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Medication

Medication Summary

Pharmacotherapy for herpes simplex encephalitis (HSE) consists of acyclovir and vidarabine. Outcome is improved with either agent, but acyclovir is more effective and less toxic. Even if the final diagnosis of HSE has not been established, intravenous (IV) acyclovir should be initiated immediately. Acyclovir is also the drug of choice for varicella-zoster virus (VZV) encephalitis, although ganciclovir is also considered an alternative option.

Ganciclovir has been used for cytomegalovirus (CMV) encephalitis, but with therapeutic failures; optimal therapy for CMV encephalitis is unknown. Ganciclovir combined with foscarnet has been used in the treatment of patients infected with HIV.

No specific treatment is available for the arbovirus encephalitides. The efficacy of ribavirin in other viral infections is being evaluated.

Class Summary

Antiviral agents shorten the clinical course, prevent complications, prevent development of latency and subsequent recurrences, decrease transmission, and eliminate established latency.

Acyclovir (Zovirax)

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Acyclovir has demonstrated inhibitory activity against both herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) and is taken up selectively by infected cells. Before the use of acyclovir, mortality from HSE was 60-70%; since acyclovir, it has been approximately 30%. Acyclovir may also be effective for VZV encephalitis.

Ribavirin (Virazole, Ribasphere)

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Ribavirin is a synthetic guanosine analogue (1-beta-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide) that inhibits viral replication by inhibiting DNA and RNA synthesis. It is phosphorylated in vivo, and the active form may interfere with viral genomic synthesis.

Clinical experience in the treatment of arenavirus infections is primarily with Lassa fever, but anecdotal experience in South American arenaviruses also exists. Ribavirin is used clinically in combination with interferon for hepatitis C, in aerosol form for respiratory syncytial virus (RSV), and as potential prophylaxis and/or treatment of Congo-Crimean hemorrhagic fever, hantavirus infections, and arenavirus hemorrhagic fevers. In vitro evidence exists for activity against West Nile virus.

The IV form of the drug is not readily available, and the manufacturer should be contacted if the need arises.

Ganciclovir (Cytovene, Vitrasert)

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Ganciclovir is a synthetic guanine derivative that is active against CMV. It is an acyclic nucleoside analogue of 2'-deoxyguanosine that inhibits viral replication in vitro and in vivo by competing with deoxyguanosine triphosphate for viral DNA polymerase, inhibiting DNA synthesis. Ganciclovir triphosphate levels are up to 100-fold greater in CMV-infected cells than in uninfected cells, possibly because of preferential phosphorylation in infected cells.

Foscarnet (Foscavir)

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Foscarnet is an organic analogue of inorganic pyrophosphate that inhibits viral replication in vitro. It exerts its antiviral activity by selective inhibition at pyrophosphate-binding sites on virus-specific DNA polymerases at concentrations that do not affect cellular DNA polymerases, inhibiting DNA synthesis.

Viral resistance should be considered in patients with poor clinical response or persistent viral excretion. Patients who show excellent tolerance of foscarnet may benefit from initiation of a maintenance dosage (ie, 120 mg/kg/d) earlier in their treatment. Individualize the dosing according to the patient's renal function status. Foscarnet has been demonstrated to be effective against CMV encephalitis.

Class Summary

These agents prevent seizure recurrence and terminate clinical and electrical seizure activity.

Phenytoin (Dilantin, Phenytek)

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Phenytoin may act in the motor cortex, where it may inhibit the spread of seizure activity. The activity of brain stem centers responsible for the tonic phase of grand mal seizures may also be inhibited.

Individualize the dose. Administer a larger dose before retiring if the dose cannot be divided equally. The rate of infusion must not exceed 50 mg per minute to avoid hypotension and arrhythmia.

Diazepam (Valium)

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Diazepam depresses all levels of the CNS (eg, limbic, reticular formation), possibly by increasing the activity of gamma-aminobutyric acid (GABA). Alternatively, lorazepam can be used when indicated.

Carbamazepine (Tegretol, Carbatrol, Epitol, Equetro)

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Carbamazepine is effective in treatment of complex partial seizures; it appears to act by reducing polysynaptic responses and blocking posttetanic potentiation.

Once a response is attained, attempt to reduce the dose to the minimum effective level or to discontinue the drug at least once every 3 months.

Valproic acid (Depakote, Depakene, Depacon, Stavzor)

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Valproic acid is chemically unrelated to other drugs that treat seizure disorders. Although its mechanism of action is not established, its activity may be related to increased brain levels of gamma-aminobutyric acid (GABA) or enhanced GABA action. It also may potentiate postsynaptic GABA responses, affect potassium channels, or have a direct membrane-stabilizing effect.

Class Summary

Mannitol is recommended by some experts to help reduce intracranial pressure. Mannitol induces diuresis, which increases serum osmotic concentration. In the brain, this causes water to flow from brain cells into vascular space, thereby decreasing intracranial pressure.

Mannitol (Osmitrol, Resectisol)

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Mannitol may be used to decrease intracranial pressure. It may reduce subarachnoid space pressure by creating an osmotic gradient between CSF in the arachnoid space and plasma. This agent is not for long-term use.

Initially assess the patient for adequate renal function by administering a test dose of 200 mg/kg intravenously over 3-5 min. It should produce a urine flow of at least 30-50 mL per hour of urine over 2-3 hours.

In children, assess for adequate renal function by administering a test dose of 200 mg/kg intravenously over 3-5 min. It should produce a urine flow of at least 1 mL/kg/h over 1-3 hours.

Class Summary

Several vaccines are available in the United States for individuals traveling to endemic areas or those working at biomedical facilities.

Japanese encephalitis virus vaccine (Ixiaro)

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Indicated for adults and children aged 2 months and older at increased risk of Japanese encephalitis virus (JEV) during travel to Asia.

Tick borne encephalitis vaccine (TicoVac)

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Indicated in adults and children aged 1 year and older for prevention of tick-borne encephalitis caused by Flaviviridae, including European or Western tick-borne encephalitis virus (transmitted by Ixodes ricinus), Siberian tick-borne encephalitis virus (transmitted by I persulcatus), and Far-Eastern tick-borne encephalitis virus, formerly known as Russian spring summer encephalitis virus (transmitted by I persulcatus).

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Table 1. Examples of Physiologic Roles of Known Viral Receptors

Virus	Receptor	Abbreviation/Synonym	Function
Measles virus	Membrane cofactor protein	CD46	Regulates complement and prevents activation of complement on autologous cells
Poliovirus	CD155	hPVR/CD155	Expressed on primary human monocytes; supports poliovirus replication in vivo
HSV	Heparan sulfate	None	Cell surface proteoglycans
	Herpesvirus entry mediator A	Hve A, HVEM	TNF receptor superfamily
	Herpesvirus entry mediator B	Hve B, Human nectin-2, or Prr2alpha-Hve B	Participate in organization of epithelial and endothelial junctions
	Herpesvirus entry mediator C	Hve C, nectin1delta, or Prr1-Hve C	Immunoglobulin superfamily
	TNFSF14	hTNFSF14/HVEM-L	TNF receptor superfamily
Rabies virus	Nicotinic AChR (a-bungarotoxin binding site)	AChR	Nicotinic AChR
	NCAM	NCAM, CD56, D2CAM, Leu19, or NKH-1	Cell adhesion glycoprotein of immunoglobulin superfamily
	NGFR	NGFR	NGFR
	p75 neurotrophin receptor (p75NTR)	p75NTR
HIV-1	CD4	CD4	T lymphocyte protein with helper or inducer function in immune system
	CCR3	CCR3	Chemotactic activity
	CCR5	CCR5	Coreceptor for macrophage-tropic strain
	CCR6	CCR65	Chemotactic activity
	CXCR4	CXCR4	Coreceptor for CD4
JC virus	N-linked glycoprotein with alpha 2-6 sialic acid	N-linked glycoprotein	Unknown
Japanese B virus^[6]	Protein GRP78	---	ER-stress response protein
AChR—acetylcetylcholine receptor; CCR—chemokine receptor; HSV—herpes simplex virus; NCAM—neural cell adhesion molecule; NGFR—nerve growth factor receptor; TNF—tumor necrosis factor.

Table 2. Common Viral Encephalitides: Part 1

Virus (Family)	Viral Structure	Transmission	Mortality	Specific Clinical Patterns	Sequelae	Season
HSV (herpesvirus)	ds DNA	Unknown	70% if untreated	Rare forms: subacute, psychiatric, opercular, recurrent meningitis HSV-1: brainstem; HSV-2: myelitis	Common	All year
VZV (herpesvirus)	ds DNA	Direct contact (air), highly contagious	Variable; low in children	Rash, encephalitis in 0.1-0.2% of children with chickenpox; cerebellar ataxia (cerebellitis)	Adults worse; cerebellitis good	Late winter, spring
Influenza virus (orthomyxovirus)	ss RNA	Direct contact (air), highly contagious	Unknown	Reversible frontal syndrome in children; Guillain-Barré, myelitis	Parkinsonism (encephalitis lethargica)	Usually winter
Enteroviruses (picornavirus)	ss RNA	Fecal-oral route	Low; high for enterovirus 71	Herpangina; hand, foot, mouth disease; enterovirus 71 causes rhombencephalitis	Mild, except for enterovirus 71	Summer, fall; tropics: no season
Rabies virus (rhabdovirus)	ss RNA	Dogs, wild animals (eg, fox, wolf, skunk)	Virtually 100%	Paresthesias; confusion, spasms, hydrophobia; brainstem features	Mortality virtually 100%	All year
ds—double strand; HSV—herpes simplex virus; ss—single strand; VZV—varicella-zoster virus.

Table 3. Common Viral Encephalitides: Part 2

Virus (Family)	Viral Structure	Transmission	Mortality	Specific Clinical Patterns	Sequelae	Season
Lymphocytic choriomeningitis virus (arenavirus)	ss RNA	Rodents	Low (< 1%)	Progressive fever and myalgia; orchitis; aseptic meningitis; leukopenia, thrombocytopenia	Rare	More in winter
Lassa virus (arenavirus)	ss RNA	Rodents	15%	Multisystem disease; proteinuria	Deafness (one third)	All year
Mumps virus (paramyxovirus)	ss RNA	Direct contact (air), highly contagious	Low	Parotitis, pancreatitis, orchitis, aseptic meningitis	Frequent sequelae	Winter and spring
Measles virus (paramyxovirus)	ss RNA	Direct contact (air), highly contagious	10%	Characteristic rash; frequent EEG changes; myelitis	Frequent: mental retardation, seizures, SSPE	Winter and spring
Nipah virus (paramyxovirus)	ss RNA	Pigs; bats	40-75%	Brainstem or cerebellar signs; segmental myoclonus, dysautonomia	SSPE-like syndrome?	All year
ds—double strand; EEG—electroencephalographic; ss—single strand; SSPE—subacute sclerosing panencephalitis.

Table 4. Common Arboviral Encephalitides

Virus (Family)	Vector	Reservoir	Mortality	Specific Clinical Patterns	Sequelae	Season
Eastern equine virus (alphavirus)	Aedes sollicitans	Birds	35%	Severe, rapid progression	Common, especially in children	June to October
Western equine virus (alphavirus)	Culex tarsalis	Birds	10%	Classic encephalitis	Moderate in infants; low in others	July to October
Venezuelan equine encephalitis virus (alphavirus)	Mosquito species	Horses, small mammals	~ 0.4 %	Low rate (4%) of CNS involvement	Mild	Rainy season
St Louis encephalitis virus (flavivirus)	Culex pipiens,C tarsalis	Birds	2% in young people; 20% in elderly people	SIADH	More in elderly people	August to October
Japanese encephalitis virus (flavivirus)	Culex taeniorhynchus	Birds	33% (50% in elderly people)	Extrapyramidal features	50% neuro psychiatric; parkinsonism	Summer
West Nile virus (flavivirus)	Culex,Aedes spp	Birds	In US: 12% (elderly people only)	Motor or brainstem involvement	Usually not prominent	Summer
Far East encephalitis virus (flavivirus)	Ixodes persulcatus (tick)	Small mammals, birds	20%	Epilepsia partialis continua	Frequent; residual weakness	Spring to early summer
Central European encephalitis virus (flavivirus)	Ixodes ricinus (tick)	Small mammals, birds	Less common than in Far East	Limb-girdle paralysis (spine/medulla)	Less common than in Far East	April to October
Powassan virus (flavivirus)	Ixodes cookei (tick)	Small mammals, birds	High	Severe encephalitis	Common (50%)	May to December
Dengue virus (flavivirus)	Aedes spp	Mosquitoes	Low, except hemorrhagic	Flulike syndrome; possible CNS involvement	Mild, except for hemorrhagic	Rainy season
La Crosse virus (bunyavirus)	Aedes triseriatus	Small mammals	Low (< 1%)	Mild, primarily in children	Mild; seizures	Summer
Colorado tick fever virus (orbivirus)	Dermacentor andersoni (tick)	Small mammals	Low		Mild
CNS—central nervous system; SIADH—syndrome of inappropriate antidiuretic hormone secretion.

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Author

Francisco de Assis Aquino Gondim, MD, PhD, MSc, FAAN Professor Adjunto of Neurology and Clinical Skills, Department of Internal Medicine, Universidade Federal do Ceará, Brazil

Francisco de Assis Aquino Gondim, MD, PhD, MSc, FAAN is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, International Parkinson and Movement Disorder Society

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Consultant for Pfizer, PTC Therapeutics and Alnylam<br/>Serve(d) as a speaker or a member of a speakers bureau for: Speaker for Shire, PTC Therapeutics and BSL Beringer<br/>Received travel grants from for: Aché, Biogen, Genzyme, Ipsen, Novartis, Baxter, Teva, Pfizer.

Coauthor(s)

Florian P Thomas, MD, PhD, MA, MS Chair, Neuroscience Institute and Department of Neurology, Director, Hereditary Neuropathy Center, Co-Director, Center for Memory Loss and Brain Health, Co-Director, ALS Center, Hackensack University Medical Center; Associate Dean of Faculty, Founding Chair and Professor, Department of Neurology, Hackensack Meridian School of Medicine

Florian P Thomas, MD, PhD, MA, MS is a member of the following medical societies: Academy of Spinal Cord Injury Professionals, American Academy of Neurology, American Neurological Association, Consortium of Multiple Sclerosis Centers, National Multiple Sclerosis Society, Sigma Xi, The Scientific Research Honor Society

Disclosure: Nothing to disclose.

Gisele Oliveira, MD Resident Physician, Department of Neurology, St Louis University School of Medicine

Gisele Oliveira, MD is a member of the following medical societies: American Academy of Neurology

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Michael Stuart Bronze, MD David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center; Master of the American College of Physicians; Fellow, Infectious Diseases Society of America; Fellow of the Royal College of Physicians, London

Michael Stuart Bronze, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Medical Association, Association of Professors of Medicine, Infectious Diseases Society of America, Oklahoma State Medical Association, Southern Society for Clinical Investigation

Disclosure: Nothing to disclose.

Additional Contributors

J Stephen Huff, MD, FACEP Professor of Emergency Medicine and Neurology, Department of Emergency Medicine, University of Virginia School of Medicine

J Stephen Huff, MD, FACEP is a member of the following medical societies: American Academy of Neurology, American College of Emergency Physicians, Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Viral Encephalitis Medication

Medication Summary

Antiviral Agents

Class Summary

Acyclovir (Zovirax)

Acyclovir (Zovirax)

Ribavirin (Virazole, Ribasphere)

Ribavirin (Virazole, Ribasphere)

Ganciclovir (Cytovene, Vitrasert)

Ganciclovir (Cytovene, Vitrasert)

Foscarnet (Foscavir)

Foscarnet (Foscavir)

Anticonvulsant Agents

Class Summary

Phenytoin (Dilantin, Phenytek)

Phenytoin (Dilantin, Phenytek)

Diazepam (Valium)

Diazepam (Valium)

Carbamazepine (Tegretol, Carbatrol, Epitol, Equetro)

Carbamazepine (Tegretol, Carbatrol, Epitol, Equetro)

Valproic acid (Depakote, Depakene, Depacon, Stavzor)

Valproic acid (Depakote, Depakene, Depacon, Stavzor)

Osmotic Diuretics

Class Summary

Mannitol (Osmitrol, Resectisol)

Mannitol (Osmitrol, Resectisol)

Vaccines, Inactivated, Viral

Class Summary

Japanese encephalitis virus vaccine (Ixiaro)

Japanese encephalitis virus vaccine (Ixiaro)

Tick borne encephalitis vaccine (TicoVac)

Tick borne encephalitis vaccine (TicoVac)

Viral Encephalitis Medication

Medication Summary

Antiviral Agents

Class Summary

Acyclovir (Zovirax)

Ribavirin (Virazole, Ribasphere)

Ganciclovir (Cytovene, Vitrasert)

Foscarnet (Foscavir)

Anticonvulsant Agents

Class Summary

Phenytoin (Dilantin, Phenytek)

Diazepam (Valium)

Carbamazepine (Tegretol, Carbatrol, Epitol, Equetro)

Valproic acid (Depakote, Depakene, Depacon, Stavzor)

Osmotic Diuretics

Class Summary

Mannitol (Osmitrol, Resectisol)

Vaccines, Inactivated, Viral

Class Summary

Japanese encephalitis virus vaccine (Ixiaro)

Tick borne encephalitis vaccine (TicoVac)

References

Tables

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