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.
Antiviral Agents
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)
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)
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)
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)
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.
Anticonvulsant Agents
Class Summary
These agents prevent seizure recurrence and terminate clinical and electrical seizure activity.
Phenytoin (Dilantin, Phenytek)
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)
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)
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)
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.
Osmotic Diuretics
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)
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.
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| 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[4] | 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. | |||
| 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. | ||||||
| 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% | Brainstem or cerebellar signs; segmental myoclonus, dysautonomia | SSPE-like syndrome? | All year |
| ds—double strand; EEG—electroencephalographic; ss—single strand; SSPE—subacute sclerosing panencephalitis. | ||||||
| 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; rare 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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