Without guile: a case of drug-induced aseptic meningitis in a patient with idiopathic - PowerPoint Presentation

Slide1

Without guile: a case of drug-induced aseptic meningitis in a patient with idiopathic CD4 lymphocytopenia

LT Benjamin S. Vipler, MD, Associate, Walter Reed National Military Medical Center, Bethesda, MD.

CPT Jason J. Nam, MD, Associate, Madigan Army Medical Center, Tacoma, WA.

LCDR Andrew G.

Letizia

, MD, Walter Reed National Military Medical Center, Bethesda, MD.

Christina M. Schofield, MD, FACP, Madigan Army Medical Center, Tacoma, WA.

MAJ David M.

Callender

, MD, FACP, Walter Reed National Military Medical Center, Bethesda, MD. Slide2

DisclosuresThe views expressed in this case are those of the author and do not necessarily reflect the official policy or position of the Departments of the Army, Navy, Defense, nor the US Government.

I have no financial disclosures.Slide3

Chief Complaint

Shaking

Fever

Neck painSlide4

History of Present Illness

62 year old African-American man

Idiopathic CD4+

lymphocytopenia

(ICL)

Diabetes mellitus type II

Psoriatic arthritis

Fever, rigors, then headache, posterior neck pain/stiffness

Acute onset, 12 hours prior to being seen in ER

“I never get headaches”

Exacerbation of chronic

polyathralgiasSlide5

History of Present Illness Continued

Started on trimethoprim/

s

ulfamethoxazole

(TMP/SMX) for

pneumocystis

prophylaxis

Last CD4+ count

120 (cells/µl

) one month earlierFirst pill of TMP/SMX was that morningDose administered 3 hours prior to symptomsSlide6

What is Idiopathic CD4+ Lympho(cyto

)

penia

Defined by CDC in 1992 (also called “severe unexplained HIV-

seronegative

immune suppression” by WHO)

Decreased CD4 T lymphocytes

<300 cells/µl

OR

<20% of total T cells

2 separate lab draws ≥6 weeks apart

No evidence of HIV-1 or HIV-2Absence of defined immunodeficiency or T cell lowering therapyNot sexually transmittedNo gender predilectionNo clear age of onset

Walker et al.

Curr

Opin

Rheumatol

18

(4): 389–95.Slide7

What is Idiopathic CD4+ Lympho(cyto

)

penia

Some evidence on BM biopsy of decreased T cell precursors

Similarities seen in CVID patients with low CD4 cell counts

Asymptomatic to severely ill

Similar illnesses as HIV infected patients

Treatment focused on prophylaxis

No guidelines for ICL

Extrapolated from HIV

Pneumocystis

More frequent cervical cancer screening

Walker et al.

Curr

Opin

Rheumatol

18

(4): 389–95.Slide8

Past Medical History

ICL

Diagnosed 2002

Multiple bone marrow biopsies unrevealing

Chronic

recurrent fevers without underlying infectious

etiologies

Not associated with headache or neck pain

Recurrent pneumonia

Moderate to severe plaque psoriasisPsoriatic arthritis

Multiple unprovoked pulmonary emboli

Lifelong anticoagulation Slide9

Past Medical History Continued

Morbid

obesity

Diabetes

mellitus type II

Hypertension

Hyperlipidemia

GERD

Left elbow surgery after trauma

Excisional lymph node biopsySlide10

Past Medical History ContinuedSimilar episode of current presentation “years ago”

Same symptoms

Body habitus prohibited acquisition of spinal fluid

Treated empirically for meningitis

Required ICU admission for “coma” per wife

Recovered

Circumstances surrounding this episode unknownSlide11

Medications

Loratidine

10mg

Lisinopril

40mg

Glipizide

XL 10mg

Triamterene/HCTZ 37.5/25mg

Nifedipine

30mgAtorvastatin 40mgEsomeprazole 40mg

Vitamin

B12

Vitamin CInsulinMetformin XR 500mg twice dailyAcetaminophen with codeineMorphine Fentanyl (transdermal) 125mcg/hrSlide12

Vital Signs

BMI

47

Temp

:

39.1

° C

(

102.4° F)

HR

93

, regular

BP 115/48RR 20SpO2 98%, room airPain score 7/10Slide13

Physical Examination

Awake, alert,

oriented

. Well developed. No acute

distress

O

ccasional shivers

. No rigors

observedMucosa moist. Oropharynx without erythema/exudatesNo nystagmus

. Mild

conjunctivitis

Neck flexion to 60 degrees, then limited by pain in the poster neckPosterior

neck

slightly tender.

No significant lymphadenopathy

Normal

respiratory depth, rhythm and

effort

Slightly

increased

rate

to low

20s

Lungs clear to auscultation without wheezes/rhonchi/crackles.Slide14

Physical Examination continued

Regular rate and rhythm

II/VI

early

systolic

murmur

at

left upper sternal borderSoft, nontender

,

nondistended

, without peritoneal signsNormoactive bowel sounds. No bruitsExtremities with limited joint mobility. No increased warmth in any particular joint.

Scattered

hyperpigmented

plaques

Consistent with known

psoriasis

Cranial nerves II-XII intact.

Brudzinski

sign

negative.

Kernig

sign difficult

to perform

with

arthropathySlide15

Labs

AST 18

ALT 18

Alk

phos

111

Total

bili

0.3

Total protein 7.4

Albumin

3.9Lipase 30

INR 1.5

Anion

gap 13

Lactate

2.4

UA negative

Cardiac enzymes negativeSlide16

Imaging / DiagnosticsSlide17

Initial Assessment/Plan

Sepsis with potential CNS source

IV fluid resuscitation

Empiric meningitis coverage for an

immunocompromised

host

Ampicillin

Ceftriaxone

Vancomycin

AcyclovirTMP/SMX heldSlide18

Hospital Course

High fevers continued despite broad spectrum antimicrobials

Blood and urine cultures no growth to date

Influenza PCR negative

Cryptococcus serum antigen negative

Body habitus prevented lumbar puncture until hospital day (HD) 3

Head CT obtained prior to LP

NegativeSlide19

Spinal Fluid Analysis

Tube #3

Color/appearance: pink, hazy

WBC: 219 cells per

mm

3

PMN: 90%

Lymph: 2%

Mono: 8%RBC: 5040 cells per mm

3

Peripheral blood contaminationWBC corrects to 207 cells per mm3 Glucose: 50 mg/dLProtein: 56 mg/

dLSlide20

Spinal Fluid Analysis Continued

Gram stain: no organisms

Arbovirus

panel negative

Cytomegalovirus negative

Varicella zoster negative

Cryptococcus negative

Enterovirus

negative

Herpes simplex 1&2 negativeBacterial and fungal cultures negativeSlide21

Hospital CourseHigh fevers continued

On HD 4, patient found altered with global aphasia

Transferred to intensive care unit

Intubated for airway protection

Neuroimaging with CT and MRI did not reveal causeSlide22

Hospital CourseCondition improved with supportive care

Extubated

the following day

Last fever noted just prior to ICU transfer

Antimicrobials weaned

Acyclovir discontinued HD 5

Ampicillin,

vancomycin

discontinued HD 6

Ceftriaxone discontinued HD 10Slide23

Hospital Course

On HD 7, started on

d

apsone

for

pneumocystis

prophylaxis

Developed a fever to

38.4°

C (101.2° F)

Dapsone

abruptly discontinued

Did not have fever recurrence for the duration of hospitalizationSlide24

Hospital Course

On HD 7, started on

d

apsone

for

pneumocystis

prophylaxis

Developed a fever to

38.4° C (101.2° F

)Dapsone abruptly discontinued

Did not have fever recurrence for the duration of hospitalization

Diagnosis:Slide25

Hospital Course

On HD 7, started on

d

apsone

for

pneumocystis

prophylaxis

Developed a fever to

38.4° C (101.2° F

)Dapsone abruptly discontinued

Did not have fever recurrence for the duration of hospitalization

D

iagnosis: drug-induced aseptic meningitis (DIAM) due to sulfa drugsSlide26

Hospital Course

On HD 7, started on

d

apsone

for

pneumocystis

prophylaxis

Developed a fever

to

38.4° C (101.2° F)Dapsone abruptly discontinued

Did not have fever recurrence for the duration of hospitalization

Diagnosis: drug-induced aseptic meningitis (DIAM) due to sulfa drugs

Dapsone, a sulfone, is structurally similar to sulfamethoxazole, a sulfonamideSlide27

DiscussionDIAM is often associated with NSAIDs,

antiepileptics

, and other drugs

Diagnosis of

exclusion

Well-documented with TMP-SMX

Most frequently cited antibiotic

Rapidly progressive

Blood brain barrier

Therapeutic levels in CSF for 15 hours

First reported case in 1983, first reported in an HIV patient in 1994

Associated with autoimmune diseases and immunodeficiency/immunosuppression

Repplinger et al. Am J Emerg

Med (2011) 29,242.e3-242.e5.

Thea

et al. Infect Dis

Clin

North Am 1989;3:553-70.

Dudley et al.

Antimicrob

Agents

Chemother

1984;26:811-4.Slide28

DiscussionFever, headache,

meningismus

, mental status changes

Confusion, coma, seizure

ICU admission

I

ntubation

Global aphasia

Generally responds to withdrawal of offending agent

Continued/repeat ingestion has been shown to worsen symptoms

Capra

et al. Intensive Care Med. (2000) 26: 212-214.

Repplinger et al. Am J Emerg Med (2011) 29,242.e3-242.e5.

Harrison et al.

Clin

Infect Dis. 1994;19:431-4.Slide29

DiscussionProposed mechanism of action

Direct

toxicity

Immunologic

Hypersensitivity reaction

Immune complex deposition

Auto-antibody induction

CSF analysis

Elevated protein

Elevated WBCNormal or borderline glucose

Not reliable in differentiating from partially treated

bacterial meningitis

Von

Reyn

et al. Ann Intern Med 99: 342-344.

River

et al. J

Neurol

Neurosurg

Psychiatry. 57:

705-708.

Carillo

et al. Rev

Neurol

23 (119): 142-144.

Capra et al. Intensive Care Med. (2000) 26: 212-214. Slide30

Trimethoprim-induced aseptic meningitis in a patient with AIDS: case report and review

41 year old HIV+ treated with TMP-SMX for pneumocystis

Suffered DIAM within hours of his first dose

P

romptly discontinued and symptoms resolved in 72 hours

On day 14, treatment with TMP/

Dapsone

attempted

Dapsone

given

4 hours

later, TMP

given4 hours later, pt had recurrence of DIAMDapsone and TMP discontinued48 hours later patient returned to neurologic baselineFelt to be due to TMP, as patient was followed on

Dapsone

pneumocystis

prophylaxis for 6 months without issue

Harrison et al.

Clin

Infect Dis.

1994;19:431-4. Slide31

ConclusionDIAM in a patient with ICL

Supported by use of

sulfone

antibiotic

Aseptic nature does not denote a benign course

Bacterial meningitis should remain high on differential diagnosisSlide32

Resources

Walker UA,

Warnatz

K (July 2006).

“Idiopathic

CD4

lymphocytopenia

”.

Curr

Opin Rheumatol 18 (4): 389–95.

Thea

D,

Barza M. Use of antibacterial agents in infections of the central nervous system. Infect Dis Clin North Am 1989;3:553-70.Dudley MN, Levitz RE, Quintiliani R, et al. Pharmacokinetics of trimethoprim and sulfamethoxazole

in serum and cerebrospinal fluid of adult patients with normal meninges.

Antimicrob

Agents

Chemother

1984;26:811-4.

Capra

C, Monza GM,

Meazza

G, et

al

. Trimethoprim-

sulfamethoxasole

-induced aseptic meningitis: case report and literature review. Intensive

Care

Med 2000;26(2): 212-4

.

Repplinger

MD, Falk PM. Trimethoprim-

sulfamethoxazole

-induced aseptic meningitis.

Am J

Emerg

Med (2011)

29,242.e3-242.e5.

Von

Reyn

CF (1988) Recurrent aseptic meningitis due to

sulindac

. Ann Intern Med 99. 343-344.

River Y,

Averbuch

-Heller L, Weinberger M,

Meiner

Z,

Mevorach

D, Schlesinger I,

Argov

Z (1994) Antibiotic induced meningitis. J

Neurol

Neurosurg

Psychiatry. 57: 705-708.

Carrilo

F,

Cubero

A, Hernandez

Gallego

J Jimenez Santana P (1995) Recurrence of

meningoencephalitis

induced by

cotrimoxazole

. Rev

Neurol

23 (119): 142-144.

Harrison MS,

Simonte

SJ, Kauffman CA. Trimethoprim-induced aseptic meningitis in a patient with AIDS: case report and review.

Clin

Infect Dis.

1994;19(3):431-4.Slide33

PRN SlidesSlide34

Healthy Individual with TMP/SMX DIAM

Capra et al. Intensive Care Med. (2000) 26: 212-214. Slide35

HIV patient withTMP/SMX DIAM

*

*and

dapsone

Harrison et al.

Clin

Infect Dis.

1994;19:431-4. Slide36

CSF

Bacterial

Appearance

Cloudy

Pressure

18-30

WBC

100-10,000 polys

Glc

<45

TP

100-1000

AsepticAppearanceClear

Pressure

9-18

WBC

<300

polys

lymphs

Glc

50-100

TP

50-100Slide37
Slide38

BM Bx

2003

NORMOCELLULAR

MARROW WITH MILD ERYTHROID AND

MEGAKARYOCYTIC DYSPLASIA

AND MEGALOBLASTOID

CHANGES

This

marrow is very small and hence, it is difficult to render a more

definitive diagnosis. This marrow was compared with the previous marrow (

NB02-200), which shows more severe leukopenia and thrombocytopenia,

however

, the rest of the marrow is more or less similar to the current marrow. The dysplasia does not show any increase in number or severity of changes. The presence of megaloblastoid changes and giant metamyelocytes

suggest

a B12 and/or folic acid deficiency. Close clinical follow-up and

clinicopathologic

correlation may be warranted.

2007

NORMOCELLULAR

BONE MARROW WITH TRILINEAGE HEMATOPOIESIS

AND INCREASED

MONOLOBATED

MEGAKARYOCYTES

Significant

morphologic evidence of dysplasia is limited to the

megakaryocytic

lineage with greater than ten percent of megakaryocytes

with

hypo/

monolobation

. Significant

erythroid

dysplasia is not apparent.

An

evolving

myelodysplastic

disorder cannot be excluded. Correlation with

cytogenetic studies

and B12/folate levels is recommended.