1. health and fitness
2. disease

56
Central Nervous System Agents in Medicinal Chemistry, 2009, 9, 56-62
Treatment of Viral Encephalitis
Renan Barros Domingues*
Department of Pathology, Santa Casa School of Health Sciences (EMESCAM), Vitória, ES, Brazil; Neurosciences Postgraduation Program, Federal University of Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
Abstract: Several viruses may cause central nervous system diseases with a broad range of clinical manifestations. The
time course of the viral encephalitis can be acute, subacute, or chronic. Pathologically there are encephalitis with direct viral entry into the CNS in which brain parenchyma exhibits neuronal damaging and viral antigens and there are postinfectious autoimmune encephalitis associated with systemic viral infections with brain tissue presenting perivascular aggregation of immune cells and myelin damaging. Some virus affect previously healthy individuals while others produce encephalitis among imunocompromised ones. Factors such evolving lifestyles and ecological changes have had a considerable impact on the epidemiology of some viral encephalitis [e.g. West-Nile virus, and Japanese B virus]. Citomegalovirus
and JC virus are examples of infections of the brain that have been seen more frequently because they occur in immunocompromised patients. In the other hand many scientific achievements in neuroimaging, molecular diagnosis, antiviral
therapy, immunomodulatory treatments, and neurointensive care have allowed more precise and earlier diagnoses and
more efficient treatments, resulting in improved outcomes. In this article, we will present the current drug options in the
management of the main acute and chronic viral infection of the central nervous system of immunocompetent and
immunocompromised adults, focusing on drugs mechanisms of action, efficacy, and side effects. The early diagnosis and
correct management of such diseases can reduce mortality and neurological sequelae; however, even with recent treatment
advances, potentially devastating outcomes are still possible.
Keywords: Virus, encephalitis, treatment, antiviral drugs, immunomodulatory agents.
INTRODUCTION
Encephalitis is a diffuse or focal inflammatory process of
the brain parenchyma associated with brain dysfunction. The
pathology of the encephalitis can be broadly divided into two
major categories. Infection-related encephalitis is a direct
consequence of viral entry into the central nervous system
(CNS). Auto-immune mediated encephalitis is associated
with systemic infections or vaccination and is mediated by a
pathologic immune response mainly directed against myelin
and affects the brain and the spinal cord [1-3].
Virus can have access to the CNS by hematogenous or
neuronal spread [4]. Enterovirus and arbovirus are examples
of CNS infections that follow a primary viremia. Other viruses, such as rabies and HSV, are introduced into the peripheral nervous system and reach the brain by peripheral
neuronal spread. In both cases the viruses replicate into the
CNS and spread cell to cell. The presence of viral antigens
elicits an immunologic response that can potentially destroy
infected cells. The clinical manifestations and the severity of
the disease are related with the specific areas involved and
the extension of the area where the virus replicate, as well as
the neuronal damage produced by the immune response [4].
The etiologies of viral encephalitis and their manifestations have dramatically changed in the last years. Some etiologies of viral encephalitis are more often seen because they
affect mainly immunocompromised patients by HIV, trans*Address correspondence to this author at the Av. Nossa Senhora da Penha,
699/sala 709, Vitória – ES, Brazil, CEP 29055-131;
E-mails: renan-domingues@uol.com.br; contato@renandomingues.med.br
1871-5249/09 $55.00+.00
plants, and chemotherapy. This is the case of the polyomavirus JCV. Some arboviruses such as West Nile and Japanese
B encephalitis have been spread to different areas of the
world. These infections are transmitted between vertebrate
hosts, especially birds, by mosquitoes of the Culex species.
Environmental changes affecting this enzootic cycle has determined the spread of these infections to new areas. Some
viral infections of the CNS have become less frequent because of the impact of vaccination. This is the case of measles, rubella, and others [5,6].
The treatment of viral encephalitis includes the use of an
antiviral drug with good CSF penetration when the infection
is caused by a treatable virus, immunomodulatory treatment
when indicated, prevention and control of the complications
of the disease. This article reviews the clinical features and
the treatment of the most important etiologies of acute and
chronic viral encephalitis, as well as post-infectious encephalitis.
1. ACUTE VIRAL ENCEPHALITIS
Acute viral encephalitis is a life threatening medical
emergency. The clinical picture usually begins with acute
systemic disease with fever, nausea, and vomiting followed
by neurological symptoms. The neurological symptoms can
be focal, with localizing manifestations such as motor deficit, aphasia, personality and behavior abnormalities, focal
seizures, visual field deficits; or diffuse, with mental status
changes and diffuse seizures. The approach of acute encephalitis requires a rapid neurological evaluation, neuroimaging studies, preferably magnetic resonance imaging, and
© 2009 Bentham Science Publishers Ltd.
Treatment of Viral Encephalitis
cerebrospinal fluid examination including antibody testing
and polymerase chain reaction [2]. The most important acute
viral encephalitis etiologies are presented bellow.
1.1. Herpes Simplex Encephalitis
Herpes simplex virus (HSV) is associated with acute and
focal encephalitis [7]. Herpes simplex encephalitis (HSE) is
the most frequently diagnosed acute viral encephalitis and
has an annual incidence of 1 in 250.000 to 500.000 [8].
Nearly 95% of the cases are associated with HSV-1 and the
remaining cases are associated with HSV-2. Most of the
cases of HSE occur in non immunocompromised patients
[9,10].
Magnetic resonance imaging is the best neuroimaging
method and can display lesions mainly in inferomedial temporal lobe, superficial temporal cortex, insular gyrus, rectus
gyrus, and cingulate gyrus in more than 90% of the cases
[11]. Computed tomography is less sensitive and shows temporal abnormalities in 40 to 50% of the cases [12]. Diagnosis
is confirmed by PCR in a CSF sample with an overall sensitivity and specificity above 95% [13,14]. Quantitative PCR
was shown to be a promising assay in the prognostic evaluation and in monitoring the treatment of the patients with HSE
[15].
The current therapy of choice for the management of
HSE is acyclovir [16,17]. Aciclovir is a guanine analogue
antiviral drug. Aciclovir is selectively converted into acycloguanosine monophosphate by viral thymidine kinase. The
monophosphate form is further phosphorylated into the
active triphosphate form by cellular kinases. The triphosphate form inhibits viral DNA polymerase resulting in chain
termination. This drug is effective against most of the
members of the Herpes family, especially HSV-I, HSV-II,
and Varicella-zoster virus. The drug is poorly absorbed
orally so intravenous administration is necessary for
achieving high CNS concentrations. Adverse effects with
this drug are rare. Intravenous therapy with high doses may
be associated with nausea, vomiting, diarrhea, dizziness,
arthralgia, and more infrequently with leukopenia,
crystalluria, allergic reactions, increased levels of hepatic
enzymes, and increased levels of blood nitrogen [18-20].
Aciclovir is used in a dosage of 10 mg/Kg every 8 hours [30
mg/Kg/day] for a period of 21 days. The treatment with
aciclovir reduces the risk of death from 70% to less than
20% [21]. Nearly half of the patients who survive have a
neurological impairment six months after the completion of
therapy [12,21]. Mechanisms of resistance to aciclovir
include deficient viral thymidine kinase, mutations of
thimidine kynase, and mutations in DNA polymerase. HSE
ence-phalitis in immunocompromised patients associated
with a mutant HSV strain resistant to aciclovir has been
described [22,23]. It is not clear if resistant strains may
provoke encephalitis in immunocompetent patients [15].
About 5% to 10% of the patients may reactivate encephalitic symptoms after the antiviral treatment [2,21]. It is not
clear if the HSE reactivation is due to a reactivation of the
viral replication, an auto-immune aggression triggered by
viral proteins, or a combination of these two mechanisms.
The Collaborative Antiviral Study Group is currently evaluating the efficacy of high doses of valaciclovir for a three
Central Nervous System Agents in Medicinal Chemistry, 2009, Vol. 9, No. 1 57
months period after the completion of 3 weeks of intravenous aciclovir [8]. Valaciclovir is a prodrug that is converted
by esterases to the active drug aciclovir via hepatic
metabolism. Valaciclovir has a good oral bioavailability and
adequate CNS levels can be achieved with oral
administration [24, 25].
1.2. Varicella-Zoster Encephalitis
Varicella-zoster virus [VZV] is associated varicella and
herpes zoster. CNS complications with varicella occur in 1 to
3/10.000 cases. Neurologic manifestations of herpes zoster,
including encephalitis, are very rare and occur more frequently among immunocompromised patients. The most
common CNS manifestation of VZV is acute cerebellar
ataxia after varicella. The symptoms include fever, vomiting,
and cerebellar findings. It is not clear if the pathogenic
mechanism is direct viral involvement or immunologic mediated demyelination. This condition is considered benign
and self limited and there is no evidence that antiviral therapy is useful. Encephalitis is a less common complication of
varicella and herpes zoster. The likelihood of such complication is highest in adults, infants less than 1 year, and immunocompromised patients. Magnetic resonance imaging
may show non specific abnormalities. Diagnosis is based on
previous history of varicella rash or herpes zoster, usually
few weeks before the encephalitic symptoms, and the demonstration of specific antibodies, antigens, or nucleic acids of
varicella-zoster virus (VZV) in CSF samples. Although there
are no specific clinical trials evaluating the efficacy of aciclovir this drug has been used in the treatment of VZV encephalitis [26-28]. In immunocompromised patients aciclovir
is given intravenously at a dose of 10 mg/Kg every 8 hours
[29]. In immunocompetent patients different schedules have
been tried including oral treatment [30]. The use of corticoids has been proposed for VZV encephalitis treatment in
order to reduce cerebral edema but there are no controlled
studies supporting their use [2].
1.3. Arthropod-Borne Viral Encephalitis
Several arthropod-borne virus (arbovirus) are associated
with encephalitis. The families of arbovirus include Togaviridae (alphaviruses), Flaviviridae, Bunyaviridae, and
Reoviridae. Alphavirus encephalitis include Eastern, Western, and Venezuelan equine encephalitis. The most important
flavivirus CNS diseases are West-Nile virus encephalitis,
Japanese encephalitis, Saint Louis encephalitis, Murray Valley encephalitis, and CNS manifestations associated with
dengue virus. Bunyaviridae encephalitis includes La Crosse
and other California serogroup viruses, Sundfly fever viruses, and Rift Valley fever viruses [31,32].
These infections are acquired after a mosquito or a tick
bite. After an initial viremia these virus enter the CNS. Inside the CNS they can directly damage the CNS cells by
intracellular viral replication or indirectly mediated by inflammatory and immune response [33-35]. In some arboviruses with important systemic involvement CNS manifestations may also be determined by a metabolic encephalopathy
[36].
Although there is a wide range of agents causing arbovirus encephalitis the clinical manifestations share great simi-
58 Central Nervous System Agents in Medicinal Chemistry, 2009, Vol. 9, No. 1
larities. Usually there is initially a febrile disease followed
by diffuse encephalitis [2,31-35]. The differential diagnoses
of these infections rely on epidemiological data and specific
laboratory tests, including antibodies, antigens, and nucleic
acids detection [37]. The neuroradiologic findings are usually non specific with abnormalities such as diffuse brain
edema and intensity abnormalities in different areas of the
CNS. Cerebrospibnal fluid analysis usually shows mild lymphocytic pleocytosis, normal glucose, and slightly elevated
protein [2].
There are no specific antiviral agents for the treatment of
any of these CNS infections. The management of such disease is based exclusively in the control of the complications
of these infections, including seizures, hyponatremia, and
raised intracranial pressure. The use of steroids is also of no
proven value [2].
There are measures in order to prevent arboviral encephalitis. Since these infections are brought to humans by an infected vector, the adequate control of vectors by eliminating
potential reservoirs and the use of larvicides can efficiently
reduce the number of cases [38, 39]. A live attenuated vaccine for Japanese encephalitis is available in endemic areas
[40].
1.4. Rabies
Rabies is usually transmitted to humans by a bite of a
rabid animal. The virus present in the saliva of the animal
initially enters peripheral nervous system then is carried towards the central nervous system. Transmission can also
occur through mucous membranes and organ transplants
[41]. After reaching the brain the virus causes encephalitis
with extremely severe behavior symptoms including hydrophobia. Rabies may also provoke myelitis resulting in
paralitic symptoms [42]
Rabies can be prevented by vaccination. Rabies vaccine
is obtained from cells infected with attenuated virus. Immunization may take more than a week to be effective and
should be given to high risk individuals potentially exposed
to rabies virus, such as laboratory staff, veterinarians, and
animal control workers [42,43].
After an exposure vaccine should be promptly given. In
such cases instead of intramuscular route multiple sites of
intradermal injections can produce a more rapid immunization [44]. The use of immunoglobulin is effective for the
clearance of the virus if it is given before the virus reaches
the CNS. Because immunoglobulin does not cross blood
brain barrier it is not clear in it is effective in the treatment of
rabies encephalitis; however, an intramuscular dose of 20
IU/Kg has been recommended. The use of rabies monoclonal
antibodies has been shown effective in clearing viral antigens from CNS in animal models and future studies should
address this strategy for human rabies [45]. Ribavarin is a
purine analogue and a RNA mutagen that acts as a template
for cytidine and uridine incorporation. This drug has demonstrated in vitro activity against rabies virus. The role of this
drug in the treatment of rabies is uncertain. It is also not
clear if ribavarin crosses blood brain barrier. Intrathecal administration of ribavarin has not been proven as an efficient
treatment. Ribavirin has an inhibitory effect on DNA
Renan Barros Domingues
synthesis, therefore there are significant teratogenic effects
with this drug. Another problem with this drug is the long
half-life in the body. Erythrocytes concentrate the drug and
are unable to excrete it, so this pool is not completely
eliminated until all red cells have turned over, a process that
can take as long as 6 months [46,47].
Interferon- [IFN-] is a natural defense against viral
infections by restricting viral replication. Experimental studies have showed potential benefits of treating rabies with
high doses of IFN-; however, the clinical use of this therapy
has not been effective for human rabies encephalitis [48,49].
Ketamine is an anesthetic agent and a non competitive antagonist of N-methil-D-Aspartate [NMDA] receptors.
NMDA has been proposed as one of the cellular receptors
for rabies virus entry. Ketamine has shown in vitro properties of inhibiting rabies virus replication. Therefore this is a
potential drug for rabies encephalitis treatment by continuous intravenous infusion in intensive care units [50,51]. Even
when all the above mentioned treatments are given rabies
remains a lethal disease in almost all cases.
1.5. Enterovirus Encephalitis
Enterovirus are commonly associated with meningitis
and eventually with encephalitis [4]. The enterovirus are
more often associated with diffuse encephalitis, however,
focal encephalitis cases may occur [52]. The diagnosis
should be suspected in patients with systemic manifestations
of an enterovirus infection such as rash and diarrhea; however, these findings may not be present. Currently the best
diagnostic confirmatory approach is the PCR of CSF samples [53].
Treatment of enterovirus encephalitis with Pleconaril has
been proposed [52]. Pleconaril is an antiviral drug developed
for prevention of asthma exacerbations and common cold
symptoms in asthmatic subjects exposed to picornavirus respiratory infections. Pleconaril is active against viruses in the
Picornaviridae family, including Enterovirus and Rhinovirus. Pleconaril binds to a hydrophobic pocket in viral protein 1 [VP1], the major protein which comprises the capsid
of picornaviruses that mediates viral adsorption and uncoating process, thus prevents the virus from releasing its RNA
interrupting viral replication. This drug has been proven to
be extremely safe. There have been no differences in the
rates of adverse events between treatment and placebo
groups in clinical studies. The safety of pleconaril is probably the result of its unique site of action on the viral capsid
[54-56]. Case reports have showed encouraging results;
however, controlled studies are still needed to better access
the efficacy of this drug in the treatment of enterovirus encephalitis [52].
2. CHRONIC ENCEPHALITIS
The chronic encephalitis may present with similar manifestations of the acute encephalitis but with a more gradual
course, often leading to a dementia. The differential diagnoses of these diseases commonly include not only infectious
diseases but also auto-immune, degenerative, and metabolic
conditions that may mimic chronic encephalitis [4]. Some
chronic encephalitis etiologies were more frequently seen in
the past. This is the case of Subacute Sclerosing Panencepha-
Treatment of Viral Encephalitis
litis (SSPE), a late complication of measles infection [57],
and Progresive Rubella Panencephalitis [58]. They are extremely rare today because immunization with attenuated
measles and rubella virus protect against these diseases.
Presently, most of the chronic encephalitis cases are seen in
immunocompromised patients.
2.1. HIV Encephalitis
HIV infection is associated with several neuropathologic
encephalitic findings such as white matter pallor, microglial
nodules, multinucleated giant cells, and gliosis [59]. Viral
antigens and neuronal loss are also seen. HIV associated
dementia may be found in patients with such brain abnormalities. This dementia includes cognitive, motor, and behavioral symptoms [60]. Clinical course is usually progressive [61]. The diagnosis is based on clinical evaluation. Neuropsychological tests are particularly useful in early stages of
the symptoms [62]. HIV does not infect and destroy neurons
directly. Viral proteins activate indirect mechanisms, such as
macrophages, cytokines, chemokines, antigens, and autoantibodies that are responsible for neuronal death [63,64].
There are evidences that antiretroviral treatment is beneficial for patients with HIV associated dementia. Highly active antiretroviral therapy (HAART) is the combination of
several antiretroviral drugs and it is used to reduce the possibility of HIV developing resistance through mutation [65].
The antiretroviral drugs are classified according to the phase
of the HIV cycle that the drug inhibits. Nucleoside reverse
transcriptase inhibitors inhibit reverse transcription by being
incorporated into the newly synthesized viral DNA and
preventing its further elongation. Non-nucleoside reverse
transcriptase inhibitors inhibit reserve transcriptase directly
by binding to the enzyme and interfering with its function.
Protease inhibitors inhibit viral assembly by inhibiting
protease, which acts in the final assembly of the new virions.
Integrase inhibitors inhibit the enzyme integrase, which is
responsible for integration of viral DNA into the DNA of the
infected cell. Fusion inhibitors interfere with binding, fusion
and entry of HIV-1 to the host cell by blocking one of
several targets. Maturation inhibitors interfere in the
formation of the mature capsid protein [p24] resulting in
viral particles with defective core, which are non infecting
viral particles [66]. The main goal of using HAART is
decreasing the plasma HIV RNA levels improving
immunodeficiency and reducing opportunistic infections
[67]. There are evidences that HAART improves cognition
in patients with HIV associated dementia; however, the ideal
combination of drugs to be used in patients with HIV
associated dementia has not been established. Some studies
have suggested that the use of antiretroviral drugs with better
CNS penetration have a better impact on CSF HIV levels
and on the neuropsychological tests; however, further studies
are still needed to determine the particularities of the
antiretroviral treatment for patients with HIV associated
dementia [68-70].
2.2. Progressive Multifocal Leukoencephalopathy [PML]
PML is a fatal demyelinating disease of the central nervous system associated with the destruction of oligodendrocytes by the lytic infection of these cells by the JC virus
Central Nervous System Agents in Medicinal Chemistry, 2009, Vol. 9, No. 1 59
(JVC) [71]. Although JCV is widespread throughout the human population, PML only develops in severely immunocompromised patients. The majority of reported cases in the
present are associated with HIV/AIDS, but other immunossupressive disorders, such as lymphomas and cancer can also
be associated with this infection [72]. Recently, there have
been some reports of PML associated with the use of a novel
immunomodulatory medication Natalizumab. This monoclonal antibody used in the treatment of autoimmune disorders such as Multiple Sclerosis [73]. Clinically PML is characterized by multiple focal neurological deficits and subcortical dementia. Magnetic resonance imaging displays the
multiple foci of demyelination. The definitive diagnosis of
PML is based on the demonstration of inclusion bodies, viral
particles, or viral nucleic acids in the CNS [74].
Several antiviral agents have been tried in the treatment
of PML. Cytarabine, topotecan, and cidofovir have not
proved to be effective. Highly active antiviral therapy
(HAART) for AIDS patients has had a modest impact on the
prognosis of PML. The three months mortality of PML has
dropped from 90% to 50% in patients using HAART. This
may be due to the fact that HAART raises CD4 T-cells and
the role of CD4 T-cell responses against JCV [72,75].
2.3. Citomegalovirus
Citomegalovirus [CMV] is associated with opportunistic
infections of the central and peripheral nervous system.
CMV ventriculoencephalitis may have an abrupt onset with
progressive confusion and lethargy. A more indolent clinical
picture is present if the encephalitis is associated with microglial nodules and parenchimal necrosis. These cases are
difficult to distinguish from HIV associated dementia in patients with AIDS. Neuroradiological findings are non specific and include ventriculitis, hydrocephalus, and rarely
mass lesions. The diagnosis can be supported by CSF analysis in which CMV culture and PCR are useful tools [76].
The antiviral agents for CMV are Ganciclovir, Foscarnet,
and Valganciclovir. Ganciclovir is an analogue of 2'deoxyguanasine. Ganciclovir phosphorylates first to monophosphate form by CMV-encoded protein kinase, then to diphosphate and triphosphate forms by cellular kinases, allowing
for a 100-fold greater concentration of ganciclovir in CMVinfected cells. The drug inhibits CMV replication by competitive inhibition of viral DNA polymerases and by incorporating itself into viral DNA, causing termination of viral
DNA elongation. Clinical toxicity of ganciclovir includes
granulocytopenia, anemia, and thrombocytopenia. It is usually given by the intravenous route due to the poor oral
bioavailability but maintenance doses can be given orally
[77]. Foscarnet shows antiviral activity by selective inhibition at pyrophosphate-binding site on virus-specific DNA
polymerases at concentrations that do not affect cellular
DNA polymerases. Viral resistance with this drug has been
shown. Foscarnet may cause decline in renal function, electrolytes disturbances, granulocytopenia, and anemia. Foscarnet is given intravenously [78,79]. Valganciclovir is a prodrug of ganciclovir and has the advantage of oral administration achieving serum levels comparable to those obtained
with IV ganciclovir [76].
60 Central Nervous System Agents in Medicinal Chemistry, 2009, Vol. 9, No. 1
In patients with AIDS the use of HAART can prevent
CMV disease by increasing CD4 counts above 100
cells/mm3. If CMV encephalitis develops ganciclovir is the
recommended therapy and should be given at a maintenance
dose while the CD4 is bellow 100 cells/mm3. If oral therapy
is feasible valganciclovir may be preferable. Foscarnet
should be limited to ganciclovir resistant infections due to
the high toxicity of this drug [76].
3. ACUTE DISSEMINATED ENCEPHALOMYELITIS
(ADEM)
ADEM is an auto-immune disorder of the CNS preceded
by a viral infection or a vaccination that predominantly affects the white matter of the brain and the spinal cord. It is
usually a monophasic disorder but it is sometimes recurrent.
The neurological picture usually begins a few days to a few
weeks after an infection or a vaccination [80]. Clinically the
most common findings are distinct localizing symptoms but
mental status involvement resembling diffuse encephalitis
may also be seen. In most cases the causative infection or
vaccination can be identified. Since there are no specific
laboratory markers for ADEM, the neuroimaging methods,
especially magnetic resonanc imaging, are extremely relevant. Magnetic resonance imaging reveals multiple, asymmetric, and large signal abnormalities in the CNS [81].
Acute hemorrhagic leukoencephalitis (AHL) of Weston
Hurst is an aggressive and hemorrhagic variant of ADEM
usually triggered by a respiratory infection [82,83].
The proposed treatments for ADEM include nonspecific
immunossupression agents. High doses of steroids are the
most used therapy for ADEM. IV methylprednisolone (10-30
mg/Kg/day up to 1 g/day for three to five days) followed by
steroid taper for one month is usually recommended [80].
Immunoglobulin [IVIG] is an alternative treatment and it is
given in a total dose of 2 g/Kg, administered over 5 days
[84,85]. There have been some reports of the use of plasma
exchange in the treatment of ADEM. Plasma exchange it is
usually recommended when steroids and IVIG have failed
[86].
Renan Barros Domingues
tion suggests ADEM immunossupresive treatment with high
doses of steroids should be given immediately. In patients
with acute encephalitis and a history of animal bite the approach is completely different and the measures for postexposure prevention of rabies should be adopted. In patients
with rapidly progressive dementia, especially individuals
under 50 and individuals with any immunossupressive disorder, chronic encephalitis should be investigated.
Viral encephalitis still represents a major medical problem. Fatal outcomes and severe neurological sequelae are
frequently seen even with correct diagnosis and adequate
antiviral therapy. The development of new antiviral drugs
with a better CNS penetration, antiviral activity, and lower
toxicity is still needed.
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Accepted: October 06, 2008
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