Viral Infections of the Central Viral Infections of the Central Nervous SystemNervous System

IntroductionIntroduction• Anatomic considerations are important in Anatomic considerations are important in

infections of the CNS.infections of the CNS.

- the brain and spinal cord are protected by bone - the brain and spinal cord are protected by bone and meningeal coverings that compartmentalize and meningeal coverings that compartmentalize infection.infection.

- they are divided by barriers from the systemic - they are divided by barriers from the systemic circulation.circulation.

- they lack an intrinsic immune system- they lack an intrinsic immune system

- they have a unique compact structure.- they have a unique compact structure.

Natural Defenses of the CNSNatural Defenses of the CNS

Skull and vertebraeSkull and vertebrae

MicroglialMicroglial cells and macrophages cells and macrophages

Restricted entry into brain (Restricted entry into brain (blood-brain barrierblood-brain barrier) )

for:for: microorganisms microorganisms medications, including antibioticsmedications, including antibiotics immune systemimmune system

• The blood-brain barrier largely prevents The blood-brain barrier largely prevents macromolecules from entering the brain macromolecules from entering the brain parenchyma. parenchyma.

• The space between cells in the brain parenchyma The space between cells in the brain parenchyma is too small to permit passage even of a virus.is too small to permit passage even of a virus.

• However, tetanus toxin and some viruses travel However, tetanus toxin and some viruses travel through the CNS by axoplasmic flow.through the CNS by axoplasmic flow.

• Most agents invade from blood. Most agents invade from blood.

• Bacteria grow rapidly in cerebrospinal fluid; viruses Bacteria grow rapidly in cerebrospinal fluid; viruses infect meningeal and ependymal cells. infect meningeal and ependymal cells.

Immune SystemImmune System

• Levels of IgG and IgA in the CSF are Levels of IgG and IgA in the CSF are approximately 0.2 to 0.4 percent of the serum approximately 0.2 to 0.4 percent of the serum levels. IgM is present at even lower levels.levels. IgM is present at even lower levels.

• There is also no lymphatic system in the usual There is also no lymphatic system in the usual

sense, and few phagocytic cells.sense, and few phagocytic cells.

• Complement is also largely excluded. Complement is also largely excluded.

• When trauma or inflammation disrupts the When trauma or inflammation disrupts the blood-brain barrier, antibody molecules blood-brain barrier, antibody molecules passively leak into the CNS along with other passively leak into the CNS along with other serum proteins. serum proteins.

• When an inflammatory reaction has been When an inflammatory reaction has been mounted against an infection, B cells from the mounted against an infection, B cells from the peripheral circulation can move into the peripheral circulation can move into the perivascular spaces of the CNS and generate perivascular spaces of the CNS and generate immunoglobulins intrathecally.immunoglobulins intrathecally.

• Types of CNS infections include; meningitis, Types of CNS infections include; meningitis,

encephalitis, myelitis, and meningoencephalitis encephalitis, myelitis, and meningoencephalitis or meningoencephalomyelitisor meningoencephalomyelitis

Meningitis• Meningitis is an infection which causes

inflammation of the membranes covering the brain and spinal cord.

• Bacterial meningitis may be referred to asBacterial meningitis may be referred to as ‘‘purulent meningitispurulent meningitis’.’. Non-bacterial meningitis is often referred to as ‘aseptic meningitis’ – eg. viral meningitis

• Causes and risks - The most common causes of meningitis are viral

infections that usually resolve without treatment. - Bacterial infections of the meninges are extremely

serious illnesses, and may result in death or brain damage even if treated.

Aseptic Meningitis

Aseptic Meningitis• Definition: A syndrome characterized by acute onset

of meningeal symptoms, fever, and cerebrospinal fluid pleocytosis, with bacteriologically sterile cultures.

• Laboratory criteria for diagnosis:

- CSF showing ≥ 5 WBC/cu mm and elevated protein

- No evidence of bacterial or fungal meningitis.

• Confirmed case: a clinically compatible illness diagnosed by a physician as aseptic meningitis, with no laboratory evidence of bacterial or fungal meningitis

• Viral meningitis is more common than bacterial Viral meningitis is more common than bacterial meningitis and it is often less severe than bacterial meningitis and it is often less severe than bacterial meningitis. meningitis.

• Recovery is almost always complete, since only Recovery is almost always complete, since only meningeal and ependymal cells are involved. meningeal and ependymal cells are involved.

• The disease is benign and tends to be seasonal. The disease is benign and tends to be seasonal.

      

Aseptic meningitis syndrome

• Acute onset of fever, headache, neck pain/stiffness, vomiting, and meningeal irritation signs

• No confusion/stupor

• CSF: WBC protein normal glucose

• Negative bacterial culture of CSF

Clinical ManifestationsClinical Manifestations• Manifestations vary depending on age; below 2 years and Manifestations vary depending on age; below 2 years and

above 2 years.above 2 years.

• In older children and adults: main manifestations of In older children and adults: main manifestations of meningitis are headache, fever, and nuchal rigidity.meningitis are headache, fever, and nuchal rigidity.

• Flexion of the neck may also cause reflex flexion of the legs Flexion of the neck may also cause reflex flexion of the legs (Brudzinski sign), and meningeal irritation may limit (Brudzinski sign), and meningeal irritation may limit extension of the leg when flexed at the knee (Kerning sign). extension of the leg when flexed at the knee (Kerning sign).

• Meningeal inflammation may also cause some degree of Meningeal inflammation may also cause some degree of obtundation (reduced consciousness), and seizures are obtundation (reduced consciousness), and seizures are common in children. common in children.

Brudzinski’s Neck Sign

Kernig’s Sign

Symptoms of meningitisAdults and children

Babies, neonates and the elderly often present atypically .

• Systemic clinical signs sometimes suggest the Systemic clinical signs sometimes suggest the agent (e.g., the rash or herpangina of agent (e.g., the rash or herpangina of enterovirus infections and the parotitis of enterovirus infections and the parotitis of mumps).mumps).

• Examination of the CSF provides the most Examination of the CSF provides the most important diagnostic information.important diagnostic information.

• In general, viruses produce a modest In general, viruses produce a modest mononuclear cell response, and although the mononuclear cell response, and although the CSF protein may be elevated, CSF sugar is CSF protein may be elevated, CSF sugar is normal or only mildly depressed. normal or only mildly depressed.

Causative Agents of Aseptic Meningitis

• Viruses Enteroviruses Herpesviruses (HSV- 1, HSV- 2, EBV, HHV- 6, VZV) HIV Lymphocytic choriomeningitis Mumps Arboviruses West Nile virus

• Numerous other causes e.g., Lyme disease, leptospirosis, 2º syphilis, partially-treated bacterial meningitis, TB, Cryptococcus, autoimmune disease, and medications

• Enteroviruses (echoviruses and Coxsackie's Enteroviruses (echoviruses and Coxsackie's viruses) are the most common cause, and they viruses) are the most common cause, and they cause disease primarily in the late summer and cause disease primarily in the late summer and early fall. early fall.

• Mumps virus is the second most common Mumps virus is the second most common cause in unvaccinated communities and it cause in unvaccinated communities and it spreads predominantly in the spring. spreads predominantly in the spring.

• Lymphocytic choriomeningitis virus is more Lymphocytic choriomeningitis virus is more common in winter, since this virus is acquired common in winter, since this virus is acquired from mice, which move indoors during cold from mice, which move indoors during cold weather and increase human exposure. weather and increase human exposure.

• Most viruses invade the CNS from the blood, and the Most viruses invade the CNS from the blood, and the risk of CNS invasion has been shown to be related to risk of CNS invasion has been shown to be related to the magnitude and duration of viremia.the magnitude and duration of viremia.

• The virus may cross the BBB directly at the capillary The virus may cross the BBB directly at the capillary endothelial level or through natural defects such as the endothelial level or through natural defects such as the area postrema and other sites that lack a BBB.area postrema and other sites that lack a BBB.

• Particles in the blood, including bacteria or viruses, are Particles in the blood, including bacteria or viruses, are normally cleared by the reticuloendothelial system, and normally cleared by the reticuloendothelial system, and speed of removal is proportional to size. speed of removal is proportional to size.

• A variety of viruses elude clearance by replicating within A variety of viruses elude clearance by replicating within blood cells. blood cells.

• Enteroviruses and some arboviruses are Enteroviruses and some arboviruses are cleared less effectively from blood because of cleared less effectively from blood because of their small size. their small size.

• Some viruses enter the CNS by infecting Some viruses enter the CNS by infecting endothelial cells or choroid plexus epithelium. endothelial cells or choroid plexus epithelium.

• Indeed, in mumps virus meningitis, choroid Indeed, in mumps virus meningitis, choroid plexus cells containing viral nucleocapsids are plexus cells containing viral nucleocapsids are frequently found within the CSF. frequently found within the CSF.

Diagnostic test for meningitis : lumbar puncture

•A lumbar puncture collects cerebrospinal fluid to check for the presence of disease or injury.

•A spinal needle is inserted, usually between the 3rd and 4th lumbar vertebrae in the lower spine.

Typical CSF findings in MeningitisBacterial meningitis

1. Presence of neutrophils in the CSF is associated with infection by N. meningitidis, S. pneumoniae etc.

2. CSF protein level reflects the degree of meningeal inflammation:- 10 X in bacterial infections

3. CSF glucose levels:-very low in bacterial infections

Viral meningitis

1. Presence of lymphocytes is associated with infection by viruses or mycobacteria. Neutrophils increase in the first 24-48 hours, then replaced by lymphocytes.

2. CSF protein level reflects the degree of meningeal inflammation:- 2-3 X in viral CNS infection

3. CSF glucose levels: normal with viral infections

EpidemiologyEpidemiology Incidence varies depending on age and Incidence varies depending on age and

geography, ranging from 11-219 cases per geography, ranging from 11-219 cases per 100,000 population.100,000 population.

Incidence is highest in children aged 1-4 years Incidence is highest in children aged 1-4 years and it decreases with ageand it decreases with age

Males are more commonly affected than Males are more commonly affected than females.females.

No specific racial predilection has been No specific racial predilection has been identified.identified.

Mortality is low being less than 1%Mortality is low being less than 1%

Management• Most cases of viral meningitis require only Most cases of viral meningitis require only

symptomatic treatment.symptomatic treatment.

• Since the disease is self-limited; the prime Since the disease is self-limited; the prime management problem is to rule out nonviral, management problem is to rule out nonviral, treatable illnesses that can mimic acute viral treatable illnesses that can mimic acute viral meningitis.meningitis.

• Examples are; partially treated bacterial Examples are; partially treated bacterial meningitis, tuberculous or fungal meningitis, meningitis, tuberculous or fungal meningitis, syphilis, Lyme disease, etc.)syphilis, Lyme disease, etc.)

Enteroviral Meningitis Enteroviruses are thought to be the most common

cause of viral meningitis Account for >50% of cases and approximately 90% of

cases in which a specific etiologic agent is identified. Majority of cases are in children or adolescents, but

patients of any age can be affected. Transmitted primarily by fecal-oral route, but can also

be spread by contact with infected respiratory secretions.

The incidence is increased in the summer months, but cases occur throughout the year.

Sporadic outbreaks are generally associated with specific serotypes (eg, ECV-30), typically related to introduction of new virus strain to a region.

Enterovirus Lab Findings CSF- findings typical of viral meningitis - Lymphocytic pleocytosis of generally <250 cells/mm3,

with modest protein elevation generally <150 mg/dl, and normal glucose

- Viral cultures positive in 40-80% of cases but it usually takes 4-12 days to become positive

- PCR is the most specific (close to 100%) and sensitive (97-100%) test and is positive in more than 2/3 of culture negative CSF in patients with aseptic meningitis

Herpes Simplex Meningitis Generally caused by HSV-2 (as opposed to encephalitis

which is caused by HSV-1)

Increasingly recognized as a cause of aseptic meningitis, with improving diagnostic techniques and a continued increase in the transmission of HSV-2

Can be due to primary or recurrent HSV infection

Between 13 and 36% of patients presenting with primary genital herpes have clinical findings consistent with meningeal involvement including headache, photophobia, and meningismus.

Occasionally patients present with more severe signs including urinary retention, paresthesias, weakness of upper or lower extremities, or ascending myelitis.

The genital lesions are typically present (85% of the time), and usually precede the CNS symptoms by seven days.

HSV meningitis can be recurrent, these patients may not have clinically evident genital lesions.

For patients with benign recurrent lymphocytic meningitis, careful analysis has revealed that over 80% are due to HSV meningitis.

It is also likely the cause of a large percentage of patients with Mollaret’s meningitis, which is a form of recurrent meningitis characterized by large monocytic/ macrophage lineage cells in the CSF.

HSV Diagnosis CSF- typical of a viral meningitis, with lymphocytic

pleocytosis, modest elevation in protein, and normal glucose.

Viral cultures are positive in about 80% of patients with primary HSV meningitis, but less frequently positive in patients with recurrent HSV meningitis.

HSV PCR of the CSF is the single most useful test for the evaluation of a patient with suspected HSV meningitis.

HIV meningitis A subset of patients with primary HIV infection will

present with meningitis or meningoencephalitis, manifested by headache, confusion, seizures or cranial nerve abnormalities.

HIV atypical meningitis is characterized by chronicity and recurrence.

Reports have suggested that as many as 5-10% of HIV infections can be heralded by meningitis.

  Aside from the usual meningeal signs, HIV infections may also

cause global encephalopathy, seizures, and focal neurologic deficits.

Diagnosis of HIV Meningitis

Serum might reveal atypical lymphocytosis, leukopenia, and elevated serum aminotransferases.

Documentation of seroconversion or detection of HIV plasma viremia by nucleic acid techniques can be used for diagnosis.

CSF- might show a lymphocytic pleocytosis, elevated protein, and normal glucose.

CSF cultures are often positive, but are not available in most centers.

Lymphocytic Choriomeningitis VirusLymphocytic Choriomeningitis Virus

• LCM is thought to be an underdiagnosed cause of viral meningitis, in one review it was noted to be responsible for 10-15% of cases.

• LCM is excreted in the urine and feces of rodents, including mice, rats, and hamsters.

• It is transmitted to humans by either direct contact with infected animals or environmental surfaces

• Transmission can occur by inhaling aerosolized particles of rodent Transmission can occur by inhaling aerosolized particles of rodent excrement, by ingesting food contaminated with the virus or by direct excrement, by ingesting food contaminated with the virus or by direct contact of mucus membranes with infected fluids (lab and pets). contact of mucus membranes with infected fluids (lab and pets).

• Infection occurs more commonly in the winter months.

• Incubation Period Incubation Period = 8 –13 days= 8 –13 days

• Symptoms:  Biphasic febrile illness.Symptoms:  Biphasic febrile illness.

Initial phase: fever, malaise, headache, muscle Initial phase: fever, malaise, headache, muscle aches, anorexia, nausea and vomiting. aches, anorexia, nausea and vomiting.

Second phase:  After a few days of remission, Second phase:  After a few days of remission, symptoms of meningitis and rarely encephalitis.symptoms of meningitis and rarely encephalitis.

• The The mortality rate mortality rate isis <1%.  Most patients <1%.  Most patients recover completelyrecover completely

• TreatmentTreatment:  Supportive care:  Supportive care

LCM Diagnosis

CSF- typical of other viral meningitis causes except that 20-30% of the time low glucose levels are present, and cell counts of > 1000/mm3 are not unusual

Diagnosis is made by documentation of seroconversion to the virus in paired serum samples.

Mumps Meningitis Prior to the introduction of the mumps vaccine

in 1967, it accounted for 10-20% of all cases of viral meningitis.

Even now this virus causes a significant minority of cases in unvaccinated adolescents and adults.

In patients who do acquire mumps, CNS infection occurs rather frequently, with CSF pleocytosis detected in 40-60%.

Males aged 16-21 years are at highest risk of developing this infection, with a 3:1 male/female ratio.

Clusters of cases occur in schools and colleges

in the winter months.

Concomitant parotitis is a helpful clinical tool

but may be absent in as many as half of cases with CNS involvement.

Mumps Diagnosis

CSF- similar to other viral causes, but like LCM it can induce a lymphocytic pleocytosis with cell counts >1000/mm3 or a decreased glucose <50mg/dl, can isolate the virus from the CSF

Can document seroconversion

Clinical correlation is very helpful, especially if the patient has parotitis or orchitis.

West Nile virus• Most infected individuals develop WNV fever

• Time from mosquito bite to illness ranges from 3-14 days

• Fever, chills, headache, fatigue can be severe

• Nausea and vomiting can develop

• Rash, usually not itchy, lasting a few days, mainly on chest, back, abdomen, and/or arms

• Persistent fatigue is common and may continue for months, even among otherwise healthy persons

In one study, “~96% of patients with WNF described post-illness fatigue that lasted a median of 36 days” (Sejvar, 2007)

West Nile VirusSeason: summerMosquito transmission (currently infects

43/ 174 different types of North American mosquitoes)

Other routes Placenta Lactation Transfusion Organ transplant

WNV Presenting symptoms

Headache, fever, mental status changes CN findings, optic neuritis Myoclonus

Flaccid Paralysis With or without encephalitis Asymmetric weakness/paralysis, no

sensory loss Anterior horn cells (polio like)

WNV Movement Disorders

Parkinsonian Tremors Bradykinesia Cogwheel rigidity Postural instability Masked facies 80-100% will have rest or intention tremor 30% will have myoclonus

WNV: Predictors Admission diagnoses:

30%: aseptic meningitis 15%: fever 18%: viral infection 14%: UTI 10% pneumonia 7% : encephalitis 5%: probable WNV (year 2001)

Mortality rates highest with: Initial diagnosis of encephalitis (35% of those who died), No headache (50% had headache, 7% those that died had

headache), and Initial mental status changes