You may be surprised to learn that the scientific literature on epilepsy identifies a long list of known causes. However, it is often unfashionable for doctors to screen for certain known causes. There is also a tendency to throw drugs at the problem repeatedly without diagnostic certainty. This harms many patients when they are prescribed drugs inappropriate for their type of epilepsy

Some of the overlooked known causes include:

Misdiagnosis . There is a long list of conditions that can be mistaken for epilepsy. Psychological causes (psychogenic nonepileptic seizures) and syncope (fainting) are the most common conditions mistaken for epilepsy. Shockingly, most sources estimate that 20-30% of epileptics are misdiagnosed (!).

. There is a long list of conditions that can be mistaken for epilepsy. Psychological causes (psychogenic nonepileptic seizures) and syncope (fainting) are the most common conditions mistaken for epilepsy. Shockingly, most sources estimate that of epileptics are misdiagnosed (!). Autoimmunity . The body’s immune system erroneously attacks the body’s own tissues. Known autoimmune conditions that cause epilepsy can be screened for via antibody tests.

. The body’s immune system erroneously attacks the body’s own tissues. Known autoimmune conditions that cause epilepsy can be screened for via antibody tests. Celiac disease and gluten sensitivity . Celiac disease is more common in epilepsy patients. A gluten-free diet happens to treat epilepsy in roughly half of the cases where the patient has epilepsy, celiac disease and cerebral calcification (CEC syndrome).

and . Celiac disease is more common in epilepsy patients. A gluten-free diet happens to treat epilepsy in roughly half of the cases where the patient has epilepsy, celiac disease and cerebral calcification (CEC syndrome). GLUT1 deficiency syndrome , a rare metabolic syndrome that often results in epilepsy.

, a rare metabolic syndrome that often results in epilepsy. Other rare genetic conditions , many of which can be detected with genetic testing.

, many of which can be detected with genetic testing. Food intolerance. In children with epilepsy and migraines (or hyperkinetic behaviour), 56% became seizure-free on an oligoantigenic diet.

Many of these known causes have treatments where the odds of seizure freedom are fairly high.

Another area where medical care may be less than ideal is the doctor’s stance on ketogenic diets (especially in adults). While the diet is becoming mainstream and more accepted among doctors, some doctors may discourage their patients from even trying it or fail to inform patients about its existence.

The story of a father’s pain

In 1993, Jim Abrahams was desperately trying to find a treatment for his son Charlie, who suffered from severe epilepsy that did not respond well to drugs. The father stumbled across the ketogenic diet, which resulted in seizure freedom for his son. However, Jim was shocked that multiple specialists did not tell him about the ketogenic diet. Some doctors even discouraged him from trying it for his son. Outraged at the situation, Jim used his talents and connections as a Hollywood producer/writer/director to make the TV movie First Do No Harm starring Meryl Streep. He was also profiled in a 1994 Dateline segment on the ketogenic diet.

He switched career paths to start The Charlie Foundation, a non-profit dedicated to raising awareness about the ketogenic diet and helping patients implement it. The Charlie Foundation and Jim Abrahams’ work was instrumental in the explosion of papers on the ketogenic diet following its creation in 1994.

So why was the ketogenic diet unpopular prior to 1994? In the 1994 Dateline segment (10:47 into the video), Dr. Donald Shields explains that the ketogenic diet lost popularity since the 1920s because there wasn’t a pharmaceutical company selling it to doctors. The history of the ketogenic diet certainly shows that medical treatment isn’t always driven by science.

For more information on the ketogenic diet, refer to Appendix A.

Other dietary treatments

Oligoantigenic diet and food intolerances

Egger at al. used an elimination diet on patients and instructed them to slowly re-introduce foods to identify their specific food intolerances. For children with epilepsy as well as migraines or hyperkinetic behavior (ADHD), 25 out of 45 (56%) became seizure free while another 11 out of the 45 (24%) had fewer seizures. Their results and diets on the diet were published in the following paper:

Egger, J., Carter, C. M., Soothill, J. F., & Wilson, J. (1989). Oligoantigenic diet treatment of children with epilepsy and migraine. The Journal of Pediatrics, 114(1), 51–58.

doi:10.1016/s0022-3476(89)80600-6 The full paper is available here.

Unfortunately, Egger’s work (while recognized among migraine researchers and cited frequently by them) has been more or less ignored by epilepsy researchers.

Some additional notes:

The elimination diet did not work in children without migraines or hyperkinetic behavior. None of the 18 such patients who tried the diet improved. Another clinician also reported ineffectiveness in such patients (see “Restricted diets for treatment of

migraine“).

migraine“). The elimination diet was not a ketogenic diet and succeeded in children who previously failed a ketogenic diet. This suggests that this diet has a quite different mechanism of action than the ketogenic diet.

Skin prick tests and IgE antibody tests are not reliable methods of detecting these food intolerances.

Paleo ketogenic diet

The paleo ketogenic (PKD) diet is even more of a pariah in the research community than the oligoantigenic diet as it is basically an all-meat diet. The PKD diet consists of meat, animal fat, fish, offal (e.g. liver and brain), and eggs. While the diet may seem extreme by Western standards, the Inuit (Eskimo) have consumed all-meat diets for generations and enjoyed excellent health before they began to adopt Western ways of eating. Arctic explorers of non-Inuit descent have also eaten all-meat diets without health problems (see Vilhjalmur Stefansson’s series of articles in Harpers magazine).

The diet shuns foods with a poor track record (or no track record) when it comes to human health. For example, it is known that gluten is a rare cause of epilepsy as well as a wide range of other conditions. One difference between the paleo ketogenic diet and the classical ketogenic diet is that the paleo ketogenic diet explicitly excludes gluten.

Regardless of the diet’s pariah status, it may be of interest in treating epilepsy. The following case studies have been published:

The PKD diet was developed by Zsofia Clemens and Csaba Toth, the brains behind a clinic in Hungary called Paleomedicina.

Potential advantages of the diet are:

Better efficacy than the classical ketogenic diet. Zsofia Clemens states in 14:55 of this interview that all but 1 patient became seizure free on the diet, although not all patients adhere to the diet fully. The efficacy is much better than the ketogenic diet, which results in seizure freedom for roughly a tenth of patients.

For information on the efficacy of the ketogenic diet, refer to the Efficacy Demonstrated section in this paper by Eric Kossoff and his colleagues on page 537: “In general, 10%–15% of children who initiated the diet were seizure free 1 year later, 30% had a 90% reduction in seizures, and 40% to 50% found that the diet was either too difficult to continue or insufficiently effective and therefore discontinued it during the first 6 months.”

than the classical ketogenic diet. Zsofia Clemens states in 14:55 of this interview that all but 1 patient became seizure free on the diet, although not all patients adhere to the diet fully. The efficacy is much better than the ketogenic diet, which results in seizure freedom for roughly a tenth of patients. For information on the efficacy of the ketogenic diet, refer to the Efficacy Demonstrated section in this paper by Eric Kossoff and his colleagues on page 537: “In general, 10%–15% of children who initiated the diet were seizure free 1 year later, 30% had a 90% reduction in seizures, and 40% to 50% found that the diet was either too difficult to continue or insufficiently effective and therefore discontinued it during the first 6 months.” Meat-only diets happen to reverse a wide range of autoimmune diseases as long as the diet is maintained. One theory is that intestinal permeability is the mechanism behind this phenomenon. I have not come across any information on whether the diet affects epilepsy with an autoimmune origin.

Fewer side effects than the classical ketogenic diet, which has sometimes been reported to result in slower growth in children. The earlier 2013 case study noted that the 7-year-old child’s weight and height did not change in the 2 years prior to the PKD diet. After the diet, she gained 3 kg (19 to 22kg), and grown 6 cm (110 to 116cm) in 4 months. She gained seizure freedom in 6 weeks after starting the diet.

Paleomedicina’s clinical experience has been that there are no lasting side effects of the diet when used to treat patients with and without epilepsy. Initial side effects of the diet include diarrhea, low energy, and headaches; these side effects are temporary and go away. Refer to 56:38 of this interview with Zsofia Clemens.

See my primer on all-meat diets for more details on the PKD diet.

Known causes

If epilepsy does not respond to standard treatments, it may be worthwhile to investigate the cause of the epilepsy.

Misdiagnosis

Various health conditions that are not epilepsy can cause seizures.

Misdiagnosis is quite common as estimates range from 20% to 30% of epileptics being misdiagnosed (refer to the discussion regarding estimates at the beginning of the article “Misdiagnosis of Epilepsy: Many Seizure-Like Attacks Have a Cardiovascular Cause“). The problem partly exists because a clinician often relies on descriptions of the seizure (or seizure-like movements) and does not observe the seizure directly. EEG recordings taken when the patient is not having a seizure (interictal EEG) can be misinterpreted and lead to a misdiagnosis. Selim Benbadis wrote an interesting editorial on EEG where he argues:

Yes, EEGs can be bad for you. This is why many feel that ‘‘routine interictal EEG recording is one of the most abused investigations in clinical medicine and is unquestionably responsible for great human suffering’’ [23]. Unfortunately, this is one thing on which almost all epileptologists agree.

The review article “Misdiagnosis in epilepsy: a review and recognition of diagnostic uncertainty” (abstract, full paper) also discusses why misdiagnosis is a clinical reality (even among epilepsy specialists). The authors argue:

The available evidence suggests that acknowledging diagnostic uncertainty in epilepsy reduces misdiagnosis rates. Trials of treatment in undiagnosed attacks are generally not recommended. Where present, uncertainty should be shared with the patient and other physicians involved in their care.

The most common conditions misdiagnosed as epilepsy are:

Syncope, or fainting. Not enough oxygen (hypoxia) to the brain can cause a loss of consciousness. There are often abnormal movements and myoclonic jerks that can be mistaken for seizures. To see what syncope looks like in healthy volunteers who make themselves faint, watch this video on Youtube.

PNES (psychogenic non-epileptic seizures), which will be discussed later on in this post.

Other conditions that can be mistaken for epilepsy include but are not limited to:

Low blood sugar (hypoglycemia). One cause of this is poorly-managed diabetes.

Migraine (severe or moderate headaches).

Hypnic jerks. These involuntary twitches occur when a person is beginning to fall asleep. They are extremely common.

Benign paroxysmal positional vertigo. Problems in the inner ear cause a brief period of vertigo, a spinning sensation, or intense dizziness.

Alcohol withdrawal.

In children with concerned parents: daydreaming, night terrors, ritualistic movements, parents being overly anxious, and parents fabricating illness in their child. (See Diagnoses made in a secondary care “fits, faints, and funny turns” clinic.)

A doctor that specializes in epilepsy (epileptologist) should be less likely to misdiagnose epilepsy than a more generalized doctor. Examples of tests used to investigate a diagnosis include taking a detailed history of the patient’s seizures/attacks, the video EEG, and the head-up tilt test (for syncope). As smartphones are widespread nowadays, recording a video of the seizure or seizure-like attack may be helpful in diagnosis.

PNES (Psychogenic Non Epileptic Seizures)

PNES refers to seizures that are thought to have a psychological trigger/origin. Notable differences from epilepsy are:

Unfortunately, the stigma surrounding mental health conditions may make it difficult for some patients to accept a PNES diagnosis. Society sometimes views mental health patients as ‘faking it’ for attention, exaggerating it, or being weak-willed because they can’t ‘tough it out’. In the case of PNES, there is the questionable view among some healthcare professionals that the seizures are voluntary and that patients ‘choose’ to behave in a socially-inappropriate manner.

While it is known that seizures can be induced by psychological suggestion (e.g. giving a placebo injection that does nothing), it is unclear as to whether or not all cases diagnosed as PNES are actually seizures caused by psychological forces. Rueber and Brown (abstract, full paper) note:

The term [PNES] is potentially problematic, however, as it makes (arguably unsubstantiated) presumptions about the etiology of these events, whilst maintaining an unhelpful narrative about the distinction between mental and physiological processes.

Accurate diagnosis

A correct diagnosis can be difficult. The 2011 review Differentiating between nonepileptic

and epileptic seizures notes that “clinicians can find differentiating between PNES and epileptic seizures challenging”. A video EEG (recording the patient on video while taking EEG readings) is considered to have high accuracy and to be the most accurate method. However, the review notes: “Sometimes video-EEG recordings are not fully diagnostic”. Epileptic seizures can occur without abnormal EEG readings.

It is possible to have both PNES and epilepsy. Some estimate that a tenth of PNES patients also have epilepsy.

Getting help

The website Non Epileptic Seizures.com has a wealth of resources for those diagnosed with PNES. See their frequently asked questions and their listing of treatment sites.

De-prescribing

A 2005 study on slowly discontinuing drugs in PNES patients found: “With appropriate diagnostic investigation and surveillance during follow up withdrawal of AED can be achieved safely in patients with NES.” Non-epileptic seizures declined in the group, though it is unclear if the discontinuation of AED had any effect on the frequency of seizures. The tapering schedule is listed in the appendix of the article.

In two patients, AEDs were restarted because of another doctor putting them back on AEDs. In both cases the patients were withdrawn from drugs successfully.

Prevalence

The prevalence of PNES among those referred to epilepsy centers is roughly 10-20% (*rough estimate). The prevalence among epileptics is likely lower.

Other names

This condition is also called:

NEAD (nonepileptic attack disorder)

Psychological nonepileptic events

Dissociative seizures

Conversion seizures

Pseudoseizures*

Hysterical seizures*

*Healthcare professionals should avoid the use of the last two terms. The “pseudo” in pseudoseizures can give the false impression that the seizures are faked. Hysterical seizures is not a great name because the word hysteria is derived from the Greek word for uterus; PNES has nothing to do with the uterus especially when it occurs in men.

Autoimmune

Autoimmune epilepsy can be diagnosed with tests such as:

Antibody tests. Here is a long list of some antibodies that can be tested for: Antiglial/Antineuronal nuclear antibody type 1 1

Collapsin response-mediator protein 5 (CRMP-5) 1

Ma2 1

Voltage-gated potassium channel (VGKC) complex 1

Glutamic acid decarboxylase 65 (GAD65) 1

N-methyl-D-aspartate (NMDA) 1

γ-aminobutyric acid B 1

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) 1

Leucine-rich, glioma-inactivated 1 (LGI1), a protein associated with the voltage-gated potassium channel (VGKC) complex 2

Contactin-associated protein-like 2 (CASPR2) 2

Contactin-2 2

Glycine receptor (GLY-R) 3

Folate receptor 4

1 Quek AML, Britton JW, McKeon A, et al. Autoimmune Epilepsy : Clinical Characteristics and Response to Immunotherapy . Arch Neurol. 2012;69(5):582–593. doi:10.1001/archneurol.2011.2985

Quek AML, Britton JW, McKeon A, et al. Autoimmune Epilepsy . Arch Neurol. 2012;69(5):582–593. doi:10.1001/archneurol.2011.2985 2 Kraichely, Robert E., et al. “Neural autoantibody profile of primary achalasia.” Digestive diseases and sciences 55.2 (2010): 307-311.

Kraichely, Robert E., et al. “Neural autoantibody profile of primary achalasia.” 55.2 (2010): 307-311. 3 Bien, Christian G., and Jan Bauer. “Autoimmune epilepsies.” Neurotherapeutics 11.2 (2014): 311-318.

Bien, Christian G., and Jan Bauer. “Autoimmune epilepsies.” 11.2 (2014): 311-318. 4Steele, Sonya U., et al. “Electroencephalographic and seizure manifestations in two patients with folate receptor autoimmune antibody-mediated primary cerebral folate deficiency.” Epilepsy & Behavior 24.4 (2012): 507-512. Cerebrospinal fluid indicating inflammation. MRI (magnetic resonance imaging) suggesting inflammation. CT or PET scan of the entire body. Cancerous tumors can trigger an immune response that affect another part of the body (paraneoplastic syndromes).

Another approach to diagnosis is to provide immunotherapy treatment in situations where autoimmune epilepsy is highly suspected. This is generally done in the context of a hospital where patients have prolonged and potentially dangerous seizures (status epilepticus) that require immediate medical care. Immune-suppressing corticosteroids may also be given in patients with certain epilepsy syndromes.

Note that the antibody tests aren’t always perfect. However, they are useful in identifying cases that will likely respond to immunotherapy (drugs that suppress the immune system). We know from other autoimmune diseases that many but not all patients will respond to immunotherapy; it is generally effective but does not always succeed. We also know that many autoimmune diseases (e.g. celiac disease, rheumatoid arthritis) can be treated with diet; however, there is currently no information as to whether or not diets like the paleo ketogenic diet have an effect on autoimmune epilepsy.

Prevalence

One study by the Nuffield Department of Clinical Neurosciences in Oxford found neurologic antibodies in 11% of patients regardless of whether they were newly diagnosed or had longstanding epilepsy.

Celiac disease and gluten sensitivity

According to a 2018 review paper:

“ Patients with epilepsy of unknown aetiology [unknown cause] should be investigated for serological markers [blood tests for AGA, tTG, EMA] of gluten sensitivity as such patients may benefit from a GFD [gluten-free diet].” Note that the authors of the paper are of the opinion that a biopsy to test for celiac disease is not entirely relevant. It is possible to have gluten sensitivity that causes epilepsy without having celiac disease.

[blood tests for AGA, tTG, EMA] of gluten sensitivity as such patients may benefit from a GFD [gluten-free diet].” Note that the authors of the paper are of the opinion that a biopsy to test for celiac disease is not entirely relevant. It is possible to have gluten sensitivity that causes epilepsy without having celiac disease. Celiac disease is over 2 times as common in epileptics ( roughly 2.1% ) compared to the general population. Among patients with epilepsy of unknown cause, the prevalence of gluten sensitivity (defined as patients with positive blood tests) is roughly 3.8% .

) compared to the general population. Among patients with epilepsy of unknown cause, the prevalence of gluten sensitivity (defined as patients with positive blood tests) is . In some patients, there is a cluster of symptoms (CEC syndrome) where patients exhibit 3 characteristics: celiac disease, epilepsy and cerebral calcifications that show up on CT or MRI brain scans. In these cases, a gluten-free diet is effective in 53% of patients. Patients see reduced seizures, can reduce their dosage of AEDs, or are able to stop their AEDs.

Currently, knowledge about gluten sensitivity among epileptologists may be quite low despite the scientific literature describing it for decades. Some reviews on difficult-to-treat (“refractory”) epilepsy do not mention gluten sensitivity, celiac disease, or CEC syndrome at all (example).

GLUT1 deficiency syndrome

The diagnosis for this syndrome is typically confirmed with one or both of the following tests. Both tests can have a low rate of false positives and/or false negatives.

Lumbar puncture . This test measures glucose levels in cerebrospinal fluid. There are some ‘grey area’ situations where the measurement is ambiguous and may lead to an incorrect negative test result. See the paper “GLUT1 deficiency syndrome 2013: Current state of the art” for more information.

. This test measures glucose levels in cerebrospinal fluid. There are some ‘grey area’ situations where the measurement is ambiguous and may lead to an incorrect negative test result. See the paper “GLUT1 deficiency syndrome 2013: Current state of the art” for more information. Molecular analysis of the SLC2A1 gene, which is basically genetic testing. False negatives can potentially occur due to the testing method or because the tissue tested has different genetics than brain tissue.

Rare genetic conditions

For an excellent overview of the scientific literature, refer to the paper “When Should Genetic Testing Be Performed in Epilepsy Patients?“. The group most likely to benefit from genetic testing are patients summarized as “epilepsy plus”. These are patients who have epilepsy alongside:

Dysmorphic features, which is another way of saying that the child does not have a typical appearance. Use Google Image Search to find examples of what this looks like. Note however that a specific genetic syndrome may not be evident early on.

Intellectual disability

Autism

Cognitive regression

In these “epilepsy plus” patients:

The yield of CMA (chromosomal microarray analysis) is about 5% .

. The yield of sequencing via panel testing or exome sequencing is 20-50%. This testing is more expensive.

If specific genetic variations are found, that information can be used to guide treatment such as what drugs to avoid or to try. Refer to Table 1 from the paper:

Or, refer to the updated version of that table from a presentation that the author gave:

Other known causes

A knowledgeable doctor/specialist can help screen for known causes such as:

Brain tumors or other abnormal growths in the brain. Some of these may be good candidates for surgery.

Epilepsy can occur after brain surgery in epilepsy-free patients. AEDs may be overprescribed in these cases. A 2015 Cochrane review concludes that the use of preventative AED treatments have no effect on reducing seizures post-surgery.

Head trauma / injuries

Stroke (poor blood flow to the brain that causes cell death)

Infectious diseases

Prenatal injury, or injuries to a baby before the baby is born (e.g. infection in the mother, poor nutrition or the baby not receiving enough oxygen).

Tapeworm parasites can travel to the brain and form cysts (neurocysticercosis). These infections are rare in developed countries and are more common in developing countries.

Severe nutrient deficiencies: thiamine (vitamin B1), pyridoxine (vitamin B6), and magnesium.

Cerebral folate deficiency. This is caused by impaired transport of folate across the blood-brain barrier into the central nervous system. This condition affects infants.

Treating epilepsy with AEDs (“anti”-epileptic drugs)

For many though not all epilepsy syndromes, there is very strong scientific evidence that AEDs are successful for many (seizure freedom with tolerable side effects). For an overview of the literature, refer to the International League Against Epilepsy’s 2013 review of the topic. Table 4 in that paper summarizes the level of evidence for various seizure types where Class I is the highest level of evidence. According to that table (shown below), certain epilepsy syndromes lack high-quality studies on the effectiveness of AEDs.

I would note some important caveats to AEDs:

AEDs sometimes increase rather than decrease the frequency of seizures. One good review is the 2007 paper “Aggravation of epilepsy by anti-epileptic drugs“. A notable area of aggravation risk is the use of carbamazepine (Tegretol) in idiopathic generalized and myoclonic epilepsies. The terms “anti”-epileptic drug and “anti”-convulsant may be misleading. Blindly throwing AEDs at the problem can aggravate seizures, lead to unnecessary side effects, and/or delay critical treatment. Due to the large number of known causes of epilepsy, we now know that specific types of epilepsy can be aggravated by AEDs or generally do not respond to AEDs. Despite that, it may be uncommon to screen for such conditions. (To be fair, screening for certain conditions can be cost-ineffective due to the rarity of that condition and/or the high cost of testing.) With autoimmune epilepsies and gluten sensitivity, there is a growing body of papers that argue for prompt diagnosis and treatment (though the supporting evidence may not be that strong at the moment). See: This 2015 review paper on autoimmune epilepsy argues: “Early recognition of autoimmune epilepsy is paramount as prompt initiation of treatment is associated with better outcomes,28,30,104 but establishing the diagnosis can be challenging.” The 1992 paper “Coeliac disease, epilepsy, and cerebral calcifications” (abstract, full paper) notes that the patients who implemented a gluten-free diet (GFD) shortly after the onset of epilepsy tended to respond better to the GFD. However, correlation does not prove causation. The efficacy of AEDs isn’t always durable. One example can be found in figure 1 of the paper “Comparison of Carbamazepine, Phenobarbital, Phenytoin, and Primidone in Partial and Secondarily Generalized Tonic–Clonic Seizures” (abstract, full paper).



Over time, some patients discontinued their drug because of side effects / toxicity, failure to control seizures, or a combination of both. Doctors may be biased towards putting patients on medications and keeping them on medications. Because certain epilepsy syndromes sometimes spontaneously go into remission, it may be desirable to safely discontinue medication to check if this has happened so that the side effects of medication can be avoided. There may be a bias to keep patients on medication while the same doctors may also be biased towards discontinuing the ketogenic diet due to its side effects (and lifestyle impact). This bias can exist even though the side effects of medications are arguably greater than those of dietary treatments. This double standard is arbitrary and has no medical or scientific justification. In video EEG testing, doctors may discontinue AEDs to try to induce seizures (the video EEG otherwise has little value if it doesn’t record a seizure). The opposition to discontinuing medication can be arbitrary and inconsistent.

Refer to Appendix B for information on de-prescribing AEDs. Suddenly discontinuing medication is dangerous for certain medications. Patients may not necessarily adhere to their medications for various reasons (e.g. side effects, disruption in getting refills especially for controlled substances, etc.). Doctors should inform their patients if a drug is known to be dangerous or problematic if suddenly discontinued rather than slowly withdrawn. Such drugs include: Benzodiazepines such as clorazepate (Tranxene), clobazam (Frisium / Urbanol / Onfi / Tapclob), clonazepam (Klonopin), diazepam (Valium), lorazepam (Ativan), and nitrazepam (Alodorm / Mogadon). Corticosteroids (e.g. prednisone), which are used for certain epilepsy syndromes. Phenobarbital (Luminal). Phenytoin (Dilantin). AEDs can be inappropriate for certain epilepsies and non-epileptic seizures. It is known that certain drugs have a tendency to increase seizures for certain types of epilepsy. For example, patients with a positive genetic test for SCN1A gene variations should generally avoid sodium channel blockers like phenytoin/Dilantin and lamotrigine/Lamictal. However, it is generally not a standard practice for doctors to screen this gene prior to recommending such drugs.

Patients with PNES (psychogenic nonepileptic seizures) are often misdiagnosed with epilepsy for years. One paper states: “the management of PNES as epileptic seizures can lead to significant iatrogenic harm” (harm caused by medical examination or treatment). We do not know if AEDs increase/decrease the risk of SUDEP (sudden unexplained death in epilepsy). One paper suggests that polytherapy (the use of more than one drug at once) and high carbamazepine levels may lead to higher risk of SUDEP. However, all of the current data on SUDEP simply looks at correlations. As correlations do not prove causation, the current level of evidence on SUDEP is weak. While some doctors may bring up SUDEP to try to scare patients into taking AEDs (“a discussion of medication compliance“), please keep in mind that correlations do not prove causation.

Some other treatments for epilepsy

CBD and medical marijuana

A 2014 Cochrane review summarized the lack of quality research on this topic: “No reliable conclusions can be drawn at present regarding the efficacy of cannabinoids as a treatment for epilepsy”.

Surgery

While there are caveats to surgery, the two randomized controlled trials that compared surgery (plus medication) to medication suggest that its benefits (strongly) outweigh the downsides. The studies are:

Wiebe, Samuel, et al. “A randomized, controlled trial of surgery for temporal-lobe epilepsy.” New England Journal of Medicine 345.5 (2001): 311-318. (Full paper.)

This study found that the surgery group was more likely to be seizure-free (38% versus 3% after 1 year) and scored better on quality of life metrics. 4 out of 40 (10%) of the patients in the surgery group had adverse effects from surgery. While visual field defects occurred in 22 out of 40 (55%) of patients in the surgery group, the authors of the paper seem to be discussing serious adverse effects when they say ‘adverse effects’. It is unclear if the visual field defects impacted driving ability as driving ability was not discussed in the paper. A different study suggests that “around 25%” of patients who have undergone temporal lobe surgery have visual field defects severe enough to fail UK’s DVLA vision criteria recommendations. It is unclear as to whether or not the Wiebe at al. study downplayed serious adverse effects.

This study found that the surgery group was more likely to be seizure-free (38% versus 3% after 1 year) and scored better on quality of life metrics. 4 out of 40 (10%) of the patients in the surgery group had adverse effects from surgery. While visual field defects occurred in 22 out of 40 (55%) of patients in the surgery group, the authors of the paper seem to be discussing serious adverse effects when they say ‘adverse effects’. It is unclear if the visual field defects impacted driving ability as driving ability was not discussed in the paper. A different study suggests that “around 25%” of patients who have undergone temporal lobe surgery have visual field defects severe enough to fail UK’s DVLA vision criteria recommendations. It is unclear as to whether or not the Wiebe at al. study downplayed serious adverse effects. Engel, Jerome, et al. “Early surgical therapy for drug-resistant temporal lobe epilepsy: a randomized trial.” Jama 307.9 (2012): 922-930. (Full paper.)

This trial was stopped early due to difficulties in recruiting patients.

Both of the studies examined the removal of parts of the temporal lobe (temporal lobe resection). Removing other parts of the brain generally leads to poorer outcomes and is less well studied (e.g. there are no randomized clinical trials to support those surgeries).

Surgery can be thought of as an epilepsy-modifying procedure rather than a cure.

Many surgery patients require AEDs to maintain seizure freedom.

Many “seizure-free” patients still experience auras.

The effect of surgery isn’t always durable as the rate of seizure freedom declines over time. Some patients eventually receive more than one surgery.

Some patients see a reduction in seizures rather than seizure freedom. (And of course some do not see any benefits from surgery.)

Surgery has unique side effects. In the study by Wiebe et al., 22/40 (55%) of patients had visual field defects. 2 had declines in verbal memory that interefered with their occupations. 1 patient developed a small thalamic infarct (brain lesion from tissue death), causing sensory abnormalities in the left thigh.

Not all patients are suitable for surgery. Patients have to be screened for epilepsy that is thought to originate from the temporal lobe or another part of the brain that can be removed with few side effects. It is not well understood as to why surgery greatly reduces seizures in most patients.

A skeptical paper from 1994 (abstract, full paper) mentions an interesting study which looked at patients who underwent brain surgery (craniotomy) for epilepsy where no brain tissue was removed. This was just as effective as the control group who had undergone anterior temporal lobectomy (removal of part of the temporal lobe).

One of the most interesting studies done in epilepsy surgery was conducted at the NIH by a neurosurgeon who retrospectively compared a group of 106 patients who received an anterior temporal lobectomy for epilepsy, and another group of 25 epilepsy patients who had a craniotomy for the same reasons as the first group but had no excision of cerebral tissue. Two-thirds of the patients in each group experienced improved seizure control. There was no statistical difference between groups. This was reported as an abstract43, making it difficult to retrieve from the medical literature. Apparently, the neurosurgeon proposed to follow up these observations with a prospective randomized trial, but was forced to terminate the study after the second patient.

Unfortunately, there does not seem to be any follow-up research looking into why brain surgery can work without removing any brain tissue.

Recap

One major issue in the treatment of epilepsy is that there are ideologies in the medical field. Some doctors express the belief that only about 30% of cases of epilepsy have a known cause. Here is a slide from a presentation by Dr. David Ficker:

While it may be true that no known cause will be detected for most cases of epilepsy, this ideology ignores the science on gluten sensitivity, autoimmunity, misdiagnosis, food intolerances, and particular genes.

A similar problem exists when it comes to treatment. Some doctors often use the phrase “drug resistant epilepsy” as they only consider drugs in treating epilepsy before they push for surgery or VNS implants. To these doctors, drug resistant and treatment resistant are the same thing (see 14:29 of Dr. Ficker’s presentation). Such doctors may briefly mention the ketogenic diet (see 16:47 of Dr. Ficker’s presentation) before dismissing it as “too difficult”, even though many everyday people (who usually do not have epilepsy) try the non-medical version of the ketogenic diet simply to lose weight. Their ideology may also ignore effective treatments for certain known causes.

At the end of the day, epilepsy is a complicated condition to diagnose accurately (and to treat) as there are so many different causes. Most of the diagnostic tests that are available aren’t 100% reliable, making an accurate diagnosis difficult. Patients need knowledgeable and caring doctors to figure out what type of epilepsy they have and how to best treat it. However, this does not always happen as many epileptics are misdiagnosed or have a known cause that is undiagnosed.

If you or a loved one is affected by epilepsy, I don’t have any simple or easy answers for you. You can try the ‘cheat sheet’ in Appendix C to see if there are noticeable signs that there may be a known cause that should be screened for. If the cause of epilepsy remains unknown, you can ask your doctor about diagnostic tests that could be used to try to identify the cause:

Video EEG is considered the best test for diagnosing PNES.

is considered the best test for diagnosing PNES. Head-up tilt test and/or other tests to diagnose syncope as well as other causes that may be confused with epilepsy.

and/or other tests to diagnose syncope as well as other causes that may be confused with epilepsy. Antibody tests or other tests for autoimmune epilepsy.

for autoimmune epilepsy. Antibody tests for gluten sensitivity.

for gluten sensitivity. Brain scans (e.g. CT or MRI) to look for brain tumors and other abnormalities.

to look for brain tumors and other abnormalities. Doing a diet trial to see if the epilepsy responds to diet.

The list above is by no means exhaustive so there is value in seeing a specialist who is knowledgeable about epilepsy. At the same time, there may be certain tests and diagnoses that the specialist may overlook. Doctors may not be familiar with gluten sensitivity or CEC syndrome; the Epilepsy Foundation website for example does not have any information on it. So, there is a time and place for patients to be their own advocates so that they are appropriately diagnosed (within the limits of current medical testing) and receive the correct treatment for their condition.

Disclaimer: Please don’t use the information on this blog post to do something that might cause harm. You probably shouldn’t self-diagnose and blindly assume that your diagnosis is accurate. Do not suddenly discontinue medication without medical help as this can be dangerous for many drugs used to treat epilepsy.

If you are affected by epilepsy, I wish you the best of luck on your journey.

Appendix A: The ketogenic diet as a treatment option

A 2014 review of the literature summarizes the pros and cons of the diet well:

In summary, KD [ketogenic diet] and MAD [modified Atkins diet] treatment show modest efficacy, although in some patients the effect is remarkable. The diets are well tolerated, but often discontinued because of their restrictiveness. In patients willing to try dietary treatment, the effect is seen quickly, giving patients the option whether to continue the treatment.

Some points of interest about the diet:

It works in adults. The 2014 review mentioned earlier summarizes the research on adults. However, it is likely that adherence is lower in adults than children and infants.

Is it difficult to adhere to? This varies from person to person. Some people love the ketogenic diet because they experience seizure freedom without the side effects of drugs, are no longer obese, feel improved mental clarity (no “brain fog”), and/or see other unexpected health benefits. Others find the initial adaptation period to be brutal, dislike how socially restrictive the diet is, and/or find the diet difficult to stick to. Perhaps the best way to find out is to simply try the diet.

The medical version of the ketogenic diet differs from the popular version that people use to lose weight. Some notable differences include:

Specific macronutrient ratios. The idea is to ensure a high level of ketosis to mimic what happens during fasting.

Careful weighing and measuring of food to ensure that the macronutrient ratios are met. This is time-consuming and less convenient.

Calorie restriction / a calorie target.

Water restriction. (Wheless argues against this practice.)

The “classical” version of the ketogenic diet begins with fasting in a hospital. (The classical ketogenic diet typically differs from the diet used in the 1920s due to the use of modern foods such as vegetable/plant oils rather than animal fats.)

It is unclear if these differences lead to a medical benefit (or harm). Similar diets used to treat epilepsy do away with many of these restrictions to make the diet easier to follow. The second most studied diet, the Modified Atkins Diet, is shown in some studies to have similar success rates and is shown in other studies to have somewhat lower success rates. The Charlie Foundation website has a good summary of the differences between the various diets used to treat epilepsy.

There are side effects. While one can argue that the ketogenic diet has fewer side effects than many AEDs, it does sometimes lead to side effects. One serious side effect is kidney stones (renal calculi) in 3-7% of children on the diet. This number could be lower via supplementation with citrate / Polycitra K where risk of kidney stones is high. Growth in children may be lower, although there is conflicting data.

The diet can lead to cholesterol levels that are considered unhealthy, although this is controversial because the scientific evidence suggests that cholesterol levels are extremely unreliable in predicting death from cardiovascular disease. For example, the Minnesota Coronary Experiment found that lowering of cholesterol was associated with higher rather than lower mortality.

For a discussion of other side effects, see:

The diet is the treatment of choice for specific conditions. Table 1 of this 2009 review paper lists epilepsy syndromes and other conditions where it is particularly beneficial:

Glucose transporter protein 1 (GLUT‐1) deficiency

Pyruvate dehydrogenase deficiency (PDHD)

Myoclonic‐astatic epilepsy (Doose syndrome)

Tuberous sclerosis complex

Rett syndrome

Severe myoclonic epilepsy of infancy (Dravet syndrome)

Infantile spasms

Children receiving only formula (infants or enterally fed patients)

Selected mitochondrial disorders

Glycogenosis type V

Landau‐Kleffner syndrome

Lafora body disease

Subacute sclerosing panencephalitis (SSPE)

For more information on how to implement a ketogenic diet (e.g. to find a dietitian who understands the diet), The Charlie Foundation’s website has a wealth of information.

Appendix B: De-prescribing

There have been a few controlled trials on the discontinuation of AEDs. These studies looked at patients who have been seizure-free for some period of time. In general, staying on AEDs leads to a somewhat higher chance of seizure freedom. However, there is still a chance of relapse regardless of whether or not AEDs are discontinued. More than half of patients remain seizure-free after discontinuing AEDs.

It is unclear from the trials as to whether or not the added risk of relapse is better or worse than the side effects of staying on AEDs; the papers generally do not address that important issue or publish data on it such as the rate of side effects from AEDs.

Bessant et al. compared no withdrawal versus slow withdrawal. Seizure freedom was somewhat higher in the no withdrawal group.



Bessant, P., et al. “Randomised study of antiepileptic drug withdrawal in patients in remission.” The Lancet 337.8751 (1991): 1175-1180. (abstract, full paper)

Similar results were reported by Swedish researchers who compared staying on AEDs for 1 year versus 3 years (abstract, full paper). Their second paper on their study indicates that EEG is highly unreliable in predicting relapse and the trial did not find a statistically significant result (full paper). It also noted that EEG readings for a single patient would also vary wildly between recordings (see Table 3). The authors argue that there may be some situations in which EEG may be useful; further research would be needed to support their theory.

A study which looked at a 6-week versus a 9-month taper period did not find a statistically significant difference between the two.

Warning: For many drugs used to treat epilepsy, it can be dangerous to suddenly discontinue drugs (e.g. seizures, withdrawal, etc.). Talk to a doctor (or pharmacist) and get information on how to safely discontinue medication if it is appropriate for you.

Appendix C: Cheat sheet

If symptoms look like any of the items that follow, the cause may (or may not) be a type of epilepsy with a known treatment option.

Please note that the list below is not exhaustive. It does not cover important areas such as misdiagnosis, various causes of non-epileptic seizures, various diagnostic tests (e.g. blood tests, lumbar puncture, video EEG, CT scan, PET, MRI, etc.), etc. etc. You should probably see a doctor (especially one who specializes in epilepsy) as a doctor will screen for many possibilities not listed below.

Migraine or hyperkinetic behaviour (e.g. hyperactivity) → Oligoantigenic diet (an elimination diet that avoids patient-specific food intolerances).

Dysmorphic features (the child does not look typical; use Google Image Search to find examples), intellectual disability, autism, and cognitive regression → Genetic testing. See the paper – “When Should Genetic Testing Be Performed in Epilepsy Patients?“.

GLUT-1 deficiency syndrome

Gluten sensitivity

Cerebral calcifications found on CT or MRI scan → Screen for gluten sensitivity.

Epilepsy of unknown aetiology/cause → Screen for gluten sensitivity via AGA, tTG and EMA blood tests. (See “Gluten sensitivity and epilepsy: a systematic review“.)

Investigate autoimmune epilepsy if there are features suggestive of it:

Sudden and dramatic onset, or somewhat sudden onset (acute or sub-acute onset). 2

Multiple seizure types or faciobrachial dystonic seizures. 2 There are videos of faciobrachial dystonic seizures on Youtube (here, here, etc.) if you would like to know what they look like.

There are videos of faciobrachial dystonic seizures on Youtube (here, here, etc.) if you would like to know what they look like. There is an unusually high seizure frequency. 1,2

Intra-individual seizure variability or multifocality. 1,2

Associated neurological or psychiatric problems. 1

Anti-epileptic drug (AED) resistance. 1,2

Personal or family history of autoimmunity. 1,2

Viral prodrome (viral infection). 2

Evidence of central nervous system inflammation. 2

Detection of neural antibody. 2

Recent or past tumors / neoplasia.1,2

1From the slide at 23:40 of this presentation.

2From “Utility of an immunotherapy trial in evaluating patients with presumed autoimmune epilepsy“. (PMID: 24706013)