Neuroleptic Malignant Syndrome due to Antipsychotics: Clinical Case Discussion

Have you ever wondered whether a medication given to save a patient’s life could become life-threatening? Well, the story of Mr. David is about such a situation. Let us listen to his story.

Mr. David, a 60-year-old known patient with schizophrenia, presented to the emergency unit in the early morning with altered consciousness and high fever. He was restless, and his clothes were wet due to excessive sweating.

His worried wife said that he has been on Haloperidol, an antipsychotic medication, for five years, and a few days back, his drug dose was increased. He had been working in their garden in the afternoon, and the symptoms have started in the previous day evening.

On general examination, he had elevated heart rate and respiratory rate, with low systolic blood pressure. His body temperature has risen to 38.2c. Generalized rigidity and tremors were found in his extremities. He had no neck stiffness, and Kernig’s sign was negative.

Laboratory investigations showed elevated white blood cell count, creatine kinase level, serum transaminases, urine myoglobin level with normal electrolyte levels. CSF culture, blood culture, thyroid profile, brain CT and chest x-ray were normal.

By excluding other possible causes, the attending doctor came to the diagnosis of Neuroleptic Malignant Syndrome. Let us dive a little into this rare but life-threatening condition so that you can make better decisions with the next Mr. David you meet

What is Neuroleptic Malignant Syndrome (NMS)?

Simply put, it is a serious adverse drug reaction. In a more descriptive way, NMS is a potentially life-threatening complication of treatment with antipsychotic drugs, which is characterized by muscle rigidity, fever, altered mental status, and autonomic changes.

According to the ICD-10 guidelines, rarely NMS can be caused by dopaminergic receptor blocking drugs used in nausea and vomiting. But here, we will mainly focus on NMS caused by antipsychotic medications, as it is the usual case in NMS.

Pathophysiology of NMS is suspected to be due to dopamine (D2) receptor antagonism but not proven. This blockage can occur in the hypothalamus, spinal cord, basal ganglia, and nigrostriatal pathways, altering the normal functions regulated by those areas. This can affect mental status, body temperature regulation, muscle rigidity and autonomic nervous system.

NMS occurs mostly around the tenth day after initiating the medication or increasing the dose of antipsychotic drugs. The incidence of NMS is about 0.2% of patients who are on antibiotics.

Why Should We Attend to this Condition Immediately?

NMS is a medical emergency. So, we have to attend to our patients immediately. Though NMS appears to be a rare disease, it has a 10% mortality rate, and surviving patients can develop residual disabilities. The outcome of the patient will depend on our interventions.

NMS comes under “idiosyncratic reaction,” a term that says we do not know what is happening. The issue we have with that is, we cannot guess who will get the disease. So, we have to suspect NMS in any patient with antipsychotics.

It would be hard to manage a patient with complicated NMS. But if we identify this condition early, we can nip it in the bud.

How Would a Patient with NMS Present?

I hope you remember our patient, Mr. David. Most of the patients will have the same type of story. They will be on antipsychotics for psychiatric illness, mostly schizophrenia. They also can have mania, depression, or psychosis secondary to a medical condition.

 We have to look into the drug type and the dose. Both typical and atypical antipsychotics can give rise to NMS. Common antipsychotics that can cause NMS are,

Chlorpromazine

Haloperidol

Olanzapine

Risperidone

Clozapine

Sulpiride

Trifluoperazine

Flupentixol

Some patients will give a history of exposure to risk factors. They can be on high drug doses or underwent rapid elevation of drug doses. Dehydration, agitation, physical exhaustion, iron deficiency, and elevated environmental temperature also can predispose to NMS.

Considering their symptoms and signs, they will present mainly with fever and muscle rigidity. Some may show features of autonomic dysfunction and altered mental status.

Well, this clinical picture can be common to many disease conditions. So, we will have to deal with a quite long differential diagnoses list.

What Should We Include in our Differential Diagnosis?

Differentials are of prime importance in a situation like Mr. David.  The patient’s life will depend on whether we include his accurate disease in our differential diagnosis list. With the history and clinical features of Mr. David, we should think about the following conditions.

Pharmacological

NMS

Malignant hyperthermia

Serotonin syndrome

Substance abuse (amphetamines, hallucinogens)

Withdrawal from dopamine agonists (hypnotics)

Salicylate poisoning

Infections

Encephalitis

Meningitis

Sepsis

Brain abscess

Pneumonia

Psychiatric disorders

Agitated delirium

Benign extrapyramidal side effects

Idiopathic malignant catatonia

Non-convulsive status epilepticus

Other

Heatstroke

Thyrotoxicosis

Intracranial hemorrhage

Among these diseases, encephalitis, serotonin syndrome, and heat stroke are common conditions difficult to distinguish from NMS. So, let us have a brief discussion about those disorders.

Encephalitis

CNS infections, especially viral encephalitis, can show same clinical picture as NMS. These patients can present with high fever, seizures, headache, and localizing neurological signs. We have to get the support of investigations to exclude this condition.

Heatstroke

Heatstroke is a systemic disorder that can mimic NMS. This disorder can cause hyperthermia, tachycardia, tachypnea, and confusion. In a patient on antipsychotics, if they have a history of exposure to high temperature, it will be challenging to differentiate heatstroke from NMS. Some heatstroke patients will have dry skin and muscle flaccidity.

What Should We Look for on Examination?

Now you might have got a brief idea about NMS. According to that, what would be your approach to examination? As our patient has a wide variety of problems, we have to go through a thorough examination.

We should inspect his skin dryness and sunken eyes to assess hydration. We have to look for restlessness and tremors. Examination and monitoring of vitals will help assess the severity. Effect on the autonomic nervous system can alter blood pressure, respiratory rate, and heart rate. Therefore, we have to do a complete motor examination and assess muscle rigidity.

Can we use examination to rule out our differential diagnosis? Considering that, we can check for hyperreflexia, myoclonus, and ataxia to exclude serotonin syndrome. You might have heard neck stiffness and Kernig’s sign are more suggestive of meningitis. We can do muscle contracture testing to exclude malignant hyperthermia.

Examination findings help us to walk in the pathway for diagnosis. But we cannot come to a final diagnosis only with the examination. To rest our case, we need the support of investigations.

What are the Investigations we Ordered?

Think for a while, how can investigations help Mr. David? Investigations can narrow down our differential diagnosis for him, assess the severity of the condition, and identify possible complications early. So, we have to order relevant investigations for our patients to achieve these goals.

Though we do not have a diagnostic test for NMS yet, investigations are the basis for arriving at the diagnosis. But we always have to avoid any unnecessary investigation for our patient.

A high white cell count is suggestive of an infection or NMS. As it is associated with coagulopathies, thrombocytosis may be seen in NMS.

Muscle rigidity and hyperthermia can damage muscle tissue. So in NMS, there will be elevated serum CPK level. This will aid to differentiate NMS from serotonin syndrome

Muscle damage can cause increased release of lactate dehydrogenase also.

Myoglobin released to blood is increased with muscle damage. So myoglobin level in blood and urine can elevate due to this. We should not forget that this can lead to renal impairment.

We have to assess whether our patient develops renal failure.

Dehydration and muscle damage can cause abnormal electrolyte levels. Some patients can even develop hyperkalemia and hyperphosphatemia, which will give an idea about severity of the patient. Electrolyte abnormality can lead to cardiac arrhythmias. So, the patient will need ECG monitoring.

This plays a vital role in ruling out an infection or sepsis.

Elevated transaminase levels will be seen in NMS.

These are important to exclude CNS infections, encephalitis, and meningitis. This is crucial as managing a CNS infection is totally different from NMS, and mismanagement can lead to death.

Brain CT and MRI can be used to exclude intracranial hemorrhage. A history of head trauma is indicative for these imaging studies.

Chest radiography is indicated in suspected pneumonia. If our patient has severe respiratory symptoms, we may have to perform this.

This is the first step investigation to rule out thyrotoxicosis. Free T3/T4 level is vital to exclude thyrotoxicosis.

Low serum iron is a risk factor for NMS. This can be associated with anemia.

These will help us to rule out substance abuse. We may have to use different tests according to the substance the patient has used.

Critical in assessing the severity of the patient. Some patients can develop metabolic acidosis in NMS.

So, you would understand MR. David has to undergo several investigations to diagnose his condition and make a proper management plan for him.

How to Arrive at the Diagnosis?

NMS is a diagnosis of exclusion. You might wonder what that means. Let us make that clear.

To arrive at the diagnosis of NMS, first, we have to think of possible differential diagnoses according to the history and clinical presentation. Then, we have to exclude all other conditions through investigations and examination.

Taking a good history and analyzing symptoms and signs will provided enough clues to suspect NMS in a patient. Laboratory investigations play a vital role in excluding other diseases conditions leaving us only with NMS. So, what we have to do to save a life is to have a high clinical suspicion for NMS and order relevant investigations to the situation.

How to Manage our Patient?

To save the life of Mr. David, we have to make a proper management plan. What should we include in that?

First, we have to withdraw the causative antipsychotic medication.  After that, supportive therapy is the mainstay in the management plan for NMS. We have to monitor the severity of the disease and treat it accordingly.

Given that most of the patients with NMS are dehydrated even in the acute phase of the illness, we should consider early volume resuscitation. Always remember that hypovolemia can deteriorate the condition of our patient.

Continuous monitoring and correction of electrolyte abnormalities is a crucial factor in NMS. If a patient develops extreme hyperthermia, physical cooling measures may be needed. We have to identify any intercurrent infection and treat it promptly.

We should not forget that Mr. David can develop many severe complications, including renal failure, arrhythmias, hypovolemic shock, aspiration pneumonia, respiratory failure, and coagulopathies. We have to monitor him for these complications and intervene early as our delay can cost the life of our patient

Renal failure is a common complication in NMS. Renal function tests and urine output monitoring should be done to assess this. Some of the complications may require support in specialized care unit.

NMS is considered a self-limiting disease. In most cases, supportive therapy and cessation of antipsychotic drug are sufficient to manage the condition. No drug treatment is found to be undoubtedly effective for NMS. So, don’t we use any drug in NMS? Some studies show that there are drugs that can help in NMS.

We can use some drugs to treat the symptoms of NMS. Antipyretics are commonly used to treat fever. In cases of extreme hyperthermia, we can use Dantrolene. Diazepam is the drug to treat muscle stiffness. Bromocriptine, a dopamine agonist, can be used to reverse Parkinsonism symptoms in NMS.

If we want to see Mr. David up and about soon, we must consider the above factors and manage him effectively. To assure his health in the future, we have to give him a continued care.

Should We Follow-up Our Patient?

Yes, we have to follow up with patients with NMS. Let us see why? Some patients with NMS may have prolonged symptoms. So, they will need a close follow-up for residual symptoms.

And also, do not forget that we have taken off antipsychotic medications of Mr. David. This can adversely affect his psychiatric illness. So, we have to evaluate the severity of his psychiatric disorder and act accordingly.

If we are to restart antipsychotic medication, we can try a low dose of an atypical antipsychotic drug.

The recurrence of NMS is an issue in some cases. What can we do to prevent this? For this, antipsychotics should be used in lowest dose possible, and gradual titration of doses should be done.

Always remember to educate the patient and the family about this condition, NMS.

We have to explain the importance of avoiding risk factors of NMS to the patients. We can advise them to hydrate adequately, avoid physical exhaustion, and not to expose to high temperatures. As NMS is a life-threatening condition, it is essential to take steps to prevent NMS.

Conclusion

NMS is a life-threatening complication of treatment with antipsychotic drugs. As it is a diagnosis of exclusion, it can be hard to diagnose. So, we have to have a high clinical suspicion for NMS in any patient treated with antipsychotic drugs. Early diagnosis will give a good outcome.

References

  1. Harrison, P., Cowen, P., Burns, T., & Fazel, M. (2017). Shorter Oxford Textbook of Psychiatry (7th ed.). Oxford University Press.
  2. ICD-10-CM 2021 Professional for Physicians with Guidelines (10th ed.). (2020). Optum360.
  3. Neuroleptic malignant syndrome: a concealed diagnosis with multi treatment approach (Velosa A.et.al) https://casereports.bmj.com/content/12/6/e225840
  4. Neuroleptic Malignant Syndrome: A Case Aimed at Raising Clinical Awareness (Madara J.et al) https://www.hindawi.com/journals/crim/2015/769576/