CNS infections

Ahmad Rizal Bagian Saraf FKUP / RSHS Bandung

Terminology
Primarily affects its coverings meningitis Affects the brain parenchyma encephalitis Affects the spinal cord myelitis A patient may have more than one affected area, and if all are affected, the patient has "meningoencephalomyelitis
Within the brain or spinal cord abscess Outside them there epidural abscess or subdural empyema

Localized pockets of infection:

Clinical syndromes
Acute presentations: <2 days duration
bacterial process (pyogenic) aggressive viral encephalitis

Subacute presentations : broader spectrum of diagnostic possibilities

Tuberculous Fungal Parasitic Viral Non infectious: encephalopathy, ADEM, other

Change in scenario
Increase in immuno-compromised patients
AIDS prolonged survival of cancer patients organ transplantation

Increase in international travel

rapid transmission to susceptible populations new diseases

Widespread antibiotic use

resistant organisms

Signs and symptoms

Headache Fever Neck stiffness (and other meningeal signs) Obtundation

Diagnosis
Suspicious clinical symptoms and signs CT of head to rule out abscess or other space-occupying lesion, if it can be done quickly Lumbar puncture Blood cultures

Acute bacterial meningitis

The big three: N.meningitides, S.pneumoniae, H.influenzae
Other: Listeria, pseudomonas, E.coli.

Headache, fever, neck stiffness, obtundation focal signs, seizures, rash, shock.. often fulminant CSF: high wbc (500- 20000 polymorphs), high protein, low glucose
But: partial treatment

CT/MRI: may be normal

Meningococcal septicaemia

Meningococcaemia

Meningococcal septicaemia Picture: With the friendly permission of Dr. Noack (photographer) and Prof.Dittman, in whose book the picture appears (German title:"Meningokokkenerkrankungen)

Bacterial meningitis: diagnosis

High index of suspicion Prompt CSF examination urgent smear for Gram stain urgent latex agglutination testing for bacterial antigens (meningococcus, pneumococcus, H.infl) not a routine procedure in Bandung Repeat CSF examination after 24 48 h

Bacterial meningitis: antibiotics

Ceftriaxone iv 4g; then 2g daily
cefotaxime benzylpenecillin chloramphenicol

Resistant pneumococcus
add vancomycin 2g bd iv +/- rifampicin

Listeria
ampicillin

Pseudomonas
gentamicin

Bacterial meningitis: steroids

Significantly reduce mortality and neurological sequelae in adults with bacterial meningitis Should be used ROUTINELY in adults with suspected bacterial meningitis Best effect to pneumococcal infection Give with/before 1st dose of antibiotics 10mg dexa 6 hourly for 4 days NOT in patients already started on antibiotics (de Gaans, NEJM 2002; 347: 1549 56) Caution: may reduce penetration through BBB
especially vancomycin

Bacterial meningitis: steroids

Dont give in
Late stage disease may be harmful septic shock post neurosurgical meningitis immunosuppressed/i.compromised patients

Stop if
No pathogen identified on CSF smear and suspect fungal/other infection No bacterial growth/other organism after 24- 48 hours

Bacterial meningitis: treatment

Other anti-inflammatory drugs?
against CSF cytokines matrix metalloproteases reactive oxygen species

Bacterial meningitis
Delay initiating treatment Delay recognising complications

high mortality more complication

Late deterioration
Subdural effusion Empyema Hydrocephalus Vasculitis:
stroke diffuse brain injury oedema

systemic

Cerebral infarction

T2

DWI

Subdural empyema

Vasculitis and stroke

Vasculitis, stroke, hydrocephalus

Acute or subacute onset global cerebral dysfunction

Three diagnostic categories
Infective encephalitis (typically viral) Encephalopathy (typically metabolic or toxic) ADEM

 Encephalopathy
Mental status steady decline Seizures generalised

Encephalitis
Fever and headache common Mental status often fluctuates Seizures focal and generalised Focal signs common
Blood wbc CSF- wbc EEG slow plus focal MRI often abnormal

Blood - wbc N CSF wbc N EEG diffuse slowing MRI often normal

Encephalitis?
The physician addresses three important questions:
How likely is the diagnosis of encephalitis? What could be the cause of encephalitis?

Which is the best treatment plan for the patient with encephalitis?

Causes of viral encephalitis

Herpes simplex virus (HSV-1, HSV-2)
- treatable Other herpes viruses: VZV, CMV,EBV, human herpes virus 6 (HHV6) Adenoviruses Influenza A Enteroviruses, poliovirus Measles, mumps and rubella viruses Rabies

Arboviruses Japanese B encephalitis, West Nile encephalitis virus

BunyavirusesLa Crosse strain of California virus Reoviruses Colorado tick fever virus

Arenaviruses lymphocytic choriomeningitis virus

HSE
Most commonly identified cause of viral encephalitis in the US (10-20% of cases) Estimated annual incidence: 1 in 250,000 to 500,000 persons Cases distributed throughout the year Biphasic age distribution, with peaks at 530 and >50 years of age HSV-1 virus causes more than 95% of cases

HSE
Without treatment, mortality >70% Major morbidity in survivors Milder forms of the illness exist but are rarely correctly identified

HSE
Clinical hallmark of HSV encephalitis: acute onset of fever and focal neurological symptoms Differentiation of HSV encephalitis from other processes is difficult. CSF , CT, MRI, PCR High index of suspicion
Even if CSF/imaging normal

HSE
Most common presentations include:
fever in up to 90% severe headache focal or generalized convulsions alterations in behavior and consciousness disorientation, dysphasia, and hemiparesis more rare motor paralysis present in < 50%

HSV treatment
Vidarabine: 1st effective antiviral therapy

Acyclovir: proved more potent

reduced mortality to 19-28%, compared with 50-54% with vidarabine (Whitley et al, NEJM 1992) dosed 10 mg/kg given 8h for 10-14 days toxicity rare: phlebitis, rash, transaminases, GI disturbance, neurotoxicity

Chronic meningitis
Signs and symptoms Headache Fever Meningismus Confusion Hydrocephalus In general, symptoms develop slowly Meningismus may be mild There may be subtle mental status changes

Diagnosis
Difficult diagnosis because signs and symptoms are often non-specific. It can be suspected in any patient with a chronic encephalopathy, or a patient with new onset of hydrocephalus MRI or CT of head may show hydrocephalus or contrast enhancement of the basal meninges Lumbar puncture

Causes
Infectious:
Bacterial Fungal Parasitic

Non-infectious

Causes
Infectious: M. tuberculosis Cryptococcus neoformans HIV Treponema pallidum Nocardia sp. Aspergillus sp. Taenia solium (cysticercosis) Toxoplasma gondii Non-infectious: Neoplasm (esp. breast, lung) Neurosarcoidosis Behcet's disease CNS vasculitis Mollaret's meningitis

TBM

TBM
High mortality
mainly due to complications
hydrocephalus infarction ventriculitis

Rapid diagnosis difficult High index of clinical suspicion

Chronicity Basal meningitis Systemic illness High risk groups

Clinical features
Fever, headache, meningismus and mental status changes Vomiting and other signs of increased intracranial pressure may occur Cranial nerve palsies occurs in approximately 25% of cases HIV infection is a risk factor for tuberculous meningitis Other mycobacteria (M. avium, M. africanus) can produce human disease, and M. avium is an opportunistic pathogen in AIDS patients Other involvement:
Spinal cord usually in the thoracic cord region Tuberculous spondylitis psoas abscess, epidural abscess

Cerebrospinal fluid
lymphocytic pleocytosis elevated protein reduced glucose Staining: positive in 5 to 25% Culture: positive in approximately 60% of cases CSF PCR may be useful

With treatment, the CSF returns to normal slowly. Glucose is the first to normalize, but it takes at least three weeks, and usually more

Imaging
Contrast-enhanced CT or MRI scans show a basilar meningitis, with contrast enhancement of the meninges in the suprasellar area, prepontine cistern, or interpeduncular fossa Obstructive or communicating hydrocephalus may occur

TBM

TBM

tuberculomas

stroke

tuberculous abcess

TBM - diagnosis

Gold standard is microscopy: ZN staining

TB culture

TBM diagnosis: other

CSF adenosine deaminase
unreliable: false positives undefined in HIV

PCR
good after treatment has begun

TB

TBM: treatment
Quadruple therapy initially
Isoniazid Rifampicin Pyrazinamide Ethambutol/streptomycin

Steroids:
Coma Dexamethasone 16mg/day 2-4 weeks

Immunocompromised patients
Multiple organisms in single or multiple organs Unusual organisms Decreased sensitivity diagnostic tests Atypical presentations
no fever in meningitis

Clinical picture complicated

multi-organ failure

AIDS/HIV
Meningitis
Cryptococcus neoformans

Encephalitis
CMV

Brain abcess
Toxoplasma

Aspergillus

Nocardia

Lumbar Puncture
Basically, LP should be undertaken on all patients with suspected CNS infection

Contraindications: signs of raised intracranial pressure

altered pupillary responses, Absent Dolls eye reflex decerebrate or decorticate posturing abnormal respiratory pattern Papilloedema hypertension bradycardia

Lumbar Puncture
Contraindications (cont.): recent (within 30 minutes) or prolonged (over 30 minutes) convulsive seizures focal or tonic seizures other focal neurological signs
hemi/monoparesis extensor plantar responses ocular palsies

Lumbar Puncture
Contraindications (cont.): Glasgow Coma Score < 13 or deteriorating level of consciousness Strong suspicion of meningococcal infection (typical purpuric rash in an ill child) State of shock Local superficial infection Coagulation disorder

Typical CSF formulas

Bacterial opening pressure WBC count (cells/mm3) PMN (%) RBC count (cells/mm3) protein (mg/dl) Glucose Gram stain culture (% positive) normal or high 1,000-10,000 >80 slight increase very high (100-500) < 40 60-90 % positive 70-85 Viral normal < 300 <20 normal normal normal negative 25 Fungal normal or high 20-500 <50 normal high usually < 40 negative 25-50 Tuberculous usually high 50-500 ~20 normal high < 40 AFB stain + in 40-80% 50-80