A 58 yo Man with Dizziness and Sweating

Susan Poe, MD Primary Care Conference 9/13/06

Case

 58 yo male with hx of IDDM and chronic migraine headaches presents with complaints of tremor and dizziness. c/o gradual onset of shakiness and difficulty with gait. Described a tremor at rest such as resting his hand on the gear shift. Intermittent dizziness was described as a lighted headed sensation and as an unsteady gait. Has to hold on to the wall to prevent falling over. Wife described jerking legs at night. Also notes he seems jerky in general such as being easily startled.

Case cont.

 Denies change in vision, urinary or bowel control. No numbness or weakness. Denies vertigo, nausea, diarrhea.  Blood sugars have been up and down as usual.

 Migraine headaches are unchanged.

PMH

       Chronic MHA-on pain contract IDDM since childhood  Gastroparesis, periph neuropathy  No retinopathy or nephropathy Fibromyalgia Restless legs Hyperlipidemia Depression Remote hx IV drug abuse

Meds

       Asa Cyclobenzaprine 10 tid Benadryl 25 bid Eletriptan 20 mg qd Lexapro 40 mg qd Hydromorphone 2mg IM 2x/wk Hydroxyzine 50 mg im 2x/wk         Insulin per pump Metoclopramide 10 qid Protonix 40 mg qd Oxytryptan powder Zocor 20 mg qd Verapamil 120 mg qd Albuterol inhaler prn L-dopa recently d/ced

PE

 Alert and oriented , NAD  BP 98/64, P 84  HEENT- pupils sl dilated but responsive  Chest clear to A & P  CV RRR no m,g,r  No carotid bruits  Abd- benign

PE cont

 Neuro exam:  Alert and oriented  Romberg neg, heel to toe walk wobbly  No resting tremor noted  Finger to nose and heel to shin sluggish but intact  Reflexes absent (chronic)  Positive cogwheeling

Impression

 Possible parkinsonian symptoms  Recommend d/c metoclopramide

F/up Urgent Care visit

 Syncope after arising from sofa  Fractured a rib  Since d/cing metoclopramide tremor is a little better but other symptoms persist.

 Reviewed his meds and decided to make some changes.

Objective

 Increase recognition of a common usually mild but potentially serious toxicity  Understand how to differentiate it from other similar toxicities  Appreciate the pathophysiology so that one might be able to prevent it  Understand management principles

Financial disclosure

 No financial incentives for this talk

Serotonin syndrome

 Clinical triad: MS change, autonomic hyperactivity, neuromusc hyperactivity  Clinical spectrum of symptoms due to toxicity, usually mild but potentially life threatening  Increased stimulation of serotonin receptors

Why the concern

 Mild cases easily overlooked which could lead to severe symptoms if new drug introduced or change in dose  Almost all fatal and most severe cases due to drug combinations.

 1980’s Libby Zion case: meperidene plus MAOI

Epidemiology

 All age groups  Increasing incidence parallels increasing use of serotonergic agents  SS occurs in 14-16% of SSRI overdoses

Barriers to diagnosis

 Protean manifestations  Strict application of diagnostic criteria can rule out mild or sub acute cases  Physician unawareness 85%  Striking number of drugs and drug combinations are associated with SS.

Serotonin pharmacology

 L-tryptophan converted to serotonin in presynaptic neuron  Incorporated into vesicles  Axonal stimulation releases serotonin  Binds to postsynaptic receptor  Reuptake into presynaptic neuron  Metabolized by monoamine oxidase A

Neurophysiology

Serotonin Biosynthesis and Metabolism Boyer E and Shannon M. N Engl J Med 2005;352:1112-1120

Multiple Receptors Implicated

 5-HT1A  5-HT2A  Probably others indirectly

Rapid onset and resolution

 Usually present within 24 hrs of new drug or change in dose  60% present within 6 hours  Respond within 24 hours usually  Exception: sub acute cases, drugs with long half lives

Clinical Triad

 Mental Status Changes  Autonomic Manifestations  Muscular hyperactivity

Mental Status Changes

 Anxiety, restlessness, startle easily  Agitated delirium, disorientation

Autonomic Hyperactivity

 Diaphoresis very common  Dry mucous membranes  Mydriasis, shivering  Tachycardia, htn  Vomiting, diarrhea, hyperactive BS’s  Hyperthermia in severe cases

Neuromuscular Hyperactivity

 Hyperreflexia  Clonus, myoclonus, B babinskis  Ocular clonus  Tremor, neuromuscular rigidity  Most pronounced in the LE’s

Clinical manifestations

Findings in a Patient with Moderately Severe Serotonin Syndrome Boyer E and Shannon M. N Engl J Med 2005;352:1112-1120

Severe case

 Agitated delirium  Severe htn, tachy  Muscular rigidity, hypertonicity  Hyperthermia due to muscle hyperactivity  Rhabdomyolysis, seizures, renal failure, DIC

Diagnosis

 Clinical  Does not correlate with drug levels  Differential diagnosis  Hunter criteria

Differential diagnosis

   Neuroleptic malignant syndrome (dopamine antagonist)  Develops and resolves over days to wks  Neuromuscular sluggishness, bradyreflexia Anticholinergic toxicity   Mydriasis, dry mucous membranes Urinary retention, decreased bs’s  Normal muscle tone and reflexes Malignant hyperthermia    Rigor mortis like rigidity Develops within minutes Halogenated anesthetics, depolarizing relaxants

Hunter Criteria: 84% sens, 97% spec Drug plus one of the following:

 Spontaneous clonus  Inducible clonus + agitation or diaphoresis  Ocular clonus + agitation or diaphoresis  Tremor and hyperreflexia  Hypertonia  Temp > 38 deg + ocular or inducible clonus

Drugs associated with SS

Increase serotonin L-tryptophan formation Increase release of serotonin Impairs reuptake Amphet, cocaine, ecstasy, L-dopa, amph. Derivatives SSRI, Meperidine, ecstasy, cocaine, ser/norepi uptake inhib, St J Wort, ondansetron, dextromethorphan

Drugs associated cont.

Inhibits serotonin MAO inhibitors metabolism Direct serotonin agonist Increases sensitivity of postsynap receptor Buspirone, sumatriptan, ergot alk, fentanyl, LSD lithium

Drugs

  Single dose of SSRI can cause syndrome MAOI’s associated with severe or fatal cases if combined with SSRI, meperidene, dextromethorphan, MDMA    Drugs that affect cytochrome P450 system Prolonged effect with long ½ life. Adding serotonergic drug within 5 wks of d/cing fluoxetine Drug level doesn’t correlate with toxicity

Treatment

 Remove precipitating drug  Benzodiazepines for agitation  No physical restraints  Chemical paralysis if hyperthermic  Cyproheptadine, 5-HT2A antagonist  Olanzapine, chlorpromazine

Treatment cont.

 Hypotension: low dose direct acting sympathomimetic amines ie norepi, epi  Avoid dopamine –prolonged htn  Htn, tachy- short acting agents ie nipride, esmolol, avoid propranolol (long acting 5HT1A antagonist)  Bromocriptine, rx for NMS, can exacerbate

Treatment cont.

 If not sure of diagnosis, supportive care:  Benzodiazepines  IV fluids  Chemical sedation  Short acting agents for htn and hypotension

This patient’s drugs:

 Cyclobenzaprine: anticholinergic  Benadryl: antihistamine, inhibits P450  Eletriptan: serotonin receptor agonist  Lexapro: SSRI  Hydroxyzine: antihistamine  Metoclopramide: dopamine antagonist  Verapamil: inhibits P450  Oxytryptan: serotonin precursor

f/up

 Discontinued metoclopramide – no significant response  Discontinued verapamil – symptoms improved  Final diagnosis: polypharmacy with serotonin toxicity likely exacerbated by adding p 450 inhibitor.

Summary

 SS is a clinical spectrum of toxicity  Rapid onset and rapid resolution with medication change  Triad of MS change, autonomic and neuromuscular hyperactivity  Distinguishing features: clonus, agitation, diaphoresis, tremor and hypereflexia

Summary cont.

 Diagnosis requires clinical suspicion esp. in mild cases  Important to recognize mild case if adding additional agent that affects serotonin neurotransmission  Treatment is supportive  Antidote cyproheptadine  Prevention requires awareness of multiple drugs affecting serotonin stimulation

Do No Harm

Bibliography

     Boyer e al. The serotonin syndrome. NEJM 2005; 352:1112.

Kent et al. Serotonin syndrome. UpToDate 2006.

Ganesky. Selective serotonin reuptake inhibitor intoxication. UpToDate. 2006.

Dunkley et al. The Hunter Serotonin Toxicity Criteria. QJM 2003; 96: 635.

Isbister e al. The Pathophysiology of Serotonin Toxicity in Animals and Humans. Clinical Neuropharmacology. 2005. 28 (5):205.