Approach

Encephalitis is a medical emergency; hence, management consists of basic resuscitation measures ensuring adequacy of the airway, breathing, and circulation, and empiric antiviral therapy in cases of suspected viral encephalitis concurrently with diagnostic steps.[47]

All suspected cases of encephalitis should be admitted and fully evaluated. Some patients with milder symptoms and signs can be managed in a regular nursing unit, with access to an intensive care unit (ICU) bed if needed. All other patients, and in particular those with complications (e.g., significant electrolyte abnormalities, strokes, elevated intracranial pressure [ICP], cerebral edema, coma, seizures activity, or status epilepticus) should be managed in an ICU, preferably a neurointensive care unit.[33][83]

Prompt isolation is required for all forms of encephalitis until the etiology is determined; encephalitides with airborne or contact transmission to immunocompetent hosts (herpes simplex virus [HSV], varicella, mumps, rubella, enteroviruses, upper respiratory viral infections) require isolation according to local regulations. The microbiology laboratory should be alerted if unusual organisms are suspected (e.g., Treponema pallidum, Listeria species, Mycoplasma species, Rickettsia rickettsii), for which special microbiologic procedures are necessary.[26]​ Most cases of infectious encephalitis involve close collaboration between the treating clinicians and infectious disease team.

Etiology is often unknown, and therefore no specific treatment options exist for the majority of cases. However, for cases where a diagnosis is reasonably certain, treatment is directed toward the underlying offending agent if available (e.g., antivirals for viral encephalitis; appropriate anti-infective measures in bacterial, fungal, or parasitic infections).

Supportive measures

Supportive care is the cornerstone of treatment in most cases. This may include endotracheal intubation and mechanical ventilation, circulatory and electrolyte support, prevention and management of secondary bacterial infections, deep venous thrombosis prophylaxis, and gastrointestinal (ulcer) prophylaxis. Antiretroviral therapy is an important treatment in all cases of HIV-associated encephalitis (whether due to HIV itself or to an opportunistic infection); in CD8 encephalitis, patients respond well to corticosteroids.[84][85]​ For certain opportunistic infections, such as cryptococcus, antiretroviral therapy should be delayed based on World Health Organization guidelines.[86][87]​​[88]​​

In patients with elevated ICP, initial measures are elevation of head of bed to 30° to 45°, avoiding compression of the jugular veins, and brief episodes of hyperventilation.[89]​ Subsequently, hyperosmolar therapy with mannitol boluses or hypertonic saline can be used to decrease ICP.[90]​ In children with elevated ICP, maintaining cerebral perfusion pressure ≥60 mm Hg, using normal saline bolus and vasoactive therapy-dopamine, may be superior to maintaining intracranial pressure <20 mm Hg, using osmotherapy while ensuring normal blood pressure, in reducing mortality and morbidity.[91]

Antiviral therapies

All cases of suspected community-acquired viral encephalitis are started empirically on acyclovir until the cause is determined.[13] As most cases of sporadic viral encephalitis are secondary to HSV, this is good clinical practice supported by biopsy-proven randomized controlled trials, and it reduces mortality.​[47][92]​​ Delays in treatment initiation beyond 48 hours after hospital admission are associated with a worse outcome in both children and adults.​[13][93]​ In an immunocompromised patient, cytomegalovirus (CMV) encephalitis is a consideration. If suspected, ganciclovir and foscarnet are given with acyclovir until HSV polymerase chain reaction is available. If HSV encephalitis is excluded, then acyclovir can be discontinued. In some cases, magnetic resonance imaging findings and clinical features strongly suggest a diagnosis of CMV encephalitis, so acyclovir may not be necessary.

Specific viruses and the drugs used against them are:[94]

  • HSV-1 and HSV-2: acyclovir.

  • Varicella-zoster virus (VZV): acyclovir.

  • CMV: ganciclovir plus foscarnet.

  • Epstein-Barr virus (EBV): acyclovir is first line in suspected viral encephalitis, but once the diagnosis of EBV is confirmed, ganciclovir or cidofovir is a possible alternative.

  • Herpes B virus: ganciclovir or acyclovir (intravenous therapy may be preferable over oral therapy). For post-exposure prophylaxis, valacyclovir is the preferred agent.

  • Human herpes 6: ganciclovir or foscarnet should be used in immunocompromised patients. However, use of these agents in immunocompetent patients can also be considered, but there are no good data on their effectiveness.

Corticosteroids

The role of corticosteroids in viral encephalitis to reduce the inflammation associated with infection is an ongoing area of study.[95]​ To date, there is limited data regarding the benefit of adjuvant corticosteroids for the treatment of viral encephalitis and guidelines do not support their routine use.​[13]​​​[47][96]​ One meta-analysis (n=281 patients with viral encephalitis; 120 received corticosteroids) did not find benefit of corticosteroid treatment on survival.[97]​ Results from a multicenter randomized controlled trial in HSV encephalitis are currently awaited.[98]

​High-dose intravenous corticosteroids are considered as first-line therapy for acute disseminated encephalomyelitis (ADEM).[18]​ High-dose corticosteroids are also recommended for autoimmune encephalitis once infection is ruled out based on basic CSF results (e.g., number of cells) and if biopsy for primary CNS lymphoma or neurosarcoidosis is not a consideration. In these patients, immunotherapy with high dose corticosteroids is recommended.[39]​ The duration of corticosteroid therapy should be short (3-7 days) to minimize adverse effects (e.g., gastrointestinal bleeds, predisposition to secondary bacterial infections, neuropsychiatric disturbance).[39]​ Corticosteroids should not be prescribed before consultation with specialists.

Surgical intervention

Monitoring devices such as catheters or bolts may be placed to measure ICP. Shunting or surgical decompression (by craniectomy) is indicated in some cases where medical management (corticosteroids, mannitol) has failed to control elevated ICP, and for impending uncal herniation.[99] This can be considered no matter the etiology of encephalitis; however, most outcome data have been published for viral encephalitis. In some cases of HSV encephalitis, surgical decompression has been shown to improve outcome.[100]

Therapy for nonviral etiologies

If the clinical picture and initial tests suggest a nonviral infective encephalitis (bacterial, fungal, parasitic) appropriate antimicrobial therapy is started.

When the initial evaluation does not support an infectious cause and an autoimmune cause is suspected, aggressive immunotherapy with intravenous corticosteroids, immune globulin, or plasma exchange should be considered.​[1][101]​​​ The decision to fight infection or suppress the immune system needs to be balanced in each case.

Blood-borne infections can rarely be transmitted by immune globulin. Immunoglobulin (Ig)A-deficient patients are at risk of allergic reactions (this is less of a problem, as technology used to prepare immune globulin ensures removal of most IgA). Plasma exchange is performed by placing a double-lumen catheter in a central vein, and mechanically filtering and replacing the patient's plasma with pooled donor plasma. This is done in consultation with a hematologist.

Cases with persistent altered mental status not responsive to first-line therapy should be treated with rituximab and/or cyclophosphamide.​​[31]​​[50][51][102][103] In most newly diagnosed cases, it is difficult to determine clinically whether autoimmune encephalitis is antibody or cell-mediated before the antibody results are available.[104] Some clinical clues may help the clinician come to a preliminary hypothesis regarding etiology (e.g., leucine-rich glioma-inactivated 1 antibodies are associated with faciobrachial dystonic seizures, such as rapid jerks of the face and/or ipsilateral arm and shoulder, while patients with known or increased cancer risk are more likely to have cell-mediated autoimmune encephalitis).[39] Based on these clues, clinicians may decide to use rituximab or cyclophosphamide as a second-line agent if antibody results are delayed, or if there is no access to antibody testing.[39] Rituximab is now generally preferred over cyclophosphamide if monotherapy is used in highly suspected antibody-mediated autoimmunity (e.g., N-methyl-D-aspartate receptor-antibody encephalitis).[105] Rituximab is less toxic than cyclophosphamide.[39][106]​ Cyclophosphamide may be considered if rituximab is contraindicated or not available in these cases.[105] Some patients may be treated with a combination of rituximab and cyclophosphamide.[104] Cyclophosphamide can be considered in known or highly suspected cell-mediated autoimmunity (e.g., classical paraneoplastic syndrome) since rituximab may not be as effective for cell-mediated inflammation.[39] Some patients may be treated with a combination of cyclophosphamide and rituximab.[104]

Management of autoimmune encephalitis associated with malignancy (i.e., paraneoplastic encephalitis) involves diagnostic testing and treatment of the underlying tumor. However, in order to avoid the risk of permanent sequelae, treatment directed toward the paraneoplastic syndrome should not be delayed by a failure to identify the underlying tumor. Oophorectomy is indicated as an acute treatment if ovarian teratomas are present. Tumor resection is associated with faster rate of recovery and reduced relapse rate.[31][107]

High-dose corticosteroids are advocated by experts for patients with acute disseminated encephalomyelitis.[108][109]​ In cases where corticosteroids fail to show benefit, plasma exchange or immune globulin can be considered.​[108]​​

Rehabilitation

The results of one systematic review suggested that rehabilitative interventions, including cognitive therapy, behavioral therapy, and physical therapy, may help to improve functionality in children and adults after infectious encephalitis. However, most of the included studies were observational in nature.[110]

One retrospective study based on 8 patients noted that, although patients with encephalitis can make some functional gains with acute rehabilitation therapy, the rate of recovery varies and is generally less than that of stroke and traumatic brain injury.[111] The most frequently used nonpharmacological treatments to treat dementia and apathy following encephalitis are music therapy and cognitive rehabilitation.[112]

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