Disclosures I have no disclosures. CNS INFECTIONS: PEARLS AND - - PDF document

3/12/2019 1

Felicia Chow, MD, MAS Assistant Professor University of California, San Francisco March 28, 2019

CNS INFECTIONS: PEARLS AND PERILS

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

Photo credit: succeedonline.asu.edu

BREAD AND BUTTER

3/12/2019 2 Case One

• 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 One

How sensitive is the CSF HSV PCR for HSV- 1 encephalitis?

• A. Sensitive enough that I would feel comfortable

discontinuing IV acyclovir based on the negative result.

• B. Pretty sensitive, but in this situation I would continue IV

acyclovir, repeat a lumbar puncture and resend the PCR in a few days.

• A. Not at all sensitive. I do not use the HSV PCR to guide

decisions in terms of stopping or starting IV acyclovir.

HSV-1 encephalitis

3/12/2019 3 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

• Diffusion weighted sequence (DWI) 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

3/12/2019 4 THE BIG THREE Case Two

• 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

Case Two

• 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

Neurosyphilis

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

3/12/2019 5

No one test has high sensitivity/specificity for neurosyphilis

SERUM Treponemal tests (TPPA, FTA-Abs) Sensitive and specific for past or current

• T. pallidum infection

False positives with other spirochetal infections, 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- treponemal tests) 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 treponemal tests 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?

• A. Any stage of syphilis + neurological signs/symptoms,
• cular or otologic disease
• A. Inappropriate serologic response (4-fold decline in RPR

titer) after treatment for syphilis

• B. Any person living with HIV with a newly positive RPR

and CD4 <350 cells/mm3

• C. A & B
• D. A, B, & C

Ghanem Clin Infect Dis 2009

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

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

3/12/2019 6 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 Three

• 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

• nset 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 Three What is the most likely diagnosis?

• A. Pyogenic brain abscess
• B. Neurocysticercosis
• C. Tuberculoma
• D. Toxoplasmosis
• E. Brain metastasis

3/12/2019 7 Case Four

• 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 Four What is the most likely diagnosis?

• A. Pyogenic brain abscess
• B. Neurocysticercosis
• C. Tuberculoma
• D. Toxoplasmosis
• E. Brain metastasis

Neurocysticercosis

• Infection of the nervous

system with larval stage

• f the helminth, Taenia

solium

• 50+ million people

affected worldwide

• One of the most

common causes of acquired epilepsy in developing world

3/12/2019 8

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

Natural history, clinical presentation, diagnostic testing, and management of NCC

Location

• f cysts

Stage of cysts Number

• f 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

Stages of NCC

Garcia et al. NEJM 2004

3/12/2019 9 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
• r 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
• r 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

DEGENERATING CYSTS SUBARACHNOID CYSTS

VENTRICULAR

CYSTS

White et al. Clin Infect Dis 2018

Treatment summary

CALCIFIED CYSTS No antiparasitic therapy indicated VIABLE CYSTS

DEGENERATING CYSTS SUBARACHNOID CYSTS

VENTRICULAR

CYSTS

White et al. Clin Infect Dis 2018

3/12/2019 10 Treatment summary

CALCIFIED CYSTS No antiparasitic therapy indicated 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

DEGENERATING CYSTS SUBARACHNOID CYSTS

VENTRICULAR

CYSTS

White et al. Clin Infect Dis 2018

Treatment summary

CALCIFIED CYSTS No antiparasitic therapy indicated 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

DEGENERATING CYSTS

Single lesion: albendazole x 7- 14 d + steroids

Multiple lesions:

albendazole + praziquantel x 10-14 d + steroids

*Retreat PRN at 6 mo

SUBARACHNOID CYSTS VENTRICULAR CYSTS

White et al. Clin Infect Dis 2018

Treatment summary

CALCIFIED CYSTS No antiparasitic therapy indicated 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

DEGENERATING CYSTS

Single lesion: albendazole x 7- 14 d + steroids

Multiple lesions:

albendazole + praziquantel x 10-14 d + steroids

*Retreat PRN at 6 mo

SUBARACHNOID CYSTS Albendazole +/- praziquantel + steroids +/- debulking prolonged courses x >1 yr

• ften needed for

resolution of cysts by imaging, nL of CSF gluc & cells, neg Ag

VENTRICULAR

CYSTS

White et al. Clin Infect Dis 2018

Treatment summary

CALCIFIED CYSTS No antiparasitic therapy indicated 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

DEGENERATING CYSTS

Single lesion: albendazole x 7- 14 d + steroids

Multiple lesions:

albendazole + praziquantel x 10-14 d + steroids

*Retreat PRN at 6 mo

SUBARACHNOID CYSTS Albendazole +/- praziquantel + steroids +/- debulking prolonged courses x >1 yr

• ften needed for

resolution of cysts by imaging, nL of CSF gluc & cells, neg Ag

VENTRICULAR

CYSTS Extraction via endoscopy vs craniotomy + steroids +/- albendazole (Pre-Rx w/ steroids, no ABZ) *Avoid removal

• f adherent,

inflamed cysts

White et al. Clin Infect Dis 2018

3/12/2019 11 Treatment summary

CALCIFIED CYSTS No antiparasitic therapy indicated 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

DEGENERATING CYSTS

Single lesion: albendazole x 7- 14 d + steroids

Multiple lesions:

albendazole + praziquantel x 10-14 d + steroids

*Retreat PRN at 6 mo

SUBARACHNOID CYSTS Albendazole +/- praziquantel + steroids +/- debulking prolonged courses x >1 yr

• ften needed for

resolution of cysts by imaging, nL of CSF gluc & cells, neg Ag

VENTRICULAR

CYSTS Extraction via endoscopy vs craniotomy + steroids +/- albendazole (Pre-Rx w/ steroids, no ABZ) *Avoid removal

• f adherent,

inflamed cysts

White et al. Clin Infect Dis 2018

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 Five

• 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 injection drug use, no history of homelessness or incarceration; no known TB contacts

• Tuberculin skin test negative, serum

Cocci immunodiffusion pending

• CSF demonstrates 290 cells/mm3,

protein 100 and glucose 40 (serum 100). CSF gram stain and fungal stains are negative

Coccidioidal meningitis

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

3/12/2019 12 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, steroids, anti-TNF therapy, transplant)
• 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:plasma glucose 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

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 99

Table adapted from Brian Schwartz, Kassis Clin Infect Dis 2015 Galgiani Clin Infect Dis 2016

• Testing for Coccidioidal meningitis should include:
• pening pressure, cell count, glucose, protein and fungal

culture, CSF Cocci immunodiffusion, Cocci complement fixation and Cocci antigen.

3/12/2019 13 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 FORGOTTEN

Photo credit: Pete Souza White House

Case Six

• 65-year-old man s/p liver transplant for chronic HCV infection

complicated by cirrhosis

• Presented with progressive memory and language impairment and

difficulty reading words on the right side of the page for several months

• Immunosuppressive regimen: mycophenolate mofetil, tacrolimus, and

prednisone

• On exam: Anxious-appearing, occasionally tearful. Oriented only to

name and “hospital.” Perseverative. Frequent paraphasic errors. Unable to register or recall objects. Difficulty with simple commands. Can repeat simple phrases but not complete sentences. When asked to write a sentence, writes, “Hi very much.” Homonymous right-sided visual field deficit.

Case Six

3/12/2019 14 Case Six

Lumbar puncture

• WBC 1 cells/μL
• RBC 0 cell/μL
• Glucose 50 mg/dL
• Protein 48 mg/dL
• HSV-1/2, VZV PCR negative
• VDRL and CrAg negative

Progressive multifocal leukoencephalopathy (PML)

https://library.med.utah.edu/WebPath/TUTORIAL/AIDS/AIDS076.html

What is the most commonly observed CSF profile in progressive multifocal leukoencephalopathy?

• A. Moderate pleocytosis,  protein, and normal glucose
• A. Moderate pleocytosis,  protein, and  glucose
• B. Marked pleocytosis (>1000 WBC),  protein, and

normal glucose

• A. Normal WBC count, normal protein, and normal glucose

Progressive multifocal leukoencephalopathy

• Demyelinating disease caused by reactivation of JC virus infection
• Subacute decline over weeks to months w/ focal deficits
• Immunocompromised populations at risk: HIV, solid organ and hematopoietic

stem cell transplant, hematological malignancy, chemotherapy, patients receiving monoclonal antibodies (e.g., natalizumab, rituximab)

• CSF profile often normal
• Very mild lymphocyte-predominant pleocytosis occurs in <25% of patients
• Mildly elevated protein in up to 20-30% of patients
• CSF JCV PCR sensitivity 75-95% but may be as low as 50% in era of

antiretroviral therapy and non-AIDS related PML

• Sensitivity in HIV decreases after initiation of ART and with higher CD4 counts
• Sensitivity also lower in non-AIDS related PML
• Specificity 92-100%
• No effective treatment available reduce immunosuppression, start ARVs

Tan Lancet Neurol 2010, Berger Cleve Clin J Med 2011, Berger et al. Neurology 2013, Marzocchetti et al. J Clin Microbiol 2005

3/12/2019 15 Case Seven

• 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

• n right

Case Seven Toxoplasmosis

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

CNS toxoplasmosis

• Most common focal brain lesion

in persons with HIV w/ CD4 < 200 in US

• Other immunocompromised

populations at risk: solid organ and hematopoietic stem cell transplant, 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

3/12/2019 16 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 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 +Mass effect and edema 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 At risk with CD4 count <50

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 +Mass effect and edema Periventricular, deep white matter Can be solitary/few lesions with solid/homogeneous enhancement; in patients with HIV, can ring-enhance +Mass effect and edema 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 At risk with CD4 count <50 Diagnosis Serum IgG (reactivation), CSF IgG and 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

Take home points

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

encephalitis

• CSF VDRL sensitivity is variable, and a negative CSF VDRL does not necessarily rule out

the diagnosis of neurosyphilis

• Patients with any stage of syphilis wand neurologic/ocular/otologic signs or symptoms should

undergo lumbar puncture, in addition to those with inappropriate decline in RPR titer after treatment for syphilis

• 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

• CSF profile is usually normal in PML, and CSF JCV PCR may be less sensitive in persons

with HIV on ART or those with non-AIDS-related PML

• CNS toxoplasmosis is typically reactivation of prior infection, and thus serum IgG status is

important to document as part of the evaluation

3/12/2019 17

THANK YOU

Questions, comments, suggestions: felicia.chow@ucsf.edu