconfusion and poor operationalization has contributed tohigh variability in reported prevalence rates [17]. That said,although the incidence of catatonia appears to have declinedover the decades, underrecognition of catatonia remainsan issue. A recent systemic review found the incidence ofcatatonia to be up to 18% in psychiatric inpatients and upto 30% of patients with delirium [18]. Our case further addsto the published notion of this under recognition, especiallythe excited subtype of this syndrome, with an opportunity forrefresher education for inpatient mental health providers.

A similar theme of misdiagnosis emerged when thepatient was assessed by the neurology service after he hadreceived lorazepam for 5 days. Due to his fluctuating clinicalcourse even within a day and interrater variability, hisBush Francis Catatonia Rating Scale (BFCRS) scores differedsignificantly on their exam from ours. They attributed hisakinesia and cogwheeling to neuroleptic-induced Parkinson-ism rather than to residual symptoms of resolving NMS (seeTable 1). Therefore, they suggested withholding amantadine,an NMDA antagonist with some dopaminergic activity. Weeducated the primary medical team regarding the intermit-tent nature of muscle rigidity and the full range of observablemovements in catatonia, as found by Castillo and colleaguesin their literature review [3]. We recommended amanta-dine as a temporary treatment bridge while awaiting ECTequipment. This recommendation was based on emergingevidence implicating a dysfunctional glutamatergic system in

BZD = Benzodiazepines AP = AntipsychoticsZ = Zolpidem and other Z drugs ECT = Electroconvulsive Therapy

Figure 1

catatonia. It has been hypothesized that the lack of glutamateinhibition due to massive GABA depletion in the supple-mentary motor areas results in a net effect of glutamatergic-mediated excitation in the striatum [4, 12, 19]. Carroll andcolleagues recommended initiating an NMDA antagonistwhen catatonia is unresponsive to benzodiazepines or ECT[20]. We suggested that the addition of an NMDA antagonistmay be useful, while awaiting coordination of ECT. It ischallenging to directly ascribe any clinical improvement toamantadine, given its relatively brief and interrupted use inthis case, in combination with other therapies. That said,it was well tolerated with no adverse effects and appearedto provide a delayed response 1-7 days after initiation, asdescribed in the literature [20].

AlthoughDSM-5 states that catatonia should not be diag-nosed if it occurs in the context of a delirium, symptoms ofcatatonia and delirium commonly overlap (see Table 1) [16],antipsychotic agents, which are typically first-line treatmentsfor hyperactive delirium, may worsen catatonia or precipitateNMS, as seen with our patient. Conversely, benzodiazepinesare the first-line treatment for catatonia but may worsendelirium (see Table 1) [17]. Given this clinical dilemma (seeFigure 1), NMDA antagonists may be particularly useful incatatonic patients with concurrent delirium [17]. Anotheretiology for his encephalopathic presentation especially inthe context of significant urine retention was thought tobe chlorpromazine-induced anticholinergic syndrome. How-ever, features such as diaphoresis, rigidity, and elevated CKlevels are not typical for this syndrome.

ECT is effective in relieving catatonia after failure of highdoses of IV within the first 72 hours [20–22]. In our patientwith clinical disagreements across providers, this had to befurther delayed due to the lack of a readily available ECTmachine in our acute medical hospital. Our service involvedpsychiatry leadership to request their assistance in expeditingECT for this patient given his tenuous clinical state andpotential for highmorbidity andmortality. Some case reportshave found reduced treatment response due to delayed useof ECT [17]. This case highlights the need for the structural

4 Case Reports in Psychiatry

capacity and clinical expertise to administer ECT emergentlyin the acute medical setting.

We also utilized benzodiazepines in a novel manner,given the aforementioned logistical challenges and subop-timal clinical response to lorazepam. We hypothesized thattroughs and peaks in his serum level of lorazepam couldcontribute to fluctuations in his clinical presentation overthe course of a day. Therefore, we switched to a longer act-ing benzodiazepine—diazepam—to ensure a steadier serumlevel, which appeared to be helpful in this case. Furtherstudies are ultimately needed to determine if there are clin-ically meaningful differences between benzodiazepines forcatatonia treatment. In the absence of rigorous comparativetrials between benzodiazepines, it is reasonable to assumethat they share a class effect via GABA-A modulation fortreatment of catatonia, similar to treatment of alcohol with-drawal. Therefore, we would suggest that pharmacodynamicand pharmacokinetic factors, such as half-life, should be astronger consideration when selecting a benzodiazepine forcatatonia treatment. As the most studied benzodiazepine intreatment of catatonia, lorazepam remains the gold standard,but a switch to a longer acting benzodiazepine may beconsidered for lorazepam partial responders or those with ahighly fluctuant course.

Of note, we did not administer dantrolene as mentionedin Table 1. Although some cases have reported success withdantrolene treatment, Reulbach and colleagues suggestedthat it may not be the evidence-based treatment of choice incases of NMS [23]. They found that combination treatmentwith dantrolene prolonged the complete time of remission,and, with monotherapy, mortality was increased, thoughpatients weremore severely ill in this group. Pileggi andCooknote in a recent review that dantrolene’s utility is typicallyreserved for severely ill patients [24]. Our patient’s clinicalcourse was tenuous with slow resolution but not severeenough to require the intensive care unit level of care.

After a 3-week washout period, clozapine was chosen forits mesolimbic selectivity and initiated with no recurrence ofNMS or catatonia. The recommendation to titrate dose forpsychotic remission was made to our inpatient psychiatriccolleagues.

4. Conclusion

This case highlights the diagnostic and treatment dilemmasin the management of general medicine service patientsadmitted with conditions such as NMS, catatonia, anddelirium. A multimodal approach that empowers medicalcolleagues through education addresses barriers to timelyECT for general medicine patients, utilizes creative phar-macologic strategies such as NMDA antagonists and longeracting benzodiazepines, and manages concurrent conditionssuch as delirium may be helpful to patients experiencing acombination of NMS, catatonia, and delirium in the generalmedical setting.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

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