1. health and fitness
2. disease

Advances in P e d i a t r i c s
Aseptic Meningitis: Diagnosis and Management
Rashmi Kumar
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: [email protected]
Key words: Aseptic meningitis; Viral meningitis
The t e r m aseptic m e n i n g i t i s is used for all t y p e s of
inflammation of the brain meninges which is not caused
b y p u s p r o d u c i n g b a c t e r i a . It is u s u a l l y a b e n i g n
syndrome. 1 Although viruses are a major cause, m a n y
different etiologies - both infective and non infective can
c a u s e a s e p t i c m e n i n g i t i s , t I e n c e the t e r m is not
synonymous with viral meningitis although the two are
often used interchangeably.
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
This is the most c o m m o n cause of aseptic meningitis, s
L
Correspondence and Reprint requests : Dr. Rashmi Kumar, Prof.
Department of Pediatrics, King George Medical University,
Lucknow, Uttar Pradesh - 226003.
Indian Journal of Pediatrics, Volume 72---January, 2005
Viral infections of the central nervous system m a y involve
p r i m a r i l y the b r a i n p a r e n c h y m a , the m e n i n g e s , the
anterior horn cells, cranial nerves etc. When the infectious
agent primarily attacks the brain parenchyma the clinical
picture of 'encephalitis' with obtundation, seizures and
coma is produced. When the inflammation is primarily of
the m e n i n g e s , a milder s y n d r o m e of viral or aseptic
meningitis is produced. Pathologically and clinically there
is a c o n t i n u u m between the two a n d s o m e d e g r e e of
meningeal inflammation is found with encephalitis and
vice versa. Therefore the term 'viral meningoencephalitis'
a p p e a r s m o r e a p p r o p r i a t e . M o s t of t h e s e v i r u s e s
c h a r a c t e r i s t i c a l l y c a u s e e i t h e r an ' e n c e p h a l i t i c ' or
'meningitic' picture. However, it must be borne in mind
that the s a m e a g e n t m a y c a u s e a v e r y w i d e r a n g e of
severity and occasionally produce an atypical illness. 6
The most common viruses causing aseptic meningitis
are the enteroviruses, which account for more than half
the cases. 7 More than 50 serotypes have been linked with
meningitis. M u m p s is another i m p o r t a n t cause of viral
meningitis. Herpes viruses both type 1 (herpes labialis)
a n d t y p e 2 (genital h e r p e s ) can c a u s e m e n i n g i t i s in
children, especially infants. Varicella zoster virus can also
c a u s e m e n i n g i t i s b u t o n l y in t h o s e w h o are
immunocompromised. HIV m a y cause aseptic meningitis
m o s t l y at the time of seroconversion. It is difficult to
assess the overall c o n t r i b u t i o n of a r b o v i r u s e s , b u t in
e p i d e m i c s a sizeable n u m b e r of p a t i e n t s e s p e c i a l l y
children will exhibit a benign illness with neurologic
manifestations. 5 This assumes special importance since
Japanese encephalitis - an arboviral encephalitis is widely
rampant in India. In the US, western equine encephalitis
virus causes more cases of meningitis than the Eastern
equine encephalitis virus, which causes a m o r e serious
illness. The St Louis encephalitis v i r u s m a y cause a
57
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
II Non infectious Causes
1. Post infectious/post vaccinial
9 Rubeola
9 Rubella
9 Varicella
9 Variola
9 Rabies vaccine
9 Pertussis vaccine
9 Influenza vaccine
9 Vaccinia
9 Yellow fever vaccine
2. Drugs
9 Non steroidal anti-inflammatory drugs (NSAIDs)
9 Trimethoprim sulfamethoxazole, amoxicillin
9 Muromonab CD3 (OKT3)
9 Azathioprine
9 Intravenous immunoglobulin
9 Isoniazid
9 Intrathecal methotrexate
9 kntrathecal cytosine arabinoside
9 Allopurinol
9 Carbamazepine
9 Sulfasalazine
3. Systemic Disease
9 Collagen vascular disorders
o Systemic lupus erythematosis
o Wegener granulomatosis
o Central nervous system vascuLitis
o Rheumatoid arthritis
o Kawasaki's disease
9 Sarcoidosis
9 Leptomeningeal cancer
9 Post transplantation lymphoproliferative disorder
9 Behcet disease
9 Vogt- Koyanagi syndrome
4. Neoplastic disorders
9 Leukemia
9 Carcinomatous meningitis secondary to primary or secondary
turnouts of the brain
5. Inflammation of neighbouring structures
9 Brain abscess
9 Epidural abscess
6. Miscellaneous
9 Arachnoiditis
9 Migraine
9 Urinary tract infection
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
Indian Journal of Pediatrics, Volume 72--January, 2005
Aseptic Meningitis: Diagnosis and Management
PATHOPHYSIOLOGY
Infectious meningitis results when the protective barriers
of the brain - skull, meninges and blood brain barrier are
overcome by the infecting agent. Meningitis can result
either by the h e m a t o g e n o u s route (as in tuberculous
meningitis, HIV meningitis, arboviruses, respiratory
viruses etc.) or by neurotropic s p r e a d o f the agent as in
herpes virus, rabies and polio. 6 Predisposing factors
include otitis media, immunosuppression, pneumonia,
sinusitis and pre-existing diabetes.
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
30 typically cause a maculopapular, nonpruritic rash
confined to the face and trunk but sometimes involving
extremities including palms and soles. Coxsackie A16
and rarely other g r o u p A s e r o t y p e s may p r o d u c e a
vesicular rash on face, feet and oropharynx. Group A
coxsackie v i r u s m a y also p r o d u c e h e r p a n g i n a
characterized by grey, vesicular lesions on the tonsillar
fossae, soft palate and uvulaT. 11 E n t e r o v i r u s 71 has
recently been recognized to cause hand-foot-and- mouth
disease and neurological manifestations like aseptic
meningitis, encephalitis and polio like paralysis in India.
The genotype isolated here was distinct from that causing
severe epidemics in the Asia-Pacific region. ~2
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
NONVIRAL INFECTIOUS ETIOLOGIES
In contrast to viral meningoencephalitis, nonviral causes
of aseptic meningitis usually have a more complicated
course and m u s t be c o n s i d e r e d because they can be
managed with specific therapy.
Partially Treated Bacterial Meningitis
This m a y be confused with a non pyogenic or aseptic
meningitis because CSF becomes sterile and cellular
reaction c h a n g e s from p o l y m o r p h o n u c l e a r to
lymphocytic. The condition is not benign or transient
however and rapid deterioration occurs in absence of
antibiotic t h e r a p y . In India, this is an i m p o r t a n t
differential diagnosis of tuberculous meningitis.
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
CSF pleocytosis with > 50% lymphocytes. TM
Lyme Disease
Essential Tests
I In Blood
9 Complete blood counts, platelet count, ESR
9 Acute and convalescent phase sera for virus specific IgG or
IgM to enteroviruses, arboviruses, adenoviruses, LCMV,
Ebstein Barr virus and HSV-2
II CSF Studies
9
9
9
9
9
9
9
Cell count - total and differential
Gram stain, Acid fast bacilli stain
Bacterialculture and sensitivity
C reactive protein
Protein, glucose and gammaglobulin
Viralisolation
PCR for viral agents and M tuberculosis
lI1 Imaging
9 Cranial CT scan
IV Other
9 Viralisolation from throat and rectal swabs
As Indicated tests
I Blood Tests
9
9
9
9
9
9
9
Antinuclear antibody, rheumatoid factor
Sjogren's syndrome antigens A & B
Serum protein electrophoresis
Lyme antibody titre (ELISA)
Serum amylase
Viralisolation
VDRL,Flourescent treponemal antibody absorption test
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
This is the most common vector borne disease in the US,
c a u s e d by Borrelia b u r g d o r f e r i - a f a s t i d i o u s ,
microaerophillic spirochete. Its prevalence in India is not
k n o w n . In a s t u d y f r o m Delhi, n o n e of 27 p a t i e n t s
p r e s e n t i n g w i t h m o n o / o l i g o a r t h r i t i s of u n k n o w n
etiology, 12 healthy blood bank donors, 25 patients with
rheumatoid arthritis and 20 deer handlers were positive
for IgG antibodies to Borrelia burgdorferi. 17The illness is
divided into early localised disease with a rash at the site
of the tick bite often a c c o m p a n i e d b y fever, myalgia,
headache and malaise; early disseminated disease with
s e c o n d a r y e r y t h e m a m i g r a n s lesions, c o n s t i t u t i o n a l
symptoms, aseptic meningitis, cranial nerve palsies and
carditis and late disease w i t h chronic p o l y a r t h r i t i s .
Central nervous system manifestations are c o m m o n in
Lyme disease. Meningitis manifests several weeks after
appearance of skin lesions, but while erythema migrans
lesions are still present. H y p o g l y c o r r h a c h i a is not a
p r o m i n e n t f i n d i n g in the CSF. Facial n e r v e p a l s y ,
sometimes bilateral, may be observed. Diagnosis m a y be
e s t a b l i s h e d b y d e t e c t i o n of specific IgM b y ELISA,
v a l i d a t e d by Western Blot a s s a y or b y c u l t u r i n g the
o r g a n i s m f r o m a s y m p t o m a t i c patient. 6,8 A s t u d y on
differentiating features between Lyme meningitis and
other aseptic meningitis s h o w e d that lyme meningitis
should be suspected in cases of meningitis with very low
CSF n e u t r o p h i l i c c o u n t s a n d h i g h p r o t e i n levels
associated with prolonged duration of s y m p t o m s , low
g r a d e f e v e r a n d a b s e n c e of p r o n o u n c e d s i g n s of
meningitis? 8
Brucellosis
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
This is a systemic infection caused by a small, aerobic, non
spore bearing, nonmotile G r a m negative coccobacillary
bacteria, seen usually in persons living or w o r k i n g in
close contact with animals, or consuming animal products
such as raw milk or cheese made from raw milk. It is most
c o m m o n in the M e d i t e r a n e a n region, Asia, Africa,
Mexico, South and Central America. Clinical features are
extremely variable. In the acute form the illness presents
with a flu like illness with fever, night sweats, malaise,
anorexia, headache and myalgias. In the undulant form,
s y m p t o m s are again fever, arthritis and e p i d i d y m o orchitis. Neurological involvement occurs in about 5% of
patients. Diagnosis is c o n f i r m e d by the isolation of
brucella organisms from bacterial culture or increase over
time of specific a n t i b o d i e s in blood. 6,9 A s t u d y f r o m
Bikaner (Rajasthan) r e v e a l e d 92 cases of b r u c e l l o s i s
d i a g n o s e d on the basis of a h i s t o r y of c o n t a c t w i t h
animals, fever, arthralgia and brucella antigen in serum in
a fitre of 1:160 or more. Of these, 12 had neurobrucellosis
- 4 aseptic meningitis, 2 myelitis, 5 polyradiculoneuropathy and 1 polyradiculomyeloencephalopathy29
Indian Journal of Pediatrics, Volume 72---January, 2005
Aseptic Meningitis: Diagnosis and Management
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~
methotrexate is known to sometimes result in aseptic
meningitis. Many antimicrobials such as trimethoprim sulfamethoxazole,
ciprofloxacin,
cephalexin,
metronidazole, amoxicillin, penicillin and isoniazid are
causes of aseptic meningitis. The xanthine oxidase
inhibitor allopurinol and many other drugs - the
nonsteroidal anti-inflammatory drugs (NSAIDs),
ranitidine, carbamazepine, vaccines against hepatitis B
and mumps, immunoglobulins, radiographic agents and
muromonab --CD3 (OKT3) have all been implicated.
Pathophysiology of meningitis varies with different
agents. A hypersensitivity reaction is considered for cases
related to NSAIDs while OKT3 cases are believed to be
mediated at least partly by cytokine release. The clinical
features and CSF profile does not help in differentiating
drug induced aseptic meningitis from infectious
meningitis. A high index of suspicion is needed to reach a
correct diagnosis. Every effort should be made to exclude
treatable causes. Treatment includes discontinuation of
the drug. Full recovery without sequelae is the rule?~
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
This is becoming more common in the AIDS era. The
secondary stage of the disease is heralded by a
generalised nonprurutic rash, fever, headache, malaise
and anorexia. Meningitis occurs in upto 30% of cases in
this stage but may not produce neurological symptoms.
Because of a lack of typical clinical presentation, CSF
VDRL test should always be included in the diagnostic
work up of aseptic meningitis.6,9.1~
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
Meningeal involvement can occur as the most serious
manifestation of disseminated fungal infections. This
occurs primarily in patients with AIDS, after organ
transplantation, on immunosuppressive therapy or long
term steroids. However, the most common fungal
pathogen, Cryptococcus neoformans can occur in
i m m u n o c o m p e t e n t patients. Subacute or chronic
meningitis is the most common clinical manifestation of
disseminated cryptococcosis. Cryptococcal antigen assay
in the CSF may be helpful in diagnosis.6,1~
CSF : Suspicion of viral meningitis is based on the clinical
presentation and presence of supportive CSF findings.
CSF pressure is usually increased. CSF shows generally
less than 500 cells/cu mm. Early examination may
occasionally show acellular fluid or predominance of
polymorphonuclear leukocytes. Typical mononuclear
pleocytosis devlops after 8-48 hours. CSF protein is
elevated upto 100 mg % wheras glucose is normal or
modestly decreased. Bacterial culture, Gram stain and
bacterial antigen tests are uniformly negative. Levels of
tumour necrosis factor (TNF) and lactate are low. Viral
isolation from CSF is the standard criterion for diagnosis
but is not positive in all patients?
Measurement of interferon alpha levels in CSF
provides evidence of active viral invasion of the CNS but
this test is not widely available, lgG index which is
Syphilitic Meningitis
DRUG INDUCED ASEPTIC MENINGITIS
The acute aseptic meningitis syndrome is being
recognized as a complication of many d r u g s ? 1-29
Intrathecal administration of anticancer drugs like
Indian Journal of Pediatrics, Volume 72--January, 2005
61
Rashmi Kumar
derived by calculating the ratios of IgG and albumen in
CSF and serum is another indicator of intrathecal
synthesis of antibodies. Specific IgG ratios in CSf and
serum can also be used to identify infection with specific
viruses but these are seldom helpful in the early stages of
the illness. ~
The polymerase chain reaction (PCR) is an important
advance in diagnosis of infectious meningitis.35~6in recent
years, it has become avalable for more and more agents.
Stellrecht et al (2002) studied the impact of enteroviral
Reverse Transcriptase PCR assay (RT-PCR) in the
diagnosis and management of enteroviral meningitis in
1056 hospitalised patients. They concluded that RT-PCR
for enteroviral meningitis is an important tool in the
diagnosis of children with meningitis and nonspecific
febrile illness which translated into shortened hospital
stay and significant health c a r e s a v i n g s . 37
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
Many patients with aseptic meningitis can be treated on
an outpatient basis, after initial lumbar puncture. Those
who have seizures, altered consciousness or severe
symptoms or those in whom the diagnosis is in doubt
should be hospitalised. Treatment is mostly supportive
and includes analgesics, antipyretics, antiemetics,
maintainence of fluid balance and prevention and
treatment of complications. No specific therapy is
presently recommended for most viral pathogens.
Whenever there is a suspicion or doubt as to presence of
bacterial meningitis, empiric antibiotic therapy should be
instituted after obtaining specimen for culture. Antiviral
therapy is available against HSV, varicella and
cytomegalovirus. Acyclovir, valacyclovir and foscarnet
are used for herpes or varicella infections and
gangcyclovir is used for cytomegaloviral infection.6
Specific antimicrobial therapy would be required for
infectious agents. For tuberculous meningitis,
antitubercular therapy with 4 drugs - Streptomycin,
isoniazid, rifampicin and pyrazinamide for the initial 2
months followed by 3 drugs for another 10 months is
generally recommended, along with 4-6 weeks of steroids
initially. Penicillin and ceftriaxone are used for meningitis
caused by actinomyces and spirochetes. Doxycycline or
rifampicin is used for Brucella infection and gentamycin
for Pasteurella tularensis. Antifungal agents that can be
used are amphoterecin B, fluconazole and flucytosine.
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
Seizures, even status epilepticus can sometimes occur
with aseptic meningitis but prophylactic anticonvulsants
are not recommended. If seizures occur, they should be
controlled with phenytoin and phenobarbital.
A variable component of encephalitis may be seen
with viral meningitis. Mumps meningoencephalitis can
result in sensorineural deafness and aqueductal stenosis
causing hydrocephalus.6 Complications of tuberculous
meningitis include hydrocephalus, infarcts, neurological
deficits, cranial nerve palsies, epilepsy and mental
regression.
PROGNOSIS
Viral meningitis is usually a benign disease, with low
rates of morbidity and mortality. Full recovery occurs
within 5-14 days in most patients. Fatigue,
lightheadedness and asthenia may persist for a few
months in some patients. Other nonviral infectious
meningitis is not so benign, however. Tuberculous
meningitis is a particularly dangerous illness with high
rate of mortality and permanent sequelae unless
diagnosed and treated very early.
PREVENTION
Patients with measles, chickenpox, rubella or mumps
Indian Journal of Pediatrics, Volume 72---January, 2005
Aseptic Meningitis: Diagnosis and Management
must be isolated. Strict handwashing especially after
n a p p y c h a n g e s a r e i m p o r t a n t in p r e v e n t i n g s p r e a d of
e n t e r o v i r u s infections. Effective v a c c i n e s are a v a i l a b l e for
polio, measles, mumps, varicella and rubella. Arboviral
vaccines are also available and should be used for
p o p u l a t i o n s l i v i n g in o r v i s i t i n g e n d e m i c areas.
21.
22.
23.
REFERENCES
1. Krugman S, Katz SI,, Gerston AA, Wi]fert C. Aseptic Meningitis
in Infectious Diseases of Children. 8 'hedn. CV Mosby Co,
Toronto, 1985: 167-173.
2. Hammer SM, Connolly KJ. Viral aseptic meningitis in the
United States: Clinical features, viral etiologies and differential
diagnosis. Curr Clin Top h~ect Dis 1992; 12 : 1-25.
3. Centre for Disease Control Morbidity & Mortality Weekly
Report 2003:52 (32); 761-764.
4. Tee WS, Choong CT, l.ui RV, I,ing AE. Aseptic meningitis in
children: The Singapore experience. Ann Acad Med Singapore
2002:31 (6); 756-760.
5. Middlekamp JN. Aseptic meningitis & viral meningitis, in
Feigin, Cherry, eds. Textbook of Pediatric Infectious Diseases.
Feigin & Cherry WB Saunders Co, 1981; 319-324.
6. Prober CG. Infections of the Central N e r v o u s System.
Behrmann, Kleigman & Jenson, eds. Nelson Textbook of
Pediatrics; 16~ edn. WB Saunders Co, 2000; 713-716.
7. Rotbart HP. Enteroviral infections of the central nervous
system. Clin Infect Dis 1995: 20(4); 971-981.
8. Shukla PC, Ramachandran T. Aseptic Meningitis. Emedicine
Article 23,d May 2002
9. Connolly KJ, Hammer SM. The acute aseptic meningitis
syndrome. Infect Dis Clin North Am 1990; 4(4); 599-622.
10. l~alton M, Newton RW. Aseptic meningitis. Dev Med Child
Neuro11991; 33(5); 446-451.
11. Muir P, van Loon AM. Enterovirus infections of the central
nervous system. Intervirology 1997; 40 (2) : 153-166.
12. Deshpande JM, Nadkarni SS, Francis PP. Enterovirus 71
isulated from a case of acute flaccid paralysis in India
represents a new genotype. Curt Sci 2003; 85(10): 1350-1353.
13. Gabudza DH. Neurological disorders associated with HIV
infections. J Am Acad Dermatol 1990; 22 (6 pt 2); 1232-1236.
14. Newton HB. Common neurologic complications of HIV -1
infection and AIDS. Am Fam Physician 1995; 51 (2) : 387-398.
15. Medical Research Council: Tuberculosis survey of England &
Wales 1978/1979. HMSO London 1980
16. Kumar R, Singh SN, Kohli N. A diagnostic rule for tuberculous
meningitis. Arch Dis Child 1999; 81: 221-224.
17. Handa R, Wali JP, Singh S, Aggarwal P. A propective study of
dengue arthritis in north India. hulian ] Med Res 1999; 110:1079.
18. Tuerlinckx D, Bodart E, Garrino MG, de Bilderling G. Clinical
data and cerebrospinal fluid findings in Lyme meningitis
versus aseptic meningitis. Eur J Pediatr 2003:162 (3); 150-153.
19. Kochar DK, Agarwal N, Jain N, Sharma BV, Rastogi A, Meena
CB. Clinical profile of neurobrucellosis - a report of 12 cases
from Bikaner (north west India). J Assoc Phys India 2000; 48 (4):
376-380.
20. Shah I, Warke S, Deshrnukh CT, Kamat JR. Leptospirosis - an
Indian Journal of Pediatrics, Volume 72---January, 2005
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
underdiagnosed clinical condition. J Postgrad Med 1999; 45: 9394.
Moris G, Garcia-Monco JC. The challenge of drug induced
aseptic meningitis. Arch Intern Med 1999; 159 (11 ); 1185-1194.
Marinac JS. Drug and chemical induced aseptic meningitis: a
review of the literature. Ann Pharmacother 1992; 26 (6); 813-822.
Shapiro WR, Young I)F. Neurological complications of
antineoplastic therapy. Acta Neurol Scand Supp11984; 100: 125132.
Min DI, Monaco AP. C o m p l i c a t i o n s associated with
i m m u n o s u p p r e s s i v e therapy and their m a n a g e m e n t .
Pharmacotherapy 199,1; 11 (5): 119S-125S.
N y d e g g e r UE, Sturzenegger M. Adverse effects of
immunoglnbulin therapy. Drug Saf 1999; 21 (3): 171-185.
Alloway JA, Mitchell SR. Sulfasalazine neurotoxicity : a report
of aseptic meningitis and a review of the literature. J Rheumatol
1993; 20(2): 409-411.
Chaudhry HJ, Cunha BA. Drug induced aseptic meningitis.
Diagnosis leads to quick resolution. Postgrad Med 1991; 90 (7):
65-70.
Dang Ct, Riley DK. Aseptic meningitis secondary to
carbamazepine therapy. Clin Infect Dis 1996; 22(4): 729-730.
Hoppmann RA, Peden JG, Ober SK. Central nervous system
side effects of nonsteroidal anti-inflammatory drugs: Aseptic
meningitis, psychosis and cognitive dysfunction. Arch Intern
Med 1991; 151 (7): 1309-1313.
W i t t m a n n A, Wooten GF. Amoxicillin induced aseptic
meningitis. Neurology 2001; 57 (9): 17,34.
Hoffmann MA, Valderrama E, Fuchs A et al. Leukemic
meningitis in B cell prolymphocytic leukemia. Cancer 1995;
75(5): 1100-1103.
Miller K, Budke H, Orazi A. l.eukemic meningitis
complicating early stage chronic lymphocytic leukemia. Arch
Path Lab Med 1997; 121(5): 524-527.
Moots PL, Harrison MB, Vandenburg SR. Prolonged survival
in carcinomatous meningitis associated with breast cancer.
South Med ] 1995; 88(3): 357-362.
Kennedy C. Acute viral encephalitis in childhood. BM] 1995;
310: 139-140.
Roos KL. Pearls and pitfalls in the diagnosis and management
of central nervous system infectious diseases. Semin Neurol
1998; 18 (2): 185-196.
Hosoya M, Sato M, Honzumi K, Katayose M, Sakuma Het al.
Application of polymerase chain reaction and subsequent
phylogenetic analysis to the diagnosis of enteroviral infection
in the central nervous system. ] Clin Viro12002; 25 (Suppl 1):
$27-$38.
Stellrecht KA, Harding I, Woron AM, I ~epow ML, Venezia RA.
The impact of an enteroviral RT-PCR assay on the diagnosis of
aseptic meningitis and patient management. ] Clin Virol 2002:
25 (Suppl 1): $19- $26.
Kumar R, Kohli N, Thavnani H, Kurnar A, Sharma B. Value of
CT scan in the diagnosis of meningitis. Indian Pediatr 1996; 33:
465-468.
Nigrovic LE, Kuppermann N, Malley R. Development and
validation of a multivariable predictive model to distinguish
bacterial from aseptic meningitis in children in the post
hemophilus influenzae era. Pediatrics 2002; 110 (4) : 712-719.
63