Neuroleptic Malignant Syndrome in a Patient with Lithium-induced Nephrogenic Diabetes Insipidus: A Case Report

Sir,

Neuroleptic malignant syndrome (NMS) is an idiosyncratic and rare but life-threatening condition with significant mortality and morbidity. Incidence of NMS among patients receiving neuroleptics vary from 0.02%–3%.^1,2 The pathophysiology of NMS is complex and still elusive, with two main postulated hypotheses, that is, dopamine receptor disturbances or blockade in the central nervous system, and insult to the musculoskeletal fibers from pharmacological compounds. ² Reported risk factors include neuroleptics, especially with high doses or rapid titration, parenteral neuroleptics, concomitant use of lithium and antipsychotics, lithium intoxication, previous history of NMS, concurrent medical comorbidities, and dehydration. ² Lithium-induced nephrogenic diabetes insipidus (NDI), a common side effect of lithium, has rarely been reported in the literature in association with NMS. We present a case of NMS in relation to lithium-induced NDI, followed by a discussion of the possible confounding factors in this complex case.

Case Report

The patient is a 46-year-old lady diagnosed with schizoaffective disorder, in full remission, on maintenance therapy of olanzapine 30 mg/day and lithium carbonate 900 mg/day. She has been on lithium for the past 30 years and olanzapine for the past 17 years, without any reported side effects. The dosage has remained the same for at least five years. She had a history of two episodes of NMS related to thioridazine more than 18 years ago. She had no significant past medical history and was not on any other medications. Relevant laboratory investigations during regular follow-ups, that is, complete blood count, renal profile, thyroid function test, and serum lithium, were within normal range, except for an isolated incident of hypernatremia (150 mmol/L) four months prior to her current presentation.

She presented in February 2020 with an acute onset of altered mental status, restlessness, and self-neglect of four-days duration. On examination, she was not cooperative, disoriented, inattentive, and observed to be wandering around. Vital signs showed fever, tachycardia, and fluctuating blood pressure. Neurological examination revealed hypotonia over all limbs, muscle power of at least 3/5, normal reflexes, and no nuchal rigidity. Admission workup revealed leukocytosis (WBC: 17.4 10⁹/L), acute kidney injury with hypernatremia (urea 6.8 mmol/L, creatinine 126 umol/L, sodium 150 mmol/L), and raised creatine kinase (CK 3131 U/L). Serum lithium was within the therapeutic range (0.8 mmol/L). Blood and urine cultures yielded no growth. Chest X-ray was normal. Contrasted tomography of the brain was unremarkable. Three days after admission, she had a sudden drop in consciousness and was intubated. She was further observed to have blank stares and nonspecific muscle twitching over the mouth and limbs. An electroencephalogram performed to rule out further organic causes was normal. She was diagnosed with NMS, based on Levenson’s criteria. ³ Her psychiatric medications were stopped whilst providing supportive treatment.

Meanwhile, persistent hypernatremia (up to 170 mmol/L) and increased urine output (> 3 liters/day) prompted further investigations and referral to the endocrinologist. Serum osmolality was 366 mOsm/kg, while urine osmolality was 272 mOsm/kg. Fluid deprivation test was not ordered at this juncture due to concerns of worsening of her medical condition. However, further history gathered revealed that the patient had been consuming more the six litres of water per day, with nocturia. The endocrinologist conferred a diagnosis of lithium-induced NDI, and the patient was started on desmopressin.

The patient was started on olanzapine after 10 days of admission due to worsening agitation and relapse symptoms of her psychiatric illness. Her medications were titrated, and she was discharged after seven weeks with olanzapine 20 mg/day and risperidone 5 mg/day with some residual irrelevant speech. Lithium was not reintroduced. Her sodium levels and urine output had stabilized by the time of discharge. She has remained in remission, with no recurrence of NMS, on the current medication regimen at the time of this writing. She is, however, still maintained on desmopressin in view of irreversible NDI.

Discussion

The diagnosis of NMS was established based on Levenson’s criteria, ³ after carefully ruling out other pertinent differential diagnoses of sepsis, lithium intoxication, catatonia, serotonin syndrome, seizures, and encephalopathy. The use of atypical antipsychotics may explain the absence of rigidity in this patient. ⁴ Secondly, lithium-induced NDI may have been missed prior to admission. Hypernatremia should have signaled an active enquiry on the polyuria-polydipsia complex. The delay in diagnosing NDI may have impeded prompt intervention, which increased her vulnerability to developing NMS on the background of dehydration as a result of self- neglect. ⁵

Confounding factors in this case include a combination of lithium and olanzapine; however, she had remained stable on this regimen for many years with no changes in the dosage or evidence of lithium toxicity. Hence, we posit antipsychotics to be of remote etiological possibility compared to NDI and the circumstances around it. In addition, there was no recurrence of NMS on rechallenging with antipsychotics upon stabilization of NDI.

Lithium was not recommenced, aiming instead for antipsychotic treatment. Chronic lithium use may result in renal impairment apart from irreversible NDI, which can impair water homeostasis, potentiating NMS. Limiting the use of lithium and hence its potential side effects may serve to reduce the risk of recurrence of NMS. ⁶ Nevertheless, vigilance in monitoring for NMS is imperative in this given clinical context.

This case proposes that lithium-induced NDI may increase the vulnerability for NMS. Patients with lithium-induced NDI are at an increased risk of dehydration, especially if adequate water homeostasis is not maintained. A medical condition can further exacerbate this. In a patient on lithium, we suggest that practitioners actively inquire on the polyuria-polydipsia complex, and remain vigilant about the monitoring of sodium levels and serum and urine osmolality. Serum lithium should also be maintained on the lower end of the therapeutic range, avoiding episodes of toxicity, and psychoeducation needs to be given regarding water intake, to avoid dehydration or overhydration. Lithium is best avoided in a patient with NDI and NMS unless absolutely necessary, after a risk-benefit analysis is performed.