Neuroleptic Malignant Syndrome in a Patient With Anti-N-Methyl-D-Aspartate Receptor Encephalitis: Case Report and Review of Related Literature

Abstract

Introduction:

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a severe but treatable disease that presents with symptoms similar to neuroleptic malignant syndrome (NMS).

Case Report:

We describe a 28-year old female who initially presented with headaches, behavioral changes, anxiety, lip tremors, and rigidity of extremities. She was prescribed with olanzapine and later manifested with neuroleptic malignant syndrome symptoms such as decrease in sensorium, muscle rigidity, hyperthermia and tachycardia. Further investigation showed presence of bilateral ovarian teratoma and anti-NMDAR antibodies in her serum and cerebrospinal fluid. Symptoms resolved after intravenous high-dose methylprednisolone, bilateral oophoro-cystectomy, and intravenous immunoglobulin administration. Overlapping pathological mechanisms of anti- NMDAR encephalitis and NMS were discussed. Ten patients with anti- NMDAR encephalitis and NMS were noted in a review of literature. Prognosis was favorable and intervention ranged from supportive to methylprednisolone and intravenous immunoglobulin administration, plasma exchange and teratoma resection.

Conclusion:

Anti- NMDAR encephalitis patients are at risk for NMS due to antipsychotic intolerance and other interrelated pathophysiological mechanisms. The overlap between the signs and symptoms of anti-NMDAR encephalitis and NMS poses a diagnostic dilemma and warrants a careful investigation and management.

Introduction

Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is an autoimmune disorder associated with antibodies against the NR1 subunit of the NMDA receptor. ¹ Eighty percent of patients with anti-NMDAR encephalitis are women; fifty-nine percent of them have ovarian teratomas.^1-3 Seventy percent of anti-NMDAR encephalitis patients have prodromal symptoms of headache and fever but they can also present with autonomic and psychiatric symptoms of tachycardia, rigidity, anxiety, insomnia and mania in the first two weeks of the disease. ¹ As a result, these patients are usually first seen by psychiatrists who subsequently prescribe anti-psychotic medications that can put them at risk for neuroleptic malignant syndrome (NMS). ⁴ NMS is characterized by the presence of fever, muscle rigidity, altered mental status and dysautonomia. ⁵ Exposure to a dopamine-blocking agent, severe muscle rigidity and fever are required for its diagnosis. The overlap between the signs and symptoms of Anti-NMDAR encephalitis and NMS can pose a diagnostic dilemma.

Case

This is a case of a previously healthy 28-year old female with no prior psychiatric illness and unremarkable family medical history presenting with a three- week history of intermittent headache and fever. A week prior to admission, her family members noticed generalized weakness and behavioral changes associated with anxiety, insomnia, lip tremors and rigidity of extremities. After consulting with a psychiatrist, she was given olanzapine 5 mg daily which she took for three days. Her behavioral changes persisted. She then developed high grade fever, muscle rigidity and decrease in sensorium; consequently, she was brought to the Emergency Department (ED) of our institution.

She was received at the ED with normal blood pressure but, febrile (39 ^oC), tachycardic (148 beats per minute) and diaphoretic. She was drowsy but was still able to follow simple commands and converse in words. She had no cranial nerve deficits but had significant generalized muscular rigidity coupled with occasional spasms of her extremities. No extensor toe response was elicited but her neck was rigid.

Initial workup included a complete blood count revealing mild leukocytosis and elevated serum creatinine (Creatinine= 156 umol/L, eGFR=30mL/min/1.73m²). Plain cranial CT scan was normal and a lumbar puncture revealed pleocytosis with lymphocytic predominance (WBC=33, Lymphocytes=93%). CSF had normal protein and glucose levels. Toxicology screening was unremarkable. Serum creatinine kinase (CK) was elevated at 10,374 U/L. Because of the patient’s history of olanzapine, persistent rigidity, fever and increase in CPK levels, she was initially managed as a case of neuroleptic malignant syndrome. Olanzapine was discontinued and she was hydrated. She was also initially treated with bromocriptine to address the rigidity. Acyclovir was given for fourteen days to cover for viral encephalitis.

She was admitted to the Neurology Intensive Care Unit (NICU) and underwent hemodialysis for progressive oliguria from rhabdomyolysis. Subsequent septic work-up revealed negative blood, urine and CSF cultures. CSF viral, bacterial and fungal panel were also negative. EEG showed generalized background slowing and no epileptiform discharges.

Other possible etiologies of encephalopathy apart from NMS was considered. A transvaginal ultrasound was done revealing bilateral dermoid cysts. This shifted our primary working impression to a paraneoplastic cause such as autoimmune encephalitis. On her sixth hospital day, she was empirically treated with high-dose IV methylprednisolone at 1 gram per day for five days. Her labile blood pressure improved after giving methylprednisolone. CPK levels peaked on the 4th day of admission and gradually declined thereafter (Figure 1). On her 12th hospital day, she developed oral dyskinesias. At this time, results of both CSF and blood serum were then found to be positive for anti-NMDAR antibodies—clinching the diagnosis of anti-NMDAR encephalitis.

Figure 1.

Evolution of CK levels U/L over time. There is an initial spike in the CK levels followed by a gradual decrease over.

Despite treatment with high dose corticosteroids, her dyskinesias persisted. Bilateral oophorocystectomy was performed on her fifteenth hospital day to resect both ovarian tumors that were later found to be mature teratomas. She had episodes of waxing and waning hallucinations and delusions post- operatively despite normal metabolic parameters. We decided to start Intravenous Immunoglobulin (0.4g/kg/day) for five days on the 39th hospital day due to the persistence of her symptoms. After the immunotherapy, her dyskinesias and psychoses resolved. On the forty- fifth hospital day, she was discharged awake, conversant, follows commands and with no maintenance medications (Figure 2).

Figure 2.

Timeline of anti- NMDAR and NMS signs, symptoms and intervention.

She followed up one month, three months and six months after discharge in the out-patient department. She was independent in all activities of daily living with no recurrence of rigidity, behavioral changes, and dyskinesias. Montreal Cognitive Assessment revealed a score of 29/30. Neurologic examination was normal.

Discussion

NMS and anti-NMDAR encephalitis share similar symptoms due to interrelated pathophysiological mechanisms. The most widely accepted model explaining NMS is the dopamine hypoactivity theory. This theory proposes that the blockade of dopamine receptors in the hypothalamus leads to temperature dysregulation while the decrease in dopamine in the basal ganglia leads to Parkinsonian symptoms.^6,7 Changes in dopamine transmission in the reticular activating system may also explain the altered consciousness. ⁷ Typical and atypical antipsychotic medications which block dopamine in the central nervous system can give rise NMS symptoms. While NMS is more common in typical antipsychotics, several reports showed that atypical antipsychotics, more specifically olanzapine, can give rise to NMS.^8-15 It has also been found that NMDA receptors control the release of dopamine through direct synaptic action on dopaminergic terminals. Decreased NMDA receptors can affect dopaminergic transmission,^1,16 NMDA receptor antibodies block the NMDA receptor in the presynaptic gamma- aminobutyric acid neurons of the thalamus and frontal cortex. This leads to a disinhibition of postsynaptic neurons and subsequent glutamatergic and dopaminergic dysregulation in the frontal cortex. ¹⁷ Hence, NMDA receptor antibodies could play a role in dopamine blockade leading to similar symptoms with NMS. ¹²

The similarity in the symptomatology of NMS and anti-NMDAR encephalitis pose a challenge in the diagnosis of this patient. In our case, two possibilities could have happened: misdiagnosis of anti-NMDAR encephalitis as NMS or co- existing NMS resulting from symptomatic treatment of anti-NMDAR encephalitis. The authors believe that the latter occurred.

There is no doubt that the patient had anti- NMDAR encephalitis because of the CSF findings. Nonetheless, the patient’s fever, rigidity and facial dyskinesias which began a few days before olanzapine was administered could have been initial signs of anti-NMDAR encephalitis already. Moreover, the increasing muscle rigidity upon examination and depicted by our patient’s increasing CKs in the absence of recurrent generalized tonic- clonic seizures is not common with anti- NMDAR encephalitis and is a striking feature of NMS. ¹⁷ It is also worth noting that patients with anti-NMDAR encephalitis patients are at exquisite risk for the development of NMS when administered antipsychotic medications. In a study of 111 anti- NMDAR encephalitis patients, twenty-one patients (47%) presented with antipsychotic intolerance characterized by high temperature, muscle rigidity, mutism or coma, and biological results suggesting rhabdomyolysis. ¹⁸ One of the anti- NMDAR encephalitis patients even presented with three psychiatric episodes; for each episode, the patient experienced severe intolerance to antipsychotic drugs. ¹⁹ Another case report also described a patient whose psychiatric symptoms progressed despite being given risperidone and valproic acid. ²⁰

We conducted a literature review on patients presenting with both NMS and autoimmune encephalitis. Cochrane Central Register for Controlled Trials (CENTRAL) by The Cochrane Library, MEDLINE by PubMed, Health Research and Development Information Network, ClinicalTrials.gov, and SCOPUS were systematically searched for relevant studies from conception until January 2020. Key search terms used included the following: “neuroleptic malignant syndrome,” “anti-NMDA receptor encephalitis” “autoimmune encephalitis” and “ovarian teratoma.” Our literature review showed ten patients diagnosed with anti-NMDAR encephalitis and NMS (Table 1). Six were female; three belong to the pediatric population. Similar to our case, olanzapine was likewise given to five patients in the review. Three of the six female patients had ovarian teratomas, all of which had their teratomas resected. All patients survived but some had mild cognitive impairment. Intervention ranged from supportive to intravenous immunoglobulin, plasma exchange, methylprednisolone and teratoma resection.

Table 1.

Case Reports on Anti- NMDAR Encephalitis Patients with NMS.

Author, year	Age/Sex	Initial Presentation	Antipsychotic given	Antibodies present	Teratomas	Intervention	Outcome
Gulyayeva, 2013 19	19/F	Persecutory delusions, hallucinations	Haloperidol, Chlorpromazine, Olanzapine, Lorazepam	Anti-NMDAR (CSF)	Yes	IV Ig, Plasma exchange, steroids, Ovarian tumor resection	Survived but cognition impaired
Punja, 2013 18	21/M	headache, insomnia	Olanzapine, Ziprasidone, Diazepam, Haloperidol	Anti- NMDAR	No	Supportive	Survived
Punja, 2013 18	27/F	headache, seizure, irritability	Haloperidol, Thorazine, Benzotropine, and Lorazepam	Anti- NMDAR (CSF)	No	IV Ig	Survived but cognition impaired
Suri, 2013 20	17/F	Irrelevant talks and disinhibition	Olanzapine	Anti- NMDAR	No	IV Ig	Survived
Kiani, 2014 21	32/F	Social withdrawal, persistently mood, hallucinations, shouts incoherently	Not stated	Anti- NMDAR (serum)	No	Methylprednisolone	Survived, mild amnesia
Kiani, 2014 21	42/M	Extreme aggression, urinary retention	Aripiprazole, Olanzapine	Anti- NMDAR	No	Methylprednisolone	Survived
Koksal, 2014 22	25/F	insomnia, agitation, irritability, fear of death	Risperidone, Benzodiazipene	Anti- NMDAR (CSF)	Yes	IV Ig, Methylpredinosolone, Ovarian tumor resection	Survived, no deficits
Berg, 2015 3	11/M	seizures, anxiety	Risperidone	Anti- NMDAR (CSF)	No	IV Ig, Methylpredinosolone, Rituximab	Survived
Rozier, 2016 23	14/F	behavioral changes, seizures, fever, tachycardia	Haloperidol, Levetiracetam, Oxcarbazepine	Anti- NMDAR	Yes	Ovarian teratoma resection, IV Ig	Survived
Wang, 2019 11	29/M	Memory deficits, decreased level of consciousness, behavioral changes	Olanzapine	Anti- NMDAR	No	Methylprednisolone and Plasmapharesis	Survived

Abbreviation: IV Ig, Intravenous Immunoglobulin.

NMS and anti-NMDA receptor encephalitis can coexist in patients because of interrelated mechanisms and intolerance of anti-NMDAR encephalitis patients to antipsychotics. Identifying these two disease entities is important because early diagnosis and treatment can improve outcomes. ¹

Conclusion

Anti- NMDAR encephalitis patients are at risk for NMS due to antipsychotic intolerance and other interrelated pathophysiological mechanisms. The overlap between the signs and symptoms of anti-NMDAR encephalitis and NMS poses a diagnostic dilemma and warrants a careful investigation and management.

ORCID iD

Robert Joseph C. Sarmiento, MD https://orcid.org/0000-0001-7708-1804