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Department of Pediatrics, King George Medical University, Lucknow, Uttar Pradesh, India.
Abstract: The term aseptic meningitis encompasses all types of inflammations of the brain meninges other than that caused
by pus producing organisms. It is usually a benign illness. Etiology of aseptic meningitis is very wide and includes many
infections - both viral and non viral, drugs, malignancy and systemic illness. The most common cause is viral infection and
enteroviruses - Coxsackie and ECHO viruses account for more than half of all cases. Clinical manifestations include headache,
fever, malaise, photophobia and meningeal signs. Convulsions, neurological deficits and severe obtundation are rare except
with certain non viral infectious meningitis. Diagnostic work up includes blood and cerebrospinal fluid (CSF) examination and
serology for infectious meningitis. The polymerase chain reaction is a rapid and accurate method for detection of microbial
DNA in CSF. Treatment is mainly supportive, except for the nonviral infectious etiology.
[Indian J Pediatr 2005; 72 (1) : 57-63] E-mail: rashmik@sancharnet.in
MAGNITUDE
A s e p t i c m e n i n g i t i s is one of the m o s t c o m m o n
inflammatory disorders of the meninges. It occurs at all
ages, a l t h o u g h m o r e c o m m o n in children. N o racial
d i f f e r e n c e s in o c c u r r e n c e h a v e b e e n r e p o r t e d . The
i n c i d e n c e of a s e p t i c m e n i n g i t i s in the US h a s b e e n
reported as 11 per 100,000 person - years, compared to 8.6
p e r 100,000 for b a c t e r i a l m e n i n g i t i s . 2 The illness is
responsible for 26,000 - 42,000 hospitalisations each year
in the US. 3 A recent s t u d y in children from Singapore
f o u n d an i n c i d e n c e of 37 cases p e r 10,000 h o s p i t a l
a d m i s s i o n s . 4 C o m p a r a b l e f i g u r e s for I n d i a are not
available.
ETIOLOGY
Aseptic meningitis m a y be considered as a s y n d r o m e
with m a n y possible etiologies. The various causes of
aseptic meningitis are listed in Table 1.
Viral Meningitis
Rashmi Kumar
TABLE1. Etiology of Aseptic Meningitis
I Infectious Causes
1. Viruses:
9 Enteroviruses - polio, coxsackie, ECHO virus
9 Herpes Group of viruses
o Herpes Simplex virus type 1 and 2
o Varicella zoster virus
o Cytomegalovirus
o Ebstein Barr virus
o Human herpesvirus 6 (HHV-6)
9 Respiratory viruses
o Adenovirus
o Rhino virus
o Influenza virus type A & B
9 Arboviruses
9 Mumps virus
9 Lymphocytic choreomeningitis
9
HIV
2. Bacteria:
9 Partially treated meningitis
9 Parameningeal infection
9 Endocarditis
9 Mycoplasma pneumoniae
9 M tuberculosis
9 Ehrlichiosis
9 Borrelia burgdorfi
9 Treponema pallidum
9 Brucella
9 Leptospirosis
3. Fungi
9 C neoformans
9 Histoplasma capsulatum
9 Coccidiodes immitis
9 Blastomyces dermatitides
9 Candida
4. Parasites
9 Toxoplasma gondii
9 Neurocysticercosis
9 Trichinosis
9 Naeglaria
9 HartmeneUa
9 Bartonella henselae
5. Rickettsiae
9 Rocky mountain spotted fever
9 Typhus
m e n i n g i t i c p i c t u r e in u p t o 60% of c h i l d r e n affected. T h e
l y m p h o c y t i c c h o r e o m e n i n g i t i s v i r u s - a n a r e n a virus, is a
rare c a u s e o f a s e p t i c m e n i n g i t i s . The r e s p i r a t o r y v i r u s e s i n f l u e n z a A & B, a d e n o v i r u s e s a n d r h i n o v i r u s e s c a n
o c c a s i o n a l l y c a u s e m e n i n g i t i s . 8' 9. ~0
v i r u s e s . Infections w i t h t h e s e v i r u s e s i n c r e a s e d u r i n g late
s u m m e r a n d e a r l y fall in t h e US. 1,9,1~ T h e i n c u b a t i o n
p e r i o d of e n t e r o v i n u ~ s v a r i e s w i d e l y ? M u m p s m e n i n g i t i s
h a s c o m e d o w n drastically in c o u n t r i e s w h e r e the v a c c i n e
is w i d e l y u s e d , b u t is still p r e v a l e n t in India. L y m p h o c y t i c
r
occurs in individuals having close
c o n t a c t w i t h r o d e n t s l i k e m i c e , h a m s t e r etc. H e r p e s
s i m p l e x is a g a i n w o r l d w i d e in d i s t r i b u t i o n , s p o r a d i c a n d
n o n s e a s o n a l . A r b o v i r u s e s t e n d to o c c u r i n f a i r l y
characteristic geographical
settings. Tuberculous
m e n i n g i t i s is s t i l l a n i m p o r t a n t c a u s e of c h i l d h o o d
h o s p i t a l a d m i s s i o n s in d e v e l o p i n g c o u n t r i e s l i k e I n d i a
a n d h a s r e s u r f a c e d in d e v e l o p e d c o u n t r i e s in a s s o c i a t i o n
w i t h H W - AIDS.
EPIDEMIOLOGY
T h e illness o c c u r s at all a g e s a n d n o racial d i f f e r e n c e s are
k n o w n . It t e n d s to o c c u r 3 t i m e s m o r e c o m m o n l y in m a l e s
t h a n f e m a l e s . E p i d e m i o l o g y of i n f e c t i o u s m e n i n g i t i s
reflects t h a t of t h e i n f e c t i o u s agent. Polio, C o x s a c k i e a n d
E C H O v i r u s a r e s p r e a d b y d i r e c t p e r s o n to p e r s o n
t r a n s f e r o f i n f e c t e d o r o p h a r y n g e a l s e c r e t i o n o r b y fecoo r a l r o u t e . E n t e r o v i r u s e s a r e w o r l d w i d e in d i s t r i b u t i o n
a n d h u m a n s a r e t h e o n l y k n o w n n a t u r a l h o s t s for t h e s e
58
CLINICAL FEATURES
Viral Meningitis
This has common clinical manifestations with variations
d e p e n d i n g on the particular virus. Although in some
cases, pointers to specific viral agents may exist, in most
cases the clinical findings are not sufficiently distinct to
allow a specific etiologic diagnosis. The most common
symptoms are headache, fever, myalgias, malaise, chills,
sore throat, a b d o m i n a l pain, n a u s e a , v o m i t i n g ,
photophobia, stiff neck and drowsiness. Occasionally the
child may exhibit altered consciousness in the form of
c o n f u s i o n , d r o w s i n e s s or visual h a l l u c i n a t i o n s .
Examination may reveal meningeal signs in the form of
neck stiffness, Kernig's or Brudzinsky's signs. Severe
meningeal irritation may result in the patient assuming
the tripod position with the knees and hips flexed, neck
extended and arms brought back to support the thorax.
M e n i n g e a l i r r i t a t i o n is also m a n i f e s t e d by jolt
accentuation of headache. Worsening of headache on
turning the head to and fro horizontally at 2-3 times per
s e c o n d c o n s t i t u t e s a p o s i t i v e sign. Seizures, focal
neurologic deficits or profound sensorial alteration are
rare manifestations. Many viruses causing the illness also
produce a characteristic rash. Papilledema or absence of
venous pulsations upon fundoscopic examination
suggests increased intracranial pressure. ~'~~
In most cases, viral meningitis runs a mild course and
is a self limiting, often transient illness. Some patients
m a y exhibit a b i p h a s i c illness w i t h n o n s p e c i f i c
c o n s t i t u t i o n a l s y m p t o m s f o l l o w e d b y meningitis.
Presence of severe or p r o l o n g e d sensorial alteration
should p r o m p t the clinician to exclude other treatable
conditions. Distinction from non viral etiologies may also
be difficult. 9,1~
Enteroviruses
These are small n o n e n v e l o p e d RNA viruses of the
picorna virus family. They are subdivided into the ECHO
viruses, Coxsackie and Polio viruses, each with several
serotypes. More than 50 serotypes have been linked with
meningitis. They are spread by hand to mouth contact
and to a lesser extent b y respiratory and fecal routes.
Some enteroviral infections produce a rash that usually
accompanies the onset of fever and persists for 4-10 days.
Coxsackievirius A 5, 9 or 16 and Echoviruses 4,6,9,16 or
Indian Journal of Pediatrics, Volume 72~January, 2005
Mumps Meningoencephalitis
Meningoencephalitis is the most frequent complication of
m u m p s in c h i l d h o o d . Subclinical i n v o l v e m e n t , as
evidenced by cerebrospinal fluid (CSF) pleocytosis has
been reported in > 65% patients with mumps and clinical
manifestations occur in >10% of patients. Males are
affected 3-5 times as frequently as females and mortality
is about 2%. Parotitis usually appears at the same time or
following the onset of meningoencephalitis. Aqueductal
stenosis and hydrocephalus have been associated with
mumps meningoencephalitis. 6
HIV: HIV directly infects the central nervous system
causing
aseptic
meningitis,
encephalitis,
l e u c o e n c e p h a l o p a t h y and m y e l o p a t h y . Aseptic
meningitis occurs mostly at the time of seroconversion.
HIV e n c e p h a l i t i s is c h a r a c t e r i s e d by p r o g r e s s i v e
intellectual impairment, b e h a v i o r disturbances, and
sensorimotor deficits. DNA analysis helps to detect HIV
in the b r a i n s of these p a t i e n t s and HIV specific
immunoglobulin is produced intrathecally. As a result of
immunodeficiency, patients are also more susceptible to
toxoplasmosis, cryptococcosis, other fungal infections,
cytomegalovirus and papova virus infection. 13,14
Tuberculous Meningitis
This remains an important cause of childhood hospital
admissions, mortality and permanent disability in India.
Tuberculosis produces a basal meningitis thereby causing
59
Rashmi Kumar
Table 2. Laboratory Tests That M a y be U s e f u l in A s e p t i c
Meningitis
Essential Tests
I In Blood
9
9
9
9
9
9
9
lI1 Imaging
9 Cranial CT scan
IV Other
9
9
9
9
9
9
9
11 CSF tests
9
9
9
9
9
9
9
9
CSF lactate
Cryptococcal antigen
Latexagglutination test for H influenzae
VDRL,FTA- abs test
Angiotensin converting enzyme (ACE) level
Tuberculostearic acid
Cytology
Specific IgM antibodies to B burgdorferi, Brucella,
Histoplasma and Coccidiodes species
III Imaging
9 Xraychest
9 MRI brain
IV Other
9 PPD test
damage especially to basal structures - brain stem, cranial
n e r v e s a n d b a s a l ganglia. The illness u s u a l l y has a
subacute onset with 3 clinical stages. In stage I, symptoms
are nonspecific with irregular fever, irritability, occasional
vomiting, h e a d a c h e , lethargy or malaise. Stage II is
c h a r a c t e r i s e d b y a p p e a r a n c e of m e n i n g e a l signs,
c o n v u l s i o n s or n e u r o d e f i c i t s w h i l e s t a g e III is
a c c o m p a n i e d by coma, d e c e r e b r a t i o n and persisting
deficits. 1~ Prognosis is closely related to the stage of the
disease in which it is diagnosed and treatment is started.
A h i g h i n d e x of s u s p i c i o n is t h e r e f o r e e x t r e m e l y
important to prevent permanent disability. A study from
Lucknow revealed 5 clinicolaboratory features which are
s u g g e s t i v e of TBM in a child h o s p i t a l i s e d w i t h
m e n i n g o e n c e p h a l i t i s : a p r o d r o m a l stage of >7 days,
extrapyramidal signs, focal deficits, optic atrophy and
60
Ehrlichiosis
Acute monocytic ehrlichiosis is a tick borne infection
caused by a small, pleomorphic obligate intracellular
bacteria that possess Gram negative cell walls. The
mammalian host is the deer or other domestic ruminants.
The usual presentation is with fever, headache, myalgia,
anorexia and vomiting. Nearly two-third of children
develop a m a c u l o p a p u l a r rash. The infection may
occasionally produce aseptic meningitis. Other
manifestations include photophobia, conjunctivitis,
pharyngitis, lymphadenopathy, hepatosplenomegaly and
arthritis. Laboratory tests may reveal pancytopenia and
elevated hepatic transaminases, blood urea nitrogen and
creatinine. Diagnosis is established by high single
antibody titres or seroconversion. PCR amplification of
DNA sequences may be helpful in early stage when
antibodies may not be detected.6
Leptospirosis
This is a zoonotic disease caused by the leptospiral
spirochete. It may have an icteric or anicteric course.
Anicteric leptospirosis usually presents as aseptic
meningitis. A large epidemiological study in Kolenchery,
Kerela after irrigation of dry lands picked up 976 cases of
leptospirosis. The main reservoir for this zoonosis is the
rat. In children and housewives, the main source of
infection is a pet dog. IgM ELISA test is very sensitive
though less specific for the diagnosis.2~
NEOPLASTIC MENINGITIS
Carcinomatous meningitis due to leukemic infiltration or
primary and secondary tumours of the brain is well
known and can produce the aseptic meningitis syndrome.
CSF examination may reveal malignant cells?133
DIAGNOSIS
Rapid, definitive differentiation of bacterial and viral
infections of the central nervous system is a common
clinical problem. Presence of severe obtundation, seizures
and focal deficits suggest the former. Analysis of CSF for
acid base changes, aminoacids, LDH and its isoenzymes,
nitroblue tetrazolium test of CSF polymorphonuclear
cells, immunoglobulins, C reactive protein and lactate
have all been suggested as differentiating tests. Table 2
lists the essential laboratory tests as well as those
indicated by clinical suspicion.
Fungal Meningitis
Laboratory Diagnosis
Syphilitic Meningitis
61
Rashmi Kumar
Viral isolation
Besides CSF, arboviruses and enteroviruses can be
isolated from blood but are seldom recoverable once
clinical meningitis has set in. Specimen for viral culture
from respiratory secretions, throat swab, CSF, blood,
urine and stool should be taken as early in the illness as
possible. Coxsackie and Echo viruses can be isolated from
stool or throat swabs. Mumps virus can be isolated from
saliva or throat swabs, HSV-2 from genital lesions and
LCMV from blood. I~
TREATMENT
Serology
Seroconversion as demonstrated by a 4 fold rise in
antobody titre in acute and convalescent phase sera can
be helpful in making a diagnosis. However, virus specific
IgM provides a quick, early and accurate diagnosis. As
IgM does not cross the blood brain barrier, presence of
CSF IgM is highly suggestive of brain invasion by the
pathogen?
Imaging
CT or MRI brain is not helpful in the usual viral
meningitis. These imaging techniques may help to
exclude other diagnoses. Imaging is particularly helpful
in later stages of tuberculous meningitis which shows
basal enhancement and hydrocephalus.38
Nigrovic, Kuppermann & Malley (2002) developed a
multivariable prediction model to distinguish bacterial
from aseptic meningitis in a retrospective cohort of 696
children aged 29 days to 19 years. 125 (18%) had bacterial
meningitis and 571 (82%) had aseptic meningitis.
Significant predictors for bacterial meningitis were gram
stain of CSF showing bacteria, CSF protein > = 80 mg/dl,
peripheral absolute neutrophil count >=10,000, seizure
before or at presentation and CSF absolute neutrophil
count >= 1000. A score giving 1 point for each of these
predictors except the first which was given 2 points
accurately identified patients with bacterial and aseptic
menigitis with sensitivity of 87%?9
62
COMPLICATIONS
21.
22.
23.
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