Restlessness, muscle twitches, and diarrhea.

Transcription

1 Restlessness, twitches & diarrhea: 1/7 Case 062: Restlessness, muscle twitches, and diarrhea. Authors: * Jason Ko MB BS, MRCP # David C Chung MD, FRCPC Affiliations: *Tuen Mun Hospital, Hong Kong SAR # The Chinese University of Hong Kong The patient was a 44 year old lawyer who came to the Emergency Department complaining of restlessness, muscle twitches, abdominal pain with diarrhea, and stuttering speech in the past 24 hours. History obtained from his wife related his current troubles to a visit to a sports clinic 3 days ago when he was prescribed tramadol 100 mg by mouth 4 times a day for back sprain sustained in a golf game. The patient was also suffering from depression in the last 2 years controlled on fluoxetine 80 mg daily. There was no recent weight loss, no heat intolerance, and he was free of hypertension, cardiorespiratory illnesses, and diabetes. Physical examination revealed a well nourished and well groomed man of stated age. He was sweating profusely but his skin color was normal. He looked anxious and distressed and his speech came in bursts so rapid that he often stumbled for words. His vital signs were: oral temperature 38.6 o C; blood pressure 156/96 mmhg; pulse rate 108/min and regular; respiratory rate 16/min. Examination of the heart and lungs revealed normal findings; increased bowel sounds were heard on auscultation of the abdomen. The thyroid was not enlarged; there was coarse tremor of the upper extremities but no exophthalmos; the pupils were 4 mm in diameter bilaterally and un-reactive. Cranial nerve examination was normal; there were no long tract signs; muscle power was 5/5 bilaterally; there was generalized increased in tone in the extremities. Tendon reflexes were brisk; test for knee jerk produced several beats of clonus which was not elicited in the upper extremities. 1. What are the differential diagnoses? o Although there was no history of drug abuse, recreational drugs (e.g. amphetamine, cocaine, ketamine) can be the cause for the clinical presentation seen in this patient.

2 Restlessness, twitches & diarrhea: 2/7 o This patient s mental state and signs are compatible with alcohol or opioid withdrawal. o This patient presented with many features of thyrotoxicosis, even thyroid storm. o Systemic infection, including that of the central nervous system, must be ruled out. o A patient with the neuroleptic malignant syndrome can also present with pyrexia, altered level of consciousness, muscle hypertonicity, and autonomic dysfunction. This syndrome represents an idiopathic reaction to dopamine antagonists (e.g. haloperidol). o Patients poisoned by anticholinergic drugs (e.g. atropine) are also pyrexic, delirious, and have dilated pupils. But their skin is red, hot, and dry. There is urinary retention, absence of bowel sounds, and no muscular abnormalities. o Malignant hyperpyrexia is another possibility but this condition is usually precipitated by exposure to anesthetic drugs. o In this patient his complaints have a temporal relationship to tramadol. Tramadol, a centrally acting analgesic, is a weak µ-opioid receptor agonist. It also inhibits serotonin re-uptake. Although the patient s manifestation may be an idiosyncratic reaction to tramadol, interaction of this drug with fluoxetine, giving rise to the serotonin syndrome, is the most likely explanation of this patient s symptoms and signs. 2. What is the serotonin syndrome? The serotonin syndrome is a drug-induced, and potentially fatal, condition resulting from excessive serotonin (5-hydroxytryptamine) activity within the central nervous system (CNS). Although it has been reported to have occurred with the overdose of a single serotoninergic drug, it is far more common to be a consequence of interaction between drugs that increase serotonin in the CNS by different mechanisms. The drug-drug interaction in this case is a prime example. While fluoxetine is a selective serotonin reuptake inhibitor (SSRI), tramadol is not only an analgesic but also a non-selective inhibitor of serotonin and norepinephrine reuptake.

3 Restlessness, twitches & diarrhea: 3/7 3. What are the clinical features of the serotonin syndrome? Clinical features of the serotonin syndrome are classically described as a triad of mental state changes, neuromuscular abnormalities, and autonomic hyperactivities: Mental state abnormalities Hyper-vigilance. Pressured speech. Easily startled. Agitation. Delirium. Neuromuscular changes Akathisia (motor restlessness). Tremor. Hyperactive stretch reflexes (lower limbs > upper limbs). Clonus (increased from inducible to sustained with increasing severity). Muscle hypertonicity and rigidity. Pyrexia: body temperature >38 o C (a consequence of increased skeletal muscle activities). Autonomic hyperactivities Tachycardia. Hypertension; possible hypotension due to cardiovascular instability. Diaphoresis. Mydriasis. Hyperactive bowel sounds (increased motility). Not all of these signs are present consistently. Presentation can range from mild to lethal with onset time from minutes to hours. Severe attacks are complicated by hyperpyrexia (body temperature > 40 o C), rhabdomyolysis, renal failure,

4 Restlessness, twitches & diarrhea: 4/7 severe metabolic acidosis, disseminated intravascular coagulation, and cardiovascular collapse. 4. Are there any diagnostic tests for the serotonin syndrome? There are no specific laboratory tests for the serotonin syndrome. Plasma serotonin level is not helpful. The most important clue to diagnosis is a history of receiving one or more serotoninergic agents. An exhaustive drug history should include the use of prescription, over-the-counter, and street drugs as well as health food products. Once the drug or drugs is identified, the presence of 3 or more of the following signs establishes the diagnosis, provided a neuroleptic drug has not be started or increased in dose recently (Sternbach criteria): Mental status changes such as confusion or hypomania. Agitation. Poor coordination. Tremor. Hyper-reflexia. Myoclonus. Diaphoresis. Shivering. Diarrhea. Fever. 5. What are the common serotoninergic drugs that can interact with SSRI drugs to cause the serotonin syndrome? Common serotoninergic drugs that can interact with SSRI drugs to cause the serotonin syndrome include:

5 Restlessness, twitches & diarrhea: 5/7 Drug / class of drugs Tryptophan Amphetamines (including "ecstasy"), bromocriptine, cocaine, L-dopa Dextromethorphan, nefazadone, pethidine (meperidine), tramadol Citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline Venlafaxine, tricyclic antidepressants Monoamine oxidase inhibitors (MAOI) Moclobemide Lysergic acid diethylamide (LSD) Lithium Serotoninergic mechanism Serotonin precursor; increases serotonin production. Releases serotonin from store depot. Impairs reputake of serotonin into presynaptic nerve. Selective serotonin reuptake inhibitor (SSRI) drugs. Inhibits serotonin and norepinephrine reuptake. Inhibition of serotonin metabolism. Non-selective MAOI. Post-synaptic serotonin receptor stimulation. Enhances post-synaptic response to serotonin stimulation. 6. How should the serotonin syndrome be managed? The first step in management of the serotonin syndrome is to remove the offending drugs. Subsequent therapy depends on the severity of its clinical presentation. Treatment plan includes supportive care; aggressive control of delirium, autonomic instability, and hyperpyrexia; and use of serotonin antagonists. Supportive care Oxygen supplement to prevent hypoxemia. Maintain fluid, electrolyte, and acid-base balance. Induce a brisk diuresis and alkalinize the urine if myoglobinuria (sign of rhabdomyolysis) is present.

6 Restlessness, twitches & diarrhea: 6/7 Control delirium Do not restrain an agitated patient. Muscle activities exerted by an uncooperative patient to fight the restrain can contribute to hyperpyrexia and lactic acidosis. Sedate the patient with a benzodiazepine (e.g. diazepam). Besides providing sedation, a benzodiazepine can blunt the sympathetic overactivity seen in this syndrome. Paralyze the patient with a non-depolarizing muscle relaxant (e.g. vecuronium), intubate the trachea, and ventilate the lungs mechanically if sedation alone fails. Control of autonomic instability Treat hypertension with nitroprusside, a direct vasodilator. Nitroprusside is an ultra-short acting agent that can be given as an intravenous infusion to titrate against its effect. Treat hypotension with a direct-acting catecholamine (e.g. norepinephrine, epinephrine, phenylephrine). Avoid using indirect-acting sympathomimetic amines (e.g. ephedrine), which can cause uncontrolled hypertension; particularly if the offending drug that causes the serotonin syndrome is a monoamine oxidase inhibitor (MAOI). This is because indirect acting drugs act by releasing intracellular catecholamines, whose concentration is limited through breakdown by the monoamine oxidase enzyme. In the presence of MAOI, intracellular store of catecholamines increases and indirect agents can cause a large release of these amines, leading to big increases in blood pressure. Treat tachycardia with the short acting cardioselective β-adrenergic antagonist esmolol. Control of hyperpyrexia The underlying cause of hyperpyrexia is excessive muscle activity. Effort should be directed at sedation of the agitated patient and induced paralysis

7 Restlessness, twitches & diarrhea: 7/7 with a non-depolarizing muscle relaxant as described above if sedation alone fails. Institute body surface or intra-gastric cooling if the body temperature is 40 o C or more. Role of dantrolene, a drug used to treat muscle rigidity in malignant hyperpyrexia (a muscle disease) is unclear. Anti-pyretic drugs have no role in management of hyperpyrexia associated with the serotonin syndrome because the cause of the raised temperature is not due to change in the hypothalamic temperature set point. Serotonin antagonists Drugs with 5HT2A antagonist activity (cyproheptadine, olanzapine) may be life-saving in a dire emergency. Cyproheptadine can only be given orally or via a nasogastric tube and olanzapine is administered sublingually. If parenteral medication is desirable, chlorpromazine can be used. Further readings Boyer EW et al. The serotonin syndrome. New England Journal of Medicine 2005;352: Birmes P et al. Serotonin syndrome: A brief review. Canadian Medical Association Journal 2003;168: Lange-Asschenfeldt C et al. Serotonin syndrome as a result of Fluoxetine in a patient with tramadol abuse: Plasma level-correlated symptomatology. Journal of Clinical Psychopharmacology 2002;22: Sternbach H. The serotonin syndrome. American Journal of Psychiatry 1991;148: