Neuroleptic malignant syndrome (NMS) is a potentially fatal diagnosis composed of hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability. This syndrome has significant systemic complications including acute renal failure, rhabdomyolysis, hyperkalemia, and seizure. It is associated with the use of both typical and atypical antipsychotics. Due to the extensive neurodegenerative destruction of dopaminergic and acetylcholinergic pathways, patients with Lewy body dementia (LBD) are particularly sensitive to antidopaminergic and anticholinergic medications, making them more susceptible to extrapyramidal side effects and NMS. We present a case of a 72-year-old female with LBD who developed muscular rigidity, vital sign instability, and altered mental status after receiving one dose of paliperidone palmitate injection two weeks prior to admission. Initial blood work was unrevealing. Extensive workup including EEG, lumbar puncture with cerebrospinal fluid analysis, and brain MRI was unremarkable. She was treated with seven days of bromocriptine and a lorazepam taper with improvement in muscle rigidity. However, her mental status never improved, and she remained comatose. She was later intubated for airway protection after an aspiration event that led to hypoxia. Her respiratory status never recovered, and she was transitioned to comfort care. This case demonstrates the complexity and potential fatality of NMS. Clinicians should be aware of this dangerous complication of antipsychotic use in patients with LBD as these patients may be more susceptible to this complication.
Neuroleptic malignant syndrome (NMS) is a rare complication of antipsychotic use, with an incidence of 1 to 2 cases per 10,000 patients treated with antipsychotics [
Risk factors for the development of NMS are the initiation or increased dosing of an antipsychotic medication, the potency of the drug, and the route of administration of the drug. The use of high-dose, high-potency, or long-acting or intramuscular forms of antipsychotics increases the risk of developing NMS [
Lewy body dementia (LBD) is characterized by Parkinsonism with visual hallucinations and fluctuating alertness. On microscopic review, Lewy bodies are seen throughout the cerebral cortex, which are often also associated with Alzheimer disease pathology. The prevalence is likely underestimated given the difficulty in making the neuropathologic diagnosis; however, LBD represents about 15% of dementias seen at autopsy [
We present a case of a 72-year-old Puerto Rican female with LBD, hypertension, and type 2 diabetes mellitus who received 1 dose of paliperidone palmitate intramuscular injection and later presented with clinical features of NMS, complicated by aspiration and pneumonia, requiring mechanical ventilation. This case demonstrates the caution that should be taken when treating LBD with atypical antipsychotics, especially in the long-acting injectable form.
A 72-year-old Puerto Rican female with a past medical history of advanced dementia with Lewy bodies, type 2 diabetes mellitus, and essential hypertension was brought to the emergency department by her granddaughter with acute change in mental status. At baseline, the patient was nonverbal, but could typically eat, use the restroom independently, and walk without significant assistance. For the past two weeks, she was unable to perform any tasks without full dependence, and she was unable to recognize her family. There was no history of drug or alcohol use. Her home medications included aspirin 81 mg daily, donepezil 10 mg daily, docusate sodium 100 mg daily, losartan 50 mg daily, linaclotide 72 mcg daily, metformin 500 mg twice daily, ranitidine 150 mg twice daily, and simvastatin 40 mg daily. Review of systems per family was negative for fevers, chills, cough, diarrhea, change in urinary frequency, or dysuria.
Lewy body dementia was diagnosed several years prior by a neurologist and had been progressive with urinary incontinence, hallucinations and paranoia, and speech difficulty. Due to her hallucinations and behavioral challenges, her primary care physician had initiated low-dose oral haloperidol. Medication adherence was difficult given her dementia, and she continued oral haloperidol inconsistently for several months. Two weeks prior to admission, her PCP initiated paliperidone palmitate extended-release intramuscular injection of 156 mg, as the patient had been off antipsychotic therapy for three months.
On admission, the patient had a temperature of 97.4°F (36.3°C), a heart rate of 102 bpm, a blood pressure of 130/67 mmHg, and an oxygen saturation of 97% on room air. On examination, the patient responded only to painful stimuli by grimacing. Pupils were equal but sluggishly reactive to light. Her head was deviated to the left and stiff when moved toward the midline. She did not follow any commands or demonstrate any voluntary movements. She had muscular rigidity of her upper extremities and lower extremities bilaterally. Her patellar and brachial reflexes were brisk at 3+, and her toes were mute bilaterally. The following day, she became hyperthermic to 101.8°F (38.8°C) with a blood pressure of 149/88 mmHg. On hospital day 3, her temperature continued to fluctuate between 97.6 and 100.7°F (36.4–38.2°C) with heart rate ranging 89–110 bpm, and her blood pressures ranged 130–172/61–93 mmHg. She was seen by toxicology, psychiatry, and neurology on hospital day 2 and was transferred to the ICU. She was started on dantrolene, bromocriptine, and benzodiazepines for symptomatic management of suspected neuroleptic malignant syndrome.
Basic laboratory workup showed no leukocytosis and no electrolyte abnormalities. See Table
Laboratory and radiographic workup.
Hemoglobin 14.3 g/dL | Blood cultures NGTD |
WBC 9.0 × 1000/mm3 | CSF cultures NGTD |
Sodium 139 mEq/L | Urine culture > 100k |
Potassium 5.2 mEq/L | Sputum culture < 10k |
BUN 19 mg/dL | |
Creatinine 0.89 mg/dL | Normal CT head |
Glucose 193 mg/dL | Normal MRI brain without contrast |
LFTs wnl | No seizure activity on EEG |
Lactate 1.2 mmol/L | |
Creatine kinase 276 | Clear color |
Ammonia wnl | 2 WBCs/ |
TSH 0.970 mU/L | Glucose 92 mg/dL |
UDS negative | Protein 27 mg/dL |
RPR nonreactive | VDRL nonreactive |
Hepatitis C Ab nonreactive | Cryptococcal Ag negative |
HIV nonreactive | AFB stain negative |
B12 wnl | NMDA receptor Ab negative |
WBC: white blood cell; BUN: blood urea nitrogen; LFT: liver function test; TSH: thyroid-stimulating hormone; UDS: urine drug screen; RPR: rapid plasma reagin; NGTD: no growth to date; VDRL: venereal disease research laboratory; AFB: acid-fast bacillus; NMDA: N-methyl-D-aspartate; wnl: within normal limits.
Lumbar puncture was performed with normal opening pressure. Cerebrospinal fluid (CSF) was clear in color with 2 WBCs/mm3, glucose 92 mg/dL, and protein 27 mg/dL, which was not suggestive of meningitis or encephalitis. CSF smear showed no organisms, and cultures grew no organisms. CSF VDRL was nonreactive. Acid-fast stain and smear showed no acid-fast bacilli. CSF cryptococcus antigen was negative. CSF anti-NMDA receptor antibody was negative. Cytology analysis of the CSF showed no malignant cells. Antibiotics were discontinued on hospital day 5 as blood cultures had no growth.
The patient remained unresponsive, but her rigidity and vital signs improved on hospital day 4. She was afebrile and normotensive. Two days later, the patient became tachypneic and hypoxic, saturating 87% on room air, with suspicion for aspiration. She was intubated for airway protection. A postintubation chest X-ray showed right lower lobe infiltrative changes, for which ampicillin/sulbactam was started. She was also started on amantadine and was titrated off all sedating medications. Unfortunately, she did not have any significant improvement in her mental status and remained mechanically ventilated. She completed a 7-day course of antibiotics for aspiration pneumonia; however, she continued to be apneic on spontaneous breathing trials.
After an ongoing discussion about the patient’s grim prognosis, the family decided on palliative extubation and transition to comfort care. The patient was ultimately discharged to inpatient hospice on hospital day 15.
The case described here is the first known case in the English literature of a patient with Lewy body dementia that suffered from neuroleptic malignant syndrome after receiving an intramuscular injection of paliperidone palmitate. Prior to making a diagnosis of NMS, other diagnoses should be excluded. The differential diagnosis includes metabolic, toxicologic, infectious, and endocrine disorders. Neuroleptic malignant syndrome may be difficult to distinguish clinically from serotonin syndrome. Serotonin syndrome generally has a more rapid onset of 2–24 hours, hyperreflexia, myoclonus, nausea, vomiting, diarrhea, and less intense muscle rigidity and fever [
Our patient was diagnosed with NMS as she experienced the tetrad of a change in mental status progressing to coma, muscular rigidity, hyperthermia >38°C, and autonomic instability in the setting of recent administration of a long-acting injection of an antipsychotic [
The mainstay of treatment for NMS is discontinuation of the offending agent and supportive care. External cooling can be utilized to reduce the patient’s temperature; however, antipyretics such as acetaminophen have not been shown to be beneficial. Sedation with benzodiazepines is recommended to decrease agitation and sympathetic activity. Those with fever and rigidity may require intubation because neuromuscular paralysis reduces muscle contraction and therefore can reduce fever. Nonpolarizing agents are preferred over depolarizing agents for intubation [
Most deaths due to NMS are related to profound muscle rigidity resulting in complications including respiratory failure, rhabdomyolysis, renal failure, disseminated intravascular coagulation, and cardiovascular collapse. No treatment has been shown to be superior to supportive care; however, reported cases have described the use of dantrolene, bromocriptine, benzodiazepines, and amantadine [
Paliperidone palmitate is a long-acting formulation of paliperidone, an active metabolite of risperidone. It is an antagonist of brain dopamine D2 and serotonin (5-hydroxytryptamine) receptors. Effects are usually seen about 8 days after injection, and peak plasma level is reached about 13 days after injection. The half-life ranges from 25 to 49 days [
This case was presented as a poster at the Annual Sol Sherry Symposium at Temple University on June 5, 2019, and orally at the Department of Neurology Annual Matthew T. Moore Conference at Temple University Hospital in June 2020.
NK, CM, SS, and HY declare no conflicts of interest.
NK, CM, SS, and HY contributed to the writing and editing of the entire manuscript and approved the submitted version of the manuscript.