What is Herpes Simplex Encephalitis?
Herpes infections have been known about since ancient Greek times. They’re caused by large viruses with double-stranded DNA. There are eight types of herpes viruses that can infect humans, causing symptoms like fever, headache, seizures, specific neurological signs, and confusion or loss of consciousness.
There’s a specific kind of illness caused by the herpes viruses, known as herpes simplex encephalitis, which can result in some loss of brain function. This can be caused by either type 1 or type 2 herpes simplex viruses. However, it’s most often due to type 1, which accounts for more than 90% of these cases. This type of encephalitis is particularly dangerous, being the leading cause of fatal encephalitis around the world. Newborns can get encephalitis from either type 1 or 2 herpes, but type 2 is more likely. Patients with weakened immune systems can also get encephalitis from type 2 herpes.
Treatment of type 1 herpes in adults often leads to significant health problems, even when receiving antiviral therapy. Children can also be severely impacted by herpes simplex encephalitis, which has a nonspecific onset and can cause serious damage regardless of treatment. Though rare, if left untreated, herpes simplex encephalitis can be fatal in up to 70% of cases, and few fully recover without ongoing issues. Newborns who get encephalitis from type 2 herpes often have widespread brain involvement, leading to a higher chance of lifelong neurological problems.
What Causes Herpes Simplex Encephalitis?
The human herpesvirus family consists of a number of different viruses, including HSV-1 and HSV-2, varicella-zoster virus, Epstein-Barr virus, cytomegalovirus, as well as HHV-6, HHV-7, and HHV-8. All of these, except HHV-8, can lead to inflammation of the brain. However, most of the cases are caused by HSV-1 (about 90%) and HSV-2 (about 10%).
The structure of HSV-1 and HSV-2 is made up of large, double-snaked DNA sequences protected by a special shell and covered with a coating that contains viral proteins. These viruses enter the host cell by attaching themselves to specific binding sites on the cell’s surface, with Nectin-1 playing a crucial role for the virus to affect the nervous system.
In adults, how severe and aggressive the virus is depends on the virus itself and the body’s immune response. The virus first infects skin or mucosal cells and is then absorbed by nearby nerve endings. The virus is transported to the nerve cell bodies, where it will lay dormant. Various complex processes helps maintain this dormancy, which includes suppressing the virus by pattern recognition proteins, activating the body’s initial immune response, and some other mechanisms. The body’s primary immune defense activates first, then the secondary defense. Normally, in healthy people, this virus doesn’t affect the entire body.
Risk Factors and Frequency for Herpes Simplex Encephalitis
HSV-1, or herpes simplex virus type 1, is globally the most common reason for severe, life-threatening brain inflammation, or encephalitis, worldwide. This virus affects without any specific seasonal pattern. A large number (60%-90%) of older people around the world test positive for HSV-1. Societies where the sexual transmission of HSV-2, another herpes virus, is high, tend to have more women than men who have the virus and the rate increases with age.
In a US study done between 2005 and 2010, out of adults aged 14 to 49, about 54% tested positive for HSV-1 and 16% for HSV-2. On a yearly basis, around two to four in a million people worldwide get affected by herpes simplex encephalitis. Without treatment, up to 70% of these patients can die. Even with proper treatment, the death rate can be as high as 20-30%. Out of all forms of encephalitis, 20-50% are caused by viral infections, and out of these, herpes virus is responsible for 50-75% of cases.
A large-scale study found herpes simplex virus as the top cause of infectious encephalitis in the UK. It’s also the most found pathogen in people hospitalized with encephalitis in Australia. The rate at which HSV-1 encephalitis occurs seems to be similar in Sweden and the United States.
- People of all ages can be infected, but it is most frequent and severe in children and older adults.
- About one-third of cases happen in children and teenagers, and half occur in patients over the age of 50.
- Men and women are equally likely to be infected.
Signs and Symptoms of Herpes Simplex Encephalitis
Herpes encephalitis is a condition where the herpes virus causes inflammation of the brain. It can occur either suddenly or develop over time. Early signs often include fever, tiredness, headache, and nausea. As the condition progresses, individuals may experience changes in thinking and behavior that span more than 24 hours. These changes are typically accompanied by signs of brain inflammation such as fever, headache, seizures, and specific neurological issues.
Patients may also exhibit changes in their cognitive abilities, behavior, and personality. Some even experience issues with urinary and fecal control. In some cases, other symptoms like a skin rash, the Guillain-Barré syndrome, or benign recurrent meningitis may occur. People might confuse personality changes for psychiatric disorders due to their similarity.
Common physical signs include fever and changes in mental functions. Signs of meningitis may be present, but this is seen in less than half the cases. Neurological deficits usually begin suddenly and often last for less than a week. These deficits may involve issues with the cranial nerves, hemiparesis (weakness on one side of the body), dysphasia (language disorder), aphasia (loss of ability to understand or express speech), ataxia (lack of muscle control), vision problems, or papilledema (swollen optic disc).
In one large study, a variety of symptoms were found in individuals with herpes simplex encephalitis:
- Fever (80% of cases)
- Confusion (72%)
- Abnormal behavior (59%)
- Headache (58%)
- Decreased mental status (58%)
- Seizures (54%)
- Specific neurological problems (41%)
- Nausea and vomiting (40%)
- Aphasia or altered speech (40%)
- Coma (33%)
- Meningismus (28%)
Children with herpes simplex encephalitis may present with symptoms such as fever, fatigue, altered behavior, sleepiness, and specific seizures or neurological abnormalities. Neonates may manifest symptoms like irritability, lethargy, and poor feeding along with shakes or fits. Skin lesions are common in neonatal encephalitis, as are altered liver functions and low platelet count.
People with a weaker immune system may show fewer early symptoms and specific neurological issues, making the diagnosis more challenging. Furthermore, some medications, especially those affect T-cells, can make individuals more susceptible to herpes simplex encephalitis.
Testing for Herpes Simplex Encephalitis
No symptoms are exclusive to herpes simplex encephalitis, so you need to get treatment without delay if you have any suspected symptoms, particularly if you have a weakened immune system and are experiencing fever and confusion. Previously, a brain biopsy was done to diagnose this disease, but now, a cerebrospinal fluid (CSF) analysis, which is obtained through a lumbar puncture as soon as possible, is considered the best method. However, this isn’t done in cases with signs of increased pressure in the brain.
Typically, the CSF analysis shows increased pressure, protein level, and abnormal white blood cells. It’s important to run an amplified polymerase chain reaction (PCR) for HSV-1 and HSV-2, which detects herpes with 96% sensitivity and 99% specificity. However, a negative result can occur if the test is done too early in the infection, in children, immunocompromised individuals, or when the patient has been on the medicine acyclovir for over 48 hours. Therefore, if the likelihood of having herpes simplex encephalitis is high, but the PCR result is negative, another PCR should be performed after a few days.
An alternative method to diagnosis might be detecting special antibodies specific to herpes in the CSF. On the other hand, blood serum tests aren’t reliable due to the common presence of herpes antibodies in the general population. Routine blood tests might show a high white cell count or they might be normal.
An immediate computerized tomography (CT) scan is often done to check for any brain abnormalities, but it’s less sensitive than a Magnetic Resonance Imaging (MRI) scan for early infections. The classic MRI result for herpes simplex encephalitis shows white matter changes in certain regions in the brain, sometimes accompanied by hemorrhage.
An electroencephalogram (EEG) generally shows abnormalities for herpes simplex encephalitis, particularly in specific brain regions. The EEG typically shows certain patterns within 2 to 15 days from the onset of the disease. Yet the absence of these EEG patterns does not exclude the possibility of herpes simplex encephalitis.
Treatment Options for Herpes Simplex Encephalitis
Emergency management strategies for certain conditions, like herpes simplex encephalitis, involve checking things like breathing and circulation, and taking the right steps when needed. A specific procedure, known as a lumbar puncture, is often done unless there’s a reason not to.
In situations where herpes simplex encephalitis is suspected or confirmed, a medicine called acyclovir is given intravenously (using an IV). The usual dose for adults is 10 mg/kg body weight every 8 hours, while children up to 11 years old and newborns get a higher dose. They calculate the dose using the ideal body weight in overweight patients.
Acyclovir works pretty well in these cases. It gets to the spinal fluid, where it needs to be, with about half of what’s in the bloodstream. The medication works by blocking a specific part of the process that the virus uses to multiply.
There is some evidence showing that in cases where acyclovir treatment was delayed more than 48 hours, the outcomes weren’t as good. The results pointed to a higher risk of death and severe disability.
Resistance to acyclovir can develop, especially in patients with weakened immune systems, but it’s not a major concern in the general population. When resistance does happen, other medicines like IV foscarnet or cidofovir are used instead.
Even though trials confirm that acyclovir is generally safe and effective, there can be side effects. These can include inflammation of a vein caused by a blood clot, kidney damage due to crystals formed from the medicine, or elevated levels of specific markers in the blood that point to kidney problems. Sometimes, side effects are gastrointestinal like nausea, vomiting, and diarrhea. Rarely, some patients may experience changes in brain function, like confusion or seizures.
When using acyclovir, it’s important to ensure that the patient is receiving adequate fluids, especially if other medicines that can potentially harm the kidneys are being used at the same time.
Acyclovir can also be used in pregnant patients, when the benefits outweigh the potential risks. A 15-year registry showed no increase in birth defects or pattern of specific disabilities.
Typically, the course of treatment is 14 to 21 days for most adults, while neonates and older children may require longer treatment with higher doses. In cases of non-availability of IV acyclovir, IV ganciclovir could be alternatives.
It’s also worth mentioning that patients often need to be admitted to the intensive care unit (ICU) to monitor things like brain function, ability to breathe, and blood pressure. Any complications, like seizures or increased pressure in the brain, are treated according to the hospital’s set protocols.
There’s some debate surrounding the use of steroids in addition to acyclovir. Steroids can help reduce damage from inflammation, but they can also potentially enhance viral multiplication by suppressing the immune system. Whether to use steroids often depends on the patient’s specific circumstances.
After the first episode of herpes simplex encephalitis, there’s a chance of relapse, with rates estimated between 5% to 27%. Relapses usually follow one of two courses: they suggest another infection or show signs of an autoimmune reaction from the body – this occurs when the immune system attacks the body’s cells as if they were foreign invaders. In some cases, new brain lesions might occur due to long-standing inflammation.
Together, these are just a few considerations and strategies in managing cases of herpes simplex encephalitis. As with many medical conditions, the best approach often depends on individual factors unique to each patient.
What else can Herpes Simplex Encephalitis be?
When trying to diagnose encephalopathy or encephalitis (brain inflammation), doctors consider certain conditions that can show similar symptoms. These could include:
- Other illnesses caused by viruses like certain strands of the herpes virus, West Nile virus, St. Louis encephalitis, equine encephalitis, Rubulavirus (which causes mumps), and many more.
- Infections in the brain caused by bacteria, fungi, prions, or parasites.
- Encephalopathies caused by low oxygen levels in the blood or by sepsis, which mimic similar mental and neurological symptoms.
- Cases of brain inflammation caused by autoimmune disorders, or conditions linked to cancer (paraneoplastic).
- Metabolic issues such as liver or kidney disease, Wernicke encephalopathy, mitochondrial disorders, blood sugar imbalances, and abnormal levels of electrolytes like calcium and sodium.
- Other causes linked to the nervous system, such as brain tumors, seizures, inflammation of blood vessels (vasculitis), neurosyphilis, and physical trauma.
- Systemic diseases like lupus and Behcet’s disease, which can impact the nervous system.
- Progressive multifocal leukoencephalopathy, a rare brain disorder caused by the JC virus.
- While rare due to widespread measles vaccination, measles can sometimes cause a progressive brain disease called subacute sclerosing panencephalitis in children, typically emerging 6 to 8 years after the initial infection.
While some of these are quite rare, considering all possibilities allows doctors to make the most accurate diagnosis when dealing with complex neurological symptoms.
What to expect with Herpes Simplex Encephalitis
Herpes simplex encephalitis, a brain inflammation caused by the herpes virus, carries a risk of serious harm or even death in adults. It is estimated that between 20 to 30% of patients can die from this condition, even if it is quickly diagnosed and treated. A large retrospective study uncovered key factors that lead to worst outcomes: a high APACHE score (a measure of severity for critical illnesses) above 27, and a delay in starting the antiviral drug acyclovir after being admitted to the hospital.
Around 20% of patients in this study ended up with severe disabilities. The risk of harm or death is also significant in newborns and children, whether they receive treatment or not. For patients with weakened immune systems, the mortality rate jumps to 36% compared to 7% for those with normal immunity.
Long-lasting health complications have also been well-documented. These include cognitive and behavioral abnormalities, loss of ability to create new memories, and Klüver Bucy Syndrome symptom, a set of behaviors caused by damage to certain parts of the brain. Even though standard mental health check-ups might seem normal, many patients struggle with naming objects and learning new things, particularly through visual and verbal means. A study from Sweden showed that 87% of patients had to be re-admitted to the hospital for various reasons, like seizures, psychiatric symptoms, or blood clots.
Possible Complications When Diagnosed with Herpes Simplex Encephalitis
In the short term, complications from certain brain conditions can include swelling of the brain, frequent seizures, increased pressure in the brain, pneumonia caused by inhaling foreign material, blood clots in the veins of the brain, stroke, and a specific form of diabetes related to an imbalance of water in the body. In the long term, people could experience changes in the brain causing issues such as speech and memory problems, coordination issues, cognitive and behavior changes, and physical and mental health abnormalities. Around 70% of patients report experiencing long-term issues with their behavior and cognitive functions.
- Brain swelling
- Frequent seizures
- Increased pressure in the brain
- Pneumonia caused by inhaling foreign material
- Blood clots in the veins of the brain
- Stroke
- A specific form of diabetes related to water imbalance
- Long-term brain changes
- Speech and memory problems
- Coordination issues
- Cognitive and behavior changes
- Physical and mental health abnormalities
There has been a proposal suggesting that an infection with the herpes simplex virus may increase a person’s risk of developing Alzheimer’s disease later in life. This is because the brain areas most impacted by the herpes virus—the temporal lobes and the base of the forebrain—are similarly affected in Alzheimer’s disease. Individuals who survive herpes simplex encephalitis, a type of brain inflammation, often have significant memory loss, similar to Alzheimer’s Disease.
Interestingly, there is a known risk factor for Alzheimer’s Disease, a gene called apolipoprotein E (epsilon) 4 (APOE-E4), but its presence alone does not definitively lead to Alzheimer’s, and the disease can occur without this gene. However, there is a significant link between this APO-E4 gene and the amount of Herpes Simplex Virus genetic material in the body, suggesting that individuals with both herpes virus latency and the APO-E4 gene may be particularly susceptible to Alzheimer’s Disease.
Preventing Herpes Simplex Encephalitis
Even with quick detection and antiviral treatment, Herpes simplex brain inflammation or ‘encephalitis’ can be quite serious and potentially fatal. Both adults and children who survive often experience varying levels of neurological issues or mental disorders. Newborns can suffer from severe neurological problems due to the HSV-2 infection, and that’s true even if they receive treatment.
Unfortunately, there are no current methods to prevent herpes simplex encephalitis in older children or adults. Protective treatments for close contacts and isolation steps are not necessary. However, some precautions can be taken to reduce the risk of passing the infection to newborns. For example, if a woman has an active herpes outbreak on the lips during pregnancy, a cesarean section can be performed to prevent the newborn from getting the virus. Also, keeping the newborn away from persons with active infections can minimize the risk.
