Thursday, August 11, 2011

Aspetic meningitis

aseptic meningitis (AM) is an inflammation of the meninges caused mainly by nonbacterial organisms or other disease processes. AM denotes a clinical syndrome with a predominance of lymphocytes in the CSF in absence of bacterial agents in CSF.

Also , AM is an acute infection of the central nervous system that occurs most frequently in infants and young children (Berlin, et al.,1993). It could be either viral, fungal , tuberculous meningitis or other causes

(A) Pathophysiology:

Organisms colonize and penetrate the nasopharyngeal or oropharyngeal mucosa , survive and multiply in the blood stream and they invade host immunological mechanisms and spread through the blood-brain barrier. Infection cannot occur until colonization of the host has taken place (usually in the upper respiratory tract).The mechanisms by which circulating viruses penetrate the blood-brain barrier and seed the CSF to cause meningitis are unclear ( CDC ; 2005).

In tuberculous meningitis infection begins in the lung and may spread to the meninges by a variety of routes.Blood-borne spread occurs and 25% of patients with miliary TB have TB meningitis by crossing the blood-brain barrier.A proportionof patients may get TB meningitis from rupture of a cortical focus in the brain (Rich focus) and little proportions get it from rupture of a bony focus in the spine. It is rare and unusual for TB of the spine to cause TB meningitis , but isolated cases have been described(Jain et al .,2006).

(B) Symptoms and signs:

Clinical presentations and courses of AM are markedly

variable. Severity of presentations are correlated with prognosis. They usually start by general viral prodroma for several days which is presented by fever, headache, nausea, vomiting , lethargy, myalgia, dysuria and pyuria

Specific prodroma in cases of Varicella zoster virus (VZV), Epstein-Barr Virus (EBV), Cytomegalovirus (CMV), Measles and Mumps viruses have been reported such as rash, lymphadenopathy, hepatosplenomegaly and parotid enlargement.Common presentation of viral meningitis and

encephalitis is encephalopathy with diffuse neurological symptoms and signs including behavioral and personality changes and/or altered mental status, decreased consciousness, generalized seizures, acute confusional or amnesia states but meningismus and headache are less common. Other nonspecific symptoms may include arthralgia, myalgia, sore throat, weakness and lethargy.. Focal signs such as cranial nerve defects, hemiparesis, focal seizures and autonomic dysfunction are encountered. Other signs of viral meningitis include ataxia , dysphagia and hydrophobia have been reported especially in rabies (

The clinical symptoms of AM are characterized by fever (>38◦C), malaise, vomiting and in some cases petechial rashes. Signs of meningeal irritation include neck stiffness,Kernig’s sign and Brudzinski’s sign .These signs are poorly noted in adults . The nonspecific nature of the symptoms and clinical signs mean that we must confirm the diagnosis.

A variety of clinical manifestations which are associated with enteroviral infections , include respiratory illness, acute hemorrhagic conjunctivitis, myocarditis, neonatal sepsis-like disease, encephalitis and acute flaccid paralysis .

The clinical features of tuberculous meningitis are non-specific , therefore the discrimination of cases of tuberculous meningitis from other causes of meningitis by clinical features alone is often impossible

(C) Epidemiology :

The epidemiology of AM and other CNS infections are not fixed and may vary according to location and season

Viral meningitis occurs worldwide as epidemics and as sporadic cases. Cases of enteroviral meningitis are observed increased in the late summer .

The incidence of tuberculous meningitis(TBM) is related to the prevalence of TB in the community, and it is still the most common type of chronic CNS infection in developing countries. TB is the seventh leading cause of death and disability worldwide

(D) Etiology of aseptic meningitis :

Many etiological agents are responsible for AM. Viruses are the most frequent causes.


a-Enterovirus :Enteroviruses(EVs)belong to the family of Picornaviridae. EVs are small, non enveloped, single-stranded RNA viruses that have been classified into 68 serotypes (Stanway et al.,2005) .

EVs include polioviruses and non polioviruses which are including echovirus and coxsackievirus(Andreoletti et al. 1998).All the EVs groups are the common etiological agents of AM (Leite & Barbosa , 2005).

Enteroviral meningitis is commonly diagnosed in children less than 5 years of age. It is a febrile illness with anorexia and general malaise or may present as a rather abrupt onset of fever, nausea and headache. It could be followed by meningeal

signs with stiffness of the neck or back and muscle weakness may occur which is clinically similar to mild poliomyelitis (Yerly et al; 1996).

b-Echovirus : Echovirus is RNA virus that belongs to the genus enterovirus(non polio type) of the picornaviridae family. Echovirus is found in the gastrointestinal tract and hence it is being part of the enterovirus genus (Hauri et al ., 2005).

Echovirus is highly infectious and its primary target is children. The echovirus is among the leading causes of acute febrile illness in infants and young children ( Chen et al ., 2005).

Echovirus causes a nonspecific exanthemas, herpangina which is a fever and skin rashes that may be maculopapular, morbilliform, macular, petechial or papulopustular in nature ( Pichichero et al ., 1998).

Severe forms of disease may be complicated by meningitis especially in infants younger than 3 months and encephalitis, neonatal sepsis and myocarditis especially in patients with altered immunity (Paananen et al ., 2003).

c-Herpesvirus : Human herpes viruses include herpes simplex virus (HSV) type I (HSVl ) and type 2 (HSV2),VZV,CMV, Human herpesvirus 6 (HHV6) and EBV(Cardone et al., 2007).

HSV AM is most commonly associated with primary genital infection with HSV type 2. Acute AM has also been associated with VZV in patients with or without typical skin lesions. Cases of recurrent Mollaret's meningitis have been associated with HSV type 1, HSV type 2 and EBV( Subramanian & Geraghty, 2007).

The structure of herpes virus is spherical in shape. Its lipid envelope encloses the nucleocapsid that arranged in a icosahedral form. Its genome is a single, linear, double-stranded molecule. The capsid is surrounded by a number of loosely associated proteins known collectively as the tegument. Many of these proteins play critical roles in initiating the process of virus reproduction in the infected cell. The tegument is in turn covered by a lipid envelope studded with glycoproteins that are displayed on the exterior of the virion (Mettenleiter et al.,2006).

The majority of patients with HSV meningitis present with subacute neurological symptoms developing over 1-7 days and the classic symptoms include: headache, neck stiffness, fever, chills, photophobia with other common meningeal symptoms such as vomiting, seizures and altered consciousness. These

manifestations are not evident in infants and elderly ( Fatahzadeh &Schwartz,2007) .

Figure 1 :Structure of herpesvirs (Roizman et al ., 2006)

d-Cytomegalovirus : Cytomegalovirus (CMV) is a viral genus of the herpesviruses group in humans and it is commonly known as human cytomegalovirus (HCMV) or human

herpesvirus 5 (HHV-5) (Adler , 2005). All herpesviruses share a characteristic ability to remain latent within the body over long periods and its structure is similar to HSV structure (Bennekov et al ., 2004).

HCMV infection may be a life threatening condition especially in immunocompromised patients. Active infection in healthy children and adults can cause prolonged high fever, chills, severe tiredness, a generally ill feeling, headache and spleenomegaly.Most infected newborns have no symptoms at birth but in some cases symptoms include poor weight gain, swollen glands, rash, liver, lung and blood involvement (Bottieau et al .,2006).

Patients with impaired immune systems are more prone to serious, potentially life-threatening illnesses, with fever, pneumonia, CNS complications as meningitis , encephalitis ,liver involvement and anaemia. Illnesses can last for weeks or months and can be fatal. In persons with human immunodeficiency virus (HIV) infection , CMV can infect the retina of the eye (CMV retinitis) and cause blindness (Griffiths & Walter , 2005).

e-Epstein-Barr virus : EBV or human herpesvirus 4 infects more than 95% of the world's population. The most common manifestation of primary infection with this virus is acute infectious mononucleosis(glandular fever) which is a self-limited clinical syndrome and frequently affects adolescents and young adults (Nicholas & Joseph ,2008).

A mature infectious viral particle consists of nucleoid , capsid and an envelope. The nucleoid contains linear double-stranded viral DNA. It is surrounded by icosahedral capsid which is constructed of capsomers which are tubular protein subunits.The envelope derived either from the outer membrane

or the nuclear membrane of the host cell encloses the capsid and nucleoid ( the nucleocapsid) (Gasser et al., 2007).

Classical symptoms of acute infectious mononucleosis include sore throat, fever, headache and myalgia with generalized lymphadenopathy and splenomegaly , mononucleosis with relative and absolute lymphocytosis. Infection with EBV in younger children is usually asymptomatic or mild. However, EBV is also a human tumor virus which is the first virus associated with human malignancy as nasopharyngeal carcinoma and Burkitt lymphoma (Chaganti et al., 2008).

Nonfatal complications are encountered as various forms of CNS and hematological affection.CNS affections are in the form of meningitis, encephalitis, hemiplegia and transverse myelitis. Hematological affection as EBV can cause autoimmune hemolytic anemia and various cytopenias ( Lockey et al., 2008).

f-Varicella zoster virus : Varicella zoster virus (VZV) or human herpesvirus 3 is a member of eight herpes viruses known to infect humans. It commonly causes chicken-pox in children and both shingles and postherpetic neuralgia in adults (Steiner et al., 2007).

VZV is closely related to the herpes simplex viruses (HSV) sharing much genome homology (CDC,1996).

Chicken-pox (varicella) may rarely causes complications as meningitis ,encephalitis or pneumonia. VZV remains dormant in the nervous system of the infected person (virus latency) in the trigeminal and dorsal root ganglia. In about 10-20% of cases, VZV reactivates later in life producing a disease known as herpes zoster or shingles. Serious complications of shingles

include postherpetic neuralgia, zoster multiplex, myelitis, AM , herpes ophthalmicus (Steiner et al., 2007).

g-Measles virus :Measles is one of the typical viral diseases of childhood. However, unlike other common viral diseases , measles often leads to severe complications that may be fatal ( Helfand et al. ,2008).

Measles virus is a member of the family of Paramyxoviruses which is enveloped,single strand RNA(ssRNA)with helical symmetry.The envelop has only one glycoprotein type which is

haemaglutinin (HA-antigen) (Leonard et al., 2008).

Figure :Structure of measles virus (MicrobiologyBytes , 2008).

The classical symptoms of measles include a four day fever up to 40°C ,cough, coryza (runny nose) and conjunctivitis (red eyes). Pathognomonic koplik's spots are seen inside the mouth.The characteristic rashs are classically described as a generalized,maculopapular and erythematous that begin several

days after the fever starts. They begin on the head before spreading to cover most of the body and often cause itching. The rashs change colour from red to dark brown before disappearing (Perry et al., 2004).

Complications with measles are relatively common ranging from relatively mild to sever include diarrhea , pneumonia , encephalitis , meningitis, corneal ulceration leading to corneal scarring (Torjesen ,2008).

h-Mumps virus : Mumps or epidemic parotids is a viral disease of the human species. It is a paramyxovirus with the same genetic structure as Measles virus (Hviid et al ., 2008).

It manifested by painful swelling of the salivary glands (classically the parotid gland) . Painful testicular swelling and rash may also occur. The symptoms are generally not severe in children. In teenage males and adults, complications such as infertility or subfertility are more common due to orchitis (testicular inflammation).Central complications include AM which is commonly occurring asymptomatically with inflammatory cells in CSF 50%–60% of patients.Symptomatic meningitis (headache, stiff neck) occurs in up to 15% of patients and resolves without sequelae in 3–10 days (Kanra et al ., 2004).

The disease is generally self-limited and the symptoms can be controlled by painkillers druges (Preveden et al ., 1996).

i-Rubella Virus : Rubella is commonly known as German measles because the disease was first described by German physicians in the mid-eighteenth century. This disease is often mild and attacks often pass unnoticed. The disease can last one to five days. Children recover more quickly than adults. Infection of the mother by Rubella virus during pregnancy is

serious especially in the first 20 weeks of pregnancy as the child may be born with congenital rubella syndrome (CRS) (Richardson et al ., 2001).

Rubella virus is the only member of the Rubivirus genus of the Togavirus family. Unlike most Togaviruses it is not arthropod-borne but is acquired via the respiratory route. It is an enveloped (toga=cloak), non-segmented, positive sense, RNA virus (Dayan et al., 2006 & Stegmann, Carey , 2002).

After an incubation period of 14-21 days, the primary symptom is the appearance of a rash (exanthema) on the face which spreads to the trunk and limbs and usually fades after three days and the rash disappears after a few days with no staining or peeling of the skin. Other symptoms include low grade fever, post cervical lymphadenopathy, joint pain, headache and conjunctivitis. ( Atreya et al., 2004).

Rubella can cause congenital rubella syndrome in the newly born. The syndrome (CRS) follows intrauterine infection by the virus and comprises cardiac, cerebral, ophthalmic and auditory defects. It may also cause prematurity, low birth weight , neonatal thrombocytopenia, anaemia and hepatitis (De Santis et al ., 2006 ).

In most cases there is neural involvement , irritability, motor tone problems, mental retardation,meningitis, encephalitis , abnormal posture and neurosensory hearing loss ( Weisinger & Pesudovs ,2002).

j- Lymphocytic Choriomeningitis virus : Lymphocytic choriomeningitis or lymphocytic meningoencephalitis (LCM) is a rodent-borne viral infectious disease that may cause AM , encephalitis or meningoencephalitis. The causative agent is the

lymphocytic choriomeningitis virus (LCMV) which is a member of the family Arenaviridae which is ssRNA , enveloped virus (Barton & Mets , 2001).

In humans LCMV infection usually causes mild illness such as fever, fatigue, loss of appetite, muscle aches, headache,

nausea and vomiting. A small number of individuals may become quite ill and develop meningitis or encephalitis .Other

individuals may not have any symptoms (Barton & Mets , 2001).

2-Other causes of aseptic meningitis:

I-Infectious causes:

a-Partially treated bacterial meningitis:

This may be confused with a nonpyogenic or AM because CSF becomes sterile and cellular pattern changes from polymorphonuclear to lymphocytic.The condition is not benign and rapid deterioration occpurs in absence of antibiotic therapy (Rashmi , 2005).

b-Tuberculous meningitis:

It causes severe neurological deficits or death in more than half of cases( Jain et al ., 2006).

The pattern of tuberculous meningitis in the population varies

in different areas of the world. In areas with high incidence of tuberculosis, tuberculous meningitis usually affects young children. It develops typically 3 to 6 months after the primary tuberculosis infection. In areas with low incidence of tuberculosis, tuberculous meningitis tends to occur more in adults. It may be due to reactivation of an old focus of tuberculosis (Dinnes et al ., 2007).

Tuberculous meningitis begins insidiously with a gradual fluctuating fever, fatigue, weight loss, behavior changes, headache, and vomiting. This early phase is followed by neurological deficits as loss of consciousness, or convulsions. A dense gelatinous exudates (outpouring) forms and envelops the brain arteries and cranial nerves. It creates resistance in the flow of the CSF, which leads to hydrocephalus. The development of arteritis and infarctions of the brain can cause hemiplegia or quadriplegia (Dinnes et al ., 2007).

c-Leptospiral meningitis :

Leptospirosis (also known as Weil's disease, Weil's syndrome) is a bacterial zoontic disease caused by spirochetes of the genus Leptospira that affects humans and a wide range of animals .The infection is commonly transmitted to humans by allowing water that has been contaminated by animal urine to come in contact with unhealed breaks in the skin, eyes or with the mucous membranes ( Langston & Heuter,2003).

Human infections with Leptospira begin after an incubation

period of 7-12 days, with fever (biphasic) and "flu-like" illness,

then patients may develop either icteric phase of intense headache, severe myalgia, abdominal pain, nausea,diarrhea,

rash,conjunctivitis and conjunctival hemorrhage. Anicteric AM leptospirosis can occur as a sequelae of either Weil's disease ( hepatic and renal form of leptospirosis in humans). The meningitis is thought to be immune-mediated, since the organism is generally not present in the CSF when clinical signs develop( Langston & Heuter,2003).


This is a systemic infection caused by a small, aerobic , non spore bearing, non motile Gram negative coccobacilli , seen usually in persons living or working in close contact with animals or consuming animal products such as raw milk or cheese made from raw milk. Clinical pictures are extremely variable. In the acute form , the illness presents with a flu like illness with fever , night sweat , malaise, anorexia , headache and myalgia.In the undulant form arthritis and epididymoorchitis may develop.Neurological complications include AM, myelitis and polyradiculoneuropathy (Kochar et al ., 2000).

e-Lyme disease:

It is caused by borrelia burgdorferi a fastidious microaerophillic spirochete. The illness is divided into early localized disease with a rash at the site of the tick bite, fever , malaise, headache and myalgia which is followed by secondary erythema migran lesions , AM, cranial nerve paresis and carditis . Late in the disease, chronic polyarthritis may develop (Tuerlinckx et al ., 2003).

f- Syphilitic meningitis :

This is becoming more common in the AIDS patients. The secondary stage of the disease is manifested by nonprurutic rash, fever , malais, headache , anorexia and meningitis (Dalton & Newton , 1991).

g-Fungus :

Candida can infect both the meninges and the parenchyma brain tissue. In practice, the majority of cases of CNS candidiasis are associated with disseminated or invasive candidiasis (IC).It is much more common in neonates than in adults. The manifestations vary according to age. In adults, the most frequent findings are fever, headache, nuchal rigidity, altered mental status, confusion, and disorientation (Voice et al ., 1994).

Another relevant and common feature of cases in adults is the prolonged interval between onset of symptoms and diagnosis. Candidal meningitis in neonates usually presents as part of the syndrome of neonatal IC. Neurological clinical signs are related to increased intracranial pressure (bulging fontanels and splitting sutures). Signs of sepsis and progressive clinical deterioration are commonly found. Therefore, a physician dealing with sepsis in a neonate should suspect candidal meningitis if candida are recovered from the blood, urine, or other site suggestive of heavy colonization (Casado et al ., 1997).

II- Noninfectious causes :

a-Post vaccination meningitis :

*MMR Meningitis:

Fever is the most common side effect occurring in vaccine recipients.More severe reactions including allergic reactions , encephalitis and meningitis which is probably caused by the measles vaccine virus (Dourado et al ., 2000).

Subsequent epidemiologic studies showed that in the vaccinated recipients there are cases of AM linked to MMR vaccination (Miller et al ., 1993).

Also,there is an increased risk of hospital admission for febrile convulsions 15–35 days after receiving MMR vaccine contained Urabe mumps strain indicating that the real risks of acute neurological consequences from the Urabe mumps component of MMR were underestimated when using methods relied on laboratory investigations (Miller et al ., 2001).

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