Disclosures Learning objectives BREAD AND BUTTER

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Felicia Chow, MD, MASAssistant ProfessorUniversity of California, San FranciscoDepartment of Neurology and Division of Infectious Diseases February 14, 2019

NEUROINFECTIOUS DISEASESEVERY CLINICIAN SHOULD KNOW

https://www.intechopen.com/books/novel-aspects-on-cysticercosis-and-neurocysticercosis/epilepsy-and-neurocysticercosis-in-sub-saharan-africa

Disclosures

• I have no disclosures.

Learning objectives

• Recognize the clinical presentation of common neuroinfectious diseases

• Identify pitfalls of diagnostic testing in the evaluation and management of common neuroinfectious diseases

• Be familiar with treatment strategies for common neuroinfectious diseases

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BREAD AND BUTTER

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Case One

• 50-year-old woman with type 2 diabetes presents to the ED with 3 days of fever, headache, and nausea/vomiting followed by confusion.

• Exam: Febrile to 103 degrees F. Somnolent, disoriented and agitated. Neck is stiff but remainder of neurologic exam unremarkable with negative Kernig’s and Brudzinski’s signs.

Case One

What is the most likely diagnosis?

A. Bacterial meningitis

B. Viral meningitis

C. TB meningitis

D. Fungal meningitis

Acute bacterial meningitis

Photo credit: http://neuropathology-web.org/chapter5/chapter5aSuppurative.html

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Clinical presentation of bacterial meningitis

1. Fever (77-95%)2. Nuchal rigidity (83-88%)3. Mental status changes (69-78%)4. Headache (87%)5. Rash (11-26%)6. Seizures (5-23%)7. Focal neurological findings (28-33%)8. Papilledema (3-4%)

*Absence of fever, nuchal rigidity and altered mental status makes acute bacterial meningitis extremely unlikely

44-66%: Triad100%: 1 or 2 or 395%: at least 2 of 4

Durand N Engl J Med 1993, Attia JAMA 1999, Van de Beek N Engl J Med 2004 Thomas et al. Clin Infect Dis 2002; Pictured credit https://i.pinimg.com/originals/da/4c/37/da4c37ad4ab794cce9b9c32bc2d963d0.png

Diagnostic accuracy of Kernig’s and Brudzinski’ssigns for meningitis

• Among 297 adults with suspected meningitis, sensitivity of Kernig’s and Brudzinski’s signs 5%, sensitivity of nuchal rigidity 30%

• For those with severe meningeal inflammation (WBC≥ 1000), sensitivity of Kernig’s and Brudzinski’sstill poor (0 and 25%) but nuchal rigidity sensitivity 100%

Case One• Lumbar puncture

• Normal opening pressure• Cloudy appearance• WBC 6250 cells/μL (95% polys)• Glucose 15 mg/dL• Total protein 405 mg/dL• Gram stain and bacterial culture pending, although LP performed

24 hours after empiric antibiotics initiated

Differences in CSF profile in viral vs. bacterial meningitisViral Bacterial

Opening pressure Normal or mildly elevated Often elevated

Color “Gin” clear Cloudy

Cells/mm3 Mild to moderately elevated (10-500 cells/mm3)

High to extremely high (100-5000+ cells/mm3)

Differential Lymphocytes Neutrophils

CSF:plasma glucose ratio Normal Low

Protein (mg/dL) Normal to mildly elevated (45-100)

Elevated (>100)

Solomon Pract Neurol 2007

Many exceptions to the rule!

*Can see lymphocyte predominant pleocytosis in partially treated bacterial meningitis or with certain organisms (e.g., Listeria)

*Can see neutrophils early in course of many infections, including viral, TB, and fungal meningitis

*Low CSF glucose is not specific to bacterial meningitisalso seen in some viral processes (e.g., herpesviruses), along with TB/fungal/parasitic infections, malignancy, sarcoid, SAH

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What is the yield of gram stain and culture after antibiotic therapy in bacterial meningitis?• Gram stain+ 60-90% before antibiotics

• 90% positive with S. pneumoniae and S. aureus• 86% positive with H. influenzae• 75% positive with N. meningitides• 50% positive with gram-negative rods• <50% positive with L. monocytogenes

• Gram stain+ 40-60% post antibiotics

• Culture+ 70-85% BUT can sterilize quickly after administration of antibiotics

• Blood cultures 50-80% yield before antibiotics, 20% after

La Scolea J. Clin Microbiol 1984, Bouwer Lancet 2012

Empiric therapy for acute bacterial meningitis is host dependent

Van de Beek et al. Lancet 2012

Patient population Pathogens Empiric therapy

2 to 50 years S. pneumoniae, N. meningitidis

Vancomycin + 3rd

generation cephalosporin (cefotaxime or ceftriaxone)

Age >50 years S. pneumoniae, N. meningitidis, L. monocytogenes, aerobic gram-negative bacilli

Vancomycin + 3rd

generation cephalosporin (cefotaxime or ceftriaxone) + ampicillin

Immunocompromised S. pneumoniae, N. meningitidis, L. monocytogenes, S. aureus, Salmonella spp., aerobic gram-negative bacilli including P. aeruginosa

Vancomycin + cefepimeor meropenem + ampicillin

Corticosteroids in bacterial meningitis

*Adjunctive dexamethasone (0.15 mg/kg q6h x 4 days) recommended for adults with acute bacterial meningitis

*Initiation before or concurrent with the first dose of antimicrobial therapy

De Gans et al. N Engl J Med 2002

Case One• CSF gram stain with small gram negative coccobacilli

• CSF and blood cultures positive for Haemophilusinfluenzae

• Empiric therapy narrowed to IV ceftriaxone

• Prolonged course complicated by hydrocephalus, vasculitis and multifocal infarcts

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Case Two• 52 year-old woman presents with 2 days of fever,

headache and confusion; her daughter who is home for winter break brings her to the ED

• Exam: T 39.2 C, decreased level of arousal and poor attention

• CSF with 11 WBC (65%L, 15%M), 680 RBC, protein 85 and glucose 53; gram stain negative, bacterial culture negative

• HSV 1/2, VZV and enterovirus PCR negative

Case Two


A. West Nile virus encephalitis

B. NMDA encephalitis

C. HSV-1 encephalitis

D. Neurosyphilis

HSV-1 encephalitis

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HSV encephalitis

• HSV is the most frequently identified viral etiology of sporadic encephalitis in the US

• Bimodal distribution: 1/3 cases <20 y, 2/3 >40 y

• Case fatality rate >70% if untreated; 1/3 of patients may be significantly disabled despite treatment

• CSF: 5-500 WBC/mm3, normal to moderately elevated protein, glucose typically normal

• Involvement on imaging of the medial temporal lobes, insula, and/or inferolateral frontal lobes

• DWI sequence most sensitive early in disease course

How reliable is HSV-1 PCR from the CSF ?

• 54 patients with biopsy-proven HSE underwent HSV-1 PCR from CSF• Sensitivity 98%

• Specificity 94%

Lakeman et al J Infect Dis 1995

Sensitivity of CSF HSV-1 PCR is lower early in the course of HSV encephalitis

Weil et al. Clin Infect Dis 2002

*In patients with a compatible clinical syndrome for HSV encephalitis and/or temporal lobe abnormalities on neuroimaging, consider repeat CSF HSV PCR in 3 to 7 days.

Treatment of HSV-1 encephalitis: Time is brain

• Earlier initiation of acyclovir associated with improved mortality

• Acyclovir 10 mg/kg every 8 hours x 14 to 21 d

• No data for use of corticosteroids as adjunctive therapy

• No role for oral antivirals after completion of IV therapy

Tunkel et al Clin Infect Dis 2008

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Case Three• 55-year-old man with no past medical history other than

“possible meningitis” several years ago presents with 5 days of fever, chills, malaise and headache.

• One day prior to presentation, developed bilateral hip and buttocks pain and paresthesias along with urinary retention

• Exam: T 101. Neurologic exam notable for decreased sensation in an S3-S5 distribution.

• LP with normal opening pressure, 310 WBC (84% L), protein 91 and glucose 40.


A. CMV

B. HSV-2

C. EBV

D. Enterovirus

• Lumbosacral myeloradiculitis associated most commonly with HSV-2 reactivation, though HSV-1 increasing in frequency

• IF occurs with genital herpes outbreak, onset often 5 to 7 days later

• Typically present with lower back/buttocks pain, paresthesias in lumbosacral distribution and bowel/bladder symptoms; s/sx of meningitis often absent

• CSF profile consistent with viral meningitis

• MRI may be normal or may show root/lower spinal cord edema with enlargement, T2/FLAIR hyperintensity and contrast enhancement

• Treatment: IV acyclovir 10 mg/kg q8h typically for 14 daysEberhardt et al. Neurology 2004

Is there any benefit of suppressive antiviral therapy to prevent HSV-2 meningitis recurrence?

• 101 patients with HSV-2 meningitis randomized to valacyclovir500 mg BID or placebo for 1 year after completing treatment for acute meningitis

Aurelius et al. CID 2012

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• In Year 1, 14 cases of recurrent meningitis in valacyclovir group (29%) vs. 8 cases in placebo group (16%), p=0.12

• In Year 2, 12 cases in valacyclovir group (24%) vs. 4 in placebo (8%), p=0.03

Aurelius et al. CID 2012

*No role for suppressive valacyclovir to reduce risk of recurrent HSV-2 meningitis

THE BIG THREE

Case Four

• 42-year-old man presents to clinic with new diffuse headache and light sensitivity for 1 week

• Exam is notable for a generalized macular rash and unilateral optic disc hyperemia with blurred disc margins

https://bpac.org.nz/BT/2012/June/06_syphilis.aspx


A. Rickettsial infection

A. VZV meningitis

B. CNS Lyme

C. Neurosyphilis

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Neurosyphilis

Camarero-Temino Nephrology 2013; https://en.wikipedia.org/wiki/Neurosyphilis#/media File:Skull_damage_from_neurosyphilis.jpg

Case Four

• RPR 1:128

• Brain MRI with a small acute infarct in right corona radiata

• LP results• Normal opening pressure• WBC 23 (83% lymphocytes)• 0 RBC• Protein 95• Glucose normal• CSF VDRL non-reactive

https://openi.nlm.nih.gov/detailedresult.php?img=PMC3095916_SRT2011-726573.008&req=4

No one test has high sensitivity/specificity for neurosyphilis

SERUM

Treponemaltests (TPPA, FTA-Abs)

Sensitive and specific for past or current T. pallidum infection

False positives with other spirochetalinfections, EBV, malaria, leprosy; false negative in HIV

*Titers do not correspond to disease activity

*Most positive for life despite treatment

Test characteristics Notes

SERUM

RPR (non-treponemaltests)

Sensitivity:1°: 78-86%2°: Near 100% 3°/Latent: Varies, ~85%

False positives 1-2%, usually titer <1:8 (autoimmune disease, IVDU, TB, pregnancy, endocarditis); false negatives in HIV, prozone effect

*Titers correspond to disease activity

*Used to assess treatment response 4-fold decline considered to be clinically significant

CSF VDRL (non-trep)

CSF treponemaltests

CSF VDRL Sensitivity: 30-80%, Specificity 99%

FTA-Abs/TPPA generally more sensitive than VDRL

*CSF VDRL considered “gold standard” for neurosyphilis

*Positive CSF VDRL at any titer =neurosyphilis

*Negative CSF FTA-Ab essentially rules out neurosyphilis

Which syphilis patients need an LP?

• Any stage of syphilis + neurological signs/symptoms

• Any stage of syphilis + ocular or otologic disease

• Tertiary syphilis w/ or w/o neurological signs/symptoms

• Inappropriate serologic response after treatment

• HIV-infected patients PLUS:• Consider for HIV-infected patients with CD4 <350 cells/mm3 and/or

RPR ≥ 1:32

Ghanem Clin Infect Dis 2009

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Which syphilis patients need an LP?

• Any stage of syphilis + neurological signs/symptoms

• Any stage of syphilis + ocular or otologic disease

• Tertiary syphilis w/ or w/o neurological signs/symptoms

• Inappropriate serologic response after treatment

• HIV-infected patients PLUS:• Consider for HIV-infected patients with CD4 <350 cells/mm3 and/or

RPR ≥ 1:32 Thorough neurologic history and exam

Ghanem Clin Infect Dis 2009

Treatment of neurosyphilis

• Aqueous crystalline penicillin G 18–24 million units per day, administered as 3–4 million units IV every 4 hours or continuous infusion, for 10-14 days

• Alternative treatment: Procaine penicillin 2.4 million units IM once daily PLUS Probenecid 500 mg orally four times a day, both for 10-14 days

• Possible alternative treatment? Ceftriaxone 2 g IV daily for 10-14 days (data are limited)

Marra et al. Clin Infect Dis 2000

Case Five• 34-year-old previously healthy man from Mexico, has lived in the US for 10 years, works as a chef in a restaurant, non-smoker, develops sudden onset left hand and face “twisting” followed by loss of consciousness

• ROS negative, including no fever/chills, night sweats, or weight loss

• General and neurologic exam unremarkable

Case Five

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A. Pyogenic brain abscess

B. Neurocysticercosis

C. Tuberculoma

D. Toxoplasmosis

E. Brain metastasis

Case Six

• 28-year-old man, originally from Mexico but has lived in the US for over 15 years, with a history of a generalized seizure 5 years ago treated with divalproex, presents with headache, blurred vision, and nausea/vomiting for 1 month

• ROS negative for fever/chills, night sweats, or weight loss; denies weakness or other neurologic symptoms

• Afebrile on exam. Somnolent. Incomplete abduction bilaterally. Mild left-sided weakness in pyramidal pattern with associated hyperreflexia and left upgoing toe.

Case Six What is the most likely diagnosis?

A. Pyogenic brain abscess

B. Neurocysticercosis

C. Tuberculoma

D. Toxoplasmosis

E. Brain metastasis

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Neurocysticercosis

• Infection of the nervous system with larval stage of the helminth, Taeniasolium

• 50+ million people affected worldwide

• One of the most common causes of acquired epilepsy in developing world

https://www.who.int/news-room/fact-sheets/detail/taeniasis-cysticercosis

Natural history, clinical

presentation, diagnostic

testing, and management of

NCC

Location of cysts

Stage of cysts Number

of cysts

Stages of neurocysticercosis

Garcia et al. Curr Opin Infect Dis 2003;16:411-419.

Courtesy of HH Garcia

Viable cyst

Degenerating cyst

Dead cyst

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Stages of NCC

Garcia et al. NEJM 2004

Location, location, location• Intraparenchymal (70%)

• Cortical (>90%), deep gray matter (5%), brainstem/infratentorial(uncommon)

• Most commonly present with seizures

• Extraparenchymal (30%)• Sylvian fissure, basal cisterns,

intraventricular, spinal (usually extramedullary)

• Most commonly present with hydrocephalus and increased intracranial pressure

• Often much more difficult to treat with worse prognosis

• Mixed (10-30% of cases)

How good is serology for the diagnosis of NCC?

• ELISA• Sensitivity and specificity range from 50-80%

• Sensitivity lower in patients w/ single lesions or calcifications (30-60%)

• Performs better in CSF than serum

• Enzyme-linked immunotransfer blot (EITB)• Sensitivity near 100% for multiple

parenchymal, ventricular, or subarachnoid cysts; specificity 100%

• Sensitivity lower in patients w/ single lesions or calcifications (33-80%)

• Performs as well (or better) in serum as CSF

• Test of choice per IDSA guidelines

• Neither can be used to distinguish prior from active infection

Tsang VC et al. J Infect Dis 1989, Rodriguez et al. J Infect Dis 2009, White et al. Clin Infect Dis 2018

Treatment summary

CALCIFIED CYSTS

VIABLE CYSTS

DEGENERATINGCYSTS

SUBARACHNOIDCYSTS

VENTRICULARCYSTS

White et al. Clin Infect Dis 2018

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Treatment summary

CALCIFIED CYSTS

No antiparasitictherapy indicated

VIABLE CYSTS

DEGENERATINGCYSTS

SUBARACHNOIDCYSTS

VENTRICULARCYSTS


Treatment summary

CALCIFIED CYSTS


VIABLE CYSTS

1-2 lesions: albendazole 15 mg/kg/d x 10-14 d + steroids

>2 lesions: albendazole +praziquantel 50 mg/kg/d x 10-14 d + steroids*Retreat PRN at 6 mo

DEGENERATINGCYSTS

SUBARACHNOIDCYSTS

VENTRICULARCYSTS


Treatment summary

CALCIFIED CYSTS


VIABLE CYSTS



DEGENERATINGCYSTS

Single lesion: albendazole x 7-14 d + steroids

Multiple lesions: albendazole +praziquantel x 10-14 d + steroids*Retreat PRN at 6 mo

SUBARACHNOIDCYSTS

VENTRICULARCYSTS


Treatment summary

CALCIFIED CYSTS


VIABLE CYSTS



DEGENERATINGCYSTS



SUBARACHNOIDCYSTS

Albendazole +/-praziquantel + steroids +/-debulkingprolonged courses x >1 yroften needed for resolution of cysts by imaging, nL of CSF gluc & cells, neg Ag

VENTRICULARCYSTS


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Treatment summary

CALCIFIED CYSTS


VIABLE CYSTS



DEGENERATINGCYSTS



SUBARACHNOIDCYSTS


VENTRICULARCYSTS

Extraction via endoscopy vscraniotomy + steroids +/-albendazole(Pre-Rx w/ steroids, no ABZ)

*Avoid removal of adherent, inflamed cysts


Treatment summary

CALCIFIED CYSTS


VIABLE CYSTS



DEGENERATINGCYSTS



SUBARACHNOIDCYSTS


VENTRICULARCYSTS

Extraction via endoscopy vscraniotomy + steroids +/-albendazole(Pre-Rx w/ steroids, no ABZ)

*Avoid removal of adherent, inflamed cysts


Management of complications of NCC should be the first priority before initiation of antiparasitic therapy!

Hydrocephalus Shunt or ventriculostomy +/- steroids

Diffuse cerebral edema Steroids

Status epilepticus Anti-epileptics

*Ocular exam for all patients prior to initiation of antiparasitics

Case Seven• 55-year-old African American

man from Modesto, CA presents with a 6 week history of progressive headache, confusion and lethargy

• HIV negative, no history of international travel, no IDU, no history of homelessness or incarceration; no known TB contacts

• CSF demonstrates 290 cells/mm3, protein 100 and glucose 40 (serum 100). CSF gram stain and fungal stains are negative


A. Pneumococcal meningitis

B. VZV meningitis

C. TB meningitis

D. Coccidioidal meningitis

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Coccidioidal meningitis

https://microbewiki.kenyon.edu/index.php/Coccidioides_immitis

Coccidioidomycosis• Most primary infections (pulmonary) are asymptomatic (~2/3)

• CNS dissemination (1%) occurs weeks to months after 1o infection

• Risk factors for extrapulmonary/disseminated disease: • African or Filipino ancestry• Immune compromise (HIV, malignancy, DM, SOT, steroids)• Pregnancy

Drake Neurology 2009, Galgiani Clin Infect Dis 2005, Johnson Clin Infect Dis 2006

~66% 50-60% 33% (focal) Imaging: • Meningeal

enhancement• Hydrocephalus• Focal lesion (e.g,

infarct, abscess)• Spinal arachnoiditis

also common

How to distinguish TB from Cocci meningitis?Viral Bacterial TB Fungal

Opening pressure

Normal or mildly elevated

Elevated Elevated Elevated

Color “Gin” clear Cloudy Cloudy/yellow Clear/cloudy/yellow

Cells/mm3 Mildly elevated (10-500 cells/mm3)

High to extremely high (100-5000 cells/mm3)

High (25-500) Mildly elevated to high (10-1000)

Differential Lymphocytes Neutrophils Lymphocytes Lymphocytes

CSF:plasmaglucose ratio

Normal Low Low to very low Normal to low

Protein,mg/dL

Normal to high (45-100)

High (>100) High to very high (100-500)

Normal to very high (45-500)

Solomon Pract Neurol 2007

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Performance of Cocci testing in CSF

CSF Parameter Sens (%) Specificity (%)

Fungal culture 7 100

Immunodiff (ID) IgM/IgG 67 99

Complement fixation (CF) IgG 70 100

ID and CF 85 99

Antigen 93 100

Antigen, ID, CF 98 99Table adapted from Brian Schwartz, Kassis Clin Infect Dis 2015 Galgiani Clin Infect Dis 2016

• Testing for Coccidioidal meningitis should include: opening pressure, cell count, glucose, protein and fungal culture, CSF Cocci immunodiffusion, Cocci complement fixation and Cocci antigen.

Treatment for Cocci meningitis• 1st line: Fluconazole 400-1200 mg/day FOR LIFE

• If failing 1st line therapy:1. Increase dose of fluconazole as tolerated

2. Consider another azole (e.g., voriconazole, itraconazole)

3. Consider IT amphotericin B

• Hydrocephalus is a common complication neurosurgery evaluation for shunt

• Consider adjunctive corticosteroids in patients with evidence of vasculitis w/ or w/o infarcts

Galgiani Clin Infect Dis 2005, Johnson Clin Infect Dis 2006, Thompson Clin Infect Dis 2018

NEITHER GONE NOR FORGOTTENPhoto credit: Pete Souza White House

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Case Eight

• 34 year-old man with new diagnosis of HIV (CD4 110, viral load 35K) presents to the ED with 1 month of worsening right-sided weakness

• No fever, stiff neck, mental status changes, headache

• Exam notable for moderate spastic right-sided weakness involving arm and leg with hyperreflexia and upgoing toe on right

Case Eight


A. Cryptococcal meningitis

A. CMV encephalitis

B. Toxoplasmosis

C. EBV-associated lymphoma

Toxoplasmosis

https://www.urmc.rochester.edu/libraries/courses/neuroslides/lab3b/slide137.cfm

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CNS toxoplasmosis• Most common focal brain lesion

in persons with HIV w/ CD4 < 200 in US

• Other immunocompromisedpopulations at risk: transplant (hematopoietic stem cell, heart), hematological malignancy, use of immunosuppressing meds (e.g., anti-TNF inhibitors)

• TMP/SMX prophylaxis reduces risk of toxoplasmosis

Tan et al. Lancet Neurology 2012, Laing et al. Int J STD AIDS 1996

Utility of toxoplasma serology• Toxoplasmosis seropositivity in general population in the

US is estimated to be 10-40%

• CNS toxoplasmosis is typically reactivation of prior infection (i.e., IgM antibodies unhelpful)

• Serum IgG is positive in most HIV patients with CNS toxoplasmosis

• CSF toxo IgG (>1:64) and PCR are very specific but sensitivity varies

Laing Int J STD AIDS 1996, Correira Trans R Soc Trop Med Hyg 2010, Vidal J Clin Microbiol 2004, Sakamoto Parasitol Int 2014

Toxoplasmosis versus CNS lymphoma in HIV

Radiologic findings

Basal ganglia, thalamus, grey-white junction

Usually multiple lesions (75%) with ring or nodular enhancement

+Mass effect and edema

Periventricular, deep white matter

Can be solitary/few lesions with solid/homogeneous enhancement; in patients with HIV, can ring-enhance


Toxoplasmosis Primary CNS Lymphoma

Clinical presentation

Focal s/sx (~75%), HA (~50%), fever (~50%); sx evolve faster than CNSL

At risk with CD4 count <200

Focal s/sx including hemiparesis,aphasia, visual field deficit


Raffi et al. AIDS 1997

Toxoplasmosis versus CNS lymphoma in HIV

Radiologic findings

Basal ganglia, thalamus, grey-white junction

Usually multiple lesions (75%) with ring or nodular enhancement


Periventricular, deep white matter

Can be solitary/few lesions with solid/homogeneous enhancement; in patients with HIV, can ring-enhance


Toxoplasmosis Primary CNS Lymphoma

Clinical presentation

Focal s/sx (~75%), HA (~50%), fever (~50%); sx evolve faster than CNSL


Focal s/sx including hemiparesis,aphasia, visual field deficit


Diagnosis Serum IgG (reactivation), CSF IgGand PCR; response to empiric Rx

CSF EBV PCR (Se 90-100%), brain biopsy; cytology has poor sensitivity (<20%)

Treatment Pyrimethamine (w/ leucovorin) and sulfadiazine or clindamycin;

AVOID steroids if possible!

Corticosteroids, XRT, methotrexate and other chemotherapy

Raffi et al. AIDS 1997

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Case Nine• 40 year-old woman s/p renal transplant (first in

1993, second in 2016) on mycophenolate, tacrolimus and low dose prednisone presented after being found down

• Blood cultures on admission positive Cryptococcus neoformans

• Brain MRI with multifocal acute infarcts, no abnormal enhancement

• Opening pressure on first LP 52 cm H20 with: • 3 WBC

• Glucose <10

• Protein 66

• CSF CrAg >1:1280

• Yeast present on gram stain and CSF culture positive for C. neoformans

Case Nine

• Clinically improved after initiation of Ambisome and flucytosine followed by fluconazole; tacrolimus also discontinued

• Readmitted from skilled nursing facility ~2 months later for worsening altered mental status

• Repeat LP with 71 WBC (lymphocyte predominant), glucose 49, protein 440, CSF CrAg 1:640; negative gram stain and culture

Case Nine What is the most likely diagnosis?

A. Refractory cryptococcal meningitis due to fluconazole resistance

B. Fluconazole toxicity

C. Another opportunistic infection

A. Cryptococcal meningitis IRIS

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Cryptococcal meningitis immune reconstituioninflammatory syndrome (IRIS)• Symptomatic recrudescence or worsening in setting of

reconstitution of immune system (e.g., initiation of ARVs in HIV, reduction in immunosuppressive therapy for transplant or rheum patients) and appropriate antifungal therapy

• Associated findings include:

• Increased CSF pleocytosis

• New or worsening elevated ICP

• New or worsening leptomeningeal enhancement on MRI

• Interval development of cryptococcomas

• Negative CSF cryptococcal cultures are essential in distinguishing cryptococcal IRIS from microbiologic relapse/treatment failure

Treatment of cryptococcal meningitis IRIS

• Consider initiation of induction therapy with Ambisome/flucytosine while awaiting CSF culture data

• Management of elevated intracranial pressure

• Transition back to maintenance fluconazole if cultures remain negative and diagnosis most consistent with IRIS

• Consider course of adjunctive corticosteroids with antifungal therapy

Take home points• Absence of fever, neck stiffness AND altered mental status makes acute bacterial meningitis

extremely unlikely

• CSF bacterial cultures can sterilize after just one or two doses of antibiotic therapy

• CSF HSV-1 PCR sensitivity is lower in patients presenting early in course of HSV-1 encephalitis

• HSV-2 myeloradiculitis can present without signs/symptoms of meningitis or genital herpes outbreak

• CSF VDRL sensitivity is variable, and a negative CSF VDRL does not necessarily rule out the diagnosis of neurosyphilis

• Location, stage, and number of cysts determine clinical presentation, sensitivity of serological testing, and management of neurocystiercosis

• Sending a combination of CSF Coccidioidal immunodiffusion, complement fixation, and antigen can improve sensitivity in the diagnosis of coccidioidal meningitis

• CNS toxoplasmosis is typically reactivation of prior infection, and thus serum IgG status is important to document as part of the evaluation

• Negative CSF cryptococcal cultures are essential in distinguishing cryptococcal IRIS from microbiologic relapse/treatment failure

THANK YOUQuestions, comments, suggestions: [email protected]

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