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Abstract: This paper discusses childhood absence epilepsy (CAE) and reviews outcomes from standard anti-seizure medication. Given the possibility of pharmacoresistance and the fact that treatment-resistant epilepsy in adulthood can be life-threatening, other complementary approaches are discussed. Dietary approaches, such as the ketogenic diet, modified Atkins diet, and the Paleolithic ketogenic diet are reviewed. The modified Atkins diet appears to have the most robust evidence of efficacy compared to the other diets for CAE, and can be offered to patients, possibly as an alternative to anti-seizure medication. Specific orthomolecular approaches, i.e., gamma-aminobutyric acid and phosphatidylserine, are advocated as complementary treatments since compelling (preliminary) data shows significant reductions in seizure activity among subjects of all ages with absence seizures. Additional information pertaining to a prior published report is also included. This advances a transdiagnostic orthomolecular approach to complement anti-seizure medication with a restorative regimen among treatment-resistant patients with epilepsy.
The disease of epilepsy is marked by repeated, but intermittent, episodes of seizure activity "in which synchronous activity of nerve cells increases so that a gigantic hyperpolarization of neurons spreads over a large area in an atypical and abnormal manner" (Banich & Compton, 2011, p. 491). A form of generalized seizures, childhood absence epilepsy (CAE) or childhood absence seizures (formerly referred to as petit mal seizures), involves the entire body when seizure activity is present, and accounts for 10-17% of all childhood-onset epilepsy cases (Berg et al, 2000; Jallon et al, 2001). According to The International League Against Epilepsy, CAE is characterized by rather frequent staring spell absences (happening several to possibly numerous times each day) in children of school age - usually having a peak manifestation at around six to seven years of age - and electroencephalographic (EEG) findings of bilateral, synchronous, and symmetric spike-wave discharges at 3 Hz (Proposal for revised classification of epilepsies and epileptic syndromes, 1989).
If one were to observe a child having absence seizures, there would be an "abrupt and brief impairment of consciousness, with interruptions of the ongoing activity, and usually unresponsiveness" lasting anywhere from several to twenty seconds, which is then followed by a sudden "resumption of the pre-absence activity" as though it had never been interrupted (Panayiotopoulos, 1999, p. 351). While CAE typically presents with impairment of consciousness, many patients also exhibit other clinical manifestations, such as mild clonic jerks (e.g., of the eyelids or corner of the mouth), atonic components (e.g., relaxation of grip and dropping of the arms), tonic muscular contractions (e.g., arching of the trunk), automatisms (e.g., aimless walking or lip licking), and even autonomic components like pallor, sweating, and less commonly, urinary incontinence (Panayiotopoulos, 1999).
This form of epilepsy is often thought to be rather benign, but yet the remission rates are variable, and affected children can experience cognitive deficits and long-term psychosocial difficulties (Bouma et al, 1996; Wirrell et al, 1997; Pavone et al, 2001). A study identified some of the general psychosocial problems encountered by children with CAE such as social isolation and low self-esteem, but these children also experienced higher rates of comorbid psychiatric symptoms, such as anxiety (nervousness and thought rumination) and depression (sadness and crying) (Vega et al, 2011).
With respect to mortality, a population-based cohort study that followed patients for 40 years demonstrated that being diagnosed with epilepsy during childhood was associated with a substantial risk of epilepsy-related death that persisted into adulthood (Sillanpää & Shinnar, 2010). Specifically, "the risk of sudden, unexplained death among subjects with epilepsy was 7% (95% CI, 5 to 12) among all subjects and 12% (95% CI, 8 to 20) among those who were not in 5-year terminal remission and not receiving medication" (p. 2527). The risk of death can also be ascertained by looking at the hazard ratio (HR), which (based on this study) refers to the probability of dying from epilepsy compared to deaths among individuals without epilepsy. For instance, among subjects that have not achieved a five-year terminal remission, the HR for sudden, unexplained deaths was determined to be 5.2 (95% CI, 1.4 to 18.5). For epilepsy-related deaths among subjects that have not achieved a five-year terminal remission, the HR was determined to be 6.4 (95% CI, 2.2 to 18.8). As can be seen, a diagnosis of epilepsy in childhood presents serious threats to an individual's overall mortality especially if the disease remains poorly controlled or resistant to treatment.
Given how challenging CAE can be, exploring complementary avenues of treatment could potentially enhance outcomes from standard treatment. The first part of this paper will review a highly-publicized study that assessed the efficacy of standard treatment among subjects with CAE. Then the paper will review several complementary approaches that have efficacy in reducing seizure activity among subjects with CAE. The final part on CAE will highlight a case in which an integrative approach demonstrated a cessation of seizure activity in a patient with CAE, although this is very preliminary. This paper will also present an addendum to a prior report (i.e., "The Adjunctive Treatment of Epilepsy with Orthomolecular Substances") published in another journal (Prousky, 2014).
Outcomes from Standard Treatment
As was mentioned earlier, treatment outcomes for CAE are variable. The most widely regarded study on the treatment for CAE evaluated the most commonly prescribed anti-seizure medications for efficacy - i.e., ethosuximide (ES), valproic acid (VA), and lamotrigine (LT) - in a double-blind, randomized, controlled clinical trial (Glauser et al, 2010). Subjects (n=453; median age: 7 years and 5 months; age range: 2.5-13 years old) were randomized to one of these treatments over a 16-week period (sometimes, up to 20 weeks). All the subjects had CAE of new onset. Doses of all medications were increased every 1-2 weeks over the study period until the subjects became seizure-free or adverse effects limited the prescribed dose.
The ES group (Glauser et al, 2010) was comprised of 156 patients, of which two dropped out. Subjects began with daily doses of 10 mg/kg of body weight, and were titrated up to doses as high as 60 mg/kg of body weight (maximal daily dose of 2,000 mg was prescribed if necessary). The mean daily dose (±SD) for 94 subjects in the ES group at final evaluation was 33.5±15.3 mg/kg of body weight, with 17.5% of the group requiring the maximal dose of medication. The results showed the following:
- Lack of seizure control in 14% ([22/154]*100);
- Intolerable adverse effects in 24% ([37/154]*100);
- Adverse psychological effects in 8% ([12/154]*100);
- Attentional problems in 33% ([35/106]*100);
- Overall treatment failure 47% ([73/154]*100); and
- Seizure-free 53% ([81/154]*100).
Possible adverse effects from ES included gastrointestinal symptoms, drowsiness, lethargy, mood changes, headache, visual changes, allergic rashes (about 5% of patients), aplastic anemia, and agranulocytosis (Wahab, 2010).
The VA group (Glauser et al, 2010) was comprised of 148 patients, of which two dropped out. Subjects began with daily doses of 10 mg/kg of body weight and were titrated up to doses as high as 60 mg/kg of body weight (maximal daily dose of 3,000 mg was prescribed if necessary). The mean daily dose (±SD) for 104 subjects in the VA group at final evaluation was 34.9±15.8 mg/kg of body weight, with 20.5% of the group requiring the maximal dose of medication. The results showed the following:
- Lack of seizure control in 12% ([18/146]*100);
- Intolerable adverse effects in 24% ([35/146]*100);
- Adverse psychological effects in 14% ([20/146]*100);
- Attentional problems in 49% ([52/106]*100);
- Overall treatment failure 42% ([61/146]*100); and
- Seizure-free 58% ([85/146]*100).
Possible adverse effects of VA included tremor, weight gain, dyspepsia, diarrhea, peripheral edema, pancreatitis, hair loss, thrombocytopenia, agranulocytosis, polycystic ovaries, Stevens-Johnson syndrome, hepatotoxicity, and teratogenicity (Wahab, 2010).
The LT group (Glauser et al, 2010) was comprised of 149 patients, of which three dropped out. Subjects began with daily doses of 0.3 mg/kg of body weight and were titrated up to doses as high as 12 mg/kg of body weight (maximal daily dose of 600 mg was prescribed if necessary). The mean daily dose (±SD) for 96 subjects in the LT group at final evaluation was 9.7±6.3 mg/kg of body weight, with 58.9% of the group requiring the maximal dose of medication. The results showed the following:
- Lack of seizure control in 47% ([69/146]*100);
- Intolerable adverse effects in 17% ([25/146]*100);
- Adverse psychological effects in 6% ([9/146]*100);
- Attentional problems in 24% ([25/104]*100);
- Overall treatment failure 71% ([103/146]*100); and
- Seizure-free 29% ([43/146]*100).
Possible adverse effects of LT included dizziness, sedation, headache, diplopia, ataxia, skin rash, and Stevens-Johnson syndrome (Wahab, 2010).
As can be ascertained from Glauser et al (2010), close to 50% of the subjects (i.e., 209 of the 446 children) became seizure-free during the study period. Overall treatment failure occurred in 42-71% of subjects (depending on the anti-seizure medication taken), which meant that a fairly large percentage of subjects failed to achieve complete remission of their seizures during the study. This is a much larger percentage when compared to the inefficacy of anti-seizure medications in general that fail to control seizures in about 30% of patients due to pharmacoresistance (Wahab, 2010). Even when treatment is initiated early (as in CAE), there is no guarantee of long-term remission despite the fact that most patients with epilepsy are treated with anti-seizure medication for the duration of their lives (Wahab, 2010).
With respect to dosing, the average doses in the trial were higher than the initial doses; and maximal doses were needed in about 20% of patients from the ES and VA groups, and almost 60% of patients from the LT group (Glauser et al, 2010). Intolerable side effects were identified in about 20% of subjects, suggesting that the tolerability of the medications was sufficient for the majority of subjects. Problems with attention were evident among a significant minority of the study subjects and persisted even when they became seizure-free, suggesting that such problems might be a core feature of CAE for some children. Overall, the results suggested that ES is the most indicated medication for initial empirical treatment, even though empirical treatment "fails in about 50% of newly diagnosed cases" and is not effective should the seizures evolve into the generalized tonic-clonic type (p. 7).
Complementary Dietary Interventions - Ketogenic Diet, Modified Atkins Diet, and the Paleolithic Ketogenic Diet
Only one published study has reviewed the clinical outcomes from either a ketogenic diet (KD) or modified Atkins diet (MAD) among patients with CAE (Groomes et al, 2011). For readers interested in understanding the macronutrient and other differences between a KD and MAD, please see Table 2 (p. 439) from Kossoff, Cervenka, Henry, Haney, and Turner (2013).
The researchers (Groomes et al, 2011) performed two types of evaluations. The first involved a historical review that assessed publications from 1922 to 2009 related to both the KD and symptoms suggestive of absence seizures (e.g., petit mal), or when the diagnosis was confirmed by standard methods of the time. The second review involved patients at Johns Hopkins Hospital who were prescribed the KD or MAD for CAE and followed from 1993 to 2009.
The historical review (n=133) demonstrated the following results from the KD:
- A total of 69% ([92/133]*100) had a greater than 50% reduction in seizures from the diet;
- A total of 34% ([45/133]*100) became seizure-free for some period of time on the diet;
- It took between 3 days and 3 months to respond to the diet; and
- The diet was continued for 9 weeks, and as long as 3 years among some patients.
The Johns Hopkins study (n=21) as reported by Groomes et al (2011) demonstrated favourable results from either the KD (n=8) or MAD (n=13). With respect to the KD, a total of 25% ([2/8]*100) became seizure-free. With respect to the patients on the MAD, the amount of seizures at baseline (i.e., before dietary changes were made) ranged from 1-150 seizures daily. During the evaluation period, 12 patients were on one anti-seizure medication; seven were on two anti-seizure medications; one patient was on three anti-seizure medications and one patient was on no medication. The patient on no medication, or those on only one anti-seizure medication fared much better compared to patients on two or more anti-seizure medications. The more medicated the patients were the less they benefited from the diet. The following results were obtained from the MAD study:
- A total of 15% ([2/13]*100) became seizure free, with a total of 31% ([4/13]*100) demonstrating greater than 90% reduction in seizures (i.e., meaning that a total of 46% of patients on the diet had an excellent clinical response);
- A total of 46% ([6/13]*100) of patients experienced greater than 50% reduction in seizures; and
- A total of 8% ([1/13]*100) of patients showed no improvement from the diet.
Overall, it took between one to three months to respond to these diets, with greater improvements happening the longer the diet was maintained. Patients did better at three months compared to one month. A total of 48% ([10/21]*100) had a greater than 90% reduction in seizures, and 86% ([18/21]*100) had a greater than 50% reduction in seizures. The researchers concluded that either diet appears to have efficacy for patients with intractable CAE because the majority of patients responded well, and many had periods where they had no seizure activity. As a result, the researchers emphasized that further prospective studies of diets for CAE are warranted.
Adverse effects and other aspects of the KD have been summarized by Kossoff, Zupec-Kania, and Rho (2009). The long-term adverse effects include carnitine deficiency, growth retardation, gastrointestinal symptoms, increased lipids, and kidney stones. More serious adverse effects, according to these researchers, have been reported in fewer patients and include cardiac abnormalities (due to selenium deficiency), Fanconi renal tubular acidosis, and pancreatitis. Moreover, children on a KD for more than six years are at greater risk of developing bone fractures, growth retardation, and kidney stones but, surprisingly, not lipid abnormalities. There are ways of mitigating some of these risks by using a broad-spectrum micronutrient supplement, adding medium chain triglycerides and carnitine to control the dyslipidemia, and adding potassium citrate at the onset of the diet to increase the urine pH and lower the risk of developing kidney stones. Children that demonstrate a greater than 50% seizure response from the KD are encouraged to remain on the diet for at least two years. There is data demonstrating that among children who experienced seizure freedom from the KD, 80% remained seizure-free even two years after discontinuing the diet.
The MAD is associated with fewer adverse effects and better compliance. In a review paper by Sharma and Jain (2014), the more common adverse effects include constipation and vomiting at the onset of treatment, but these gastrointestinal effects typically improve the longer the diet is maintained. Some children can lose weight on the diet, but they tend to be heavier or overweight to begin with. Total cholesterol levels do increase, but the elevations are half that of the levels associated with a KD. Kidney stones, while a concern, have not been reported among children on the diet. It is probably a good idea for the child to take a broad spectrum micronutrient supplement to offset potential deficiencies and/or insufficiencies resulting from the diet. As mentioned earlier, it takes around one to three months to determine if the diet is efficacious. If the response is positive, the diet should be followed for at least two years before it is discontinued to determine if it is required on a long-term basis.
The only other dietary intervention for CAE that has been reported is that of a Paleolithic ketogenic diet. A case report (Clemens et al, 2013) documented the efficacy of the diet for a seven-year-old girl with CAE. The patient was having approximately 50 seizures daily prior to the dietary changes. Once the diagnosis was confirmed following an EEG study, the patient was offered VA, but the parents refused due to their concerns about the medication's adverse effects. The parents then consulted with a physician experienced with the clinical uses of the Paleolithic ketogenic diet and decided to place their child on it. Essentially, the diet consisted of meat, offal (refers to internal organs and entrails of butchered animals), fish, egg, and animal fat without any caloric restrictions. To review what a sample Paleolithic ketogenic diet looks like, please see Table 1 (p. 74). The patient's diet was complemented with vitamin D3 (2,000 IU/day), and omega-3 essential fatty acids (500 mg/day). It took six weeks for the child to become seizure-free on this diet, and this result was maintained for 20 months (i.e., before the paper was published).
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