Introduction

Neuroleptic Malignant Syndrome (NMS) is a rare condition associated with the use of antipsychotics or in anti-Parkinson medication withdrawal. It is a potentially life-threatening disorder. High potency conventional antipsychotics such as Haloperidol have greater risk of developing NMS compare to low potency and atypical antipsychotics. The typical NMS present with core symptoms of hyperthermia, muscle rigidity, elevated CK, autonomic dysregulation and altered mental status based on Nierenberg criteria.(3) However, it should be recognized that atypical presentations such as lack of hyperthermia and muscle rigidity may still be NMS. (1) This is especially true in patients with atypical antipsychotics where less extreme CK, temperature elevation or mild to absent rigidity may be present. (2) A spectrum approach to the diagnosis of NMS such as the Levenson criteria allows for the flexibility to include atypical presentation of NMS in the absence of either fever or rigidity.

Table 1.Comparison of Levenson criteria and Nierenberg and colleagues criteria for the diagnosis of NMS.

Although typical antipsychotic medications are commonly associated with NMS, it is not unusual for the atypical antipsychotic medication to present with NMS symptoms. While atypical antipsychotic medication is marketed as a safer profile with reduced side effects and is considered the first line treatment for neuropsychiatric disorders, we challenge this claim. In this case, we present a patient on atypical antipsychotic medication and developed NMS and subsequently improved her psychosis with typical antipsychotic medication.

Case Report

This is a 48 year old married white female with a history of bipolar disorder who presented to AMCH ER for agitation and severe confusion. She was initially admitted to the medical floor for evaluation of leukocytosis. At the medical floor she was treated with antibiotics for 3 days and was transferred to psychiatry floor E2 for treatment of psychosis. She allegedly had a reaction to lithium in the past admissions that led to kidney failure and had a history of liver toxicity secondary to Depakote. She was unable to communicate in Unit E2 during her hospitalization. She was started on aripriprazole 20mg on first day then increased to 30mg the following days. On average, she received average 10mg Haldol prn a day. The patient remained on aripriprazole for 7 days and her mental status initially improved but deteriorated again. She presented with high CK of 3500, altered mental status and dysautonomia, suggestive of neuroleptic malignant syndrome. Aripriazole was discontinued and sent to medical floor for stabilization. On Day 13 patient was medically cleared and was readmitted to E2. Her vitals and CK improved but her mental status continued to be poor with pressured speech and disorganized thought process. Her mood was irritable and labile. She was seen self-dialoguing but remained oriented to person, place and time.Initially she was managed with clonazepam. On Day 28, she was started on 40mg Geodonpo and 60mg the next day. Her behavior improved and she was less disorganized. However, on Day 32 her CK went up to 1800 four days later and presented with NMS episode. Geodon was discontinued and patient was sent to the medical floor. After all her antipsychotic medication was discontinued, her labs had stabilized and CK had returned to normal. She remained to have episodes of confusion, episodes of disorientation, fluctuating paranoia, signs and symptoms suggestive of chronic delirium and at times appearing catatonic. She continued to demonstrate poor insight and judgment and poor impulse control. This patient needed a long-term hospitalization with close monitoring and high level of care. She was discharged to CDPC and was started on Tegretol 100mg bid, Klonopin 1mg qAM/1.5mg qHS, and Ativan 2mg prn.

Upon admission to CDPC, the patient was uncooperative, agitated, angry and physically threatening staff. She was brought into a seclusion room with the door open while the staff tried to calm her for 15 min and the patient calmed down after IM Ativan 2mg. On examination, she was able to answer some questions. She was significant for poor hygiene and concentration. Her mood was dysphoric and affect was labile. She appeared to be responding to internal stimuli with poor impulse control and judgment.

During the first 5 days, the patient was pacing throughout the day. Her mood was labile. She was agitated where she chased a peer and bang on the plexi glass. She had been taking her medicationbut remained tangential and preoccupied with marital problems and paranoid thoughts. She also showed aggression toward her husband during the visit. She had been given Ativan for prn.

On Day 6 to 12, the patient continued to be paranoid, irritable, anxious and delusional. Her bipolar disorder with psychotic features continued to be active. She was started with thorazine 25mg prn and had shown no aggressive behaviors. She was compliant with her medication however she demonstrated minimal verbalism to mutism and thought blocking.
On Day 13, she started on Thorazine 50mg twice a day and 50mg for prn. She was compliant with medication and became more cooperative with staff. She continued to remain isolative and non-talkative, confused and disorganized On Day 16, Thorazine was increased to 100mg twice a day with 200mg qHSand Klonopin decreased to 1g twice a day. She remained delusional, confused and responded internal stimuli and was minimally verbal.

On Day 19, the patient was near fainted but did not fall and had no loss of consciousness. Her skin was clammy and her blood pressure was 88/60, HR 96, T 97.8 and O2 sat 97%, blood sugar 91. She was encouraged to drink fluids. Her medication for thorazine and klonopin was held due to hypotension. On Day 20, the patient was influenced by a peer that she should not eat and take her medication. She was self-deprecatory, and remained paranoid and delusional . She was depressed and often tearful. She became agitated when her husband came to visit. She banged her head and her behavior regressed. On Day 21, she started on Cymbalta 30mg qAM. For her well-being to be separated from other peer, she was guest on a different unit for 7 days. She was restarted on Thorazine and Klonopin and added 200mg ThorazineqHS.She presented with flat affect and was not alert and oriented. Her speech is normal rate and low tone. She was cooperative but disorganized. She had not reported any auditory hallucinations and did not appear to be responding to internal stimuli. Her mood remained dysthymic and easily became tearful. She had not had sleep disturbances. Her appetite and concentration remained poor. She was guarded around staff and paranoid about the ulterior motive of the staff as well as her family members.

On Day 35, her Thorazine increased to 200mg twice a day and 300mg qHS. She reported auditory hallucination and remained self-isolative. Following Day 36, the patient appeared to be alert and oriented. Speech was normal rate and tone. Her thought process remained disorganized at times. Her mood improved and was less depressed. On Day 37, Cymbalta was increased to 60mg QD. She began to attend some of her therapy groups. She was verbally responsive to all questions. She inquired learning about her mental illness. She remained paranoid and delusional. She believed she ate her grandchildren, testicles and penises. She also believed people were calling her name at night. She accepted her prn medication with moderate effects. On Day 40, the patient bolted into the nurse station to get soda. She was manually restrained by staff and kicked one staff in the right rib. Shortly after she received her prn, she began hitting and body slamming the door to the nurse station. She was redirected without further problems.

From Day 41 to 44, she continued needed her prn for paranoid and anxiety. She believed everyone was talking about her and stated she continued to hear voices.

From Day 45 onwards, her cognitive function improved and was evidenced by increased participation in her program. Her thought process was more organized. Her delusional thinking lessened. She greeted her staff with smile during holidays. She appears alert and oriented. Her speech was normal rate and tone. She denied auditory hallucinations. Her mood was less labile. She continued to receive her prn medication. Since Day 51, she was able to advocate and articulate for additional therapies to her schedule. She was able to discuss at length about her delusion in the past. She stated her mental health had been the best.

On Day 64, she was alert and oriented. Her speech is moderate tone and level. She denied auditory hallucinations and did not appear to be responding to internal stimuli. Her thought process was logical and goal oriented. Her mood was not depressed. Activities of daily living improved significantly. She did not show any disturbances in sleep, appetite or concentration. She denied suicidal ideation or homicidal ideation. The patient had good impulse control, insight and judgment. Her condition was stable and discharged the following day with Thorazine 200mg bid/300mg qHS, Cogentin 1mg prn, Tegretol 200mg bid, Klonopin 0.5mg bid, Cymbalta 60mg QD, Trazodone 100mg prn.

Discussion

Typical antipsychotic drugs have potential adverse effects including extrapyramidal reactions and tardive dyskinesia and are historically associated with life-threatening condition of NMS. This led to a wide-spread use of atypical antipsychotics as first-line treatment in neuropsychiatric disorders. We present a case on a patient who received both typical and atypical antipsychotic but presented with elevated CK, autonomic dysregulation and altered mental status without fever and rigidity. Her presentation did not fulfill the most commonly used criteria for NMS but it is suggestive of an early form of or an atypical NMS. While atypical antipsychotics were marketed as low side effects than typical antipsychotic medication, its safety profile is questionable. In our patient, her symptoms of NMS were most likely caused by the atypical antipsychotics. We believe atypical antipsychotic is no safer than the typical antipsychotic because atypical antipsychotic induced NMS can often be misdiagnosed or underdiagnosed and thus leads to a delay treatment. The confusion for clinicians is because NMS caused by atypical antipsychotics don’t always meet the criteria for typical NMS and currently there is no standardization for the criteria of atypical NMS.

NMS is a medical emergency that can lead to death. The recommended treatment for NMS is to stop the antipsychotic medication that caused the NMS. If a patient presents with hyperthermia or muscle rigidity, aggressive hydration, the use of dantrolene and bromocriptine to reduce muscle rigidity, benzodiazepines to control agitation have shown benefits. After treatment has stabilized the patients, patients with history of NMS may still need antipsychotic treatments. The likelihood of developing NMS again is as high as 30%. (3, 4) It is suggested at least two weeks after resolution of NMS to be allowed before low potency antipsychotic or atypical antipsychotic is introduced. (5) As our patient was transferred to a long term inpatient care, her agitation was controlled with benzodiazepine and her psychosis was slowly tapered with thorazine. Despite her history of atypical NMS, she did not develop recurrence on thorazine. We believe this patient is highly sensitive to atypical antipsychotic medication and rechallenge with atypical antipsychotic medication would likely to induce recurrent episode of NMS. While typical antipsychotic drugs are historically associated with NMS, this patient did not develop symptoms of NMS after she was rechallenged with thorazine. She was stabilized on thorazine and discharged.

Conclusion

NMS is an acute and potentially lethal reaction to antipsychotic medication or anti-Parkinson medication withdrawal. Typical antipsychotic is very well known for its association with NMS. The criteria includes fever, muscle rigidity, autonomic dysregulation, elevated CK and altered mental status. However, not all NMS present with all cardinal symptoms. Atypical cases may be an early form or an atypical presentation of NMS. Patients with typical or atypical antipsychotic medication may present differently. Due to the debatable criteria for atypical NMS with atypical antipsychotic medication, the diagnosis and treatment are often delayed. We believe atypical antipsychotic medication is no safer than typical medication due to its diagnostic challenges. In addition, starting an antipsychotic medication after resolution of NMS remains a challenge. It is paramount to personalize a patient’s antipsychotic medication because there is no safer profile between typical and atypical antipsychotic medication. In patients who developed NMS from typical or atypical antipsychotic medication, we recommend considering challenge the patient with an alternative class of antipsychotic medication with slowly taper to prevent relapse of NMS.

Reference
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