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: rashmik@sancharnet.in

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. 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

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

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

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

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.

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. 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

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~

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.

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

Tuberculous Meningitis
This remains an important cause of childhood hospital admissions, mortality and permanent disability in India. Tuberculosis produces a basal meningitis thereby causing
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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

CSF pleocytosis with > 50% lymphocytes. TM

Lyme Disease

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 9 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 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

11 CSF tests

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

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

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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

Syphilitic Meningitis
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
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~

Laboratory Diagnosis
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
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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
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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

TREATMENT

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~ 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?

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.
COMPLICATIONS

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
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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

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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. 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.

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