Levosulpiride-induced neuroleptic malignant syndrome in rheumatoid arthritis

Abstract

A 53-year-old woman, known case of diabetes mellitus and rheumatoid arthritis, presented with a 4-day history of hyperthermia, rigidity, tremor and altered sensorium. She developed these symptoms after having been administered parenteral levosulpiride to control vomiting due to secondary adrenal insufficiency. We managed her as a case of life-threatening neuroleptic malignant syndrome (NMS) requiring mechanical ventilation, bromocriptine and other supportive care. She subsequently recovered and was discharged in a stable condition. To the best of our knowledge, this is the first documented case report describing levosulpiride-induced NMS.

Background

Levosulpiride is a D2 receptor antagonist that is fast gaining popularity among physicians as an antiemetic and prokinetic agent. Levosulpiride has been associated with extrapyramidal symptoms (EPS), chiefly parkinsonism. To the best of our knowledge, this is the first reported case of levosulpiride-induced neuroleptic malignant syndrome (NMS).

Case presentation

A 53-year-old woman, home maker, a resident of Mathura, presented to the emergency services of our hospital with a 4-day history of fever, rigidity, tremor and altered sensorium.

She had a history of rheumatoid arthritis (RA) for 15 years and type 2 diabetes mellitus for 5 years. She had recently undergone incision drainage for a right breast abscess at a local clinic 4 weeks ago and had subsequently received 2 weeks of intramuscular gentamicin 60 mg thrice a day which she was administered at home. Her relatives reported that while receiving this therapy, she had developed nausea, vomiting and increasing frequency of urination, but had neglected these symptoms initially and was persuaded to seek further medical attention only after her vomiting became intractable. She was readmitted in the same clinic where doctors told her relatives that she had ‘kidney damage’. Her vomiting reportedly did not improve at that hospital, and her relatives were alarmed when, on day 5 of admission, she developed spiking fever, rigidity, tremor and altered sensorium. She continued to worsen over the next 4 days when she was referred here due to her deteriorating condition. (For the timeline of events see figure 1.)

Figure 1.

Timeline of events. AIIMS, All India Institute of Medical Sciences. MPS, methylprednisolone.

At presentation, we found her to be in a delirious state with tachycardia (138/min), tachypnoea (46/min) and hypotension (70/40) for which she was intubated, started on intravenous fluids with vasopressor support and shifted to the intensive care unit (ICU). She was found to be severely dehydrated with hyperthermia (40.5°C), generalised rigidity with cogwheeling and a violent, shaking tremor that appeared to be continuous and unrelated to fluctuations in temperature. Differential diagnoses considered at this point were meningoencephalitis (infective/autoimmune), uraemic/metabolic/septic encephalopathy, thyrotoxicosis, non-convulsive status epilepticus and NMS.

Investigations

Investigations revealed deranged renal parameters, hypokalaemia, hypocalcaemia, hypomagnesaemia and hypernatraemia (table 1). She was found to have neutrophilic leucocytosis; however, repeated endotracheal aspirate, blood and urine cultures were sterile and serum procalcitonin was within normal limits. She underwent a non-contrast CT head and MRI brain, both were unremarkable. Cerebrospinal fluid (CSF) analysis showed the non-specific elevation of protein with nil cells and sterile cultures. Electroencephalogram was done which showed diffuse slowing suggestive of a metabolic cause of encephalopathy. Thyroid function tests were indicative of a sick euthyroid state. The autoimmune profile was found to be normal except for rheumatoid factor positivity.

Table 1.

Laboratory values of the patient at the time of hospital admission

	Reference range*	Day 1	Day 4	Day 8
Haemoglobin (g/dL)	12–15	10.4	10.6	10
Total leucocyte count (x109/L)	4–11	20.7 N90 L6.2	10.6 N75 L13.4	7.8 N79 L12
Platelet count (x109/L)	150–400	216	233	421
Urea (mg/dL)	10–50	83	59	49
Creatinine (mg/dL)	0.5–1.8	3.5	2.3	1.3
Sodium (mEq/L)	130–149	157	148	143
Potassium (mEq/L)	3.5–5	3.2	3.6	3.7
Total calcium (mg/dL)	8.5–10.5	7.2	9.6	8.7
Ionised calcium (mmol/L)	1.10–1.40	0.95	1.25	1.1
Magnesium (mg/dL)	1.8–2.2	1	1.78
Phosphate (mg/dL)	2.5–4.5	6.3	2.1	2.9
Uric acid (mg%)	2–7.4	4.5	2.9	2.5
Total bilirubin (mg/dL)	0.20–1.20	0.6	0.3	0.4
Total protein (g/dL)	6–8	5.5	5.8	6
Albumin (g/dL)	3.5–5	2.3	2.4	2.7
Globulin (g/dL)	2–3.5	3.2	3.4	3.3
AST (U/L)	0–50	105	84	75
ALT (U/L)	0–50	19	30	41
ALP (U/L)	80–240	312	371	403
Creatine kinase (U/L)	40–226	1460	736	156
LDH (U/L)	200–420	513		401
CSF
Total cells (per mm3)	0–15	Nil
Protein (mg/dL)	15–45	69
Glucose (mg/dL)	45–80	108 (RBS 184)
Serum procalcitonin (ng/mL)	<0.15	<0.15
TSH (U/mL)	0.3–5	0.553
Free T3 (pg/mL)	2.3–4.2	1.82
Free T4 (ng/dL)	0.8–2	0.91
Rheumatoid factor (IU/mL)	0–20	256
Intact PTH (pg/mL)	15–68	403
HbA1c (%)	<5.7	9.5
Serum cortisol (μg/dL)
0 min	7.49
30 min	14.35
60 min	15.29

*Reference value at the All India Institute of Medical Sciences, New Delhi; may vary from different laboratories.

ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate aminotransferase; CSF, cerebrospinal fluid; LDH, lactate dehydrogenase; PTH, parathyroid hormone; RBS, random blood sugar; TSH, thyroid stimulating hormone.

While reviewing her medical records, it was found that she had been administered levosulpiride at the clinic where she had been previously admitted. Her relatives confirmed that the hyperthermia, rigidity, tremors and altered sensorium began soon after levosulpiride had been administered parenterally to the patient. The specificity of the clinical features with the history of antecedent exposure to a plausible agent (levosulpiride is a D2 receptor antagonist) strongly favoured the diagnosis of NMS. Serum creatine kinase was sent which was reported to be very high. Creatine kinase levels were measured 13 days after her last intramuscular injection. Given the clinical context and temporal relation, the elevated creatine kinase was explained best by NMS with rhabdomyolysis. She was provisionally diagnosed as a case of levosulpiride-induced NMS, rhabdomyolysis, aminoglycoside-induced non-oliguric kidney injury with dyselectrolytaemias and hypovolaemic shock on a background of diabetes mellitus and RA.

Treatment

The patient’s urine output was initially >5 L/day. Aggressive intravenous fluid resuscitation with electrolyte correction was initiated to compensate for polyuria and increased insensible losses, to restore volume status and prevent rhabdomyolysis-induced renal shutdown. Hyperthermia was controlled with the use of cooling blankets and intravenous acetaminophen. The patient was started on tablet bromocriptine 2.5 mg thrice daily which was uptitrated daily with monitoring of liver function parameters and severity of extrapyramidal signs. Blood sugar levels were kept under control with insulin infusion. Other supportive treatment included thromboprophylaxis, bedsore care and stress ulcer prevention.

Norepinephrine was gradually tapered with the restoration of volume status, but she continued to have persistent low-dose vasopressor requirement (injectable norepinephrine 3 μg/min). Any attempt to further taper would result in sudden hypotension. The patient was re-evaluated in view of persistent shock. It was noticed that the patient had truncal obesity and thin limbs. Relatives were asked regarding past treatment for RA. They reported that the patient was maintained on only non-steroidal anti-inflammatory drugs. Keeping a high index of suspicion for adrenal insufficiency, her relatives from her village were contacted, who revealed to us that the patient regularly used to take tablet methylprednisolone at home for relief of joint pains. It was decided to do an adrenocorticotropic hormone (ACTH) stimulation test to substantiate the hypothesis of secondary adrenal insufficiency. Synacthen, the brand for which the test is described, is unfortunately not marketed in India. Due to this difficulty, the test was performed using Acton Prolongatum (Ferring Pharmaceuticals), a synthetic porcine sequence corticotrophin carboxymethylcellulose. As per the procedure followed by Gundgurthi et al¹ in their study validating the use of Acton Prolongatum in diagnosing adrenal insufficiency, 25 units of ACTH was injected intramuscularly. Cortisol samples were drawn at 0, 30 and 60 min. As serum cortisol failed to rise above 18 μg/dL 1 hour after intramuscular stimulation with ACTH, the results were interpreted as indicative of adrenal insufficiency. She was started on intravenous hydrocortisone infusion at replacement doses.

Outcome

The patient responded to treatment with resolution of tremor (2 days), hyperthermia (5 days), altered sensorium (7 days) and rigidity (10 days). Polyuric phase of acute kidney injury resolved and serum creatinine returned to baseline. Serum creatine kinase levels returned to within normal limits and myoglobinuria-induced anuric renal failure was averted. Resolution of shock, which plateaued after initial fluid resuscitation, was complete within 24 hours of starting glucocorticoid replacement. The patient was successfully extubated after 7 days of mechanical ventilation and shifted out of the ICU. She was started on methotrexate and hydroxychloroquine for RA, oral hypoglycaemic agents for diabetes and discharged on tapering doses of oral prednisolone and bromocriptine.

Follow-up

Bromocriptine was discontinued 7 days after discharge without recurrence of EPS. She is currently on a tapering dose of prednisolone with a plan to stop on an outpatient basis.

Discussion

Retrospective analysis of the case highlights the sequence of events that resulted in the patient developing NMS. Immunosuppression due to chronic steroid use and diabetes mellitus contributed to the development of a non-lactational breast abscess which was inappropriately treated with aminoglycosides and led to acute kidney injury. Concurrent discontinuation of methylprednisolone led to uncontrolled nausea and vomiting, for which the patient was administered levosulpiride, leading to the development of NMS. It can be reasonably inferred that inappropriate steroid use for RA led to a cascade of events that culminated in the patient’s current condition.

Levosulpiride is a selective central and peripheral D2 antagonist and has been marketed extensively as a prokinetic, antidepressant and antipsychotic agent in many fixed-dose combinations.² As a prokinetic agent in acid-peptic disorder its usual oral dose is 25 mg three times a day and is categorised as an atypical neuroleptic agent only when used at higher doses (200–300 mg daily).³ Despite the perception of an apparently safe medication for minor gastrointestinal complaints, its use may result in potentially life-threatening complications, especially in the vulnerable patient population.²

Usually, levosulpiride-associated EPS occur more frequently in women, children and the elderly. This could either be due to changes in the blood–brain barrier, sensitivity of dopamine receptors or slower rates of metabolism, necessitating dose modification. It requires dose modification in renal failure as well.⁴ The incidence is greater in patients receiving high intravenous doses during antiemetic therapy. Our patient had deranged renal function and therefore had higher chances of toxicity. Immediately after administration of levosulpiride, our patient developed hyperthermia, muscle rigidity, tremor and altered sensorium, consistent with NMS. The pathophysiology of NMS involves central dopaminergic blockade especially within the corpus striatum and hypothalamus, sympathetic hyperactivity as well as peripheral muscle effects causing rhabdomyolysis.⁵

Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition criteria⁶ for diagnosing NMS necessitate the presence of hyperthermia (oral temperature >38°C on at least two occasions), rigidity, creatine kinase elevation >4 times upper limit of normal, altered mental status, autonomic dysfunction in the form of tachypnoea (>50% from baseline), tachycardia (>25% from baseline), blood pressure elevation systolic or diastolic (25% above baseline), urinary incontinence, diaphoresis and other EPS. Our patient had hyperthermia, rigidity, altered mental status, tachycardia, tachypnoea and elevated lactate dehydrogenase (LDH) and creatine kinase levels. Although the interpretation of LDH and creatine kinase is tricky on a background of deranged renal function,^{7 8} the clinical picture fits into the diagnosis of NMS. Leucocytosis with left shift, transaminitis and non-specific elevation of CSF protein may also be seen in NMS.⁹

Although levosulpiride-induced movement (LIM) disorders have been reported in the literature,^{2 10 11} and NMS has been described as a potential side effect,¹¹ no case of levosulpiride-induced NMS has ever been formally documented. In a study on drug-induced movement disorders in South Korea, among 132 consecutive patients studied over the period from 2002 to 2008, ninety-one (68.9%) had LIM. Among LIM, Parkinson’s disease was the most common (85, 93.4%). Interestingly, after 1 year of follow-up, LIM was reversible in only about 52% patients.¹⁰ While levosulpiride continues to be a popular drug for many gastrointestinal symptoms, physicians need to be vigilant for the occurrence of EPS, especially among the vulnerable population. With this case report, the spectrum of EPS induced by levosulpiride may now be considered to include NMS as well.

This case also highlights the dangers of prolonged use of corticosteroids and the consequences of their abrupt discontinuation. In the case of our patient, steroids were initially prescribed, as per history obtained later, by a local practitioner presumably to tide over symptoms of RA. However, the continued intake was at the patient’s behest without the knowledge of the practitioner, and was carried out without any knowledge of the risks of prolonged steroid use and sudden cessation.

Learning points.

• Levosulpiride can cause extrapyramidal symptoms and requires careful dosing in the elderly and in renal failure. The neuroleptic malignant syndrome, though biologically plausible, had not been reported as a complication of this drug until now.

• Abrupt cessation of glucocorticoid intake following prolonged use may be associated with dangerous consequences like adrenal insufficiency.

• Aminoglycosides are commonly associated with kidney injury when used in supratherapeutic doses or for extended periods of time.