- Encephalitis is an inflammatory disorder of brain parenchyma.
- Two main causes of encephalitis include infections (mainly herpes virus) or autoimmune dysregulations.
- Herpes simplex virus enters the body through skin and may cause primary or latent infections.
- Autoimmune encephalitis occurs when body’s immune system starts attacking healthy brain cells causing inflammation of the brain.
- Symptoms of infectious encephalitis include headache and fever while that of autoimmune encephalitis include neurological and psychiatric abnormalities.
- Diagnosis of encephalitis is done by physical examination, CT scan, MRI, EEG, CSF testing or brain biopsy.
- Encephalitis may be treated with various anti-viral drugs like acyclovir.
- Infectious encephalitis may be prevented by proper vaccination and preventing contact with mosquitoes.
Encephalitis is an acute inflammation of the brain parenchyma that may be life-threatening. Encephalitis may be infectious (viral or bacterial) or non-infectious (autoimmune mediated) (Venkatesan et al. 2013). It exhibits variable levels of severity in humans. Mostly it affects children or adults with compromised immune systems.
It may cause memory loss and epilepsy in the affected patients. If the infection occurs in brain or spinal cord, it is called primary encephalitis. However, if infection starts in some other part of the body and eventually spread in brain, it is called secondary encephalitis (Venkatesan, 2015).
Two main causes of encephalitis include infections caused by some viral, bacterial, fungal incursions or autoimmune dysregulations. The viral encephalitis is the most commonly occurring infectious encephalitis that is caused by a viral attack to brain parenchyma followed by further viral duplication in the central nervous system.
Herpes simplex virus-1 and 2, rabies virus, poliovirus, mumps, varicella zoster virus (VZV), measles and arboviruses are most common causes of infectious encephalitis.
Herpes Simplex Virus-1 Encephalitis (HSE):
The most common type of infectious encephalitis is herpes simplex virus-1 encephalitis (HSE) which accounts for 50% of total detectable cases. HSE is caused by herpes simplex virus-1 that belongs to a class of 8 human herpes viruses including HSV2, HHV-3, HHV-4, HHV-5, HHV-6, HHV-7 and HHV-8. The genome of herpesviruses consists of a double- stranded DNA molecule. They are larger in size and cause a long life infection in humans.
Pathophysiology of Herpes Simplex Virus-1 Encephalitis (HSE):
Herpes viruses spread quickly between the human hosts and occasionally cause death in humans. Herpes simplex virus enters into host tissues through skin abrasions or mucous epithelium. HSV infects sensory neurons of host through interactions with cell-surface markers and cell adhesion molecules like glycosaminoglycan and nectin-1(Shukla et al. 2012).
The detailed process of HSV infection in human central nervous system is unclear but much research also is still going on. The most probable passage for primary infection of HSV in the human hosts is by retrograde transport through olfactory or trigeminal nerves or distribution through blood (Jennische et al. 2015).
HSE may occur by primary infection or reactivation of the dormant/latent virus within the temporal and frontal lobes or brain parenchyma (Steiner, 2011).
Primary infection: Primary infection with HSV elicits a strong innate immune response until adaptive immunity comes in action to clear viral infection (Zhang et al. 2007). HSV encephalitis causes a high rate of morbidity and mortality. Approximately 90 percent of HSV encephalitis in adults and children occurs due to HSV-1 infection and its prevalence around worldwide is supposed to be between 2 and 4 case per million (Steiner and Benninger, 2013).
Latent infection: Herpes simplex viruses adopt a dormant phase after primary infection of host for a longer period of time. For the maintenance of latent phase, HSV virus carries certain mechanisms of evade host defense such as silencing of lytic phase genes and evasion of innate and acquired host immunity (Knipe and Cliff A, 2008). On reactivation from latent phase, virus can cause recurrent disorder by discharging viral particles to other neighboring neurons (Egan et al. 2013).
It is one of the most prevalent types of noninfectious encephalitis and it accounts for 20% of all encephalitis reports in the northern Europe (Granerod et al. 2010). Some factors can further stimulate autoimmune encephalitis such as tumors, infections or some unknown factors (cryogenic) (Linnoila et al. 2016).
It exhibits several clinical symptoms including autonomic dysregulations, sleep disturbances, behavioral changes, movement disorders and seizures (Sabater et al. 2014).
Pathophysiology of Autoimmune Encephalitis
Autoimmune encephalitis is characterized by an immune response in which anti-neuronal antibodies are produced against healthy brain cell antigens. The anti-neuronal antibodies may be divided into three different types including antibodies against synaptic antigens, antibodies against cell surface antigens and antibodies against intraneuronal antigens.
The antibodies against cell surface antigens may block receptors and ion channel pores and lower the expression level of cell surface receptors. The antibodies against synaptic antigens lead to modifications in the release of neurotransmitters (Coevorden et al. 2014).
There are following major types of autoimmune encephalitis:
- Anti-N-methyl-D-aspartate receptor (Anti-NMDAR) encephalitis: It is one of the most significant causes of autoimmune encephalitis in which body starts forming antibodies against the N-methyl-D-aspartate receptor. In a recent study, researchers from German Center for Neurodegenerative Diseases have used an anti-cancer drug, bortezomib that acts as a proteasome inhibitor to successfully treat the patients who were not responding to previously available treatments. They found that cells producing high levels of antibodies have high metabolic activity that makes them sensitive to anti-cancer drug, bortezomib. However, randomized trials need to be performed with this method of treatment.
- Anti-anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (Anti-AMPAR) encephalitis: It involves formation of anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antibodies.
- Anti-gamma-aminobutyric acid A receptor encephalitis: It involves formation of anti-GABA-AR antibodies.
- Anti-Glycine receptor encephalitis: It involves formation of anti-GR antibodies.
- Anti-dipeptidyl peptidase-like protein 6 encephalitis: It involves formation of DPPX antibodies.
- Anti-Glutamic acid decarboxylase encephalitis: It involves the formation of GAD antibodies.
Signs and Symptoms
Encephalitis generally begins with headache and fever. These symptoms further worsen with time leading to recurrent seizures, severe headache, parenchymal inflammation, high intracranial pressure (ICP) linked with brain edema and focal neurological dysfunctions such as abnormal behaviors, confusion and loss of consciousness (Sili et al. 2014).
Some patients with herpes simplex encephalitis may also present upper respiratory tract or circulatory abnormalities. Viral encephalitis has flu like symptoms that last for 2-3 weeks. Mortality depends on age and severity of the disease. For instance, young people may recover from the disease without many health issues while people of old age tend to have more complications and often death (Singh et al. 2016).
Autoimmune encephalitis leads to neurological symptoms like abnormal movement, defective memory, impaired cognition, seizures, and problems in speech, balance and vision. Additionally, psychiatric symptoms like aggression, psychosis, panic attacks, fear, euphoria and abnormal sexual behaviors may be observed (Herken and Pruss, 2017).
Anearly diagnosis of encephalitis is critical for accurate and timely treatment. The precise diagnosis of encephalitis is based on detailed patient’s history evaluation and physical examinations.
For the diagnosis of encephalitis many medical routine tests are performed including CT scans, MRI scanning to determine inflammation in brain parenchyma, electroencephalogram (EEG) for observing electrical activity of brain, blood and urine tests. Cerebrospinal fluid testing through PCR to identify viral DNA is a basic diagnostic test of encephalitis.
Brian biopsy may also be done in which a brain tissue sample is removed and tested for infection. However, brain biopsy is only performed when treatments are not working.
Besides, focusing on general medical examinations including laboratory testing, viral DNA identification and instant neuroimaging; some other important diagnostic elements should be considered for a definite diagnosis such as the use of immune suppressive drugs, travel history, weight loss, fever, rash and other neurological disabilities like seizures, movement disorders, aphasia and behavioral changes (Solomon et al. 2012).
Antiviral Therapy of HSE
Acyclovir, an acyclic guanine nucleoside, is a well-known specific antiviral drug for the treatment of HSE. It is considered as a first line drug for herpes simplex encephalitis. It shows strong antiviral activity against HSV-1, HSV-2 and VZV.
Intravenous administration of acyclovir should be started at a dose of 10 mg/kg for 14-21 days. It has comparatively short half-life and >80% of the drug remains in a non-metabolized state and finally excreted in urine. Medication with acyclovir results in a considerable lower mortality rates up to 28% (Stahl et al. 2012).
After administration and uptake into the cell acyclovir becomes phosphorylated and converted into an active form i.e. acyclovir triphosphate which integrates only into viral DNA and results in chain termination during viral DNA replication (Solomon et al. 2012). Apart from an early treatment of HSE with acyclovir which specifically terminates viral DNA replication other medication approaches should also be considered.
This supportive treatment includes the use of anticonvulsants to cure seizures, regulation of increased intracranial pressure, obstruction of other related medical problems like cardiac, respiratory abnormalities, cerebral infraction and improper release of antidiuretic hormones.
Current Anti-herpetic Drugs
In HSE, duration for acyclovir administration is normally about 15 days but if viral DNA is still identified at the end of course, its use should be continued. Acyclovir and penciclovir both are effective drugs against HSV-1 and HSV-2.
There are two other well-known antiviral drugs such as foscarnet and cidofovir which are administrated for severe herpes simplex viral infections. Foscarnet is an inclusive antiviral drug used against DNA viruses as well as RNA viruses (retroviruses).
It is a pyrophosphate analogueue having a half-life of 48 hours. It can be injected intravenously only due to its lower oral absorption. Unlike acyclovir, the antiviral activity of foscarnet against herpes simplex is independent of the phosphorylation process.
Cidofovir, a second drug of choice for herpes simplex virus encephalitis, is an acyclic nucleotide analogue. It is a broad spectrum antiviral drug against DNA viruses. It adopts an intravenous route of administration due to its poor oral absorption.
Its recommended dose is 5 mg/kg once in a week. Like acyclovir, cidofovir also requires phosphorylation for its activation. After activation it inhibits the viral DNA synthesis by viral DNA polymerase (De clercq, 2003).
Viral encephalitis may be prevented by getting all the recommended vaccines including measles, rubella and mumps. Locations where mosquitoes carrying encephalitis causing viruses are abundant, people should take preventive measures to avoid contact with mosquitoes.
These preventive measures may include the use of mosquito repellents, appropriate clothing, preventing stagnant water and avoiding outdoor games especially in the evening and night times.
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