VIRAL DISEASES OF THE CENTRAL NERVOUS SYSTEM

The CNS plays critical role in the life of any organism, as such it is highly protected by complex
tissues such as blood brain barriers (BBB). The nervous system is sterile. The CNS is well
protected by bone and meninges from invasion by pathogens. Microglial cells can destroy
invading pathogens. The brain capillaries form the blood-brain barrier. Despite such complex
barrier system, viruses and other pathogens, have found a way to bypass these systems and
cause devastating neurotropic diseases, especially among the children and the elderly.
Interestingly, viral-induced CNS diseases tops those caused by bacterial, fungi and protozoa
combined. Viral ability to infect the CNS speaks to their evolutionary adaptation to be
preserved and disseminated. In this lesson we will explore central nervous system (CNS) viral
pathogens that infect and damage specific anatomic sites.

By the end of the lesson, you will be able to explain how different viruses enter various
anatomic sites and cause the following inflammatory diseases:
a. Viral Meningitis (Enteroviruses, HSV-2, LCMV, HIV, Adenovirus, Arboviruses)
b. Viral Encephalitis (HSV-1, Arboviruses)
c. Viral Myelitis (Poliovirus)
d. Rabies (Rabies virus)
 e. Microcephaly (Zika virus)

ENTRY PATHWAY OF VIRAL PATHOGENS

o Respiratory passages (Mumps and Measles virus)

o Oral–intestinal route (Polioviruses and other Enteroviruses)
o Oral or genital mucosal route (HSV 1& 2)
o Inoculation through animal bites (e.g., Rabies virus) or mosquitoes (arthropod-borne or
arbovirus infections).

VIRAL-INDUCED MENINGITIS

Meningitis is an inflammation of the meninges membrane that surround the brain and the spinal
cord. membranes (meninges) surrounding your brain and spinal cord. Usually affects children
under 5 years. Milder disease than either bacterial or fungal meningitis. Viral infection triggers
unregulated heighten immune response resulting in swelling of the meninges. This swelling
trigger symptom such as headache, fever, and stiff neck. Other signs and symptoms may
include seizure, light sensitivity, skin rush, and lack of appetite. Majority of meningitis are
caused by the human enteroviruses (HEV). St. Louis encephalitis virus (SLEV), bunyaviruses,
mumps virus, choriomeningitis virus (LCMV), HSV2, and human immunodeficiency virus
(HIV)-1 also cause meningitis. In healthy adults most of these infections resolve without need
of treatment. In children and immunocompromised individuals these infections can have
devastating effects and need immediate medicate attention.
Other viruses that can cause meningitis.
• Herpes Simplex Viruses, and Varicella-Zoster Virus
• Mumps virus
• Measles virus
• Influenza virus
ENTEROVIRUSES

• Enteroviruses are picornaviruses (small, naked, +ssRNA, icosahedral)

• Replication and assembly take place in cytoplasm.
• Resistant to acid, detergents, and many disinfectants
• Formaldehyde and hypochlorite are active against enteroviruses.
• Antigenic mutations and drifts occur.
• Humans are the major natural host for the polioviruses, coxsackieviruses, and echoviruses.
• The enteroviruses have a worldwide distribution, and asymptomatic infection is common.
• Non polioenteroviruses cause asceptic meningitis while polio virus causes myelitis
(inflammation of the spinal cord)

COXSACKIEVIRUSES (A & B), ECHOVIRUSES, AND ENTEROVIRUSES

EPIDEMIOLOGY

• Often spread via fecal contamination of food, water, or hands.

• Contagious, being spread in respiratory droplets and in feces.
• Patients become contagious when symptoms develop (up to 10 days)
• Exposure to a patient with meningitis may result in an infection resembling a cold but rarely
causes meningitis.

PATHOGENESIS
• When ingested enteroviruses attack cells lining the intestinal tract and URT.
 • They then spread via the bloodstream (Viremia)to infect other organs, including the
meninges.
• They do not cause gastrointestinal illnesses but can cause colds.
• The viruses kill their target cells to trigger meningitis.
• Incubation period 3-7 days

CLINICAL MANIFESTATIONS

• Most infections are subclinical.

• Fever, severe headache, stiff neck, drowsiness, confusion, nausea, and vomiting
• This syndrome can be mild and self-limiting, lasting 5 to 14 days.
• However, it is sometimes accompanied by encephalitis, which can lead to permanent
neurologic sequelae.

DIAGNOSIS
• Spinal tap to collect CSF (6 ML)
• Chemistry (ie, CSF glucose and protein)
• Absence of bacteria in CSF analysis from spinal tap.
• RT PCR
• Antibody titres (Raised levels of IgM)

TREATMENT AND PREVENTION

• No specific treatment exists for viral meningitis.
• Resting, drinking plenty of fluids, and taking medication to reduce fever and headache
pain are recommended.
• Avoiding crowded swimming pools, and refraining from bringing contaminated hands
near the mouth, nose, or eyes limit the chance of infection.

HERPES VIRUS MENINGITIS

• HSV meningitis is caused by HSV 2 which is more often cause of genital herpes.
• HSV-1,VZV, EBV, CMV, and HSV-6 collectively can cause cases of viral meningitis,
with HSV-2 being the most common offender.
• HSV-2 is associated with sexual activity.
PATHOGENESIS

• HSV-2 initially replicate in the muco-epithelial cells and initiate lytic infection.
• Virus then spreads to neurons and establishes latency in sensory ganglia.
• Upon reactivation, virus travels down the neuronal axons near the site of initial
infection.
• The virus can travel to the CNS and cause inflammation of meninges to cause
meningitis.

CLINICAL MANIFESTATIONS
• Meningitis caused by these viruses is often self-limiting.
• When associated with encephalitis, however, the mortality rate can be high.
HSV-2 genital infection may precede meningitis.

DIAGNOSIS AND TREATMENT

• Spinal tap to collect CSF (6 ML)
• Chemistry (ie, CSF glucose and protein)
• Microbiology (ie, Gram stain and cultures)
• RT PCR
• Antibody titres (Raised levels of IgM) Multiple serologic (antibody detection) methods
using e.g. ELISA
 Early treatment with acyclovir can significantly reduce morbidity.

LYMPHOCYTIC CHORIOMENINGITIS VIRUS

• LCMV belongs to the family of arenaviruses.

• A rare cause of meningitis.
• Virus is transmitted to humans by contact with rodents (eg, hamster, rats, mice) or their
excreta.
• Infection without symptoms or mild febrile illnesses are common.
• Onset of symptoms usually occurs 8-13 days after exposure.
• Initial phase may last a week;
• Fever, malaise, lack of appetite, muscle aches, headache, nausea, and vomiting.
• Other symptoms appearing less frequently include sore throat, cough, joint pain, chest
pain, testicular pain, and parotid (salivary gland) pain.
• Second phase of illness may occur;
• Meningitis (fever, headache, stiff neck, etc.), encephalitis (drowsiness, confusion,
sensory disturbances, and/or motor abnormalities, such as paralysis)
• Meningoencephalitis (inflammation of both the brain and meninges).

DIAGNOSIS
• Spinal tap to collect CSF (Glucose levels reduced)
• Multiple serologic (IgM antibody detection) in serum using e.g. ELISA
• RT PCR on CSF

TREATMENT
• Requires supportive treatment based on severity.
• Anti-inflammatory drugs, such as corticosteroids, may be considered under specific
circumstances.
ADENOVIRUS
• Rare cause of meningitis in immuno-competent individuals but a major cause in
patients with acquired immunodeficiency syndrome (AIDS).
• The infection may occur simultaneously with an upper respiratory infection.
• In uncomplicated viral meningitis, usually self-limiting (7-10 days)
 • Treatment of adenovirus infections is usually supportive and aimed at relieving
symptoms of the illness

HIV
• It can cause meningitis during the early stages of HIV infection.
• This may be the first sign of infection with HIV
• HIV infections may cause encephalopathy and seizures.
• HIV often can be isolated from the CSF.

ARBOVIRUSES

• Some of the important arboviruses include;

• The eastern and western equine encephalitis viruses, from the Togavirus family
• St. Louis encephalitis’, West Nile, Japanese B, and Murray Valley viruses, from
the Flavivirus family;
• California viruses, from the Bunyaviridae family

PATHOGENESIS

• Arboviruses enter target cells via endocytosis and replicate within them.
• Produce viremia, cross the blood brain barrier by an unknown mechanism to cause
encephalitis.
• Clinical manifestation is meningoencephalitis rather than pure meningitis.
• Seizures common with arboviral meningitis than with any other viruses.
• Less than 10% of infected people develop clinical disease.

DIAGNOSIS AND TREATMENT

• Multiple serologic (antibody detection) methods using e.g., ELISA.

• RT-PCR is also used.
• As with viral meningitis, treatment for arboviral meningoencephalitis is supportive.
VIRAL ENCEPHALITIS

• Viral encephalitis is an inflammation of the brain caused by a variety of togaviruses

,flavivirus or Herpes virus.
• Acute viral encephalitis (brain inflammation) is involvement of the brain, sparing the
meninges.
• Most viral infections involve the meninges leading to aseptic meningitis or causing
mild meningoencephalitis rather than pure encephalitis.
• Viral encephalitis include:
• Herpes Simplex Encephalitis
• California Encephalitis
• Eastern Equine Encephalitis
• Japanese Encephalitis
• St Louis Encephalitis
• Venezuelan Encephalitis
• Western Equine Encephalitis
• West Nile Encephalitis

HERPES SIMPLEX ENCEPHALITIS

• The majority of cases of herpes encephalitis are caused by herpes simplex virus-1
(HSV-1), the same virus that causes cold sores.
• It is spread through droplets, casual contact, and sometimes sexual contact, though
most infected people never have cold sores.
• About 10% of cases of herpes encephalitis are due to HSV-2.
• Pathogenesis is unclear
• Most common symptoms :
• Fever
• Headache
• Seizures
• Vomiting
• Focal weakness
• Memory loss
 • The initial presentation may be mild

Herpesviral Encephalitis can be treated with high-dose intravenous acyclovir.

ARBOVIRUS ENCEPHALITIS

• Caused with an arbovirus, and transmitted by a mosquito, tick or another arthropod.

• Carlifornia / LaCrosse encephalitis, eastern equine encephalitis, western equine
encephalitis, and St. Louis encephalitis are transmitted by mosquitoes.
• Most mosquito-borne arboviruses cause only mild, cold like symptoms.
• Arboviruses in the blood cross the blood-brain barrier to cause arboviral encephalitis.

CLINICAL SYMPTOMS
• High fever, weakness, nausea, vomiting, abrupt headache, and changes in mental state
such as confusion, disorientation, and coma.
• Some patients report body aches and develop a skin rash.
• Neurological effects may be permanent.

DIAGNOSIS
• Multiple serologic (antibody detection) methods using e.g. ELISA
• RT-PCR is also used

POLIOMYELITIS

• Polioviruses are naked capsid, double-stranded, circular DNA virus

• Poliomyelitis is caused by three serotypes of polioviruses (types 1, 2 and 3).
 • Most poliovirus infections are inapparent or mild and nonparalytic.
• Polioviruses reaches the nervous system in 1% to 2% of cases.
• Risk of paralysis from infection increases with age
• Improvement of sanitary conditions tends to impede spread of the viruses.
• Polio cases significantly reduced due to vaccination.

PATHOGENESIS
• It is spread by fecal–oral route.
• Virus enters oropharynx and multiplies in mucosa, shed in oral secretions, and
swallowed, and then multiplies in the intestine.
• After primary replication in epithelial cells and lymphoid tissues spreads to other sites
(Viremia).
• Virus replicates in the CNS and motor neurons causing neuronal destruction.

CLINICAL MANIFESTATION

• Most infections (90%) are either subclinical or very mild.

• Incubation period ranges from 4 to 35 days in symptomatic disease.
• Three types of disease can be observed.
• Abortive poliomyelitis is a nonspecific febrile illness of 2 to 3 days’ duration
(fever, headache, sore throat).
• Aseptic meningitis (nonparalytic poliomyelitis) is characterized by signs of
meningeal irritation (stiff neck, pain, and stiffness in the back), muscle spasms
and back pain.
• Paralytic poliomyelitis occurs in less than 2% of infections.
PARALYTIC POLIOMYELITIS

POLIOMYELITIS

• In its most serious forms, all four limbs may be completely paralyzed.
• Brainstem may be attacked, with paralysis of the cranial nerves and muscles of
respiration (bulbar polio).
• Temporarily damaged neurons may regain their function, recovery begins and may
continue for as long as 6 months; paralysis persisting after this time is permanent.
• Malnutrition, physical exhaustion, and pregnancy can increase the severity of the
disease.
DIAGNOSIS
• PCR on pharyngeal swabs or feces
• ELISA test for identifying antibodies to the virus in serum.
TREATMENT AND MANAGEMENT

• There is no specific treatment for polio besides managing the symptoms of infection.
• Two types of poliovirus vaccines are currently available: Inactivated or killed polio
vaccine (IPV)
• live, attenuated virus, oral polio vaccine (OPV).
• Each contains all three polio virus serotypes.
• The World Health Organization (WHO) is working with governments and private
groups to certify the world polio-free.

ORAL POLIO VACCINE

RABIES
• It is an acute fatal viral illness of the central nervous system (CNS).
• The rabies virus is a rhabdovirus, which is a bullet-shaped, enveloped, RNA virus
• It can affect all mammals and is transmitted between them by infected secretions, most
often by bite.
 PATHOGENESIS

• Rabies virus binds to the acetylcholine or NCAM receptor present on the cell surface.
• The virus is internalized by endocytosis
Two epizootic forms of rabies: urban (unimmunized dogs and cats) and sylvatic (wild
bats, foxes, raccoons, skunks, wolves)

A RABID DOG

• The incubation period is between 10 days and 1 year (average 20-90 days).
• Replicates initially in muscle at the site of entry and then enters peripheral nervous
system
• In the absence of immunity, spreads to CNS and replicates exclusively in gray matter
• Passes along autonomic nerves to other tissues (salivary glands, kidneys, and lungs)
Passage into the salivary glands facilitates further transmission of the disease by
infected saliva.
The Negri bodies found in neurons

RABIES INFECTION
 CLINICAL MANIFESTATION

• Four phases of clinical manifestations:

• Incubation period:- 20 to 90 days (range 10 days to 1 year),
• Prodrome stage:- nonspecific illness marked by fever, headache, malaise, nausea, and
vomiting
• Acute neurologic stage:- onset of encephalitis is marked by periods of excess motor
activity and agitation.
• Hallucinations, combativeness, muscle spasms, signs of meningeal irritation,
seizures, and focal paralysis occur.
• Coma

WATCH VIDEO OF PATIENT WITH RABIES

DIAGNOSIS
• PCR of CSF or saliva to detect RNA
• Virus or antigen detected in brain tissue (Immunohistochemistry)
• The Negri bodies by histologic examinations

TREATMENT AND PREVENTION

• No specific treatment is available.
• Vaccination immediately after animal bites to prevent rabies disease.
• Currently, the prevention of rabies is divided into preexposure and postexposure
prophylaxis.
PS: Interesting read of the only documented case of a rabies survivor
https://childrenswi.org/newshub/stories/jeanna-giese-rabies
MENINGITIS AND ENCEPHALITIS
• The hallmark signs of meningitis include some or all of the following:
• sudden fever, severe headache, nausea or vomiting, double vision, drowsiness,
sensitivity to bright light, and a stiff neck.
• Encephalitis can be characterized by fever, seizures, change in behavior, and
confusion and disorientation.
• Related neurological signs depend on which part of the brain is affected by the
encephalitic process as some of these are quite localized while others are more
widespread.
• Meningitis often appears with flu-like symptoms that develop over 1-2 days.
• Distinctive rashes are typically seen in some forms of the disease.
• Individuals with encephalitis often show mild flu-like symptoms.
• In more severe cases, people may experience problems with speech or hearing, double
vision, hallucinations, personality changes, and loss of consciousness.
• Other severe complications include loss of sensation in some parts of the body,
muscle weakness, partial paralysis in the arms and legs, impaired judgment, seizures,
and memory loss.

ZIKA VIRUS INFECTION

ZIKA VIRUS
• Discovered in monkeys in Zika forest Uganda in 1947
• Flavivirus, +ssRNA, enveloped
• Arbovirus ( Transmitted by mosquito bite)
• Aedes genus, mainly Aedes aegypti
• Emerging arboviral infection associated with human illness
• Transmitted from mother to fetus during pregnancy
• Through sexual contact
• Transfusion of blood and blood products
• Organ transplantation

CLINICAL MANIFESTATION
• Incubation 3-14 days
 • Symptoms generally mild (fever, rash, conjunctivitis, muscle and joint pain, malaise,
and headache, and usually last for 2–7 days)
Complications
• Zika virus infection during pregnancy is a cause of microcephaly and other congenital
abnormalities in the developing fetus and newborn.
• Fetal loss, stillbirth, and preterm birth
• Neuropathy and myelitis in adults and older children
• Guillain-Barre syndrome

BABY WITH SEVERE MICROCEPHALY

DIAGNOSIS
• Diagnosis primarily based on clinical symptoms.
• RT-PCR
• Zika-ELISA (blood and urine)
• Zika MAC-ELISA (blood and urine)
• MAC-ELISA typically gives significant improvement in the specificity of an ELISA assay. In
the MAC-ELISA assay a solid phase support such as a microtitre plate is coated with anti-
human IgM antibodies (the capture antibody) that can bind to IgM type antibodies present in
the specimen.

TREATMENT AND PREVENTION

• There is no specific treatment available for Zika virus infection or disease.

• Supportive care (rest, drink fluids, and treat symptoms with antipyretics and/or analgesics)
• Protection against mosquito bites (mosquito net, light coloured clothing, window screens, insect
repellents.
• Abstinence/use of condoms
• No vaccine available

ACTIVITY

Read the following article and watch these video1 and video 2 then answer the following
questions
1. What symptoms would a patient with AFM present
2. What is the only form of treatment available for AFM patients?
3. In a paragraph explain why there is reemergence of AFM even after poliovirus has long
been eradicated through vaccination
What are major challenges facing clinicians and researchers in the treatment and study of
viral induced AFM