Central Nervous System

Infections
 CNS infection is a significant cause of morbidity &
mortality in children.

 Identification of CNS infections can be problematic for

clinicians because symptoms can be nonspecific in younger
infants

 Delayed or missed diagnosis contributes to the morbidity &

mortality rates associated with these diseases.
 implementation of multiple conjugate vaccines has greatly
reduced the incidence of bacterial infection of the CNS.

 viral infections remain a significant cause of CNS disease.

 Atypical bacterial, fungal, and parasitic pathogens also

contributing to a smaller number of pediatric CNS infections.
 …

 Common symptoms include headache, nausea,

vomiting, anorexia, photophobia, restlessness, altered state
of consciousness & irritability.

 Common signs of CNS infection include fever, neck pain

& rigidity, focal neurologic deficits, seizures, obtundation &
coma.
 …

 Meningitis describes primary involvement of the

meninges.
 Encephalitis indicates brain parenchymal involvement.
 Meningoencephalitis may better describe diffuse
infections of the CNS by pathogens such as viruses.
 Brain abscess is the most common example of a focal
infection of the CNS.
 The diagnosis of CNS infection depends on a combination
of imaging of the brain and testing the CSF by culture, PCR
& serologic methods.

 Pending many of these tests, standard CSF studies provide

initial data to help differentiate bacterial from viral
infections.
Acute Bacterial Meningitis
Beyond
the Neonatal Period
 Bacterial meningitis is one of the most serious pediatric
infections.

 It is associated with a high rate of acute complications & a

risk of long-term morbidity and mortality.
 Risk factors

 lack of pre-existing immunity to specific pathogens &

serotypes.
 recent colonization with pathogenic bacteria
 close contact with individuals having invasive disease
caused by N. meningitidis or H. influenzae type b
 crowding
 Poverty
 black or Native American race
 male sex
 …

 Defects of the complement system (C5-C8)

 defects of the properdin system
 Splenic dysfunction (e.g., in sickle cell anemia) or asplenia
 T-lymphocyte defects (congenital or acquired by
chemotherapy, AIDS, or malignancy)
 children with congenital or acquired CSF leak across a
muco-cutaneous barrier
 Lumbosacral dermal sinus
 Myelomeningocele
 CSF shunt infections
 Streptococcus pneumoniae

 PCV7 was included in the routine U.S. vaccination schedule

in 2000 and contained serotypes 4, 6B, 9V, 14, 18C, 19F,
and 23F, responsible for ~ 85% of invasive pneumococcal
infections in the countries.

 PCV13 was licensed in the United States in 2010,

containing the serotypes in PCV7 plus serotypes 1, 3, 5, 6A,
7F, and 19A.
 Children with anatomic or functional asplenia secondary to
sickle cell disease & those infected with HIV have infection
rates that are 20- 100x higher than those of healthy
children in the 1st 5 yr of life.

 Additional risk factors for contracting pneumococcal

meningitis include otitis media, mastoiditis , sinusitis,
pneumonia, CSF otorrhea or rhinorrhea, the presence of a
cochlear implant & immunosuppression.
 Haemophilus influenzae Type b

 Before universal H. influenzae type b vaccination in the

US, approximately 70% of cases of bacterial meningitis
occurring in the 1st 5 yr of life were caused by this
pathogen.
 Invasive infections occurred primarily in infants 2 mo - 2 yr
of age, the peak incidence was at 6-9 mo of age & 50% of
cases occurred in the 1st yr of life.
 Neisseria meningitidis

 Six serogroups of meningococcus, A, B, C, X, Y, and W-135, are

responsible for invasive disease in humans.
 Meningococcal meningitis may be sporadic or may occur in
major epidemics
 In the African meningitis belt, where serogroup A accounts for
80–85% of outbreaks.
 In the US serogroup B is the most common cause of meningitis
in infants.
 Children < 5 yr of age have the highest rates of meningococcal
infection
 Second peak in incidence occurs in persons between 15 - 24 yr
of age.
 Pathology and Pathophysiology

Mostly results from hematogenous dissemination of

microorganisms
 Bactremia may precede meningits or occur concomitantly
 Nasopharyngeal colonization is most common source
 Pathogenicity increases with URTI
 Pathogen entry to the circulation is facilitated by
attachment to mucosal epithelial pili
 Bacterial capsules interfere opsonic phagocytosis 
survival of bacteria in the blood stream & increased
virulence.
 Continued

 Pathogens enter to the CSF through choroid plexus of the

lateral ventricles & meninges.
 Circulate to the extracerebral CSF and subarachnoid
space.
 C’ & Ab concentration is inadequate in CSF promoting
rapid bacterial multiplication.
 Chemotactic factors bring inflammatory response
predominantly PMN cells.
 …

2. Contagious focus
Rarely meningitis follow invasion from contiguous
foci
 Otitis media / mastoiditis
 Paranasal sinusitis
 Orbital cellulitis
 Cranial / vertebral osteomyelitis
 Penetrating trauma to the cranium
 Congenital defects - NTD
 Increased ICP
-cytotoxic cerebral edema - cell death
- vasogenic cerebral edema - cytokine induced increased
capillary vascular permeability
-interstitial cerebral edema- increased hydrostatic
pressure after obstructed reabsorption of CSF in the
arachnoid villus or obstruction of the flow of fluid from the
ventricles.
 Hydrocephalus can occur as result of adhesive thickening
of the arachnoid villi around the cisterns at the base of the
brain.
 -This thickening leads to interference with the normal
resorption of CSF and development of hydrocephalus.
 Obstructive hydrocephalus develops after fibrosis &
gliosis of the cerebral aqueduct or the foramina of
Magendie and Luschka.
 Elevated CSF protein levels are partly a result of
increased vascular permeability of the BBB & the loss of
albumin-rich fluid from the capillaries and veins traversing
the subdural space.
 Continued transudation may result in subdural effusions,
usually found in the later phase of acute bacterial
meningitis.
 Hypoglycorrhachia is attributable to altered glucose
transport by the cerebral tissue.
 Clinical Manifestations

 Meningitis is preceded by several days of fever

accompanied by URT or GI symptoms, followed by
nonspecific signs of CNS infection such as increasing
lethargy and irritability.
 less common presentions --sudden and progressive shock,
purpura ,DIC & reduced levels of consciousness often
resulting in progression to coma or death within 24 hr.
 fever, anorexia & poor feeding, headache,
photophobia ,upper respiratory symptoms
 myalgias, arthralgias, tachycardia, hypotension
 cutaneous signs, such as petechiae, purpura, or an
erythematous macular rash.
 Meningeal irritation is manifested as
 Nuchal rigidity, back pain
 Kernig sign (flexion of the hip 90 degrees with
subsequent pain with extension of the leg)
 Brudzinski sign (involuntary flexion of the knees &
hips after passive flexion of the neck while supine.
 In those younger than 12-18 mo, the Kernig & Brudzinski
signs are not consistently present.
 In adults, fever, headache, and nuchal rigidity are present
in only 40% of cases of bacterial meningitis.
 Increased ICP is suggested by headache, emesis, bulging
fontanel or diastasis (widening) of the sutures, oculomotor
(anisocoria, ptosis) or abducens nerve paralysis,cushing
traids , decorticate or decerebrate posturing, stupor, coma, or
signs of herniation.
 Papilledema is more common in complicated meningitis &
is suggestive of a more chronic process, such as the
presence of an intracranial abscess, subdural empyema, or
occlusion of a dural venous sinus.
 FNDs usually are as a result of vascular occlusion.

 Approximately 10–20% of children with bacterial

meningitis have focal neurologic signs.
 Seizures are related to cerebritis, infarction, or electrolyte
disturbances occur in 20–30% of patients with meningitis.

 Poor prognosis is suggested when seizures persist after the

fourth day of illness, which can be refractory to treatment.

 Cranial neuropathies may also be the result of focal

inflammation
 Alteration in mental status is common among patients
with meningitis & may be the consequence of increased
ICP, cerebritis, or hypotension
 Manifestations include irritability, lethargy, stupor,
obtundation & coma.
 Comatose patients have a poor prognosis.
 Diagnosis

 LP, in order to obtain CSF for WBC, protein ,glucose,Gram

stain and culture, is the most important step in the
diagnosis of meningitis.
 Head CT scan
 Blood cultures reveal the responsible bacteria in up to 80–
90% of cases of meningitis.
 Elevations of the CRP, ESR & procalcitonin
 Contraindications for LP

(1) evidence of increased ICP (other than a bulging fontanel)

such as 3rd or 6th cranial nerve palsy with a depressed level
of consciousness, or the Cushing reflex;
(2) severe cardiopulmonary
(3) infection of the skin overlying the site of the LP.
(4) Thrombocytopenia is a relative contraindication for LP
 Lumbar Puncture

 The CSF leukocyte count in bacterial meningitis often is

elevated to > 1,000/mm3 and, typically, there is a
neutrophilic predominance (75–95%).
 Turbid CSF is present when the leukocyte count exceeds
200-400/mm3 .
 Normal healthy neonates may have as many as 20
leukocytes/mm3
 older children without viral or bacterial meningitis have <
8 leukocytes/mm3 in the CSF; all are lymphocytes or
monocytes.
 Pleocytosis may be absent in patients with severe
overwhelming sepsis associated with meningitis this is a
poor prognostic sign.
 Pleocytosis with a lymphocytic predominance may be
present during the early stage of acute bacterial meningitis.
 Neutrophilic pleocytosis may be present in patients in the
early stages of acute viral meningitis.
 The shift to lymphocytic-monocytic predominance in viral
meningitis invariably occurs within 8-24 hr of the initial LP.
 The Gram stain is positive in > 70% of patients with
untreated bacterial meningitis.
 CSF can be negative on Gram stain & culture as early as 2-
4 hr after administration of antibiotics.
 PCR for non-culturable or fastidious pathogen
 A traumatic LP may complicate the interpretation of CSF
leukocytes & protein concentration.
 The Gram stain, culture, and glucose level are unlikely to be
influenced by blood in a CSF sample.
 DIFFERENTIAL DIAGNOSIS

A) INFECTIONS
1) Generalized infection of the CNS
Bacteria
 M . Tuberculosis (Tb meningitis)
 T . Pallidum (Syphilis )
Fungi (Histoplasma ,Candida ,Cryptococcus , Aspergillus)
Parasites (T .gondii , Cysticercosis)
Viruses (Enteroviruses , HSV
Viral meningoencephalitis )
 2) Focal infections of the CNS
Brainabscess
Para meningeal abscess

Subdural empyema
Cranial epidural empyema
Spinal epidural empyema
B) NON-INFECTIOUS ILLNESSES
-Cause generalized inflammation of the CNS
-Uncommon
Malignancy
Collagen vascular syndromes
Exposure to toxins
 All acute febrile illnesses can be D.DX of acute bacterial
meningitis especially in its early phase
 Treatment

 Frequency of resistance of S. pneumoniae to β-lactam

antibiotics are increasing throughout the world.
 In the US 25–50% of strains of S. pneumoniae are
currently resistant to penicillin.
 Resistance to cefepime , cefotaxime & ceftriaxone is also
evident in up to 25% of isolates.
 most strains of N. meningitidis are sensitive to penicillin &
Cephalosporins.
 30–40% of isolates of H. influenzae type b produce β-
lactamases & therefore are resistant to ampicillin.
 These β-lactamase–producing strains remain sensitive to
third- and fourth-generation cephalosporins.
 …

 Empirical antibiotic regimen in a suspected case of

meningitis outside the neonatal period is vancomycin
combined with a third generation cephalosporin
(ceftriaxone 50 mg/kg/dose given every 12 hr).

 vancomycin (60 mg/kg/day given every 6-8 hr; some

experts would start as high as 80 mg/kg/day
 Patients allergic to penicillin or cephalosporin antibiotics
can be treated with meropenem (40 mg/kg/dose every 8
hr)
 other alternative drugs include fluoroquinolones or
chloramphenicol.
 If L. monocytogenes infection is suspected, ampicillin (300
mg/kg/day, divided every 6 hr) also should be given.
 IV trimethoprim-sulfamethoxazole is an alternative
treatment for L. monocytogenes & has documented
clinical efficacy.
 If Gram-negative bacterial meningitis is suspected, initial
therapy might include cefepime or meropenem.
 The recommended treatment duration for uncomplicated
S. pneumoniae meningitis is 10-14 days with a 3rd-
generation cephalosporin or intravenous penicillin.
 For N. meningitidis meningitis, the recommended
treatment duration is 5-7 days with intravenous penicillin
or ceftriaxone.
 Uncomplicated H. influenzae type b meningitis should be
treated for 7- 10 days with ampicillin or ceftriaxone .

 Pre-treated Patients with IV/oral antibiotics prior to LP &

do not have an identifiable pathogen should receive therapy
with ceftriaxone or cefotaxime for 7-10 days.
 Escherichia coli or P. aeruginosa may require therapy with
a 3rd or 4th-generation cephalosporin or carbapenem.
 Repeat examination of CSF is indicated in all patients with
meningitis from Gram negative bacilli, & in patients with
infection caused by a β-lactam–resistant S .pneumoniae.
 The CSF should be sterile within 24-48 hr of initiation of
appropriate antibiotic therapy.
 Gram-negative bacillary meningitis should be treated for 3
wk or at least 2 wk after CSF sterilization, which may occur
after 2- 10 days of treatment.
 If focal signs are present or the child does not respond to
RX a parameningeal focus may be present, and a CT or MRI
scan should be performed.
 Corticosteroids

 Rapid killing of bacteria =releases toxic cell products

===cytokine-mediated inflammatory cascade.
 Steroids reduced hearing loss in children with meningitis
due to H. influenzae type b but not due to other pathogens.
 use of IV dexamethasone, 0.15 mg/kg/dose given every 6 hr
for 2 days in children older than 6 wk of age.
 Corticosteroids appear to have maximum benefit if given 1-
2 hr before antibiotics are initiated.

 They also may be effective if given concurrently with or

soon after the first dose of antibiotics.
 Complications

 Acute CNS complications can include seizures, increased

ICP, cranial nerve palsies, stroke, cerebral or cerebellar
herniation & thrombosis of the dural venous sinuses.
 Collections of fluid in the subdural space develop in 10–
30% of patients with meningitis & are asymptomatic in 85–
90% of patients.
 SIADH occurs in some patients with meningitis, resulting
in hyponatremia & reduced serum osmolality.
 Thrombocytosis, eosinophilia, anemia & DIC.
 Prognosis

 Mortality rate of bacterial meningitis beyond the neonatal

period is < 10%.
 Severe neurodevelopmental sequelae may occur in 10–20%
of patients.
 prognosis is worse among infants younger than 6 mo & in
those with a high bacterial burden in their CSF.
 Those with seizures occurring more than 4 days into
therapy
 Those with coma or FND at presentation also have an
increased risk of long-term sequelae.
 most common neurologic sequelae from meningitis include hearing
loss, cognitive impairment, recurrent seizures, delay in acquisition of
language, visual impairment & behavioral problems.
 Sensori-neural hearing loss is the most common sequela of bacterial
meningitis.
 It occurs in as many as 30% of patients with pneumococcal meningitis,
10% with meningococcal meningitis & 5–20% of those with H.
influenzae type b meningitis.
 Prevention

N. meningitides
Prophylaxis for close contacts – rifampicin 10mg/kg/dose po
BID for 02 days
Vaccination against sero-group A, C, Y, W135
H. influenzae type b
Prophylaxis for house hold contacts - Rifampicin
20mg/kg/day, max of 600mg, for 04 days
Vaccine after 02 month of age
S. pneumoniae
No chemoprophylaxis
Vaccination for high risk – e.g. immunosuppressed, asplenia…
 Viral Meningoencephalitis

 is an acute inflammatory process involving the meninges

and/or brain parenchymal tissue.
 These infections are caused by a number of different
pathogens, and quite often, no pathogen can be identified
from the CSF and brain tissue specimens.
 The CSF is characterized by pleocytosis & the absence of
microorganisms on Gram stain and routine bacterial culture.
 Outcomes are quite variable because cases of
meningoencephalitis caused by some pathogens are self-
limited whereas others cause significant long-term
neurologic sequelae.
 Etiology

Enteroviruses
- Most common cause , small RNA viruses
- More than 80 serotypes
Herpes viruses
- HSV-1,HSV-2,VZV,CMV,EBV,HHV-6
Mumps
Arboviruses
-Mosquitoes and ticks are most common
vectors
-Birds or small animals ……Humans
e.g. West Nile virus
Other viruses/occasional causes/
- Rubella , rubeola , rabies
- Respiratory viruses : Adenovirus,
Influenza virus , parainfluenza virus
 Live virus vaccinations/rare causes/
- Polio , measles ,mumps , rubella
 Epidemiology

Enteroviruses :
- Direct spread from person to person, IP is 4-6 days
- Other factors : Season , geography ,
climateconditions , animal exposures
 Clinical Manifestations

Mild self-limited illness to severe encephalitis with

sequelae or resulting in death.
Fever, headache, nausea, vomiting, photophobia,
pain in the neck , back and legs.
Nuchal rigidity, irritability , change in mental status ,
convulsions , bizarre movements , hallucinations
Exanthemas precede or accompany CNS signs.
 Diagnosis

 Diagnosis of meningo -encephalitis relies on a combination

of analysing the CSF by PCR, serology, and in rare
situations, brain biopsy.
 The diagnosis is supported by associated symptoms &
examination of the CSF, which usually shows a mild
mononuclear predominance.
 EEG and MRI.
 Mainly clinical :
- Nonspecific prodrome followed by
progressive CNS symptoms
 CSF
- WBC : 10-100/mm3(up to 1000/mm3)
Mononuclear cells predominate later
- Protein : 50-200 mg/dl
- Glucose : normal
- PCR : for HSV & enteroviruses
- Culture : for enteroviruses(70% detection)
 The CSF findings in meningo-encephalitis are characterized
by a pleocytosis of leukocytes with counts typically <
1,000/mm3.
 Very early in the disease, the cells are often PMN whereas
mononuclear cells predominate for the remainder of the
duration of the illness.
 This change in cell type often occurs over 8-12 hr.
 Treatment

1) Supportive
- Rest
- Analgesics
( Acetaminophene is best )
- Reduction in room light ,noise
- IV fluids : if poor oral intake
- In severe cases : ICU care
2) Acyclovir for HSV encephalitis
3) Rx of complications :
- Increased ICP, SIADH ,seizures
 Prognosis

 Most children recover completely

 Depends on :

1) Severity of clinical illness

2) Specific etiologic agent
3) Age of the child (Poor for infants)
 Potential deficits in severe cases :

- Intellectual , motor, epileptic , psychiatric,

- Auditory , visual
 Brain Abscess

 Brain abscess is a focal collection within the brain

parenchyma.
 It is complication of a variety of infections, trauma, or
surgery.
 incidence of brain abscess is between 0.3 and 1.3 cases per
100,000 people per year.
 underlying aetiology

 contiguous spread from an associated infection

 direct compromise of the BBB due to penetrating head
injuries or surgical procedures
 Embolic phenomena (endocarditis)
 right-to-left shunts (congenital heart disease
 Immunodeficiency
 infection of foreign material inserted into the central
nervous system (CNS), including VPS.
 Pathology

 Cerebral abscesses occur in both hemispheres in children,

but in adults, left sided abscesses are more common.
 Nearly 80% of abscesses occur in the frontal, parietal, and
temporal lobes, while abscesses in the occipital lobe,
cerebellum, and brainstem account for the remainder of
cases.
 In 18% of cases, multiple brain abscesses are present
 In nearly 20% of cases, no predisposing risk factor can be
identified.
 PATHOGENESIS

 Bacteria can invade the brain either by direct spread-

accounts for 20 - 60 % of cases.
 Hematogenous seeding .
 Bacteremic spread typically causes multiple lesions .
 Etiology

 Streptococci account for one third of all cases in children,

with members of the Streptococcus anginosus group.
 Staphylococcus aureus is the second most common
organism in pediatric brain abscesses
 In up to 27% of cases, more than one organism is cultured.
 Abscesses associated with mucosal infections frequently
are polymicrobial include anaerobic organisms.
 Clinical Manifestations

 Early stages of cerebritis and abscess formation are

asymptomatic
 Associated with nonspecific symptoms, including low-grade
fever, headache & lethargy.
 As the inflammatory process proceeds, vomiting, severe
headache, seizures, papilledema, focal neurologic signs
(hemiparesis) & coma may develop.
 A cerebellar abscess is characterized by nystagmus,
ipsilateral ataxia and dysmetria, vomiting, and headache.

 If the abscess ruptures into the ventricular cavity,

overwhelming shock and death occur in 27–85% of cases.
 Diagnosis

 The key to diagnosis of brain abscesses is prompt imaging

of the CNS.
 Brain MRI with contrast is the diagnostic test of choice
because it can aid in differentiating abscesses from cysts &
necrotic tumors.
 Both MRI and CT scans with contrast can demonstrate a
ring-enhancing abscess cavity.
 The peripheral WBC count is elevated in 60% of cases
blood cultures are positive in 28% of cases.
 LP is not routinely recommended
 CSF is normal in 16% of cases
 71% of cases exhibit CSF pleocytosis
 58% will have an elevated CSF protein level.
 CSF cultures are positive in only 24% of cases; therefore, a
culture obtained from the abscess fluid is essential for
identifying bacterial pathogens
 Treatment

 Empiric therapy consists of a combination of a 3rd-

generation cephalosporin & metronidazole, often with
vancomycin.
 If resistant Gram-negative organisms are suspected, as in
cases of infected VPS, cefepime or meropenem
 Listeria monocytogenes may cause a brain abscess in the
neonate and if suspected, penicillin G or ampicillin with
gentamicin is recommended.
 amphotericin B should be considered immuno-
compromised patients
 Aspiration of the abscess is recommended for diagnostic
cultures and decompression.
 Administration of glucocorticoids can reduce edema.
 The duration of parenteral antibiotic therapy depends on
the organism and response to treatment but is most
typically 6 wk.
 Indications for surgical drainage

 Traumatic brain abscesses (to remove bone chips & foreign

material)
 Encapsulated fungal brain abscesses
 Multi-loculated abscesses
 No clinical improvement within one week
 Depressed sensorium
 Signs of increased ICP
 Progressive increase in the diameter of the abscess size
>2.5cm in diameter.
 Prognosis

 Mortality rate range from 5–10%.

 Factors associated with high mortality rates at the time of
admission include delayed administration of
antimicrobials, age < 1 yr, multiple abscesses & coma.
 Long-term sequelae occur in about 1/3rd of the survivors &
include hemiparesis, seizures, hydrocephalus, cranial nerve
abnormalities, and behavioral & learning difficulties.
 Reading assignment

Neuromuscular disorders