Central Nervous System Infections

Cerebrum
Frontal lobe Parietal lobe

Temporal lobe
Occipital lobe

Cerebellum
Brain Stem

Pia mater, Arachnoid, Dura mater Subdural space, Subarachnoid space

The meninges of the spine cord is the continuation of the meninges of the brain

General Introduction
1. Acute infection of the central nervous system(CNS) is the most common cause of fever associated with signs and symptoms of CNS disease in children 2. The specific pathogen is influenced by the age and immune status of the host and the epidemiology of the pathogen.

3. Regardless of etiology, most patients with

acute CNS infection have similar clinical syndromes. Common symptoms and signs:
fever, headache, vomiting, photophobia, restlessness, irritability, stupor, coma, seizures

neck pain and rigidity, positive Kernigs and Brudzinskis signs, and focal neurologic deficits.
The severity and constellation of signs are

determined by the specific pathogen, the host, and the anatomic distribution of the infection

4. The anatomic distribution of infection may be

diffuse or focal
Meningitis: primary involvement of meninges Diffuse Encephalitis: brain parenchymal involvement Meningoencephalitis: involvement of both Brain abscess: The neurologic expression of this infection is determined by the site and extent of the abscesses

Focal

5. The diagnosis of diffuse CNS infections

depends on careful examination of cerebrospinal fluid(CSF) obtained by lumbar puncture(LP).

Production, circulation and function of CSF: Produced by the choroid plexus in the cerebral ventricles Circulates in the subarachnoid space surrounding the spinal cord and brain, protect them from injury

Etiology
Epidemiolgy

Pathogenesis

Acute Bacterial Meningitis

Pathology Clinical manifestations Complications Laboratory examinations

Diagnosis
Differential diagnosis Treatment

Etiology
Most common causes : Neisseria meningitidis Streptococcus pneumoniae Haemophilus influenzae Individuals with alterations of host defense due to anatomic defects or immune deficits

Neisseria meningitidis

Streptococcus pneumoniae

Haemophilus influenzae

Epidemiology
Meningitis can occur at any age, but the risk is greatest among infants between 1 and 12 mo of age; 95% of cases occur between 1 mo and 5 yr of age The lack of immunity to specific pathogens associated with young age. The mode of transmission is probably person to person contact through respiratory tract secretions or droplets. The predisposing season is the winter or spring

Pathogenesis
1. Bacteria reach the subarachnoid space a. By hematogenous route(bacteremia) from a distant site of infection (nasopharynx) b. By invasion directly from a contiguous focus of infection( paranasal sinusitis, otitis media, mastoiditis, orbital cellulitis, dermal sinus tracts, cranial or vertebral osteomyelitis, penetrating cranial trauma, or meningomyeloceles) 2. Bacteria cause inflammatory responses in CSF.

Bacteria reach the subarachnoid space by hematogenous route

Colonization of bacteria on nasophyrnx by pili Bacteria locally invade tissue and gain access to the bloodstream Bacterial virulence factors (outer polysaccharide capsule) overcome host defense mechanisms (opsonophagocytosis) Bacteria survive and replicate in the blood stream Bacteria cross the blood-brain barrier and invade the subarachnoid space

Large occipital encephalocele

Small encephalocele high in the occipital region

Posterior parietal encephalocele

Lumbar myelomenigocele

Inflammatory responses in CSF caused by baterial invasion

Bacterial replication and accumulation of WBCs Production and release of inflammatory mediators: cytokine, interleukins, TNF, prostaglandins, leukotrienes Vasculitis (increased capillary permeability, obstruction of blood flow), Damage to CSF circulation system.

Pathology
Meningeal exudates Cerebral edema Cerebral vascular inflammatory changes Damage to the cerebral cortex(vasculitis, bacterial
invasion, toxic encephalopathy, raised ICP)

Subdural effusion Hydrocephalus(communicating, obstructive) Changes of protein and glucose levels in CSF
Raised CSF protein levels, Hypoglycorrhachia

Cerebral edema
Mechanism:
1.cytotoxic cerebral edema(cell death) 2.vasogenic cerebral edema(increased permeability) 3.interstitial cerebral edema(increased hydrostatic pressure)
4.ISADH(inappropriate secretion of anti-diuretic)

Cerebral edema
Increased intracranial pressure(ICP) Brain herniation

Raised CSF protein levels:

increased vascular permeability of the blood-

brain barrier
Hypoglycorrhachia(reduced CSF glucose levels) :
decreased glucose transport by the

inflamed meninges and

increased glucose utilization by the

inflamed cerebral tissue and bacteria which may produce a local lactic acidosis.

Clinical Manifestations
. Symptoms and signs:
Systemic Neurologic Features of neonatal meningitis

Systemic symptoms
Fever 90% Headache 90% Photophobia Lethargy Anorexia, nausea, vomiting Myalgia, arthralgia Shock, rash, petechiae or purpura, DIC Tache Cerebrale - stroke skin with a blunt instrument -> 30-60 sec ->raised red rash

Neurologic manifestation
Signs of meningeal irritation(50%) neck stiffness(nuchal rigidity) Brudzinskis sign Kernig sign Increased ICP Generalized or focal seizures(30%) Cranial nerve palsies and focal cerebral signs(hemiparesis, quadriparesis) (10-20%) Papilledema (1%)

Definitions
Nuchal rigidity Passive or active flexion of the neck will usually result in an inability to touch the chin to the chest Brudzinskis sign The Brudzinski sign refers to spontaneous flexion of the hips during attempted passive flexion of the neck Kernig sign The Kernig sign refers to the inability or reluctance to allow full extension of the knee when

the hip is flexed 90 degrees

Symptoms and signs of increased ICP

Headache Emesis(projectile vomiting) progressive decreased consciousness, may become coma,seizures Bulging fontanel or diastasis(widening) of the sutures In severe cases, the respiratory and circulatory functions may be damaged (a combination of hypertension and bradycardia with apnea or hyperventilation), even coma or herniation (anisocoria, respiratory and cardic arrest) occurs.

Normal papilla of optic nerve

Papilledema

Clinical features of neonatal meningitis

Symptoms and signs at onset can be variable and quite nonspecific(Apnea and bradycardia, cyanosis,
diarrhea, disinterest in feeding, jaundice, lethargy, respiratory distress, temperature instability (hypothermia or fever), vomiting ,high-pitched crying)

the symptoms and signs of increased ICP are less common . High index of suspicion Fever (50%) Seizure (40%) Bulging fontanelle (33%) Irritable +/- change in consciousness & poor muscle tone (33%)

Complications
Subdural effusions and empyema ISADH with hyponatremia Hydrocephalus

Subdural effusions and empyema

Accumulation of excess fluid or pus in the subdural space Clinical features: Diagnosis of subdural effusion: History and associated symptoms and signs Transillumination test CT scan Subdural aspirate

Clinical features of of subdural effusion

Fever is persistent or reappears several days after the patient has become afebrile during the therapy for bacterial meningitis. Progressive bulging fontanel, diastasis of sutures, enlarging head circumference , emesis ,seizures and abnormal consciousness develop during the course of bacterial meningitis

ISADH with hyponatremia

Inflammatory changes in the hypothalamus and pituitary 30-50% of cases of meningitis

hyponatremia reduced serum osmolarity Exacerbate cerebral edema Produce hyponatremic seizures.

Hydrocephalus

Communicating

adhesive thickening of the arachnoid villi lack of absoption of CSF

Obstructive

fibrosis and gliosis of the narrow outlets of the cerebral ventricular system after Ventriculitis and ependymitis an obstruction to flow of CSF

Laboratory Findings
1. CSF Analysis
Can be diagnostic, and every patient with meningitis should have CSF obtained by lumbar puncture(LP)unless the procedure is contraindicated Features of normal CSF Typical CSF features of bacterial meningitis:

2. Other investigations

 Gram stain
Bacterial cultrue Define the specific pathogen

Special test for CSF:

Countercurrent immunoelectroporesis Latex particle agglutination Determination of CSF C-reactive

antigens

protein and tumor necrosis factor levels

Indication of LP:
LP should be performed when diffuse

infection of CNS is suspected

Contraindications for an immediate LP :

cardiorespiratory compromise increased intracranial pressure (ICP) infection in the area of needle insertion bleeding diathesis (low platelet, hemophilia,DIC)

Features of normal CSF:

A clear colourless fluid, contains little protein(<40mg/dl), glucose(2.8~4.4mmol/L or 50~80mg/dl) and some other components (chlorides:118~128mmol/L), and few cells(0-8/mm3 in infants and 0-5/mm3 in adults, 0-30 mm3 in neonates; lymphocytic or monocytic predominance) Pressure of CSF is 25-70mmH2O in infants, 65195mmH2O in adults

Typical CSF features of bacterial meningitis:

Appearance: cloudy (turbid), puric Pressure: >200-300mmH2O Cells: pleocytosis 1000- 10,000 WBC/mm3 Neutrophilic predominance 75-95% Protein: Elevated protein concentration (100-1000mg/dL) Glucose: Hypoglycorrhachia(<1.1mmol/L)

Glucose level Ratio of CSF to serum<0.4

(Continued)

Other investigations:
Peripheral WBC: leukocytosis(20000-40000/mm3), neutrophilic predominant( >80%) But in very severe cases, WBC may be low. Blood culture: Culture and staining of petechial lesions: meningcoccal meningitis. Head CT scan: brain abscesses subdural effusions or empyemas ventriculitis hydrocephalus

Diagnosis
History taking suspected symptoms and signs LP CSF analysis confirm the diagnosis: Head CT scan confirms the complications

Treatment
Antibiotic therapy Supportive care Symptomatic treatment Dexamethasone treatment Treatment of complications

Principles of antibiotic therapy

Early, intravenously Administered immediately after LP in the absence of increased ICP Administered immediately before LP in the presence of increased ICP which should be treated simultaneously. Highly lipid soluble to cross the inflamed blood -brain barrier and achieve bactericidal levels in the CSF and

Initial(Empiric) therapy without defining the etiologic agent:

Ampicillin (300mg/kg.d) and Chloramphenicol(100mg/kg.d)less recommended) Ampicillin and penicillin(400,000~800,000u/kg.d) Third or fourth-generation cephalosprin: Cefotaxime(200mg/kg.d), Ceftriaxone(100mg/kg.d) The treatment course: at least 10~14d.

Supportive care
Reapted medical and neurological assessments pulse rate, blood pressure, and respiratory rate pupillary reflexes, level of consciousness, motor strength, cranial nerve signs and evaluation for seizures important laboratory studies : BUN, serum sodium, chloride possium, and bicarbonate levels, urine output and specific gravity, complete blood and platelet counts, and coagulation factors in the presence of petechiae, purpura, or abnormal bleeding. Maintenance of the fluid and electrolyte balance

Symptomatic treatment
Control high fever Control infectious shock Control increased ICP to prevent herniation
20% Mannitol(0.5-1g/kg/dose) furosemide(1mg/kg) controlled ventilation to keep PCO2 30~35mmHg

Control seizures
Intravenous diazepam(0.1-0.2mg/kg/dose) or lorazepam(0.05mg/kg/dose), phenytoin or phenobarbital(1520mg/kg loading dose, 5mg/kg/24hr maintenance)for further control.

Specific therpay for hypoglycemia, hypocalcemia, or hyponatremia

Dexamethasone treatment
Limit the overproduction of inflammatory mediators and may have a beneficial effect on the outcome of bacterial meningitis Intravenous dexamethasone(0.15mg/kg/dose, given every 6 hr for 4 days) is suggested to be given at the same time as antibiotics

Treatment of complications
Aspiration for subdural effusion, drainage for vasculitis and ependymitis fluid restriction and supplement of sodium for hyponatremia due to ISADH Surgical shunt for hydrocephalus

Prognosis
Neurodevelopmental sequelae(20%) include hearing deficit, seizures, language disorder, mental retardation, motor abnormalities, visual impairment, behavior disorders learning disorders, attention deficits, etc. Hearing loss is the most common. All children should undergo hearing evaluation after meningitis.