Case Report - Journal of Neurology and Neurorehabilitation Research (2017) Volume 2, Issue 2
Myoclonic encephalopathy associated with the use of indomethacinSuranjana Basak*, Gunjan Malavia, Archana Bhate, Neeraj Jain, Dineshchandra Gupta
Department of Medicine, Dr. D. Y. Patil Medical College and Hospital, Navi Mumbai, Maharashtra, India
- Corresponding Author:
- Suranjana Basak
Department of Medicine
Dr. D. Y. Patil Medical College and Hospital
Tel: 020 2780 5000
E-mail: [email protected]
Accepted Date: December 30, 2017
Citation: Basak S, Malavia G, Bhate A, et al. Myoclonic encephalopathy associated with the use of indomethacin. J Neurol Neurorehabil Res. 2017;2(2):30-33.
Neurologic disorders, Myoclonic encephalopathy, Convulsion, Neurotransmitters, Indomethacin.
The emergence of new neurologic side effects of drugs worsens the challenges that neurologists face while prescribing medicines. These side effects can result in potential misdiagnoses, including false psychiatric diagnoses, as seen in some drugs. Certain unanticipated and unpredictable drug interactions can result in a confusing range of symptoms that may altogether be identified as a new medical condition. For instance, Serotonin Syndrome is a known adverse effect caused by overuse of drugs such as MAOIs, TCAs, SSRI, SNRI, Triptans, Tramadol, Lithium, Valproate to name a few . Often, it is difficult to determine whether a neurologic condition is caused by a drug. The most difficult aspect in such cases is ensuring the specificity of the event related to the drug by ruling out other potential causes of the disorder. This is particularly true of less severe presentations of serotonin syndrome, which still contribute to patient morbidity . Physicians are encouraged to consider the possibility of serotonin like syndrome in patients who present with autonomic changes, mental status changes, and neurological hyperexcitability despite of being on medications that are not known to cause Serotonin Syndrome. Here we present to you one such rare interaction of Indomethacin causing Serotonin like syndrome with minimal dose.
A 49-year-old male presented to the ER after being referred from a local hospital with the complaint of convulsion followed by prolonged altered sensorium. There was no history of fever, cough in the recent past nor is he a known epileptic, as reported by next of kin. The course of management at the local hospital stated, administration of intravenous fluids and Inj. Eptoin 500 mg. Following which a CT Brain (Plain) was done and concluded, Normal. When brought to the ER, his GCS was 9 (E3 V2 M4). He had no episodes of convulsions since the one on the previous day, but was delirious. There was no myoclonus and movements were present. He was admitted in ICU. MRI Brain (Plain + Contrast) done was Normal. CSF study showed elevated proteins (83), elevated glucose (85), HGT at time of LP 122, elevated cells (8-all lymphocytes), RBC 1670. Blood Culture provisionally showed GPCs, reported on 3 days later showed MRSA and sensitive to Gentamycin, Tetracycline,Doxycycline, Ciprofloxacin, Levofloxacin, Clindamycin, Chloramphenicol, Linezolid and Tobramycin. He was started empirically on Inj. Monocef 2 gm TDS, Inj. Vanco 1 gm TDS, Inj. Acyclovir 750 gm TDS for 5 days and anti-epileptics i.e. Inj. Levipil 1 gm TDS, Inj. Eptoin 100 mg TDS. He improved in sensorium within 2 days and was shifted out of ICU on 4th day of hospitalization.
He complained of swelling and tenderness of both ankles which was reviewed by Orthopedic Surgeon and diagnosed as reactive arthritis. He was started on T. Indomethacin 25 mg TDS from 5th day of admission. He developed delirium from the next day and became restless, aggressive (punching people). In the next 24 hours, he became mute, irritable and developed myoclonus. He was not eating or speaking. He did not improve with Olanzepine. On examination, he was awake, confused, agitated, had akinetic rigidity and did not respond to verbal commands. He was afebrile and had opsoclonus, photophobia, intermittent clenching of teeth, multifocal myoclonus especially of face, eyelids, limb and trunk that increased on touching, moving limbs. He was unable to close his eyes. No aerophobia, hydrophobia noted. He had profuse sweating of forehead and body, but pupils were normal, heart rate 83 bpm and blood pressure 130/84 mm of Hg i.e. no signs of any autonomic instability were noted. He had mild neck, limb rigidity and clonus in ankles. DTJ UL 3+, LL 3+, plantar reflexes were withdrawal. His investigations revealed normal hemogram, renal function, liver function, CPK, antithyroid antibodies, thyroid profile, ANA negative. His post contrast MRI was normal. EEG showed occasional sharp waves and no evidence of non-convulsive status epilepticus. Repeat CSF study was done, and it showed persistent elevated proteins but not RBCs/cells. Repeat Blood Culture tested Negative. The patient improved slowly when Indomethacin was stopped and on administration of Lorazepam for 7 days.
Cochrane Database of Systematic Reviews, PubMed, and Google were searched from January 1960 to December 2012 for articles on neurological effects of indomethacin, indomethacin psychosis, and serotonin syndrome, serotonin toxicity. Although there are a few research papers on Serotonin Syndrome, but hardly any on serotonin like syndrome induced by indomethacin. No guidelines or consensus statements have been published for either diagnosis or management. Recommendations were drawn from the literature, but there is minimal high-level evidence, especially in the realm of treatment. Patient initially had MRSA sepsis for which he was treated with antibiotics and was being considered to be discharged. However, he suddenly developed altered sensorium with akinetic rigidity, mute with multifocal myoclonus without fever, hyperCKemia or marked autonomic dysfunction. He was suspected to have Serotonin Syndrome, but no obvious agent i.e. antidepressant/anti emetics were used prior to this development  (Table 1).
|Seriousness||Autonomic Signs||`Neurological Signs||Mental Status||Other|
|Mild||Afebrile or low-grade fever||Intermittent tremor||Restlessness||-|
|Diaphoresis or shivering||Mukd hyperreflexia|
|Moderate||Increased tachycardia||Hyperreflexia||Easily startled||Rhabdomyolysis|
|Fever (up to 41 °C)||Induciblr clonus||Increased confusion||Metabolic Acidosis|
|Ocular clonus (slow continuous lateral eye movements0||Agitation and hypervigillance||Renal failure|
|Diarrhoea with normal skin colour||Myoclonus||Disseminated intravascular coagulopathy (secondary to hyperthermia)|
|Severe||Temperature often more than 41°C (Secondary to increased tone)||Increased muscle tone (lower limb>upper)||Delirium||As above|
|Substantial myoclonus or hyperreflexia|
Table 1. Signs and symptoms of serotonin syndrome.
|Major||Fever, rigidity, elevated creatine phosphokinase concentration|
|Minor||Tachycardia, abnormal arterial pressure, tachypnea, altered consciousness, diaphoresis, leucocytosis|
Neuroleptic Malignant Syndrome, Hashimoto’s Encephalitis, Rabies were ruled out by tests and history review  (Table 3).
|In the resence of 1 or more serotonergic drugs (within the past 5 weeks)||Yes, they have serotonin syndrome or toxicity|
|If patients have spontaneous clonus||Yes|
|If patients have inducible clonus and either agitation or diaphoresis||Yes|
|If patients have ocular clonus and agitation or diaphoresis||Yes|
|If patients have tremor and hyperreflexia||Yes|
|If patients are hypertonic and have a temperature > 38°C and have ocular clonus or inducible clonus||Yes|
Table 3. Decision rules for diagnosing serotonin syndrome in the presence of serotonergic agents within the past 5 weeks: Hunter serotonin toxicity criteria.
On review of charts and medical literature, it became obvious that starting of Indomethacin was temporally related to development of Serotonin Syndrome (Indomethacin related Psychosis). Even though Indomethacin is not well known to develop CNS reactions and hasn’t been established in the list of drugs causing Serotonin Syndrome [6-10] (Table 4).
|Mechanism||Drugs causing serotonin toxicity without drug interaction||Drug combinations causing moderate to severe toxicity|
|Increased production of serotonin||L-Tryptophan||L-Tryptophan with MAOI|
|Increased serotonin release from neurons ||Amphetamines||Amphetamines and MAOI|
|NMDA||NMDA and MAOI|
|NMDA and SSRI (lower risk)|
|5-HT1A Antagonism7||Buspirone||Paroxetine and Buspirone|
|Decrease serotonin reuptake||SSRIs||Analgesics with MAOI or SSRI|
|Venlafaxine||Clomipramine with MAOI|
|Clomipramine, imipramine||SSRIs, Venlafaxine with MAOI|
|Tramadaol, meperidine, methadone, fentanyl||SSRIs, Venlafaxine, Buproprion|
|St John's wort|
|MAO Inhibition9,10||MAOIs||Moclobemide and SSRIs or venlafaxine|
|Selegiline||Irreversible MAOIs with all serotonergic drugs|
|Linzolid||Linezolid and SSRIs|
Table 4. Drugs causing serotonin syndrome.
The vast majority of serotonin (90%) is synthesized in the periphery, but brain serotonin levels are the main factor in development of serotonin toxicity. On the other hand, Indomethacin is a non-steroidal anti-inflammatory drug (NSAID) that has antipyretic and analgesic properties which is used to treat acute and chronic pain, primarily of neurological, rheumatic and orthopedic origin. The exact mechanism of action hasn’t been established. However, it is believed that Indomethacin works by inhibiting the enzyme cyclo-oxygenase (COX-2) of the two distinct isofroms COX1, COX2 . Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain. Moreover, prostaglandins are known to be among the mediators of inflammation. Since Indomethacin is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues . It is used to treat reactive arthritis, hemicranias continua, ankylosing spondylitis etc. to name a few. Depending on the dosage, studies show mild to severe adverse effects (mainly, gastrointestinal) in among eight to thirty seven percent of cases . The exact mechanism of indomethacin causing psychosis is unclear. However, the molecular structure of indomethacin and serotonin are alike, as both of them have an indole moiety, which may explain the development of psychosis . Some studies suggested effects on prostaglandins and neurotransmitters . There is also evidence of decreased cerebral blood flow with indomethacin, which coincides with its peak levels and hence may contribute to adverse CNS effects .
Our case report has noteworthy similarities with the scientific literature published before. However, our case is unique as the patient had specific symptoms, which have been more different as compared to the other case, after exposure to indomethacin, which were resolved with its discontinuation. It is plausible that a higher dose of indomethacin may have contributed to a more diverse and severe reaction during the hospital admission, suggesting a strong link of adverse CNS reactions with the dose. Rapid resolution of symptoms after the discontinuation of indomethacin and lack of behavioural problems gradually makes our case infallible.
As of 2010, 14 cases of psychosis associated with the use of indomethacin have been reported to the Committee on Safety of Medicines/Medicine Control Agency (Committee on Safety of Medicines; personal communication) . There must be many medications that can cause serotonin toxicity, which are not typically included in the list of drugs known to do so and drug interactions are an important factor. The findings of multifocal clonus, agitation followed by mutism, hyperreflexia, and hypertonicity should prompt evaluation and medication review . Treatment is based on severity and focuses on prompt cessation of offending agents, symptomatic treatment, and use of benzodiazepines to decrease hypertonicity and neurological excitability. We report here a case of Indomethacin Psychosis.
The effects of Indomethacin on Central Nervous System are not well known. The similarities between Serotonin and Indomethacin i.e. Indolic moiety, effects on neurotransmitters and the mechanism of action need to be studied more.
Even though a few cases have been reported, the association has not been adequately highlighted. With the widespread use of Indomethacin especially by Orthopedic Surgeons, Neurologists, Rheumatologists, patients getting delirium/psychosis might be getting misdiagnosed and it may be causing fatality.
- Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352:1112-20.
- Gillman PK. The spectrum concept of serotonin toxicity. Pain Med. 2004;5:231-2.
- Delay J, Pichot P, Lempiere T, et al. Un neuroleptique majeur non phenothiazinique et non réserpinique, l’halopéridol, dans le traitement des psychoses. Ann Med Psychol. 1960;18:145-52.
- Dunkley EJ, Isbister GK, Sibbritt D, et al. The Hunter serotonin toxicity criteria: simple and accurate diagnostic decision rules for serotonin toxicity. QJM. 2003;96:635-42.
- Levenson JL. Neuroleptic malignant syndrome. Am J Psychiatr. 1985;142:1137-45.
- Gillman PK. A review of serotonin toxicity data: Implications for the mechanisms of antidepressant drug action. Biol Psychiatry. 2006;59:1046-51.
- Isbister GK, Bowe SJ, Dawson A, et al. Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose. J Toxicol Clin Toxicol. 2004;42:277-85.
- Linde K, Mulrow CD, Berner M, et al. St John’s wort for depression. Cochrane Database Syst Rev. 2005;2:CD000448.
- Lawrence KR, Adra M, Gillman PK. Serotonin toxicity associated with the use of linezolid: A review of postmarketing data. Clin Infect Dis. 2006;42:1578-83.
- Berman AF. Herbdrug interactions. Lancet. 2000;355:134-8.
- John RV, Regina MB. Mechanism of action of nonsteroidal anti-inflammatory drugs. Ame J Med. 1998;104:2S-8S.
- Indomethacin. Martindale: The Complete Drug Reference. Brayfield A (ed). Pharmaceutical Press, London, UK. 2014.
- Boardman LP, Hart DF. Side effects of indomethacin. Ann Rheum Dis. 1967;26:127-32.
- Spittle BJ (1982) Drug-induced psychiatric syndrome. N Z Med J 95:349-352.
- Tollefson GD, Garvey MJ. Indomethacin and prostaglandins: their behavioural relationship in an acute toxic psychosis. J Clin Psychopharmacol. 1982;2:62-64.
- Seideman P, Arbin MV. Cerebral blood flow and indomethacin drug levels in subjects with and without central nervous side effects. Br J Clin Pharmacol. 1991;31:429-432.
- Tharumaratnam D, Bashford S, Khan SA. Indomethacin induced Psychosis. Postgrad Med J. 2000;76:736-7.
- Christopher F. Recognition and treatment of serotonin syndrome. Can Fam Physician. 2008;54:988-92.