CNS Infections

Margrit Carlson, M.D.

November 2003

How are infections in the CNS different?

Separated by the blood brain barrier

Immunologically distinct

Unique anatomic considerations dictate the spread of infection within the CNS

Closed space

Limited capacity for regeneration or compensation for injury

Blood Brain Barrier

Between blood and brain formed by the tight junctions of the cerebral capillary endothelium

Between blood and CSF formed by the tight junctions of the choroid plexus epithelium

Immune Response in the CNS

Access of immune effector cells to CNS is limited by the BBB

T lymphocytes can enter and exit the CNS in small numbers

Low expression of MHC molecules limits antigen presentation

Entry into the CNS

Bypassing the blood brain barrier direct extension from a local focus,

sinuses

middle ear or mastoid

dental source foreign body trauma

Entry through the BBB

direct penetration of the choroid plexus epithelium into the CSF (meningitis)

direct penetration of the capillary endothelium into the brain parenchyma (encephalitis)

disruption of the tight junctions

transportation across the barrier inside leukocytes

Types of infections

Meningitis- subarachnoid Encephalitis-brain parenchyma Abscess

subdural

brain

epidural

Cerebrospinal Fluid in Meningitis

Pressure Glucose Protein WBCNormal 180mm 2/3 of serum up to50 0-5

Bacterial I <40 50-1500 50-5000P

Viral N N N <100L

Chronic I 10-45 45-500 25-1000L

I=Increased N =Normal

P=polymorphonuclear leukocytes L=Lymphocyte

CSF Parameters

Pressure Glucose Protein WBCNormal 180mm 2/3 of serum 50 0-5

Abscess I N 30-20010-500 L

Encephalitis N N 20-125 20-200 L

I=Increased N =Normal

P=polymorphonuclear leukocytes L=Lymphocyte

Acute Meningitis

19 yo student is seen for sore throat x2 days. His symptoms worsen and he develops a terrible headache and photophobia. He is brought to the ER the next morning by his roommate. In the ER he is hypotensive, confused, complaining of headache and photophobia. He has a seizure.

He is given antibiotics and taken for a CT scan which is unremarkable.

CSF RBC 10 WBC 1230 93% PMNs glucose 33protein 276

Acute meningitis

Meningeal signs and symptoms worsen over a few days

symptoms: headache, fever, neck stiffness, photophobia and vomiting.

signs: nuchal rigidity, altered level of consciousness, seizures and cranial nerve palsies(sensorineural hearing loss)

Bacterial Meningitis 0-4 weeks Streptococcus agalactiae, E.

coli, Listeria monocytogenes

4-12 weeks H. influenzae, E. coli, L. monocytogenes, S.agalactiae,

3mo-18 years H. influenzae, N. meningiditis, S. pneumoniae

18-50 years S. pneumoniae, N. meningiditis

36 YO G3P2, 33 week IUP brought in by her sister for chest pain and confusion increasing over the last 3 days.

PE: temp was 38.5, she had photophobia but no nuccal rigidity. A vesicular rash was seen on her L chest

CSF: 320 RBC, 460 WBC, 50% lymphs and 34% monos

protein 623, glucose 91

Her MRI had diffuse meningeal enhancement

Meningitis in the Immunocompromised Host

Bacterial Syphilis, Listeria, Nocardia

Viral VZV, HSV

Fungal cryptococcus, coccidioidomycosis, histoplasmosis

Mycobacterial tuberculosis

44 yo construction worker had upper respiratory symptoms 1 month ago. He has had worsening fevers, a constant headache and photophobia for a month. His thinking has been slowed and he had an episode of aphasia lasting 1 day.

CSF: glucose 27protein 203RBC <1WBC 203

45%lymphs/40% mono/5% eos MRI: enhancement of the basal

cisterns, along the midbrain, pons, right optic tract, and the right caudate head.

Chronic meningitis

Gradual onset and progression

Focal symptoms

Increased intracranial pressure

History of exposure

Immunocompromised ?

Symptoms of Increased Intracranial Pressure

headache nausea, vomiting altered mental status ataxia incontinence papilledema 3rd or 6th nerve palsy

Infectious causes of chronic meningitis

Coccidioidomycosis, Cryptococcus, Histoplasmosis, Sporotrichosis

Tuberculosis

Syphilis, Lyme Disease

HIV, Enterovirus

Non-infectious causes of Chronic Meningitis

Behcet’s disease

Systemic lupus erythematosis

Sarcoidosis

Carcinomatous or lymphomatous meningitis

Granulomatous angiitis

Complications of Chronic Meningitis

hydrocephalus

vasculitis, cerebrovascular occlusion

cranial nerve palsies

32 yo Hispanic man has new onset confusion developing over 24 hours, aphasia, hallucinations and seizures following a bone marrow transplant for CML. He has no known ill contacts. He has had mucositis

Putting it all together

Sudden or gradual onset? Meningeal symptoms, encephalopathy? Focal findings? Fever ? Predisposing conditions and exposures Imaging LP results

CSF: glucose 67

protein 158RBC 179WBC 124 25% P /74% L

His MRI shows diffuse periventricular white matter disease and enhancement in the temporal lobes.

Acute Encephalitis

Fever Headache Altered level of consciousness: lethargy,

confusion, stupor, coma Seizures Hypothalamic or pituitary dysfunction

Causes of Acute Encephalitis

Herpes simplex, Varicella zoster

California, St Louis, Japanese, Western and Eastern equine encephalitis viruses

Enteroviruses (coxsackie, echo and enteroviruses)

Post measles, post influenza encephalomyelitis

HSV Pathogenesis

Retrograde transport of virus from mucous membranes to the sensory ganglia and rarely to the CNS

Anterograde transport from the sensory ganglia to the periphery during cutaneous exacerbations

33 yo with AIDS,CD4 cells 5, brought in by his partner who has noticed he has become more forgetful and withdrawn over the last 3-6 months.

He’s had no fevers or headache. No recent infections. He has been off antiretrovirals because of side effects.

MRI showed diffuse atrophy

CSF glucose 88protein 78RBC <1WBC 12 74% lymphs

26% monos

Chronic Encephalitis

Predominantly viral

Non-viral: Neurosyphilis, Lyme disease,

Neurotropic viruses:

Retroviruses: HTLV I and II, HIV

Herpes viruses: HSV, VZV and CMV

Chronic Encephalitis

Other:

JC virus: Progressive multifocal leukoencephalopathy

Subacute Sclerosing panencephalitis (Measles)

Rubella

Creutzfeldt-Jakob

HIV EncephalopathyAIDS Dementia Complex

7-27% of persons with CD4<200 have some impairment including:

decreased attention and concentration psychomotor slowing personality change, loss of initiative, drive,

animation hyperreflexia, ataxia, frontal release signs

Pathogenesis of ADC

HIV is present in the CSF and brain in primary infection.

HIV infects cells of monocyte lineage (macrophages, microglia, multinucleated giant cells).

Viral burden (HIV qPCR) in CSF or brain correlates with neurologic disease.

Pathogenesis of ADC

Release of neurotoxins from macrophages (nitric oxide, arachidonic acid, quinolinic acid).

Cytokine mediated release of neurotoxins.

Direct toxicity of viral proteins, i.e. gp120.

73 yo man with a fever who is brought in by his wife because he is confused and unable to move his right side.

He was complaining of a headache for a few days. He started vomiting this morning and was bumping into the wall on his way to the bathroom.

Brain Abscess

hematogenous spread through the blood brain barrier

direct extension via the the emissary veins into the cerebral venous circulation

Development of an abscess

Local area of cerebritis, inflammation and edema (1-3 days)

Expansion and development of a necrotic center (4-9 days)

Formation of a ring enhancing capsule by gliosis and fibrosis (14 days)

Clinical Presentation

Headache with gradual worsening Fever <50% Focal neurologic signs Seizures CSF: elevated protein, normal glucose

and mild leukocytosis Increased ICP: Nausea,vomiting, lethargy

Brain Abscess

Location

Source

Organism

Treatment

Brain Abscess

Paranasal Sinuses Frontal lobe

Otogenic Infection Temporal lobe, cerebellum

Hematogenous spread Multiple lesions MCA distribution

Post traumatic Site of wound

Post operative Site of surgery

Pathogens

Sinuses Streptococci, Haemophilus, Bacteroides, Fusobacterium

Otogenic as above, and Pseudomonas

Endocarditis Staphylococcus, Viridans streptococci

Lung abscess Streptococci, anaerobes, Actinomyces

Trauma Staph aureus

A 28 YO father of 3 develops worsening sinus headaches and is seen repeatedly at an outside ER. He has low grade fevers. His headache becomes excruciating and he subsequently becomes unresponsive during his evaluation.

Brain Abscess in the Immunocompromised

AIDS

Toxoplasmosis, Tuberculoma, Cryptococcoma, Coccidiodomycosis, Blastomycosis

Transplant

Aspergillus, Nocardia, Candida, Zygomycetes in addition to the above

35 YO man with 2 weeks of worsening headache, low grade fever and rash. He also has had myalgias and L knee pain and swelling.

He has no recent travel or outdoor activities, not sexually active x 6 months

CT Scan is unremarkable

CSF: 2 RBC, 25 WBC;20%segs, 60% lymphs, 20% monocytes, glucose 64, protein 45.

Fever, Headache,Rash and mild CSF pleocytosis

Enterovirus

Primary HIV

Epstein Barr

Secondary syphilis

Mycoplasma

Drug Reaction

Neurosyphilis

Primary, chancre 10-90 days Secondary,rash 4-10 weeks later (up to

6 months after initial infection Meningeal within 1st year after infection Meningovascular 4-7 years later Parenchymal disease decades later

Syphilis 50-75% of exposed partners were

infected. 30-70% of those with secondary syphilis

have CSF mononuclear pleocytosis, elevated protein or + RPR in CSF

25% untreated patients have recurrances 1/3 of untreated patients develop late

sequelae