CNS infections

Ahmad RizalBagian 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“

• Localized pockets of infection:– Within the brain or spinal cord abscess– Outside them there epidural abscess or subdural

empyema

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

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

Meningococcaemia

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

• Don’t 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: steroids

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

Bacterial meningitis: treatment

Bacterial meningitis

Delay initiating treatmentDelay recognising complications

high mortalitymore 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

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

• 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

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

• Bunyaviruses—La 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 5-

30 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

• 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%

HSE

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 slowlyMeningismus may be mildThere 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

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

Causes

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 Doll’s eye reflex– decerebrate or decorticate posturing– abnormal respiratory pattern– Papilloedema– hypertension– bradycardia

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

Lumbar Puncture

Typical CSF formulas

Bacterial Viral Fungal Tuberculous

opening pressure

normal or high normal normal or high usually high

WBC count (cells/mm3)

1,000-10,000 < 300 20-500 50-500

PMN (%) >80 <20 <50 ~20

RBC count (cells/mm3)

slight increase normal normal normal

protein (mg/dl)

very high (100-500)

normal high high

Glucose < 40 normal usually < 40 < 40

Gram stain  60-90 % positive

negative negativeAFB stain + in 40-80%

culture (% positive)

70-85 25 25-50 50-80