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AuliVerkkoniemi-Ahola

Encephalitis

Essentials

  • Encephalitis should be suspected in patients with acute-onset headache, confusion, fever or clouding of consciousness when no other causative factor is evident.
  • If encephalitis is suspected, the patient should be immediately referred to a hospital with adequate resources for testing and treatment.
  • In the acute phase, the diagnosis of encephalitis is clinical, and treatment should be started quickly on the basis of the clinical picture. In herpes encephalitis, in particular, delayed treatment may increase the risk of fatal outcome or permanent residual symptoms.
  • Usually caused by viruses but bacteria or other rarer pathogens may be involved, too.

Epidemiology

  • In Finland , the incidence of encephalitis is approx. 3-5/100 000/year.

Aetiology

  • Encephalitis is usually caused by viruses but bacteria, fungi, parasites or rickettsias may also be involved.
  • The most important viral causes are:
  • Other causes
    • Viruses causing respiratory tract infections, such as adenovirus, influenza A and B viruses, parainfluenza virus
      • Of the herpes group viruses Epstein-Barr virus (EBV)
      • Parotitis virus
      • Arboviruses belonging to the group of flaviviruses, particularly in tourists (Japanese encephalitis)
      • Rickettsias
  • In patients with HIV infection, the causative pathogen may be the HI virus, or, in immunosuppressed patients, some other pathogen, especially toxoplasma.
  • Bacterial diseases with encephalitic manifestations:
    • Borreliosis, with polymorphic clinical picture
    • Mycoplasma infections
    • Chlamydia pneumoniae infections
    • Listeriosis
    • Tuberculosis
    • Syphilis
  • Other rare causes particularly in patients with immune deficiency and in organ transplant recipients
    • Of the herpes group viruses cytomegalovirus (CMV), HHV-6
    • Toxoplasma gondii
    • Fungi, such as Aspergillus and Cryptococcus
  • Despite extensive further studies, the aetiology will remain unclear in about half of the cases. Nevertheless, laboratory tests should always be performed to find out the aetiology, and any curable aetiologies should be treated as soon as possible.

Symptoms

  • The most common form of encephalitis is meningoencephalitis but symptoms of meningitis may also be missing. In encephalitis, the inflammation is not restricted to the meninges but the actual brain tissue may be either locally or widely inflamed, causing clinical symptoms consistent with this.
  • The neurological and neuropsychiatric symptoms are new and acute, and may include:
    • headache
    • fever and other general symptoms of an infectious disease
    • decreased level of consciousness
    • restlessness and confusion
    • cognitive slowing or lowered cognitive level
    • change in personality and behaviour
    • psychiatric symptoms, such as hallucinations
    • epileptic convulsive or absence seizures
    • localizing symptoms - dysphasia, sometimes cranial nerve-related findings, seldom hemiparesis
    • hallucinations without other causative factor.
  • In some patients, headache and fever subside before the actual symptoms of encephalitis appear.

Patient history

  • It is important to ask patients or their relatives about:
    • susceptibility to herpes infections
    • tick bite or spending time in an environment where ticks may occur
    • vaccination (TBE and influenza vaccinations)
    • travel history of the last few months
    • any disease or medication impairing the patient's immunity
    • any concurrent infections in people living in the same household.
  • If there are herpes blisters on the skin or mucosa, the cause is evident. Isolation of the virus from the blister fluid may confirm the diagnosis. The absence of blisters does not, however, exclude the possibility of herpes encephalitis.
  • It is important for differential diagnosis to know whether the patient has a history of alcohol and/or drug addiction or psychiatric disease.

Differential diagnosis

  • Other cerebral and metabolic systemic diseases
  • Head injury
  • Sequela of a neurosurgical operation
  • Sepsis
  • Delirium
  • A confusional phase caused by a dementing disease that has not been diagnosed earlier.
  • Illegal drugs, drug overdose and other toxic causes
  • Acute stage psychiatric disease
  • Progressive multifocal leukoencephalopathy (PML) Uncommon Infections of the Central Nervous System
  • Acute disseminated encephalomyelitis (ADEM)
  • Autoimmune encephalitis
    • Most commonly causes cognitive or psychiatric symptoms with subacute onset especially in young adults.
    • Symptom picture often incudes epilepsy or motor disturbances.
    • An underlying postinfectious state or paraneoplasia are possible.
    • Diagnosis is made and investigations are carried out in a hospital neurology clinic.
  • Cerebrospinal fluid (CSF) leukocyte reaction and associated low glucose levels developing within a few days after subarachnoid or cerebral haemorrhage

Encephalitis associated with herpes group viruses

Herpes encephalitis

  • A disease caused by the HSV-1 virus, where fever, fatigue, and headache are usually associated with symptoms indicating damage to the temporal lobe
    • Cognitive impairment, with memory problems often emphasized
    • Dysphasia
    • Unclear confusion
    • Hallucinations
    • Epileptic seizures
    • Clouding of consciousness or restlessness
    • Personality change

Diagnosis

  • Clinical suspicion of encephalitis is based on the clinical picture, which can be validated outside office hours by appropriate CSF or cranial MRI findings.
  • Lymphocytic pleocytosis can nearly always be seen in CSF, and the CSF protein level may be slightly elevated. However, this is not a specific finding, and in about 10% of patients the first CSF finding is normal.
    • In the acute stage, a PCR test of the CSF demonstrates HSV-1, HSV-2 and VZV infections. However, the result will only be available in a few days or a week, and treatment must therefore be started based on clinical suspicion and any emergency examinations supporting it.
    • Sometimes, CSF will also be tested for antibodies, and this is significant particularly if another CSF sample is drawn later. The diagnosis will be supported by later increase in CSF herpes antibodies.
    • If CSF glucose concentrations are reduced, as they may be in rare cases, the possibility of tuberculosis, fungal or listerial infection or a malignancy must be kept in mind.
  • As MRI of the brain is the most sensitive machine examination, a temporal lobe finding typical for herpes encephalitis can be obtained in emergency MRI at the acute stage of the disease already.
  • Cranial CT is not sufficiently sensitive for the diagnosis of acute herpes encephalitis.
  • The EEG is abnormal and shows evidence of damage in one or both temporal lobes. MRI has reduced the significance of EEG as a diagnostic tool. EEG may be needed in unclear cases or if it is necessary to find out whether the patient has nonconvulsive status epilepticus associated with encephalitis or with some other disease.

Treatment

Treatment of herpes encephalitis

  • Treatment should be initiated upon clinical suspicion without delay, because mortality in untreated cases is ca. 70%, and survivors often suffer severe sequelae.
  • Intravenous aciclovir should be given at a dose of 10 mg/kg three times daily for at least 14 days. Early treatment is effective and restricts further damage. Aciclovir is also effective against central nervous system infections caused by VZV, HSV-2 and EBV.

Other antimicrobial treatment required

  • Before the diagnosis is confirmed by further examinations, patients are often given concomitant treatment for the most common bacterial diseases causing encephalitis (so-called triple therapy), and aciclovir is combined with 100 mg intravenous doxycycline twice daily (mycoplasma, borrelia, chlamydia and rickettsias).
  • In rare cases, suspicion may arise of a less common virus (such as CMV) as the cause of encephalitis or of a rarer bacterial disease, such as tuberculosis. A specialist in infectious diseases should be consulted in such cases, normally even before or after office hours.
    • Hospital departments of infectious diseases normally give specific instructions for each epidemic, e.g. on the treatment of influenza-associated encephalitis with oseltamivir.
  • If the diagnosis of encephalitis cannot be confirmed by further examinations or if another aetiological cause is found for the symptoms, the antimicrobial treatment of encephalitis can be withdrawn.

Symptomatic treatment

  • Analgesics and antipyretics
  • Thromboprophylaxis
  • Normal treatment of any epilepsy forming a part of the clinical picture

Prognosis

  • Even among treated patients mortality is ca. 20%, and 50-60% will recover well or satisfactorily.
  • The most common sequelae of encephalitis include cognitive disturbances, epilepsy and psychiatric symptoms.

Encephalitis following chickenpox and VZV encephalitis

  • One of the most common types of encephalitis in patients who have not been vaccinated against the VZV.
  • Typically appears 2-4 weeks after other symptoms of infection.
  • Aciclovir treatment is considered necessary even in previously healthy individuals, and intravenous aciclovir is absolutely necessary for patients who have received immunosuppressive or monoclonal medication.
  • Patients with VZV encephalitis are often either adults who have been given immunosuppressive or immunomodulating drugs or elderly people who have developed herpes zoster.
  • Cranial MRI findings may remain normal.
  • Intravenous aciclovir should be given as for herpes encephalitis.

Tick-borne central nervous system infections

Tick-borne encephalitis

  • The disease is caused by the tick-borne encephalitis (TBE) virus (a flavivirus) contracted via a tick bite.
  • There are three types of TBE virus: Western, Siberian and Far-Eastern.
  • Ticks infected by the tick-borne encephalitis virus are encountered widely in Europe and Asia, including Finland, all Baltic countries, the Stockholm archipelago and, various locations in Europe, Russia and China.
  • For epidemiological data and geographical distribution, see ECDC http://www.ecdc.europa.eu/en/tick-borne-encephalitis/surveillance-and-disease-data and CDC http://www.cdc.gov/tick-borne-encephalitis/geographic-distribution/index.html.
    • In Finland, the infection was originally detected in the archipelago and coastal areas, but today the virus is widespread, and occurs widely in inland regions. On the Åland Islands, the share of infected ticks has been assessed at about 1:200.
    • Find out about local policies concerning vaccination and its reimbursement.

Symptoms

  • 10-30% of those infected will develop clinical disease.
  • The incubation period is 7-14 days.
  • The disease manifests itself in two stages.
    • Initial common cold-like illness lasting slightly less than a week
    • After the cold, the patient is asymptomatic for about a week, followed by a stage lasting from one week to two months, when typical symptoms of meningeal encephalitis are present.
  • In the acute stage, the level of consciousness may be greatly reduced or there may be severe confusion or fatigue. Also ataxia, limb tremor, nystagmus and associated nausea, balance problems, dysphasia, epileptic seizures and paralysis of extremities may occur.

Prognosis, treatment, and prevention

  • The most important test is serum TBE antibodies. During the initial stage of the disease, the test result may be false negative, and consequently the test should be repeated if clinical suspicion persists. Sometimes CSF testing may be performed, but a positive serum sample is sufficient for diagnosis.
  • In Finland, most cases are mild but symptoms occurring during the recovery period may be persistent. About 20% of cases are severe.
  • Mild irritability, fatigue, depression, and other neuropsychiatric symptoms commonly occur for several weeks or even several months after the disease has run its course. A small share of patients have epileptic seizures during the acute and convalescence stages. Permanent damage, such as paralysis, is possible but rare.
  • Treatment consists of symptomatic treatment of headaches, fever, epilepsy and any behavioural symptoms. The level of consciousness may be greatly reduced. Bed rest and hospitalisation are recommended in the stage with neurological symptoms. The patients may also need, for example, physiotherapeutic rehabilitation during the acute stage.
  • In addition to symptomatic treatment, it is important to provide treatment preventing complications due to long bed rest, such as aspiration pneumonia and pulmonary embolism. It should be taken into consideration that a patient may have simultaneously both tick-borne encephalitis and borreliosis requiring ceftriaxone treatment.
  • A vaccine containing inactivated whole viruses is available. The inoculation series includes two injections at 1-3-month intervals and a booster in one year Vaccinations. Depending on the vaccine manufacturer and the age of the patient, boosters should be given every 3 to 5 years. Accelerated schedules are also available if immunization has to be achieved rapidly. The vaccine provides good protection, and side effects are minor Vaccines for Preventing Tick-Borne Encephalitis.

Chronic neuroborreliosis

  • See Lyme Borreliosis (LB).
  • Possible clinical manifestations may take many forms and vary widely, including:
    • progressing dementia
    • MS-like clinical presentation
    • neuropathic pain
    • ataxia
    • cranial nerve pareses
    • extrapyramidal symptoms
    • chronic paroxysmal vertigo
    • loss of hearing
    • myelitis
    • polyradiculitis
    • central nervous system vasculitis
    • polyneuropathy
    • various psychological symptoms.
  • Antibody testing and treatment are the same as for borrelia meningitis (see Meningitis in Adults). Testing CSF simultaneously for CXCL13 and borrelia antibodies is recommended, since it is possible that in a fresh infection a detectable increase in antibody levels has not yet taken place.

Nervous system syphilis

  • Both primary syphilis and late forms of the disease continue to be diagnosed regularly, also in industrialized countries. See http://www.ecdc.europa.eu/en/syphilis/surveillance-and-disease-data for epidemiological information.
  • The possibility of syphilis should be noted in association with:
    • meningitis
    • differential diagnosis of myelitis, or spinal meningitis
    • diagnosis of progressive vascular symptoms or cerebral infarction in young patients because treponema may also cause inflammation in the middle cerebral artery or the basilar artery.
  • Dementia paralytica is the classic manifestation of dementia associated with late-stage syphilis.
  • Tabes dorsalis involves sensory loss caused by damage to the dorsal column system and ataxia as well as neuralgic pain sensations.
  • Serum TPHA or treponemal antibody assay can be used as a diagnostic screening test.

References

  • Tunkel AR, Glaser CA, Bloch KC ym. The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2008;47(3):303-27.
  • Ellul M, Solomon T. Acute encephalitis - diagnosis and management. Clin Med (Lond) 2018;18(2):155-159. [PubMed]