case report

Oman Medical Journal [2016], Vol. 31, No. 4:309–311

Neuroleptic Malignant Syndrome Associated with Lithium Toxicity

Vaibhav Patil, Rishab Gupta, Rohit Verma and Yatan Pal Singh Balhara*

Department of Psychiatry, National Drug Dependence Treatment Centre, All India Institute of Medical Sciences,
New Delhi, India

article info

Abstract

Neuroleptic Malignant Syndrome (NMS) is an idiosyncratic and potentially life-threatening reaction to neuroleptic drugs. Lithium is a first-line mood stabilizer used in the treatment and prophylaxis of bipolar disorder. There are several case reports of lithium-associated NMS, but only when it was given in combination with antipsychotics. Therefore, the possibility of NMS being secondary to the antipsychotics could not be ruled out in those cases. Here we present a case of lithium-induced NMS in a patient who was not being treated concomitantly with any other agent known to cause NMS. The patient, a 74-year-old female with a 30-year history of bipolar affective disorder, was admitted to the emergency room of the All India Institute of Medical Sciences, New Delhi, with history of high fever and generalized weakness for 10 days before the admission. NMS was established based the presence of three cardinal symptoms. She was started on intravenous fluids to correct her sodium levels slowly and requested to follow-up at the psychiatry clinic.

Neuroleptic Malignant Syndrome (NMS) is an idiosyncratic and potentially life-threatening reaction to neuroleptic drugs. It is usually characterized by hyperpyrexia, muscle rigidity, autonomic dysfunction, altered mental status, tremors, leukocytosis, and creatine kinase (CK) elevation.1 Although its incidence has decreased in the last few decades due to the availability and increased use of the newer generation antipsychotics, NMS still represents a significant cause of morbidity and mortality in patients treated with antipsychotics. Its incidence is reported to be around 0.01–0.02%.2

NMS is mostly found associated with the use of traditional antipsychotics, but may also occur when atypical antipsychotics such as risperidone, olanzapine, and clozapine are used.3–5 There are some cases of NMS associated with the use of non-neuroleptic drugs, like carbamazepine6 and metoclopramide,7 or drugs without known antidopaminergic activity, such as lithium.8

Lithium is a first-line mood stabilizer used in the treatment and prophylaxis of bipolar disorder. There are several case reports of lithium-associated NMS, but only in combination with antipsychotics.9,10 Therefore, the possibility of NMS being secondary to the antipsychotics could not be ruled out in those cases. To the best of our knowledge, there are only two reports of isolated lithium-induced NMS.11,12

Here we present a case of lithium-induced NMS in a patient who was not being treated concomitantly with any other agents known to cause NMS.

Case Report

A 74-year-old female with a 30-year history of bipolar affective disorder and hypothyroidism was brought by her family members to the emergency department of the All India Institute of Medical Sciences, New Delhi. She presented with a 10-day history of high fever and generalized weakness. She was found to have rigidity in her limbs. According to her family, her oral intake had dramatically reduced in the preceding week. Four days before admission, her consciousness was affected. Her bipolar affective disorder corresponded to code 296.46 of Diagnostic and Statistical Manual of Mental Disorders (DSM) 5 and F31.7 of International Classification of Diseases (ICD) 10. She was on lithium 400 mg/d, valproate 500 mg/d and levothyroxine 100 µg/d tablets for the last two years with no change in dosage. Her family members denied any use of neuroleptics or other dopamine receptor-blocking agents, including antiemetics, by the patient. They also denied the possibility of medication overdose or any suicidal ideas expressed by the patient. The patient had no history of substance abuse or other medical or neurological illness and no family history of psychiatric illness.

On admission, the patient was disoriented and confused. There was history of fever, recorded by her family members. However, she was afebrile at the time of examination. Her blood pressure was 150/70 mmHg. Generalized rigidity was evident on examination. Blood counts showed marked leukocytosis (21.5 × 103 /µL). Biochemistry revealed elevated CK levels (637 IU/L) and her serum sodium levels were low (107 mEq/L). Her serum lithium level was deranged (2.5 mEq/L; normal range = 0.6–1.2 mEq/L). As she did not have any clinical or biochemical features suggestive of valproate toxicity (tremors, ataxia, dysarthria, or deranged liver function tests), her serum valproate level was not measured. We did not perform an electroencephalogram (EEG) since we did not suspect non-convulsive status epilepticus.

Neuroimaging showed age-related cerebral and cerebellar atrophy. Physical examination of chest and abdomen was unremarkable and cerebrospinal fluid (CSF) analysis showed no abnormalities. Urine toxicology, blood, urine, and CSF cultures were negative. Her thyroid hormone levels were normal.

In light of the above findings, the possibility of sepsis was ruled out, and a diagnosis of NMS and lithium toxicity was made. NMS was diagnosed based on the presence of three defining symptoms: fever, muscle rigidity, and elevated CK. The diagnosis can also be made in the presence of two out of three of the aforementioned symptoms and at least two other supplementary symptoms, including tachycardia, abnormal blood pressure, tachypnea, altered consciousness, diaphoresis, or leukocytosis.13

The patient was shifted to the intensive care unit (ICU) and her psychotropics were discontinued. She was started on intravenous (IV) fluids to correct her sodium level slowly. With supportive management, her serum lithium levels, serum sodium levels, and serum CK levels normalized. She showed a gradual improvement in her mental status, had no problems with articulation, and was fully oriented after two weeks. Her vitals stabilized, and there was minimal rigidity at the time of discharge.

She was discharged on valproate 500 mg/d and levothyroxine 100 µg/d tablets and requested to attend the psychiatry clinic.

Discussion

Lithium is usually used as a first-line mood stabilizer in bipolar affective disorder with proven efficacy.14 It has a narrow therapeutic index, and its toxicity varies from mild tremors to serious side-effects such as renal impairment, convulsions, and altered mental status. The concomitant administration of drugs such as antipsychotics, diuretics, non-steroidal anti-inflammatory drugs (NSAIDs), antiemetics or dopaminergic agents may result in lithium toxicity. Factors that increase the risk of lithium toxicity are dehydration, infection, and the presence of other medical condition. Prior to the onset of symptoms, the medical condition of our patient was satisfactory, and she was not on any medications other than lithium, valproate, and levothyroxine.
There was no change in the medications or their doses in the last two years. Her family members reported that they ensured compliance to medications. They denied any possibility of overdose. Her thyroid status was also normal.

Serotonin syndrome was considered as one of the differential diagnosis. However, its possibility was considered very low owing to the absence of concomitant use of another serotonergic drug and symptoms suggestive of hyperserotonergic state (e.g., myoclonus, diarrhea).15

In this particular case, we suspected a possibility of dehydration induced lithium toxicity, which probably led to NMS. The patient’s old age, which is an important risk factor for psychotropic neurotoxicity, might have contributed to her developing this complication. Another possibility is that she might have developed idiosyncratic and slowly progressive symptoms of NMS despite being on a stable lithium dose, and that could have led to decreased oral intake and subsequent
lithium toxicity.

Lithium alters neurotransmitter activity and reduces the effects of dopamine by preventing the accumulation of cyclic adenosine monophosphate at the intracellular level.16 Dopamine hypoactivity has been widely accepted as a hypothesis for the occurrence of NMS.17 This might be the causal mechanism of NMS in our case.

There are few reports available that have described the association of valproate use with the appearance of NMS; however, in these cases, patients were also on antipsychotics.18,19 To the best of our knowledge, no literature exists on the occurrence of NMS with valproate monotherapy. Verma et al,20 reported the development of NMS in a patient after the addition of valproate while he was maintained on olanzapine. NMS in that case could be attributed solely to olanzapine since NMS can occur even after prolonged use of antipsychotics.

Conclusion

In our patient, lithium seemed to be the likely offending drug causing NMS. We recommend that treating physicians should remain cautious about the risk of NMS during lithium monotherapy.

Disclosure

The authors declared no conflicts of interest.

references

  1. 1. Gurrera RJ, Caroff SN, Cohen A, Carroll BT, DeRoos F, Francis A, et al. An international consensus study of neuroleptic malignant syndrome diagnostic criteria using the Delphi method. J Clin Psychiatry 2011 Sep;72(9):1222-1228.
  2. 2. Stubner S, Rustenbeck E, Grohmann R, Wagner G, Engel R, Neundörfer G, Möller HJ, et al. Severe and uncommon involuntary movement disorders due to psychotropic drugs. Pharmacopsychiatry 2004;37(1):S54-S64.
  3. 3. Arslankoylu AE, Kutuk MO, Okuyaz C, Toros F. Neuroleptic malignant syndrome due to risperidone misdiagnosed as status epilepticus. Pediatr Rep 2011 Jun;3(3):e19.
  4. 4. Tripathi P, Agrawal H, Goyal P, Kar SK. Olanzapine-induced neuroleptic malignant syndrome in a patient with bipolar affective disorder: Does quetiapine holds the solution? Ind Psychiatry J 2013 Jul;22(2):159-160.
  5. 5. Erol A, Putgül G, Sert E, Mete L. Clozapine-associated neuroleptic malignant syndrome followed by catatonia: a case report. Turk Psikiyatri Derg 2013;24(2):140-144.
  6. 6. Sharma B, Sannegowda RB, Gandhi P, Dubey P, Panagariya A. Combination of Steven-Johnson syndrome and neuroleptic malignant syndrome following carbamazepine therapy: a rare occurrence. BMJ Case Rep 2013 Jun11;2013.
  7. 7. Supariwala A, Kant G, Jean RE. Neuroleptic malignant syndrome with metoclopramide overdose coexisting with Clostridium difficile diarrhea. Intensive Care Med 2011 Oct;37(10):1706-1708. Published online 18 Jun 2011.
  8. 8. Trollor JN, Chen X, Sachdev PS. Neuroleptic malignant syndrome associated with atypical antipsychotic drugs. CNS Drugs 2009; 23(6):477-492.
  9. 9. Ali S, Pearlman RL, Upadhyay A, Patel P. Neuroleptic malignant syndrome with aripiprazole and lithium: a case report. J Clin Psychopharmacol 2006 Aug;26(4):434-436.
  10. 10. Borovicka MC, Bond LC, Gaughan KM. Ziprasidone- and lithium-induced neuroleptic malignant syndrome. Ann Pharmacother 2006 Jan;40(1):139-142.
  11. 11. Gill J, Singh H, Nugent K. Acute lithium intoxication and neuroleptic malignant syndrome. Pharmacotherapy 2003; 23(6):811-815.
  12. 12. Argyriou AA, Drakoulogona O, Karanasios P, Kouliasa L, Leonidou L, Giannakopoulou F, et al. Lithium-induced fatal neuroleptic malignant syndrome in a patient not being concomitantly treated with commonly offending agents. J Pain Symptom Manage 2012 Dec;44(6):e4-e6.
  13. 13. Levenson JL.Neuroleptic malignant syndrome. Am J Psychiatry 1985; 142 (10):1137-1145.
  14. 14. Hirschowitz J, Kolevzon A, Garakani A. The pharmacological treatment of bipolar disorder: the question of modern advances. Harv Rev Psychiatry 2010 Sep-Oct;18(5):266-278.
  15. 15. Birmes P, Coppin D, Schmitt L, Lauque D. Serotonin syndrome: a brief review. CMAJ 2003 May;168(11):1439-1442.
  16. 16. Manji HK, Potter WZ, Lenox RH. Signal transduction pathways. Molecular targets for lithium’s actions. Arch Gen Psychiatry 1995 Jul;52(7):531-543.
  17. 17. Factor SA. Neuroleptic malignant syndrome. In: Factor SA, Lang AE, Weiner WJ, editors. Drug induced movement disorders. New York: Blackwell Publishing; 2005. p 174-212.
  18. 18. Gortney JS, Fagan A, Kissack JC. Neuroleptic malignant syndrome secondary to quetiapine. Ann Pharmacother 2009 Apr;43(4):785-791.
  19. 19. Ladds B, Thomas P, Mejia C, Hauser D. Extreme elevation of creatinine phosphokinase levels in neuroleptic malignant syndrome associated with atypical antipsychotics. Am J Psychiatry 2009 Jan;166(1):114-115.
  20. 20. Verma R, Junewar V, Rathaur BP. An atypical case of neuroleptic malignant syndrome precipitated by valproate. BMJ Case Rep. 2014 Mar 6; 2014.