Valproate Toxicity

What is Valproate Toxicity?

Valproate is a key ingredient in medications like valproic acid, sodium valproate, and divalproex. These medications are often used to treat a variety of conditions, like general and partial seizures, bipolar disorders, schizoaffective disorders, nerve pain, and as a preventative measure for migraines.

However, the buildup of too much valproate in the body can lead to what’s known as valproate toxicity. This can happen unintentionally, like when the dosage is increased, the level of albumin (a protein) in your blood is decreased, there are drug interactions, or intentionally, like in cases of self-harm.

When someone overdoses on drugs containing valproate, they may experience a range of health problems, including high levels of ammonia in their blood (hyperammonemia), brain disease (encephalopathy), and liver damage (hepatotoxicity). Other severe overdose symptoms can include low blood pressure (hypotension), fast heartbeat (tachycardia), slow breathing (respiratory depression), too much acid in the body (metabolic acidosis), swelling in the brain (cerebral edema), and a specific form of brain disease caused by high ammonia levels because of valproate (valproate-related hyperammonemic encephalopathy).

What Causes Valproate Toxicity?

Valproate poisoning often happens when the dosage is increased to achieve the desired effect. It can also occur when there is too much of the unattached drug in the body. High levels of this free drug are often found in older people and those with a low level of the protein albumin in their blood. It’s also common in those who are pregnant, have kidney problems, liver disease, or in those who take medications that compete with valproate for protein binding sites. Furthermore, trying to hurt oneself by taking too much valproate can lead to different degrees of valproate poisoning.

Risk Factors and Frequency for Valproate Toxicity

Based on data from the American Association of Poison Control Centers, there’s been an increase in cases of people accidentally consuming valproate, a substance that could be harmful if ingested. They reported that cases rose from 2,717 in 1994 to 8,705 in 2005. But, in recent years, these cases have leveled off a bit, with 3,211 reported in 2010 and 2,996 in 2018. Children might be particularly at risk for accidentally consuming valproate and experiencing harmful side effects, but it can happen to people of all ages.

History of valproate ingestion cases increased from 2,717 in 1994 to 8,705 in 2005.
Recently, these cases have stabilized with 3,211 cases in 2010 and 2,996 in 2018.
Children are particularly prone to valproate toxicity, but this can occur at any age.

Signs and Symptoms of Valproate Toxicity

If a doctor suspects a patient might be suffering from toxicity due to the drug valproate, they need to find out certain details. This includes when the patient last took valproate, which specific type of valproate they took and how much, and whether they could also have taken other substances like acetaminophen or alcohol. They also need an understanding of any past psychiatric or medical issues the patient has had.

A high dose of valproate (specifically 200mg per kg of body weight), or high levels of the drug in the patient’s bloodstream (above 180mg per liter), can cause issues with the central nervous system. This might become apparent through symptoms like shaking, restlessness, unusually small pupils, and other neurological problems.

Another condition, called hyperammonemic encephalopathy, could arise from valproate toxicity. This is characterised by confusion, fits, and sleepiness, and can potentially escalate into unconsciousness, or even death. There may also be changes in breathing, blood pressure, and heart rate, as well as vomiting, diarrhea, and stomach pain.

Shaking
Restlessness
Unusually small pupils
Other neurological problems
Confusion
Fits
Sleepiness (can lead to unconsciousness)
Changes in breathing, blood pressure, and heart rate
Vomiting
Diarrhea
Stomach pain

In some cases, the skin-related changes associated with valproate toxicity might align with those seen in hypersensitivity vasculitis and psoriasis-like skin rashes.

Furthermore, people who have been on valproate for a long time might have symptoms that indicate hair loss through a process called telogen effluvium. These include widespread hair loss, thinning hair, and hair turning grey. Valproate also has potential harmful effects on the unborn babies of pregnant women, leading to a broad spectrum of congenital malformations, such as spina bifida, anencephaly, abnormalities of the face and skull, and defects of the urinary and reproductive systems.

Testing for Valproate Toxicity

If a person is suspected of having valproate toxicity – or an overload of the drug valproate – certain tests and measurements are recommended. Typically, the normal levels for this medication in the blood are between 50 to 100 mg/L. In cases where toxicity is suspected, it’s advised to measure these levels every 2 to 4 hours until the levels start decreasing. If the levels are going down, it signifies that the highest point has been reached.

Additional testing is helpful to check for people who have low protein levels in their blood or if they are showing symptoms of toxicity despite normal or low levels of the medication.

It’s also recommended to get other tests such as a complete blood count, if the patient has possible valproate toxicity. Signs of toxicity may include a low platelet count, a decrease in a type of white blood cell known as granulocytes, or low blood sugar. Other things to watch out for are liver toxicity, abnormal electrolyte levels, acid-base balance disorders, or elevated blood ammonia levels, which could indicate a brain disease. It may also be necessary to test for other substances that might have been ingested, such as other seizure medications, aspirin, or acetaminophen. Women who are able to become pregnant should also be given a pregnancy test.

Further testing might include a type of heart scan known as a 12-lead echocardiogram to identify any blockages in the electrical signals within the heart. It’s also been noted that severe valproate toxicity can be associated with a fast heartbeat. Patients showing signs such as specific brain symptoms, severe brain depression, or suspicion of brain swelling should get a CT scan of the head as well.

Treatment Options for Valproate Toxicity

If a person accidentally takes too much valproate, a type of medication used to treat certain seizure disorders, bipolar disorder, and migraines, they may need immediate medical attention to help stabilize their condition. The first steps a doctor will take usually include making sure the person can breathe and has good blood flow. If the person is having trouble breathing, they might need a tube inserted into their windpipe and a machine to help them breathe. They might also need intravenous (IV) fluids, which are given through a small tube that goes into their vein, and medicatons to help increase their blood pressure, if it’s dangerously low. If the person is having seizures due to the overdose, doctors will typically administer medications known as benzodiazepines to stop the seizures.

Beyond ensuring that the person is stabilized, doctors may use specific treatments to help remove excess valproate from their body. One of these treatments is called gastrointestinal decontamination, which involves using activated charcoal to absorb the valproate in the stomach and intestines. Activated charcoal is most effective if given within two hours of the person taking too much valproate. However, doctors may consider using it beyond this time-frame if the person has taken slow-release or enteric-coated (designed to dissolve in the intestines, not the stomach) versions of the drug. If the person cannot reliably swallow the charcoal, doctors will usually choose not to use this method. Another treatment that doctors can apply is gastric lavage, or “stomach pumping,” where a tube is inserted through the mouth or nose into the stomach to wash out the medication. It’s considered effective up to 10 or 12 hours after the drug intake.

Once the person is stable, doctors may use a substance called L-carnitine to help treat valproate overdose, especially if the person’s alertness is affected. L-carnitine is usually given IV, and can help to reduce levels of ammonia, a harmful substance that can build up due to valproate overdose. At the same time, doctors will usually monitor ammonia levels in the person’s blood to figure out when to stop the therapy. For kids, the use of L-carnitine decrease potentially harmful byproducts of the medication, although it may not necessarily improve their condition. In certain cases, an antidote to opioid drugs called naloxone may be used to help reverse the effects of the valproate on the central nervous system, or brain and spinal cord. Naloxone can also be used for chronic valproate overdoses.

In severe cases, where the valproate levels are extremely high or the patient is experiencing severe symptoms such as shock or brain swelling, hemodialysis might be needed. Hemodialysis is a medical procedure where a machine is used to clean the person’s blood. Not only can this greatly reduce the time it takes for valproate to be eliminated from the body, but it can also lead to a major improvement in the person’s condition. Usually, doctors will use a method called intermittent hemodialysis, where the treatment is given in sessions rather than continuously. However, if the person cannot tolerate this method, doctors can use a continuous form of the treatment. Once the valproate levels drop below a certain level and the person is showing signs of improvement, such as normal blood pressure, returning alertness, improved balance of body’s acidity and electrolyte levels, hemodialysis can typically be stopped.

Diagnosing valproate toxicity can be complicated because its symptoms are similar to numerous other conditions. To determine whether someone has valproate toxicity, a doctor needs to look at the patient’s medical history, carry out a physical exam, run lab tests, and possibly do brain imaging. Common signals of valproate toxicity include changes in mental state and a slowdown in central nervous system activity. Many factors can cause these symptoms, so it’s important to look out for them.

If a patient has a fever and stiff neck along with changes in mental state, the doctor should consider whether the patient might have meningitis. If brain scans show that the patient’s temporal lobe is affected, this might indicate Herpes simplex virus-1 encephalitis. Other potential causes of such symptoms that should not be overlooked include brain tumors, bleeding inside the skull, hydrocephalus (a buildup of fluid in the brain), and traumatic brain injury.

About 10% of patients on valproate experience tremors. The doctor needs to determine whether these tremors are caused by the medication or if they could be a sign of essential tremors or Parkinson’s disease.

The doctor should also order a comprehensive metabolic panel. This series of tests will look for any imbalances in the patient’s metabolism, such as low blood sugar or high sodium levels. Given that high levels of ammonia in the blood often accompany valproate poisoning, the doctor should also consider conditions that affect the urea cycle and liver-related brain dysfunction. Finally, the doctor should investigate other potential causes of anion gap metabolic acidosis, a condition characterized by high acid levels in the blood. Common causes of this condition include:

Kidney failure
Methanol poisoning
Diabetic ketoacidosis
Lactic acidosis

What to expect with Valproate Toxicity

The outcome for patients who have taken too much of a medication called valproate can depend on several factors: how much was taken, whether specific treatments were used to get rid of the drug from the body, and the overall medical care received. Even if the overdose was severe, it is possible to make a full recovery if aggressive treatments were implemented promptly.

In a study of 316 patients, it was found that the outlook for patients with acute valproate overdose was generally good, especially if they received supportive care such as close monitoring and treatment of symptoms. However, it was noted that if a patient was in a coma when they first came to the hospital, it could suggest a worse outcome.

Other factors linked to a poorer outcome include being older in age, having changes in the body’s normal chemical balance (metabolic derangements), and having ingested large amounts of valproate.

Possible Complications When Diagnosed with Valproate Toxicity

Acute valproate toxicity, typically a medication overdose, can harm the liver, although this effect usually reverses when the drug therapy ends and liver function often returns to normal. However, severe cases can lead to complete liver failure and even death. It’s worth noting that liver transplants in children affected by valproate-induced liver failure have lower survival rates compared to transplants due to other drug-related liver injuries.

Further, acute valproate toxicity can cause cerebral edema—an excess accumulation of fluid in the brain spaces—which may result in brain herniation, extended periods of central nervous system depression, and coma. Additionally, valproate can lead to a condition known as hyperammonemic encephalopathy which triggers confusion, lethargy, and an increase in seizure frequency. If severe valproate toxicity isn’t treated promptly, it could prove fatal.

Possible Effects of Acute Valproate Toxicity:

Harm to the liver
Complete liver failure
Lower survival rates after liver transplants in children
Cerebral edema
Brain herniation
Extended periods of central nervous system depression
Coma
Hyperammonemic encephalopathy (leading to confusion, lethargy and increased seizure frequency)
Potential death if untreated

Preventing Valproate Toxicity

When leaving the hospital, it’s important for patients, and parents of patients, to understand the potential risks and side effects of a medicine called valproate. If too much of this medicine is taken, it might lead to serious damage to the liver which in some cases, tragically, can be deadly. Of note, kids younger than 2 years old have a higher risk of severe liver problems, including a rare but serious condition known as Alpers-Huttenlocher syndrome.

Moreover, women who are pregnant or might become pregnant should be aware that valproate could potentially lead to serious birth defects like spina bifida, which can affect a baby’s spinal cord, and developmental disorders that impact how the brain grows and works. Therefore, during the period of taking valproate, birth control methods should be applied if sexually active.

All patients should be informed about the risk of pancreatitis, an inflammation of the pancreas, with long-lasting use of valproate. Notably, if symptoms such as sudden stomach pain, nausea, vomiting, or fever occur, they should instantly reach out to their doctor or go to an emergency room.

Frequently asked questions

The prognosis for Valproate Toxicity depends on several factors: - The amount of valproate taken - Whether specific treatments were used to remove the drug from the body - The overall medical care received - Supportive care, such as close monitoring and treatment of symptoms, can lead to a generally good outlook - Coma upon arrival at the hospital may suggest a worse outcome - Older age, metabolic derangements, and ingestion of large amounts of valproate are linked to a poorer outcome.

Valproate toxicity can occur when the dosage is increased to achieve the desired effect, when there is too much of the unattached drug in the body, or when there are high levels of the free drug in the bloodstream. It is also common in older people, those with low levels of the protein albumin in their blood, pregnant women, individuals with kidney problems or liver disease, and those taking medications that compete with valproate for protein binding sites. Additionally, intentionally taking too much valproate can lead to different degrees of valproate poisoning.

The signs and symptoms of Valproate Toxicity include: - Shaking - Restlessness - Unusually small pupils - Other neurological problems - Confusion - Fits - Sleepiness (which can lead to unconsciousness) - Changes in breathing, blood pressure, and heart rate - Vomiting - Diarrhea - Stomach pain In addition to these symptoms, skin-related changes associated with Valproate Toxicity may resemble those seen in hypersensitivity vasculitis and psoriasis-like skin rashes. Long-term use of Valproate can also result in hair loss through a process called telogen effluvium, characterized by widespread hair loss, thinning hair, and hair turning grey. It is important to note that Valproate can have harmful effects on unborn babies if taken by pregnant women, leading to a range of congenital malformations such as spina bifida, anencephaly, abnormalities of the face and skull, and defects of the urinary and reproductive systems.

The types of tests that are needed for Valproate Toxicity include: - Measurement of valproate levels in the blood every 2 to 4 hours until levels start decreasing - Complete blood count to check for low platelet count, decrease in granulocytes, or low blood sugar - Liver function tests to check for liver toxicity - Electrolyte levels to check for abnormal levels - Blood ammonia levels to indicate a brain disease - Testing for other substances that might have been ingested, such as other seizure medications, aspirin, or acetaminophen - Pregnancy test for women who are able to become pregnant - 12-lead echocardiogram to identify any blockages in the electrical signals within the heart - CT scan of the head for patients showing specific brain symptoms, severe brain depression, or suspicion of brain swelling.

The doctor needs to rule out the following conditions when diagnosing Valproate Toxicity: - Meningitis - Herpes simplex virus-1 encephalitis - Brain tumors - Bleeding inside the skull - Hydrocephalus - Traumatic brain injury - Essential tremors - Parkinson's disease - Imbalances in metabolism such as low blood sugar or high sodium levels - Conditions that affect the urea cycle and liver-related brain dysfunction - Anion gap metabolic acidosis caused by kidney failure, methanol poisoning, diabetic ketoacidosis, or lactic acidosis.

The possible side effects when treating Valproate Toxicity include harm to the liver, complete liver failure, lower survival rates after liver transplants in children, cerebral edema, brain herniation, extended periods of central nervous system depression, coma, hyperammonemic encephalopathy (leading to confusion, lethargy, and increased seizure frequency), and potential death if left untreated.

A general practitioner or a specialist in toxicology or neurology.

Valproate toxicity is treated by first stabilizing the person's condition. This includes ensuring that they can breathe and have good blood flow. If necessary, a tube may be inserted into their windpipe to help them breathe, and intravenous fluids and medications may be given to increase their blood pressure. If the person is experiencing seizures, benzodiazepines will be administered to stop the seizures. Specific treatments to remove excess valproate from the body may also be used, such as gastrointestinal decontamination using activated charcoal or gastric lavage. L-carnitine may be given to help reduce levels of ammonia in the blood. In severe cases, hemodialysis may be needed to clean the person's blood and eliminate valproate from the body.

Valproate toxicity refers to the buildup of too much valproate in the body, which can lead to various health problems such as hyperammonemia, encephalopathy, hepatotoxicity, hypotension, tachycardia, respiratory depression, metabolic acidosis, cerebral edema, and valproate-related hyperammonemic encephalopathy.