Serotonin Syndrome and NMS — Clinical Case

DCE Long Case

Patient brief (provided to trainee)

Patient: Mr David Okafor, 54 years old, warehouse supervisor. [1]

Presenting complaint: Review on the medical ward, 10 days after admission with neuroleptic malignant syndrome. He is preparing for discharge. [1]

History of presenting complaint (the index admission): Mr Okafor has chronic schizophrenia, managed for the past four years with olanzapine 15 mg nocte with reasonable symptom control. Four weeks ago his psychiatrist changed him to aripiprazole 15 mg daily and cross-titrated over two weeks, discontinuing olanzapine. Two weeks into the aripiprazole, he became increasingly stiff and confused. His family brought him to the emergency department when he stopped speaking and was found rigid and unresponsive. On presentation: temperature 41.1 degrees, heart rate 128, blood pressure 90/55 then 176/104, GCS 12 (E3 V4 M5). He had marked lead-pipe rigidity, greater in the upper limbs, with bradyreflexia, a coarse tremor, and diaphoresis. Creatine kinase was 14,200 U/L, creatinine 320 micromol/L (baseline 90), white cell count 18.4, INR 1.8, ALT 180. Urine was dark brown. He was diagnosed with severe neuroleptic malignant syndrome complicated by rhabdomyolysis and acute kidney injury. [1]

Inpatient course: Aripiprazole was ceased. He was admitted to the ICU for three days, given intravenous fluids aggressively (target urine output 1.5 mL/kg/hour), active cooling, intravenous dantrolene (cumulative 5 mg/kg over 24 hours), and nasogastric bromocriptine 2.5 mg every 8 hours. He required two sessions of haemodialysis for refractory hyperkalaemia and acidosis on days 2 and 3. His creatine kinase peaked at 18,600 and fell over 10 days. His renal function is recovering (creatinine now 165). His mental state has improved — he is now conversant but reports residual stiffness. [1]

Past history:

• Chronic paranoid schizophrenia, diagnosed at age 24. Multiple admissions. Last relapse 18 months ago.
• Hypertension, on amlodipine 10 mg daily.
• Obesity, BMI 33.
• Ex-smoker, ceased 10 years ago.
• No known drug allergies previously. [1]

Current medications:

• Bromocriptine 2.5 mg every 8 hours (being weaned)
• Amlodipine 10 mg daily
• Enalapril 5 mg daily (added for renal protection)
• No antipsychotic currently (held since admission) [1]

Social history: Lives with his partner in a unit; two adult children. Previously worked as a warehouse supervisor but on sickness benefits for 2 years due to schizophrenia. His partner is supportive but reports he was functionally better on olanzapine than he has been on aripiprazole. [1]

Examination findings (trainee elicits):

• Alert and conversant, GCS 15. Mild residual cogwheel rigidity in both upper limbs, more on the right. Reflexes are present but reduced (bradyreflexic). No clonus.
• Temperature 36.9 degrees, heart rate 84 regular, blood pressure 138/82.
• Mild residual tremor in both hands.
• Urine output is good (75 mL/hour); urine now clear. [1]

Investigations (current):

• FBC: white cells 9.8, haemoglobin 132, platelets 230.
• U and E: sodium 138, potassium 4.2, creatinine 165 (baseline 90, peak 320), eGFR 42.
• Creatine kinase 620 (down from peak 18,600).
• LFTs: ALT 45, AST 38, albumin 34.
• INR 1.1.
• Iron studies: ferritin normal, iron 9 (low-normal). [1]

Candidate's structured presentation (model)

SASPOP opening statement: [1]

"Mr David Okafor is a 54-year-old warehouse supervisor with chronic schizophrenia who is recovering from severe neuroleptic malignant syndrome, triggered two weeks after a switch from olanzapine to aripiprazole. He presented with the classic tetrad of hyperthermia to 41.1 degrees, lead-pipe rigidity, altered mental status, and autonomic instability, complicated by rhabdomyolysis with a creatine kinase peaking at 18,600 and acute kidney injury requiring two sessions of haemodialysis. He is now 10 days into his admission, his CK is falling, his renal function is recovering, and the immediate question is how to manage his schizophrenia safely going forward given that he has now had NMS." [1]

Structured problem list: [1]

1. Recovery from severe neuroleptic malignant syndrome — CK falling but renal function not yet at baseline; bromocriptine being weaned
2. Acute kidney injury secondary to rhabdomyolysis — recovering, creatinine 165 (baseline 90); needs monitoring and renal-protective therapy
3. Chronic schizophrenia — currently untreated; high risk of relapse; needs a safe antipsychotic re-challenge plan
4. Residual extrapyramidal and rigidity signs — mild cogwheel rigidity and tremor
5. Cardiovascular risk — hypertension, obesity, ex-smoker
6. Psychosocial — supportive partner, functional decline, needs coordinated community support [1]

Integrated management plan

1. Completion of NMS recovery and bromocriptine wean:

• Continue bromocriptine 2.5 mg every 8 hours for a further 5 to 7 days, then taper over one week to prevent recurrence. Abrupt cessation of bromocriptine can precipitate rebound NMS [1][3].
• Monitor CK daily until stable below 500, then twice weekly.
• The residual cogwheel rigidity and tremor are likely a combination of recovering NMS and underlying antipsychotic-related parkinsonism; these should resolve as the dopamine system recovers.

2. Acute kidney injury and renal recovery:

• Creatinine has fallen from 320 to 165 (baseline 90). Maintain intravenous hydration, then oral hydration, to ensure ongoing renal perfusion and clearance of myoglobin.
• Continue enalapril for renal protection and hypertension once renal function is stable and potassium is normal.
• Nephrology follow-up at 2 to 4 weeks to confirm return to baseline and exclude persistent CKD; the eGFR is 42 now but expected to improve.
• Avoid nephrotoxins (NSAIDs, aminoglycosides, contrast where possible). [1]

3. Schizophrenia — the antipsychotic re-challenge decision: This is the central issue. The principles [1][3][4]:

• Do not restart antipsychotics until the patient is clinically stable and CK is near-normal — typically a 2-week symptom-free period. Mr Okafor is approaching this point.
• The recurrence rate after NMS is roughly 10 to 30 per cent on re-challenge, so re-challenge is feasible but must be done cautiously.
• Switch to a chemically distinct, lower-potency agent at low dose, titrated gradually. Options include quetiapine (lowest D2 affinity and lowest NMS risk among atypicals) or clozapine (reserved for refractory cases, requires monitoring).
• Critically, involve the psychiatry team now to plan the re-challenge in a supervised setting (inpatient or closely monitored outpatient), and to weigh this against the very real risk of psychotic relapse — his partner reports he was functionally better on olanzapine, but olanzapine was the agent from which he was cross-titrated; the aripiprazole is the more likely trigger here given the temporal relationship.
• Consider the role of a mood stabiliser or benzodiazepine as a bridge during the antipsychotic-free period.

4. Residual extrapyramidal signs:

• These should resolve as the dopamine system recovers; no specific treatment needed at present. If tremor or rigidity persists after 4 to 6 weeks, reassess in conjunction with the psychiatry team when the new antipsychotic is established. [1]

5. Cardiovascular risk optimisation:

• Continue amlodipine and enalapril; target blood pressure below 140/90.
• Address obesity and lifestyle once recovered; consider a weight-neutral antipsychotic (aripiprazole, ziprasidone) in the re-challenge plan given his BMI 33 and the metabolic risks of olanzapine. [1]

6. Psychosocial and prevention:

• Engage the community mental health team and his partner to support medication adherence and detect early signs of relapse or recurrence.
• Document the NMS reaction clearly in his medication record, with aripiprazole flagged as a precipitant.
• Provide education on the early signs of NMS (rigidity, fever, confusion) so the family can seek urgent review.
• Address the functional decline — consider vocational rehabilitation and supported employment. [1]

Examiner discussion questions

Q1: "Why did he develop NMS two weeks after the switch to aripiprazole, rather than immediately?" [1]

"NMS typically develops within the first one to four weeks of starting an antipsychotic or after a dose increase, with a median onset of about 4 to 7 days but a range up to 30 days [1][2]. Mr Okafor developed it around 14 days into aripiprazole, which is within the expected window. The cross-titration from olanzapine is relevant: during the overlap period, he had residual olanzapine D2 blockade plus new aripiprazole D2 partial agonism, and once olanzapine was fully discontinued, the net effect may have been a sudden shift in his dopaminergic equilibrium. Risk factors that lowered his threshold include his underlying schizophrenia, possible dehydration, and his obesity. The message is that NMS is a risk throughout the first month of any antipsychotic initiation or switch, not just in the first few days [4]."

Q2: "How do you explain the creatine kinase of 18,600 and the need for dialysis?" [1]

"The lead-pipe rigidity of NMS produces sustained, intense muscle contraction that breaks down skeletal muscle, releasing myoglobin and intracellular contents — this is rhabdomyolysis. The creatine kinase reflects the degree of muscle injury; values above 5000 are associated with acute kidney injury [3]. Myoglobin is directly toxic to the renal tubules, causes intrarenal vasoconstriction, and casts form in the distal tubule, producing pigment nephropathy and acute tubular necrosis. He developed oliguria with hyperkalaemia (refractory to medical therapy) and metabolic acidosis, which are absolute indications for renal replacement therapy. The two sessions of haemodialysis treated the immediate metabolic threats while the rhabdomyolysis resolved. His kidneys are recovering because the insult was acute and the tubular epithelium can regenerate — most rhabdomyolysis-induced AKI recovers fully within weeks to months if the patient survives the acute episode [3]."

Q3: "How confident are you that this is NMS and not malignant hyperthermia?" [1]

"Confident. Malignant hyperthermia is triggered by volatile anaesthetic agents (halothane, sevoflurane, desflurane) or succinylcholine, with onset within minutes to hours of exposure, and classically presents with masseter rigidity. Mr Okafor had no anaesthetic exposure, his onset was over days rather than minutes, and the trigger was an antipsychotic switch. Furthermore, he meets the Gurrera international Delphi consensus criteria for NMS: recent dopamine exposure (aripiprazole), hyperthermia (41.1 degrees), rigidity (lead-pipe), and altered mental status [2]. The markedly elevated CK, leukocytosis, and transaminitis are all consistent. That said, if he ever requires general anaesthesia in future, his NMS history does raise the possibility of an underlying susceptibility, and I would inform the anaesthetist — though NMS and malignant hyperthermia are genetically and mechanistically distinct, a careful anaesthetic plan with avoidance of known triggers is prudent [1]."

Q4: "What is your plan for his schizophrenia — will you re-challenge, and with what?" [1]

"Yes, re-challenge is indicated because untreated schizophrenia in a patient with a 30-year history carries a high risk of relapse, and his partner reports he was struggling even before this admission [1][3]. My plan, in partnership with psychiatry, is: first, wait until he is clinically stable with a CK near-normal for at least 2 weeks; second, re-challenge with a chemically distinct, lower-potency agent — quetiapine is my first choice because it has the lowest D2 affinity among the atypicals and the lowest reported NMS risk; start at a low dose (25 mg twice daily) and titrate gradually over 2 to 4 weeks; third, monitor closely for early signs of rigidity, fever, or CK rise; fourth, involve his community mental health team and partner for early detection of relapse or recurrence. I would avoid re-using aripiprazole and document it as an NMS precipitant. I would also consider clozapine if he fails the quetiapine re-challenge or has refractory symptoms, recognising clozapine has its own NMS risk (often atypical, without classic rigidity) and requires blood monitoring [4]. The risk of recurrence on re-challenge is 10 to 30 per cent, so this is a shared decision made with the patient and family, weighing psychosis control against NMS risk."

Q5: "What counselling would you give him and his partner at discharge?" [1]

"I would be honest and structured. I would explain that he had a serious but treatable reaction to his medication, that his kidneys are recovering, and that he needs close follow-up. I would warn him and his partner about the early signs of NMS — muscle stiffness, high fever, confusion, dark urine — and instruct them to seek urgent medical attention if these occur. I would explain that his schizophrenia still needs treatment and that we are working with the psychiatry team to find the safest medication, starting cautiously. I would give him a written medication alert card for aripiprazole and NMS, ensure his GP and community mental health team are informed, and arrange a renal follow-up appointment. I would acknowledge the disruption to his life and the anxiety this episode has caused, and offer the support of the social work and community mental health teams. Finally, I would discuss the elevated mortality of untreated schizophrenia and reassure him that a monitored re-challenge is the safer path than leaving his illness untreated [6]."