A 58 yo Man with Dizziness and Sweating

Susan Poe, MDSusan Poe, MD

Primary Care ConferencePrimary Care Conference

9/13/069/13/06

Case

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

Case cont.

Denies change in vision, urinary or bowel Denies change in vision, urinary or bowel control. No numbness or weakness. Denies control. No numbness or weakness. Denies vertigo, nausea, diarrhea. vertigo, nausea, diarrhea.

Blood sugars have been up and down as Blood sugars have been up and down as usual.usual.

Migraine headaches are unchanged.Migraine headaches are unchanged.

PMH

Chronic MHA-on pain contractChronic MHA-on pain contract IDDM since childhoodIDDM since childhood

Gastroparesis, periph neuropathyGastroparesis, periph neuropathy No retinopathy or nephropathyNo retinopathy or nephropathy

FibromyalgiaFibromyalgia Restless legsRestless legs HyperlipidemiaHyperlipidemia DepressionDepression Remote hx IV drug abuseRemote hx IV drug abuse

Meds

AsaAsa Cyclobenzaprine 10 tidCyclobenzaprine 10 tid Benadryl 25 bidBenadryl 25 bid Eletriptan 20 mg qdEletriptan 20 mg qd Lexapro 40 mg qdLexapro 40 mg qd Hydromorphone 2mg IM Hydromorphone 2mg IM

2x/wk2x/wk Hydroxyzine 50 mg im Hydroxyzine 50 mg im

2x/wk2x/wk

Insulin per pumpInsulin per pump Metoclopramide 10 qidMetoclopramide 10 qid Protonix 40 mg qdProtonix 40 mg qd Oxytryptan powderOxytryptan powder Zocor 20 mg qdZocor 20 mg qd Verapamil 120 mg qd Verapamil 120 mg qd Albuterol inhaler prnAlbuterol inhaler prn L-dopa recently d/cedL-dopa recently d/ced

PE

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

PE cont

Neuro exam:Neuro exam: Alert and orientedAlert and oriented Romberg neg, heel to toe walk wobblyRomberg neg, heel to toe walk wobbly No resting tremor noted No resting tremor noted Finger to nose and heel to shin sluggish but Finger to nose and heel to shin sluggish but

intactintact Reflexes absent (chronic)Reflexes absent (chronic) Positive cogwheelingPositive cogwheeling

Impression

Possible parkinsonian symptomsPossible parkinsonian symptoms Recommend d/c metoclopramideRecommend d/c metoclopramide

F/up Urgent Care visit

Syncope after arising from sofaSyncope after arising from sofa Fractured a ribFractured a rib Since d/cing metoclopramide tremor is a Since d/cing metoclopramide tremor is a

little better but other symptoms persist.little better but other symptoms persist. Reviewed his meds and decided to make Reviewed his meds and decided to make

some changes.some changes.

Objective

Increase recognition of a common usually Increase recognition of a common usually mild but potentially serious toxicitymild but potentially serious toxicity

Understand how to differentiate it from Understand how to differentiate it from other similar toxicitiesother similar toxicities

Appreciate the pathophysiology so that one Appreciate the pathophysiology so that one might be able to prevent itmight be able to prevent it

Understand management principlesUnderstand management principles

Financial disclosure

No financial incentives for this talkNo financial incentives for this talk

Serotonin syndrome

Clinical triad: MS change, autonomic Clinical triad: MS change, autonomic hyperactivity, neuromusc hyperactivityhyperactivity, neuromusc hyperactivity

Clinical spectrum of symptoms due to Clinical spectrum of symptoms due to toxicity, usually mild but potentially life toxicity, usually mild but potentially life threateningthreatening

Increased stimulation of serotonin receptorsIncreased stimulation of serotonin receptors

Why the concern

Mild cases easily overlooked which could lead Mild cases easily overlooked which could lead to severe symptoms if new drug introduced or to severe symptoms if new drug introduced or change in dosechange in dose

Almost all fatal and most severe cases due to Almost all fatal and most severe cases due to drug combinations.drug combinations.

1980’s Libby Zion case: meperidene plus MAOI1980’s Libby Zion case: meperidene plus MAOI

Epidemiology

All age groupsAll age groups

Increasing incidence parallels increasing Increasing incidence parallels increasing use of serotonergic agentsuse of serotonergic agents

SS occurs in 14-16% of SSRI overdosesSS occurs in 14-16% of SSRI overdoses

Barriers to diagnosis

Protean manifestationsProtean manifestations

Strict application of diagnostic criteria can rule out Strict application of diagnostic criteria can rule out mild or sub acute casesmild or sub acute cases

Physician unawareness 85%Physician unawareness 85%

Striking number of drugs and drug combinations Striking number of drugs and drug combinations are associated with SS.are associated with SS.

Serotonin pharmacology

L-tryptophan converted to serotonin in L-tryptophan converted to serotonin in presynaptic neuronpresynaptic neuron

Incorporated into vesiclesIncorporated into vesicles Axonal stimulation releases serotoninAxonal stimulation releases serotonin Binds to postsynaptic receptorBinds to postsynaptic receptor Reuptake into presynaptic neuronReuptake into presynaptic neuron Metabolized by monoamine oxidase AMetabolized by monoamine oxidase A

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

Serotonin Biosynthesis and Metabolism

Neurophysiology

Multiple Receptors Implicated

5-HT1A5-HT1A

5-HT2A5-HT2A

Probably others indirectlyProbably others indirectly

Rapid onset and resolution

Usually present within 24 hrs of new drug Usually present within 24 hrs of new drug or change in doseor change in dose

60% present within 6 hours60% present within 6 hours Respond within 24 hours usuallyRespond within 24 hours usually Exception: sub acute cases, drugs with long Exception: sub acute cases, drugs with long

half liveshalf lives

Clinical Triad

Mental Status ChangesMental Status Changes

Autonomic ManifestationsAutonomic Manifestations

Muscular hyperactivityMuscular hyperactivity

Mental Status Changes

Anxiety, restlessness, startle easilyAnxiety, restlessness, startle easily

Agitated delirium, disorientationAgitated delirium, disorientation

Autonomic Hyperactivity

Diaphoresis very commonDiaphoresis very common Dry mucous membranesDry mucous membranes Mydriasis, shiveringMydriasis, shivering Tachycardia, htnTachycardia, htn Vomiting, diarrhea, hyperactive BS’sVomiting, diarrhea, hyperactive BS’s Hyperthermia in severe casesHyperthermia in severe cases

Neuromuscular Hyperactivity

HyperreflexiaHyperreflexia Clonus, myoclonus, B babinskisClonus, myoclonus, B babinskis Ocular clonusOcular clonus Tremor, neuromuscular rigidityTremor, neuromuscular rigidity Most pronounced in the LE’sMost pronounced in the LE’s

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

Findings in a Patient with Moderately Severe Serotonin Syndrome

Clinical manifestations

Severe case

Agitated delirium Agitated delirium Severe htn, tachySevere htn, tachy Muscular rigidity, hypertonicityMuscular rigidity, hypertonicity Hyperthermia due to muscle hyperactivityHyperthermia due to muscle hyperactivity Rhabdomyolysis, seizures, renal failure, Rhabdomyolysis, seizures, renal failure,

DICDIC

Diagnosis

ClinicalClinical Does not correlate with drug levelsDoes not correlate with drug levels Differential diagnosisDifferential diagnosis Hunter criteriaHunter criteria

Differential diagnosis

Neuroleptic malignant syndrome (dopamine antagonist)Neuroleptic malignant syndrome (dopamine antagonist) Develops and resolves over days to wksDevelops and resolves over days to wks Neuromuscular sluggishness, bradyreflexiaNeuromuscular sluggishness, bradyreflexia

Anticholinergic toxicityAnticholinergic toxicity Mydriasis, dry mucous membranesMydriasis, dry mucous membranes Urinary retention, decreased bs’sUrinary retention, decreased bs’s Normal muscle tone and reflexesNormal muscle tone and reflexes

Malignant hyperthermiaMalignant hyperthermia Rigor mortis like rigidityRigor mortis like rigidity Develops within minutesDevelops within minutes Halogenated anesthetics, depolarizing relaxantsHalogenated anesthetics, depolarizing relaxants

Hunter Criteria: 84% sens, 97% specDrug plus one of the following: Spontaneous clonusSpontaneous clonus Inducible clonus + agitation or diaphoresisInducible clonus + agitation or diaphoresis Ocular clonus + agitation or diaphoresisOcular clonus + agitation or diaphoresis Tremor and hyperreflexiaTremor and hyperreflexia HypertoniaHypertonia Temp > 38 deg + ocular or inducible clonusTemp > 38 deg + ocular or inducible clonus

Increase serotonin Increase serotonin formationformation

L-tryptophanL-tryptophan

Increase release of Increase release of serotoninserotonin

Amphet, cocaine, Amphet, cocaine, ecstasy, L-dopa, ecstasy, L-dopa, amph. Derivativesamph. Derivatives

Impairs reuptake Impairs reuptake SSRI, Meperidine, SSRI, Meperidine, ecstasy, cocaine, ecstasy, cocaine, ser/norepi uptake ser/norepi uptake inhib, St J Wort, inhib, St J Wort, ondansetron, ondansetron, dextromethorphandextromethorphan

Drugs associated with SS

Inhibits serotonin Inhibits serotonin metabolismmetabolism

MAO inhibitorsMAO inhibitors

Direct serotonin Direct serotonin agonistagonist

Buspirone, Buspirone, sumatriptan, ergot sumatriptan, ergot alk, fentanyl, LSDalk, fentanyl, LSD

Increases Increases sensitivity of sensitivity of postsynap receptorpostsynap receptor

lithiumlithium

Drugs associated cont.

Drugs

Single dose of SSRI can cause syndrome Single dose of SSRI can cause syndrome MAOI’s associated with severe or fatal cases if MAOI’s associated with severe or fatal cases if

combined with SSRI, meperidene, combined with SSRI, meperidene, dextromethorphan, MDMAdextromethorphan, MDMA

Drugs that affect cytochrome P450 systemDrugs that affect cytochrome P450 system Prolonged effect with long ½ life. Adding Prolonged effect with long ½ life. Adding

serotonergic drug within 5 wks of d/cing serotonergic drug within 5 wks of d/cing fluoxetine fluoxetine

Drug level doesn’t correlate with toxicityDrug level doesn’t correlate with toxicity

Treatment

Remove precipitating drugRemove precipitating drug Benzodiazepines for agitationBenzodiazepines for agitation No physical restraintsNo physical restraints Chemical paralysis if hyperthermicChemical paralysis if hyperthermic Cyproheptadine, 5-HT2A antagonistCyproheptadine, 5-HT2A antagonist Olanzapine, chlorpromazineOlanzapine, chlorpromazine

Treatment cont.

Hypotension: low dose direct acting Hypotension: low dose direct acting sympathomimetic amines ie norepi, episympathomimetic amines ie norepi, epi

Avoid dopamine –prolonged htnAvoid dopamine –prolonged htn Htn, tachy- short acting agents ie nipride, Htn, tachy- short acting agents ie nipride,

esmolol, avoid propranolol (long acting esmolol, avoid propranolol (long acting 5HT1A antagonist)5HT1A antagonist)

Bromocriptine, rx for NMS, can exacerbateBromocriptine, rx for NMS, can exacerbate

Treatment cont.

If not sure of diagnosis, supportive care:If not sure of diagnosis, supportive care: BenzodiazepinesBenzodiazepines IV fluidsIV fluids Chemical sedationChemical sedation Short acting agents for htn and Short acting agents for htn and

hypotensionhypotension

This patient’s drugs:

Cyclobenzaprine: anticholinergicCyclobenzaprine: anticholinergic Benadryl: antihistamine, inhibits P450Benadryl: antihistamine, inhibits P450 Eletriptan: serotonin receptor agonistEletriptan: serotonin receptor agonist Lexapro: SSRILexapro: SSRI Hydroxyzine: antihistamineHydroxyzine: antihistamine Metoclopramide: dopamine antagonistMetoclopramide: dopamine antagonist Verapamil: inhibits P450Verapamil: inhibits P450 Oxytryptan: serotonin precursorOxytryptan: serotonin precursor

f/up

Discontinued metoclopramide – no Discontinued metoclopramide – no significant responsesignificant response

Discontinued verapamil – symptoms Discontinued verapamil – symptoms improved improved

Final diagnosis: polypharmacy with Final diagnosis: polypharmacy with serotonin toxicity likely exacerbated by serotonin toxicity likely exacerbated by adding p 450 inhibitor.adding p 450 inhibitor.

Summary

SS is a clinical spectrum of toxicitySS is a clinical spectrum of toxicity Rapid onset and rapid resolution with Rapid onset and rapid resolution with

medication changemedication change Triad of MS change, autonomic and Triad of MS change, autonomic and

neuromuscular hyperactivityneuromuscular hyperactivity Distinguishing features: clonus, agitation, Distinguishing features: clonus, agitation,

diaphoresis, tremor and hypereflexiadiaphoresis, tremor and hypereflexia

Summary cont.

Diagnosis requires clinical suspicion esp. in mild Diagnosis requires clinical suspicion esp. in mild casescases

Important to recognize mild case if adding Important to recognize mild case if adding additional agent that affects serotonin additional agent that affects serotonin neurotransmissionneurotransmission

Treatment is supportive Treatment is supportive Antidote cyproheptadineAntidote cyproheptadine Prevention requires awareness of multiple drugs Prevention requires awareness of multiple drugs

affecting serotonin stimulationaffecting serotonin stimulation

Do No Harm

Bibliography

Boyer e al. The serotonin syndrome. NEJM 2005; Boyer e al. The serotonin syndrome. NEJM 2005; 352:1112.352:1112.

Kent et al. Serotonin syndrome. UpToDate 2006.Kent et al. Serotonin syndrome. UpToDate 2006. Ganesky. Selective serotonin reuptake inhibitor Ganesky. Selective serotonin reuptake inhibitor

intoxication. UpToDate. 2006.intoxication. UpToDate. 2006. Dunkley et al. The Hunter Serotonin Toxicity Dunkley et al. The Hunter Serotonin Toxicity

Criteria. QJM 2003; 96: 635.Criteria. QJM 2003; 96: 635. Isbister e al. The Pathophysiology of Serotonin Isbister e al. The Pathophysiology of Serotonin

Toxicity in Animals and Humans. Clinical Toxicity in Animals and Humans. Clinical Neuropharmacology. 2005. 28 (5):205.Neuropharmacology. 2005. 28 (5):205.