CNS INFECTIONS

•	Bacterial meningitis.
•	Aseptic meningitis.
•	Brain abscess.
•	Viral encephalitis and myelitis.

Bacterial meningitis

1.	Epidemiology

a.	Incidence in developed countries: 3 – 5 / 100,000.

b.	70% of cases occur in children younger than 5 years of age.

c.	Common pathogens:

i.	Neisseria meningitidis.

ii.	Streptococcus pneumoniae.

iii.	Haemophilus influenzae type b (conjugated Hib vaccines has almost eliminated this illness.

2.	Predisposing factors and risks

a.	Neonates and children aged 3 – 24 months are at greatest risk.

b.	Children with impaired immunity or neuroanatomical defects.

c.	Lower socio-economic status.

d.	Overcrowding.

3.	Pathogenesis

a.	Infection of the upper respiratory tract.

b.	Invasion of the blood.

c.	Seeding of the choroid plexus.

d.	Inflammation of the CSF, meninges and brain.

4.	Virulence of Pathogens

a.	Encapsulated bacteria possess several virulence mechanisms which allow:

i.	adherence to epithelial cells. 

ii.	evasion of mucosal immunity. 

iii.	passage through the mucosa. 

iv.	survival within the bloodstream.

v.	disruption of the blood-brain barrier.

vi.	invasion of the subarachnoid space.

b.	Bacterial cell wall products:

i.	lipopolysaccharide and lipoteichoic acids liberated during replication or lysis, stimulate endothelial and astroglial cells to release chemotaxins, vasodilators and inflammatory mediators.

ii.	these facilitate migration of activated neutrophils into the subarachnoid space, where their cytotoxic molecules cause direct neuronal injury.

c.	Cerebral edema arises from increased blood-brain barrier permeability, damage to tissues of the brain and inhibition of CSF.

d.	The reduced perfusion from cerebral edema, loss of cerebrovascular autoregulation, vasculitis and thrombosis can result in ischaemic injury and focal neurological deficits. 

5.	Clinical features

Infants	Children	
•	Fever.
•	Pallor.
•	Vomiting.
•	Lethargy.
•	Respiratory distress.
•	Jaundice.
•	Poor feeding.
•	Convulsions.
•	Bulging fontanelle.
•	High-pitched cry.	•	Headaches.
•	Photophobia.
•	Seizures.
•	Bulging fontanelle.
•	Neck stiffness.
•	Kernig’s sign. 
•	Morbilliform rash over trunk and lower limbs or acute mania in meningococcal meningitis. 	

6.	Diagnosis

a.	Clinical signs and symptoms.

b.	CSF: microscopy and culture.

c.	Blood culture.

d.	Lumbar puncture establishes the diagnosis and aids identification of the causative organism and its antibiotic sensitivities. 

e.	Cerebral imaging

a.	Not recommended unless conditions which may mimic meningitis such as intracranial mass lesions are suspected and a lumbar puncture is contraindicated.

b.	Useful in identifying subdural collections, brain abscess, cerebral vascular thrombosis and ventricular dilatation.

c.	These tests are considered for patients with:

i.	prolonged coma, irritability or seizures.

ii.	persisting neurological deficits.

iii.	enlarging head circumferences.

iv.	persistent elevation of CSF protein. 

v.	recurrent disease.

7.	Contraindications to Lumbar puncture

a.	Signs of cerebral herniation, circulatory compromise or DIC.

b.	Rapid onset of coma with absent responses to pain.

c.	Focal neurological signs.

d.	A very bulging fontanelle.

e.	Abnormalities of pupil size or reaction.

f.	Tonic seizures with decerebrate or decorticate posturing.

g.	Irregular breathing.

h.	Papilloedema. 

8.	Lumbar puncture findings

	Normal	Bacteria	Viral	TB	
Appearance	Clear	Turbid	Clear	Viscous or clear	
Lymphocytes / mm3	< 5	< 50	10 – 100	100 – 300	
Polymorphs / mm3	Nil	> 200	Nil	0 – 200	
Protein g/l	0.2 – 0.4	0.5 – 3	0.4 – 1.0	0.5 – 6.0	
Glucose 	> ½ serum	< ½ serum	> ½ serum	< 1/3 serum	

9.	Rapid diagnostic tests

a.	Available to detect specific bacterial antigens in the CSF or urine.

b.	The major value of antigen tests is in partly treated meningitis when cultures may be negative.

c.	The tests are also useful in fulminating bacterial meningitis with few cells and many organisms visible on Gram staining but which are difficult to identify by their morphology alone.

d.	The most widely used rapid diagnostic test is the latex particle agglutination assay.

10.	Principles of antibiotic treatment of bacterial meningitis

a.	Bactericidal antibiotic to which the organism is sensitive.

b.	Good CSF penetration.

c.	Adequate doses.

d.	Adequate duration of therapy.

11.	Immediate Management

a.	Antibiotics:

i.	IV therapy to commence immediately, do not delay for LP.

ii.	blind therapy: ceftriaxone and ampicillin.

iii.	antibiotic resistant pneumococcus: ceftriaxone and vancomycin.

iv.	rifampicin 2 days following treatment of meningococcal disease.

b.	Supportive measures:

i.	initial resuscitation with oxygen and fluids.

ii.	as meningitis is frequently accompanied by SIADH, fluids are reduced to a maximum of 50% of maintenance requirements; this reduces the risk of cerebral edema and hyponatraemic seizures.

iii.	intubation and ventilation if necessary and circulatory support with fluids, inotropes and CVP as needed.

c.	Monitoring of response to treatment:

i.	clinical: fever, general condition, seizures, neurological deficits, head circumference.

ii.	CSF: culture becomes negative, decrease WBC count, predominance of lymphocytes. 

12.	Management of Complications

a.	Convulsions:

i.	present in 20 – 30% of children.

ii.	clonazepam will control most convulsions.

iii.	administration of phenytoin or phenobarbitone and mechanical ventilation are often indicated.

iv.	it is important to suspect hyponatraemia as a cause of convulsions in a child with meningitis.

b.	Cerebral edema:

i.	this may occur shortly after onset and usually is a measure of disease severity.

ii.	manifest as signs of raised ICP: loss of consciousness, irregular breathing, pinpoint pupils and respiratory arrest..

iii.	management involves fluid restriction, circulatory and respiratory support.

c.	SIADH:

i.	results in dilution of ESF compartment and fluid shifts into cells, leading to cerebral edema.

ii.	diagnosis of SIADH is made when serum sodium < 130 mmol/l.

iii.	fluid restriction to 250 ml / m2 / day or iv hypertonic saline, mannitol or frusemide in an emergency.

d.	Circulatory shock:

i.	present in 5 – 10% of children.

ii.	care is required to avoid worsening cerebral edema and provoking hyponatraemic seizures.

iii.	inotropic agents are used to support the circulation.

e.	Neurological lesions:

i.	hemiparesis, persistent hypotonia, ataxia and isolated cranial nerve palsies are present in 10 – 20% of children.

ii.	often reversible.

13.	Subdural effusions

a.	These are accumulations in the subdural space, usually sterile fluid with a high protein content.

b.	Usually they are asymptomatic.

c.	Can be associated with:

i.	continuing or recurring high fever.

ii.	local or generalized convulsions.

iii.	persistent vomiting.

iv.	increase in head circumference or fontanelle tension.

v.	development of focal neurological deficits.

d.	Diagnosis is established by CT scanning.

14.	Causes of persistent (> 7 days) or secondary fever

a.	Viral nosocomial infections.

b.	Subdural effusions.

c.	Thrombophlebitis.

d.	Other suppurative lesions.

e.	Reactive arthritis.

f.	Inadequately treated meningitis.

g.	Parameningeal focus.

15.	Prognosis and Follow-up

a.	Mortality: 5% and higher for pneumococcal meningitis (10 – 15%).

b.	1 in 8 survivors have one or more major adverse outcomes:

i.	severe intellectual disability.

ii.	spasticity.

iii.	paresis.

iv.	seizures.

v.	deafness.

c.	1 in 4 survivors have:

i.	a functionally important behavior disorder.

ii.	neuropsychological or auditory dysfunction.

d.	The risk for long term complications is greatest when:

i.	meningitis is in the first year of life.

ii.	diagnosis is delayed.

iii.	there are late convulsions.

iv.	there are focal neurological signs. 

e.	All children should have their hearing tested following meningitis either by brain stem evoked potentials or formal audiometry.

f.	Regular reviews should be continued in children with persisting auditory and neurological abnormalities. 

16.	Prevention

a.	Vaccination: polysaccharide based polyclonal vaccines against pneumococcal and meningococcal strains used for:

i.	children aged more than 2.

ii.	immunocompromised: HIV infection, nephrotic syndrome, CSF leak.

b.	Chemoprophylaxis:

i.	household and child care contacts, and persons exposed to oral secretions of a patient with meningococcal disease should received rifampicin 20 mg/kg for 2 days.

ii.	alternatively a single dose of either IM ceftriaxone or ciprofloxacin is given. 

17.	Special circumstances

a.	Neonatal meningitis:

i.	premature neonates are at increased risk.

ii.	20% of septic neonates have concomitant meningitis.

iii.	initial therapy is with amoxycillin and cefotaxime.

b.	Meningococcaemia:

i.	60% of meningococcal disease is severe meningococcaemia and two thirds have meningitis.

ii.	half the cases occur in children aged less than 2 years.

iii.	majority of patients present with a petechial or purpuric rash with the time from onset of fever until death as short as 12 hours.

iv.	clinical features are initiated by release of cell wall lipopolysaccharide, activating complement leading to endothelial injury with capillary leak and loss of vasomotor tone.

v.	major cause of death is circulatory collapse from a combination of capillary leak, intravascular volume depletion, vasodilatation and myocardial failure.

vi.	hemodynamic collapse with DIC leads to multiorgan dysfunction.

vii.	Penicillin G is the drug of choice given 60 mg/kg iv 4 hourly.

viii.	management should be in an intensive care unit and includes plasma expanders, circulatory and respiratory support. 

c.	Tuberculous meningitis:

i.	most common in children younger than 5 years.

ii.	onset is gradual with malaise, fever and irritability, progressing over 1 – 2 weeks to drowsiness, neck stiffness, seizures, cranial nerve palsies and coma.

iii.	gastric lavage, urine and CSF are sent for culture for mycobacteria.

iv.	treatment is with isoniazid, rifampicin and pyrazinamide.

d.	Recurrent meningitis:

i.	underlying immunodeficiency is an uncommon cause.

ii.	lumbosacral defects should be searched for if enteric bacteria or Staphylococcus aureus are cultured from CSF. 

Aseptic meningitis

1.	Non-viral causes

a.	Partially treated bacterial meningitis.

b.	Mycobacterium tuberculosis.

c.	Spirocaetes: leptospirosis, syphilis, Lyme disease.

d.	Fungi: cryptococcus, candida.

e.	Protozoa: malaria, toxoplasmosis.

f.	Parameningeal focus of infection.

2.	Clinical features

a.	Acute onset of meningeal symptoms and fever.

b.	CSF pleocytosis.

c.	Bacteriologically sterile cultures. 

3.	Prognosis

a.	A benign disease and requires symptomatic treatment only.

b.	Complete recovery without sequelae is expected within a few days.

Brain abscess

1.	Predisposing factors

a.	Adjacent focus of infection or penetrating wound.

b.	Congenital heart disease.

c.	Bacterial endocarditis.

d.	Suppurative disease in the lung.

2.	Clinical features

a.	Focal neurological signs.

b.	Signs of raised ICP.

c.	Fever.

3.	Investigations

a.	Brain imaging: CT or MRI scan.

b.	Plain X-ray skull and sinus.

c.	Lumbar puncture should not be done if brain abscess is suspected.

4.	Management

a.	Neurosurgical intervention.

b.	Antibiotics.

Viral encephalitis and myelitis

1.	Etiology

Cause	Specific features	
HSV 1 and 2	•	Temporal lobe abnormalitis on EEG & MRI.
•	70% mortality untreated.
•	Acyclovir treatment.	
VZV	•	Post-infectious cerebellar ataxia.	
Mumps	•	VIII nerve damage, with deafness.	
Enteroviruses	•	Echovirus, coxsackie virus.	
Measles
Rubella
HIV-1
Rabies	•		

2.	Clinical features

a.	Non-specific: fever, headache, vomiting, lethargy.

b.	Meningeal irritation: neck rigidity, photophobia.

c.	Brain involvement: change in behavior, sleep, disorientation, stupor, coma, focal neurological signs.

3.	Investigations

a.	Serum: glucose, FBC, blood cultures, bacterial rapid antigen tests, serology.

b.	Urine and stool: microscopy and culture.

c.	Throat swab: microscopy and culture.

d.	CSF: glucose, protein, viral PCR, microscopy and culture.

e.	Imaging: CT or MRI.

f.	Other: EEG.

4.	Management

a.	Supportive:

i.	coma nursing.

ii.	control of fever and seizures.

iii.	reducing raised ICP: fluid restriction, mannitol, hyperventilation.

b.	Specific: acyclovir 10 mg/kg every 8 hours iv for 21 days for herpes simplex encephalitis.

5.	Symptoms and signs of HSV Encephalitis

a.	Headache, fever, alteration of consciousness (80 – 100%).

b.	Personality changes, aphasia, autonomic dysfunction (50 – 80%).

c.	Focal seizures and less commonly generalized seizures (60%).

d.	Ataxia, hemiparesis, visual field disturbances, cranial nerve palsies, papilloedema.

6.	Herpes encephalitis cannot be diagnosed by:

i.	viral culture from CSF.

ii.	immunofluorescence tests on CSF cells.

iii.	assay of an antibody response in the serum alone.

7.	Investigations

a.	CSF:

i.	lymphocytic pleocytosis, slightly elevated protein, normal glucose.

ii.	herpes virus is cultured in CSF in < 5% of patients.

iii.	HSV-specific DNA can be detected by PCR in > 95% for 1 – 2 weeks from onset of symptoms.

iv.	HSV antibody becomes positive > 2 weeks after onset of illness.

b.	CT scans: progressing hypodensity in the orbitofrontal and anteromedial temporal regions, mass effect, irregular zone of contrast enhancement, areas of haemorrhage.

c.	MRI: orbitofrontal and temporal lobe areas of T1-hypointense and T2-hyperintense signal, mass effect, edema, patchy enhancement with gadolinium contrast.

8.	Prognosis of HSE

a.	Mortality > 70% without specific therapy.

b.	Acyclovir treatment: mortality of 19%.

c.	Patients aged < 30 years, alert at onset of treatment: all survive.

9.	Spinal epidural abscess

a.	Spinal ache with local tenderness and high fever.

b.	Root pain.

c.	Weakness of voluntary muscles and sphincters.

d.	Paralysis.

10.	Slow virus infection

a.	Subacute sclerosing panencephalitis, a rare late complication of measles, especially if measles occurs early in life.

b.	Manifest by:

i.	a progressive deterioration of behavior, personality and intellect.

ii.	myoclonic seizures and motor disturbances. 

c.	Myoclonic spasms:

i.	consist of flexion of the head, trunk and limbs, followed by a gradual relaxation phase.

ii.	they are repetitive, occurring at intervals of 10 – 60 seconds and are often provoked by sensory stimuli.

d.	As the disease progresses, spastic paresis, tremors, athetosis and ataxia develop.

e.	The disease runs a variable, but progressive course and is usually fatal within 2 years.

f.	The diagnosis is established by the typical clinical picture and high titre CSF measles antibody.