54 year old male with hiv, fever, altered mental status

54 year old male with 54 year old male with HIV, fever, altered HIV, fever, altered

mental statusmental status

Brian Crabtree, MD PGY-3Brian Crabtree, MD PGY-3

Maine ACP Conference 2013Maine ACP Conference 2013

September 28, 2013September 28, 2013

Identification and Chief Identification and Chief ComplaintComplaint

►54 year old Cuban American man with 54 year old Cuban American man with a history of HIV positivity, a history of HIV positivity, schizoaffective disorder, glaucoma, schizoaffective disorder, glaucoma, recent diagnosis of ankylosing recent diagnosis of ankylosing spondylitis presents with three days of spondylitis presents with three days of fevers and chillsfevers and chills, worsening , worsening headacheheadache and and confusion.confusion.

History of Present IllnessHistory of Present Illness

►Mr. B was in his usual state of health Mr. B was in his usual state of health until four days before admission when he until four days before admission when he reports developing low grade fevers and reports developing low grade fevers and night sweats with generalized malaise. night sweats with generalized malaise. Over the next two days he developed a Over the next two days he developed a worsening headache, confusion and worsening headache, confusion and ataxia. His significant other brought him ataxia. His significant other brought him to the ED by car for failure to improve to the ED by car for failure to improve and worsening mental status.and worsening mental status.

Review of SystemsReview of Systems

General: +malaise, +fever, no weight lossGeneral: +malaise, +fever, no weight lossHEENT: +headache, no photophobia, +ulcer on lip for HEENT: +headache, no photophobia, +ulcer on lip for

the last week, no visual changesthe last week, no visual changesCV: no chest pain, no DOE, no orthopneaCV: no chest pain, no DOE, no orthopneaRespi: no cough, no SOBRespi: no cough, no SOBGI: +nausea, no vomiting, no bowel changes, no GI: +nausea, no vomiting, no bowel changes, no

abdominal painabdominal painGU: +polydipsia and polyuria, no dysuriaGU: +polydipsia and polyuria, no dysuriaNeuro: no focal weakness, no sensory deficits or Neuro: no focal weakness, no sensory deficits or

paresthesiasparesthesiasSkin: no rashes, no jaundiceSkin: no rashes, no jaundicePsych: +somnolence, +confusion, no hallucinations, Psych: +somnolence, +confusion, no hallucinations,

delusionsdelusionsMSK: +neck stiffness, +low back pain, no joint painMSK: +neck stiffness, +low back pain, no joint pain

Past Medical HistoryPast Medical HistoryActiveActive

ProblemProblemListList

1. Fever1. Fever2. AMS2. AMS

HIV – diagnosed in 1990s, currently on HIV – diagnosed in 1990s, currently on antiretroviral therapy, most recent CD4 antiretroviral therapy, most recent CD4 count 369 with low viral load (30)count 369 with low viral load (30)

Schizoaffective disorder – diagnosed in his Schizoaffective disorder – diagnosed in his mid twenties and on valproic acidmid twenties and on valproic acid

Anklyosing spondylitis – HLA-B27 positive, Anklyosing spondylitis – HLA-B27 positive, diagnosed in the last yeardiagnosed in the last year

History of uveitis and glaucomaHistory of uveitis and glaucomaGilbert’s diseaseGilbert’s diseaseChronic Hepatitis B carrierChronic Hepatitis B carrierHyperlipidemiaHyperlipidemia

Past Medical HistoryPast Medical HistoryActiveActive



PMHPMH1. HIV1. HIV2. Schizo-2. Schizo-

affective affective disorderdisorder

3. Akylosing 3. Akylosing spondylitispondylitiss

4. Chronic 4. Chronic Hepatitis Hepatitis BB

HIV – diagnosed in 1990s, currently on HIV – diagnosed in 1990s, currently on antiretroviral therapy, most recent CD4 antiretroviral therapy, most recent CD4 count 369 with low viral load (30)count 369 with low viral load (30)

Schizoaffective disorder – diagnosed in his Schizoaffective disorder – diagnosed in his mid twenties and on valproic acidmid twenties and on valproic acid

Anklyosing spondylitis – HLA-B27 positive, Anklyosing spondylitis – HLA-B27 positive, diagnosed in the last yeardiagnosed in the last year

History of uveitis and glaucomaHistory of uveitis and glaucomaGilbert’s diseaseGilbert’s diseaseChronic Hepatitis B carrierChronic Hepatitis B carrierHyperlipidemiaHyperlipidemia

Past Surgical HistoryPast Surgical History

ActiveActive

ProblemProblem

ListList

1. Fever1. Fever

2. AMS2. AMS

PMHPMH

1. HIV1. HIV

2. Schizo-2. Schizo-affective affective disorderdisorder



TonsillectomyTonsillectomy

Rectal fistula repairRectal fistula repair

Social HistorySocial History

ActiveActive

ProblemProblem

ListList

1. Fever1. Fever

2. AMS2. AMS

PMHPMH

1. HIV1. HIV




Mr. B was Mr. B was born in Cubaborn in Cuba and moved to the and moved to the United States at age 9. He is United States at age 9. He is homosexualhomosexual with a long term partner. with a long term partner. He was sexually active in New York City He was sexually active in New York City in the 1980’s and was diagnosed with in the 1980’s and was diagnosed with HIV in the early 1990’sHIV in the early 1990’s. He has a . He has a history of drug usehistory of drug use including cocaine including cocaine and acid. Minimal current alcohol use, and acid. Minimal current alcohol use, history of social tobacco use. He moved history of social tobacco use. He moved to southern Maine in 2009 to to southern Maine in 2009 to run a run a kennelkennel with his partner. He is with his partner. He is on on disabilitydisability for his schizoaffective disorder. for his schizoaffective disorder.

Medications and AllergiesMedications and AllergiesActiveActive





3. Akylosing 3. Akylosing spondylitisspondylitis

4. Chronic 4. Chronic Hepatitis BHepatitis B

Ritonavir 100mg cap dailyRitonavir 100mg cap dailyAtazanavir 300mg cap dailyAtazanavir 300mg cap dailyEmtricitabine-tenofovir 200-300mg tab dailyEmtricitabine-tenofovir 200-300mg tab dailyValproic acid 500mg 3 tabs at bedtimeValproic acid 500mg 3 tabs at bedtimePerphenazine 16mg tab twice dailyPerphenazine 16mg tab twice dailyBupropion 450mg XR once dailyBupropion 450mg XR once dailyPravastatin 20mg tab dailyPravastatin 20mg tab dailyEtodolac 400mg tab twice dailyEtodolac 400mg tab twice dailyLoratadine 10mg tab daily as neededLoratadine 10mg tab daily as neededDorzolamide-timolol solution one drop twice dailyDorzolamide-timolol solution one drop twice dailyLoteprednol etabonate 0.5% solution once dailyLoteprednol etabonate 0.5% solution once daily

Physical ExaminationPhysical ExaminationActiveActive







T 39.7 HR 107 RR 20 142/88 97% OT 39.7 HR 107 RR 20 142/88 97% O22

General: drowsy, poor attention, orientedx3General: drowsy, poor attention, orientedx3HEENT: PERRL, EOMI, +1cm ulcer on left lower lip, HEENT: PERRL, EOMI, +1cm ulcer on left lower lip,

+nuchal rigidity+nuchal rigidityCV: regular rhythm, normal rate, normal S1 and S2 CV: regular rhythm, normal rate, normal S1 and S2

without murmurswithout murmursRespi: good air movement, clear to auscultationRespi: good air movement, clear to auscultationAbd: soft and nontender, normal bowel sounds, no Abd: soft and nontender, normal bowel sounds, no

organomegalyorganomegalyExt: no peripheral edema, good pulsesExt: no peripheral edema, good pulsesNeuro: cranial nerves 2-12 tested and intact, 5/5 Neuro: cranial nerves 2-12 tested and intact, 5/5

strength throughout, normal reflexes, negative strength throughout, normal reflexes, negative Kernig and Brudzinski signs, normal tone, Kernig and Brudzinski signs, normal tone, normal sensationnormal sensation

Initial Lab TestingInitial Lab Testing

ActiveActive

ProblemProblem

ListList

1. Fever1. Fever

2. AMS2. AMS

PMHPMH

1. HIV1. HIV




CBC: WBC 7.0, Hb 13.2, Hct 37.2, Plt 177CBC: WBC 7.0, Hb 13.2, Hct 37.2, Plt 177

BMP: BMP: Na 122Na 122, K 3.8, Cl 84, CO, K 3.8, Cl 84, CO22 24 24

BUN 10, Cr 1.2, Glu 109BUN 10, Cr 1.2, Glu 109

UA/sediment: pH 5.0, negative leukocytes UA/sediment: pH 5.0, negative leukocytes and nitrites, +urobilinogen, no casts, 3-5 and nitrites, +urobilinogen, no casts, 3-5 RBCs, occasional WBCsRBCs, occasional WBCs

Differential DiagnosisDifferential DiagnosisActiveActive


1. Fever1. Fever2. AMS2. AMS3. Hypo-3. Hypo-

natreminatremiaa





Infectious: Sepsis of any origin, Infectious: Sepsis of any origin, meningoencephalitis, brain abscessmeningoencephalitis, brain abscess

Autoimmune: CNS vasculitis, Still’s diseaseAutoimmune: CNS vasculitis, Still’s diseaseMalignancy: Lymphoma, leukemiaMalignancy: Lymphoma, leukemiaEnvironmental: Heat strokeEnvironmental: Heat strokeToxins: Neuroleptic malignant syndrome, Toxins: Neuroleptic malignant syndrome,

salicylate overdose, serotonin salicylate overdose, serotonin syndrome, anticholinergic toxicity, syndrome, anticholinergic toxicity, sympathomimetic toxicitysympathomimetic toxicity

Metabolic: ThyrotoxicosisMetabolic: Thyrotoxicosis

Chest X rayChest X ray

CT HeadCT Head

MR BrainMR Brain

Clinical Course in the EDClinical Course in the EDActiveActive



natremianatremia





Lumbar puncture was attempted six times and was Lumbar puncture was attempted six times and was finally successful. The patient remained febrile. finally successful. The patient remained febrile.

Results of lumbar puncture showed:Results of lumbar puncture showed: WBC 206/mmWBC 206/mm33 with 86% lymphocytes with 86% lymphocytes Glucose 52 mg/dLGlucose 52 mg/dL Protein 91 mg/dLProtein 91 mg/dL No RBCsNo RBCs Gram stain negativeGram stain negative

Blood cultures were taken and empiric acyclovir Blood cultures were taken and empiric acyclovir was initiated.was initiated.

Interpreting CSFInterpreting CSFActiveActive



natreminatremiaa





Results of lumbar puncture showed:Results of lumbar puncture showed: WBC 206/mmWBC 206/mm33 with 86% lymphocytes with 86% lymphocytes Glucose 52 mg/dLGlucose 52 mg/dL Protein 91 mg/dLProtein 91 mg/dL No RBCsNo RBCs Gram stain negativeGram stain negative

EtiologyEtiology WBC WBC cells/mmcells/mm33

Primary cell Primary cell typetype

Glucose Glucose mg/dLmg/dL

Protein Protein mg/dLmg/dL

BacterialBacterial 1000-1000-50005000

NeutrophilNeutrophil <40<40 100-500100-500

ViralViral 50-100050-1000 MononuclearMononuclear >45>45 50-20050-200

FungalFungal 20-50020-500 MononuclearMononuclear <45<45 >45>45

TuberculoTuberculousus

50-30050-300 MononuclearMononuclear <40<40 50-30050-300

NormalNormal 0-50-5 ---- 4545 4545

Differential Diagnosis for Aseptic Differential Diagnosis for Aseptic MeningitisMeningitis

ActiveActiveProblemProblem

ListList1. Aseptic 1. Aseptic

MeningitiMeningitiss

2. Hypo-2. Hypo-natremianatremia





Viral – enteroviruses, arboviruses, HSV, Viral – enteroviruses, arboviruses, HSV, HIV, measles, mumps, VZV, CMV, EBVHIV, measles, mumps, VZV, CMV, EBV

Bacterial – Parameningeal abscess, Bacterial – Parameningeal abscess, Leptospirosis, Listeria, Brucella, Coxiella, Leptospirosis, Listeria, Brucella, Coxiella, Borrelia, TB, Syphilis, Rickettsia, Borrelia, TB, Syphilis, Rickettsia, EhrlichiaEhrlichia

Fungal – Crypotococcus, coccidiodes, Fungal – Crypotococcus, coccidiodes, histoplasmahistoplasma

Parasitic – Toxoplasmosis, taenia soliumParasitic – Toxoplasmosis, taenia solium

Infectious

Differential Diagnosis for Aseptic Differential Diagnosis for Aseptic MeningitisMeningitis









Drug Induced – Ibuprofen, TMP-SMX, other Drug Induced – Ibuprofen, TMP-SMX, other NSAIDs, Azathioprine, Lamotrigine, IVIg, NSAIDs, Azathioprine, Lamotrigine, IVIg, monoclonal antibodiesmonoclonal antibodies

Malignancies – Lymphoma, leukemia, Malignancies – Lymphoma, leukemia, metastasesmetastases

Autoimmune – Sarcoidosis, Systemic Autoimmune – Sarcoidosis, Systemic Lupus Erythematosis, Behcet’s, vaccine Lupus Erythematosis, Behcet’s, vaccine reactionreaction

Non-Infectious

Clinical CourseClinical CourseActiveActive


1. Aseptic 1. Aseptic MeningitiMeningitiss






The patient was admitted to the hospital The patient was admitted to the hospital floor on a hospitalist team. Neurology floor on a hospitalist team. Neurology and infectious disease were consulted. and infectious disease were consulted. The patient continued having fevers The patient continued having fevers >38>38ººC multiple times per day for three C multiple times per day for three days. Vancomycin and ceftriaxone were days. Vancomycin and ceftriaxone were added empirically, but he continued to added empirically, but he continued to have fevers that would respond to have fevers that would respond to acetaminophen. His mental status acetaminophen. His mental status continued to fluctuate and he continued continued to fluctuate and he continued to have back pain and stiff neck.to have back pain and stiff neck.

Clinical CourseClinical Course

Work-up for Aseptic Work-up for Aseptic MeningitisMeningitis



MeningitisMeningitis2. Hypo-2. Hypo-

natremianatremia





Infectious workup:Infectious workup:Blood and CSF cultures – negative at 48 hoursBlood and CSF cultures – negative at 48 hoursCSF Cryptococcal antigen: negativeCSF Cryptococcal antigen: negativeT-spot: negativeT-spot: negativeT pallidum Ab: negativeT pallidum Ab: negativeLyme IgG and IgM Ab: negativeLyme IgG and IgM Ab: negativeCSF HSV PCR: negativeCSF HSV PCR: negativeCSF arbovirus panel: negativeCSF arbovirus panel: negativeCD4 count: 342CD4 count: 342HIV viral load: 30 copies/mLHIV viral load: 30 copies/mL

Rheumatologic workup:Rheumatologic workup:ESR: 22ESR: 22CRP: 0.56CRP: 0.56

Work-up for Aseptic Work-up for Aseptic MeningitisMeningitis









Drug Induced Aseptic Meningitis – Drug Induced Aseptic Meningitis – - Most common offending medications - Most common offending medications include ibuprofen, other NSAIDs, include ibuprofen, other NSAIDs, lamotrigine.lamotrigine.

- Difficult to test for and is often a - Difficult to test for and is often a diagnosis of exclusion. Diagnosis diagnosis of exclusion. Diagnosis depends on causal relation with drug depends on causal relation with drug administration and is confirmed with administration and is confirmed with pharmacologic challenge testing where pharmacologic challenge testing where medication is given and clinical medication is given and clinical response is monitored.response is monitored.

= ibuprofen administration

Drug-Induced Aseptic Drug-Induced Aseptic MeningitisMeningitis


ListList1. Drug-1. Drug-

induced induced Aseptic Aseptic MeningitiMeningitiss






First described in 1978 in a 26 year old First described in 1978 in a 26 year old female with lupus who developed female with lupus who developed meningitis while taking ibuprofen. The meningitis while taking ibuprofen. The diagnosis was confirmed with challenge diagnosis was confirmed with challenge testing.testing.

Body of evidence regarding drug-induced Body of evidence regarding drug-induced aseptic meningitis (DIAM) is largely based aseptic meningitis (DIAM) is largely based on case reportson case reports

A 2006 review article reviewed 71 cases of A 2006 review article reviewed 71 cases of NSAID-induced meningitis. 61% of cases NSAID-induced meningitis. 61% of cases had an underlying connective tissue had an underlying connective tissue diseasedisease

HIV has been mentioned as a predisposing HIV has been mentioned as a predisposing condition as wellcondition as well

Exact incidence is unknownExact incidence is unknown

History and EpidemiologyHistory and Epidemiology










Clinical FeaturesClinical Features

Rodriguez, SC. Rodriguez, SC. Characteristics of Characteristics of meningitis caused by meningitis caused by ibuprofen: report of 2 ibuprofen: report of 2 cases and review of cases and review of the literature. the literature. Medicine (Baltimore) Medicine (Baltimore) 2006 Jul; 85(4) 214-2006 Jul; 85(4) 214-20.20.










Thought to be a type III hypersensitivity Thought to be a type III hypersensitivity reaction against the drug or metabolitereaction against the drug or metabolite

One suggested mechanism is One suggested mechanism is hypersensitivity to the drug as a hapten hypersensitivity to the drug as a hapten with an CSF-protein which would explain with an CSF-protein which would explain the limitation of the inflammation to the limitation of the inflammation to only the central nervous system.only the central nervous system.

Some patients have idiosyncratic reactions Some patients have idiosyncratic reactions to only one NSAID while others have to only one NSAID while others have been described as having reactions to been described as having reactions to several drugs within the classseveral drugs within the class

Proposed MechanismProposed Mechanism










CSF evidence of meningitis with neutrophil CSF evidence of meningitis with neutrophil or lymphocyte predominance, usually or lymphocyte predominance, usually elevated protein and normal glucoseelevated protein and normal glucose

Exclude infectious causesExclude infectious causesThere must be temporal relationship There must be temporal relationship

between a known offending agent and between a known offending agent and symptomssymptoms

Symptoms should resolve rapidly after Symptoms should resolve rapidly after withdrawing offending agentwithdrawing offending agent

Can be confirmed with challenge testing, Can be confirmed with challenge testing, though no evidence based protocol though no evidence based protocol existsexists

DiagnosisDiagnosis










Discontinue offending agentDiscontinue offending agentUse other drugs in the class with cautionUse other drugs in the class with cautionConsider workup for underlying Consider workup for underlying

autoimmune conditionautoimmune condition

ManagementManagement

Follow-up with patientFollow-up with patientActiveActive


1. Drug-1. Drug-induced induced Aseptic Aseptic MeningitiMeningitiss






Ibuprofen was discontinued and both Ibuprofen was discontinued and both ibuprofen and etodolac were placed on ibuprofen and etodolac were placed on the patient’s allergy list. Empiric the patient’s allergy list. Empiric antibiotics were discontinued as well.antibiotics were discontinued as well.

The patient had no further fevers once The patient had no further fevers once ibuprofen was discontinued and delirium ibuprofen was discontinued and delirium improved over the next 24 hours.improved over the next 24 hours.

Did well for six months, then began Did well for six months, then began developing ataxia of hands, cognitive developing ataxia of hands, cognitive slowing, fixed dilated right pupil, tremor. slowing, fixed dilated right pupil, tremor. He was diagnosed with Parkinsonism by He was diagnosed with Parkinsonism by neurology and it is unclear if this is neurology and it is unclear if this is related to psychotropic medications, HIV related to psychotropic medications, HIV or underlying Parkinson disease. or underlying Parkinson disease.

Take Home Points from CaseTake Home Points from CaseActiveActive


1. Drug-1. Drug-induced induced Aseptic Aseptic MeningitiMeningitiss






Drug-induced aseptic meningitis is a Drug-induced aseptic meningitis is a syndrome that can be clinically syndrome that can be clinically indistinguishable from bacterial indistinguishable from bacterial meningitis but should be suspected in a meningitis but should be suspected in a patient on commonly offending agents patient on commonly offending agents (NSAIDs, TMP-SMX, lamotrigine, (NSAIDs, TMP-SMX, lamotrigine, azathioprine, IV Ig) especially in those azathioprine, IV Ig) especially in those with underlying connective tissue with underlying connective tissue disease.disease.

Ibuprofen and other NSAIDs are widely Ibuprofen and other NSAIDs are widely used drugs and it is important for used drugs and it is important for physicians to be aware of the potentially physicians to be aware of the potentially severe side effectssevere side effects

ReferencesReferences

1.1. Mandell, Douglas, and Bennett. Principles and Practice Mandell, Douglas, and Bennett. Principles and Practice of Infectious Disease. Seventh Edition. 2010of Infectious Disease. Seventh Edition. 2010

2.2. Jolles, Stephen. Drug Induced Aseptic Meningitis – Jolles, Stephen. Drug Induced Aseptic Meningitis – Diagnosis and Management. Drug Safety 2000 Mar; Diagnosis and Management. Drug Safety 2000 Mar; 22(3): 215-226.22(3): 215-226.

3.3. Moreno-Ancillo, A. Ibuprofen-Induced Aseptic Moreno-Ancillo, A. Ibuprofen-Induced Aseptic Meningoencephalitis Confirmed by Drug Challenge. J Meningoencephalitis Confirmed by Drug Challenge. J Investig Allergol Clin Immunol 2011; Vol 21(6): 484-Investig Allergol Clin Immunol 2011; Vol 21(6): 484-487.487.

4.4. Rodriguez, SC. Characteristics of meningitis caused by Rodriguez, SC. Characteristics of meningitis caused by ibuprofen: report of 2 cases and review of the ibuprofen: report of 2 cases and review of the literature. Medicine (Baltimore) 2006 Jul; 85(4) 214-literature. Medicine (Baltimore) 2006 Jul; 85(4) 214-20.20.

5.5. Lee, RZ, Ibuprofen-induced aseptic Lee, RZ, Ibuprofen-induced aseptic meningoencephalitis. Rheumatology. 2002 41(3): meningoencephalitis. Rheumatology. 2002 41(3): 353-355.353-355.

54 year old male with hiv, fever, altered mental status

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