Down Syndrome and Epilepsy: A Nutritional Connection?

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Thiel R.J., Fowkes S.W. Down syndrome and epilepsy: A nutritional connection? Medical Hypotheses, 2004 Jan; 62(1): 35-44

Non-Asian individuals with Down syndrome are much more likely to develop epileptic seizure disorders than individuals without Down syndrome. Examination of nutrient and metabolite levels in patients with these two seemingly disparate disorders reveals numerous similarities. Compared to individuals without these disorders, individuals with Down syndrome and individuals with seizures may have lower levels of vitamin A, vitamin B1, folate, vitamin B12, vitamin C, magnesium, manganese, selenium, zinc, carnitine, carnosine, choline, and possibly serine. Excesses of copper, cysteine, phenylalanine, and superoxide dismutase are also sometimes encountered in both disorders. In addition to common nutritional lower levels and excesses, disorders of metabolism involving vitamin B6, vitamin D, calcium, and tryptophan may play a common role. This paper hypothesizes that nutritional factors may account for the high joint occurrence of these conditions. Further examination of this data may provide insights into nutritional, metabolic and pharmacological treatments for both conditions.

People with Down syndrome (DS) appear much more likely to develop seizures disorders than the general public. There is no accepted hypothesis for this joint occurrence. This paper hypothesizes that there may be nutritional factors which, at least partially, account for this high joint occurrence.

In DS (also known as trisomy 21), there is an overexpression of the 21st chromosome. Many enzymes that are encoded on the extra 21st chromosome are known to be actively transcribed, which results in overexpression of the enzymes, overconsumption of enzymatic substrates, and overproduction of metabolic end-products. For example, the SOD-1 gene on the 21st chromosome is approximately 50% overexpressed (1,2), which decreases the levels of superoxide (the enzyme's substrate) and increases the levels of hydrogen peroxide (the enzyme’s metabolite, end-product or output). These primary consequences of genetic overexpression may then produce secondary metabolic adaptations as homeostatic systems attempt to compensate. Thus, decreased levels of superoxide might alter levels of nitric oxide, peroxynitrate, and nitric oxide synthetase or they may impair aromatic hydroxylation enzymes, and thereby impair neurotransmitter synthesis. For another example, increased levels of hydrogen peroxide might induce glutathione peroxidase production and thereby increase selenium requirements (3). Such genetically driven enzymatic and metabolic disturbances may help explain why individuals with DS appear to be more likely than those without it to develop various forms of epilepsy.

The overall risk of developing epilepsy (for those without, but including those with, DS) is 1% for those under age 20 and approximately 3% by age 75 (4). Studies have come to different conclusions regarding the combined prevalence of these disorders. A twelve year study found that 36.8% of people with Down syndrome (DS) developed adult-onset epilepsy (5). A U.S. study involving 405 with DS (from 0.5 to 45 years of age) found 8.1% had a seizure disorder by age 1 and 40% in the third decade of life (6). Another U.S. study involving 737 with DS (newborn through age 22) found that 6.4% had experienced at least one seizure (7), while an Israeli study involving 350 children with DS found that 8.0% had epileptic seizures (8). A British study involving 191 adults with DS found 9.4% with epilepsy, but that the prevalence increased with age with 46% over age 50 having epilepsy (9). A Belgian study involving 96 older DS adults (70 were at least 40) found epileptic seizures present in 16.7% of the cases (10). An Italian study involving 113 individuals with both DS and epilepsy concluded that the DS population had a higher incidence of both febrile (5.3%) and afebrile (7.9%) seizures than the general population (11).

While Western studies have universally shown increased seizure incidence in DS, Eastern studies have not. A Japanese study with 844 children under age 15 with DS found that only 1.4% had epilepsy, a rate similar to that of the general population (12). Kwong and Wong examined with records of 124 Chinese children with DS, found only 2 (1.6%) with epilepsy and concluded, “Chinese children with DS, compared with other races, were similarly intellectually disabled, but were less likely to develop epilepsy” (13). The basis of this Asian/non-Asian difference remains unexplained (all the Asian studies thus far done, were performed in Asia; no studies involving individuals of Asian heritage in Western nations have been found, thus the impact of diet, for example, is not clear).

These different results suggest that ethnicity, age, and perhaps environment are factors that influence the overall prevalence of epilepsy in the DS population. The remainder of this paper will discuss the nutritional and metabolic similarities between those with DS and those with epilepsy.

No studies have been found which specifically compare various nutrients as they pertain to both epilepsy and DS [though this paper was partially inspired by a comparison of two separate monographs by Werbach (14,15)]. There are many studies, however, which involve nutritional assessments of epileptics of varying types, and of DS. The following sections will briefly look at some of those nutrients which published studies suggest may have involvement in both conditions.

Vitamin A A recent study found that epileptics plasma vitamin A concentrations were significantly lower than non-epileptics (16).

Based on a review of several published studies, Baer et al concluded, “Serum vitamin A levels have been reported to be lower in individuals with Down syndrome...possibly due to malabsorption...However other workers have failed to confirm these findings” (17). It has been speculated that the alteration of the conjunctival epithelium in patients with DS may be due to altered metabolism of vitamin A (this could take the form of decreased conversion of beta-carotene to vitamin A) (18).

Vitamin B1 (Thiamin) Thiamin deficiency may provoke seizures in those predisposed towards them (19). A double-blind crossover study found that epileptics taking phenytoin alone or in conjunction with phenobarbitol had improved neurophysiological functions in verbal and non-verbal IQ testing after taking 50 mg of thiamin for 6 months (20). This same study found that 31% had subnormal thiamin levels prior to the study’s onset. Others have concluded that blood levels of thiamin seem to be low in epileptics (21).

A blood study of 90 children up to 16 years old with DS found that marginal thiamin deficiency existed in this population at higher rates than the general public (22). A smaller study found that non-institut-ionalized children with DS tended to consume thiamin below the recommended dietary allowance (23).

Vitamin B6 Decades ago many infants developed epileptic seizures when inadvertently placed on a formula that was deficient in vitamin B6 which disappeared after they were given the vitamin (24). Experimentally induced vitamin B6 deficiency has been shown to cause seizures in humans and animals (25,26). Adult epileptics who take various anticonvulsants seem to have reduced vitamin B6 levels (26). It has been speculated that defective binding of pyridoxine may reduce GABA levels (and increase glutamate), causing a lowering of the seizure threshold, which may be corrected by large doses of pyridoxine (27,28). Glauser and Morita advise vitamin B6 as a safe "first line" treatment for Lennox-Gastaut Syndrome (one of the most intractable forms of epilepsy) (29). Vitamin B6 has safely even been found to enhance the effectiveness of antiepileptic drugs (30). Goto et al found that vitamin B6 was helpful for seizures even for those who had normal CFS and serum concentrations prior to treatment (31). After studying children below age 15, Baxter concluded, “A trial of pyridoxine is justified in all cases of early onset intractible seizures or status epilepticus, whatever the suspected cause” (32). Even low doses have been reported to help infants (33).

Vitamin B6 metabolism may be abnormal in those with DS (34,35). A three year double-blind placebo controlled longitudinal DS study found that vitamin B6 supplementation helped normalize brain function by reducing elevated cortical auditory evoked potentials to a more normal level (36).

Folate (once known as vitamin B8) “Folate metabolism appears to be intimately involved in the epileptic process” (15). Smith & Obbens found that experimentally induced seizures have been found to reduce folate levels and that phenytoin, primidone, and phenobarbital reduce folate in the blood and cerebrospinal fluid (37). One study found that 30% of medically-treated epileptics had subnormal folate levels prior to the study’s onset (20). Folate supplementation may lower the levels of anticonvulsant medication (38).

Children with DS often have below normal levels of folate (39-41). Erythrocyte macrocytotis is more common in children and adults with DS and may be due to an alteration of the folate remethylation pathway (39). As those with DS age, further declines in folate levels seem to occur (42). This may be one of the reasons that the DS population tends to become more seizure prone with age.

Vitamin B12 Vitamin B12 deficiencies can trigger seizures (43). Plasma levels of vitamin B12 have been found to be lower in epileptics with an early age onset, higher seizure frequency, and higher doses of anticonvulsant medications (44). One type of cobalamin deficiency is characterized by seizures and often mental retardation (45). A case report of a mentally retarded child with severe folate deficiency found that supplemental folate did not reduce convulsions, but that folate combined with vitamin B12 and methionine “spectacularly reduced the convulsions” (46).

Some reports suggest that serum vitamin B12 levels are reduced for those with DS (47) while others have not found this (39).

Vitamin C Plasma levels of vitamin C are often reduced in epileptics (16,48). Lower vitamin C levels have been associated with poorer test results of central and peripheral nervous system for those with epilepsy (21).

One study found that many children with DS had a deficiency of vitamin C according to serum tests (49). A case report found the same result (50), yet a small study found that institutionalized children with DS tended to consume more vitamin C than the recommended daily allowance (23).

Vitamin D Anticonvulsant treatments can reduce serum levels of both 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D (51). Werbach reports a prospective study of epileptics taking carbamazepine, phenytoin, and/or phenobarbitol required up to 4,000 i.u. daily of vitamin D3 (10 times the RDI) to maintain normal serum levels of 25-hydroxyvitamin D (15). One study concluded that nonambulatory epileptics using anticonvulsants seem to be at risk for low serum calcidiol and osteopenia and that prophylactic vitamin D supplementation is warranted (52).

Disorders of vitamin D metabolism have also been speculated for Down’s patients (53,54). Not only have poor dietary intakes of vitamin D been found in those with DS (55), low levels have been found even in cases of high exposure to sunlight (54).

Vitamin E A controlled study involving 24 epileptic children found that vitamin E supplementation reduced seizures (56). Vitamin E and other antioxidants have been found to decrease the incidents of seizures and to prevent lipid peroxidation (57). One study found involving anticonvulsant-resistant epileptics have a 2-10 fold increase in lipid peroxidation, which decreased after supplementation with vitamin E supplementation (58).

A recent study found that children with Down syndrome have significantly less vitamin E levels than those without it (59). Down syndrome patients with dementia have lower plasma levels of vitamin E than those that do not (14).

Calcium Calcium has been implicated in many seizures, probably because “when the calcium ion concentration falls below about one half of normal, a person is likely to experience tetantic contraction of muscles throughout the body because of spontaneous of nerve impulses in the peripheral nerves” (60). Seizures may be the presenting symptom of hypocalcemia, especially in neonates or when tetany is present (15). During idiopathic tonic-clonic seizures, serum and cerebrospinal fluid levels of calcium can become elevated for as much as 24 hours (61).

Turkel & Nusbaum speculated that those with DS often have disorders of calcium metabolism (53). A small study found that children with DS tended to consume more calcium than the recommended daily allowance (23). Decreased intracellular calcium levels have been found in those with DS (62). Decreased hair levels of calcium have also been noted in the DS population (63).

Copper Copper deficiency is an acknowledged cause of seizures (64). Yet epileptics often exhibit elevated serum copper levels (65). Although this may appear to be a contradiction on first appraisal, copper sequestration mechanisms do produce elevations in serum copper at the expense of copper bioavailability. Sequestration-induced cellular copper deficiency would be another example of a secondary (non-dietary, or metabolically induced) deficiency.

DS patients have often been found to have elevated levels of copper. These elevations have been found in erythrocytes, neutrophils, platelets, and serum (14,66-68). One study found normal copper levels in those with DS who had poor dietary intakes of copper (56).

Iron Iron deficiencies are not believed to be related to most types of epilepsy (15). A study involving 156 children between 6 and 24 months by Piscane et al found those with febrile seizures to be about twice as likely as controls to be iron-deficient (69).

Anneren et al found that median levels of iron in erythrocytes and neutrophils were significantly lower in those with DS than in controls without it (68), but this may not be relevant. A small study found that children with DS tended to consume less iron than the recommended dietary allowance (23).

Magnesium Magnesium depletion increases the irritability of the nervous system and can cause acute epileptic seizures (70), as well as cause other types of epileptic seizures (71). Serum and erythrocyte magnesium is reduced in epileptics (61). For some individuals, lower magnesium levels have been correlated with the severity of epilepsy (72,73).

One study found that magnesium levels in erythrocytes and thrombocytes, but not neutrophils were lower in children with DS (68). Another found lower red blood cell levels of magnesium lower in the DS group as compared to the non-DS group (74).

Manganese Blood and hair manganese levels have been found to be reduced in those with epilepsy (15,75). The cause of low manganese levels seems to be related to the epileptic condition and not anticonvulsants commonly used for the condition (75). Two human trials suggest that supplemental manganese raises the threshold for seizures (76,77). One study found that chronic seizures decreased blood manganese levels in rats (77).

One study found that manganese levels in erythrocytes and thrombocytes were lower in children with DS (68). Another study found that hair levels of manganese seems to be lower in those with DS (78).

Selenium “Several case reports have appeared describing the successful treatment of early childhood seizures with selenium supplementation. The children were found to be deficient in selenium as well as in glutathione peroxidase activity, suggesting that brain selenium depletion may trigger seizures and subsequent neural damage due to its important role in the defense of neuronal cells against oxygen radical formation and peroxidative processes” (15). Selenium deficiency has been found to be a triggering factor in intractable seizures (79).

DS patients may have below normal plasma levels of selenium (67,74,80). This may be a direct consequence of increased incorporation of selenium into glutathione peroxidase, which is induced to higher-than-normal levels by excessive SOD-mediated hydrogen peroxide production. Hamilton reports that one study found that supplementation with selenium reduced (by 50%) elevated mononuclear cell copper content in DS (80).

Zinc Zinc deficiency is known to cause seizures (81). In chronic alcoholics seizures can be caused by zinc deficiency and tend to improve with zinc supplementation (82). It is known that zinc ions limit the excitatory responses in the dentate granule cells of those with temporal lobe epilepsy presumably by blocking the N-methyl-D-aspartate receptors (83). Studies involving three different animal models of epilepsy showed that zinc supplementation protected against the development of seizures, which suggest that zinc may be an essential component of a natural anticonvulsant tissue response to abnormal excitation (84); more human tests are needed (15). Fukahori & Itoh found that mice who were zinc-deficient had increased seizure susceptibility, those with adequate dietary zinc had no change, but those who took supplemental zinc had decreased seizure susceptibility (85).

Several reports suggest that DS patients have below normal plasma levels of zinc (66,67,80,86). One study concluded that supplementation with zinc has been shown to increase DNA synthesis in Down’s patients with low zinc levels (87). Another study found that zinc reduced TSH by 34% for hypothyroid Down syndrome patients (88). It has been speculated that zinc deficiency may be a cause of subclinical hypothyroidism in children with DS (88). In addition, it has been found that children with DS become deficient in a zinc-containing insulin-like growth factor type 1 (IGF-1) after one year of age (89). Not only has supplementation with zinc been shown to increase IGF-1, Napolitano et al found that zinc supplementation increased growth in 15 of 22 children with DS (89). Even though zinc is a constituent in cytoplasmic superoxide dismutase (SOD1), zinc supplementation was reported by Abdalla & Samman to reduce SOD1 levels in non-DS female subjects (90). Since SOD1 is 50% overexpressed in DS individuals, zinc nutriture may be especially important in moderating the degree of metabolic disturbance from SOD and hydrogen peroxide.

Carnitine Valproate often lowers carnitine levels (91,92). Some epileptics may have a metabolic disorder that causes carnitine to be deficient (91).

Deficient blood levels of carnitine are much more common in children with DS than in children without it (14). Supplementation with acetyl-L-carnitine has been shown to improve memory and attention in patients with DS (93).

Carnosine Petroff et al found that the anti-epileptic drugs gabapentin (94), topiramate (95), valproate (96), lamotrigine (96), and vigabatrin (97) increase homocarnosine levels in epileptics and that homocarnosine has an anticonvulsant effect. An earlier long-term study also found that vigabatrin raised homocarnosine levels (98). However, it appears that ACTH therapy reduces homocarnosine for those with infantile spasms (99).

Carnosine and related compounds (such as homocarnosine) have been found to have protective effects against hydrogen peroxide-mediated Cu,Zn-superoxide dismutase fragmentation (100) and Cu,Zn-superoxide mutants (101) which may cause problems for those with DS. Accelerated brain glycation (glucose cross-linking with proteins)--and the resulting brain damage--occurs early in the life of those with DS (102) and carnosine is also an antiglycation agent that may prevent or at least reduce this brain damage (103).

Choline A study involving choline for 4 with intractable epilepsy found that 3 reported improvement (104); the three that improved had at least a 3x greater increase in plasma choline than the one that did not improve.

DS is associated with a presynaptic cortical cholinergic deficit involving an extensive loss of choline acetyltransferase (105). A case report showed that the EEG pattern of a 2 1/2 year old with DS improved after phosphatidyl choline supplementation (14).

Cysteine L-cysteine can induce seizures (106,107). There is also a case report of status epilepticus being induced by the injection L-acetyl-cysteine (108).

People with DS have been found to have abnormally high levels of cysteine (109). This is likely due to the overexpression of cystathionine-beta-synthase, which diverts homocysteine into cysteine, thus preventing it from being recycled (remethylated) into methionine within the S-adenosylmethionine cycle. As an attempt to compensate, this may be why abnormally high levels of cathepsin S (a lysosomal cysteine protease) have been found, postmortem, in those with DS and Alzheimer’s (110).

Phenylalanine Children with phenylketonuria tend to be more prone to certain seizure disorders than others and low phenylalanine diets have helped prevent some seizure disorders (111,112). However, those epileptics successful with vagus nerve stimulation tend to have increases in phenylalanine levels (113).

Excess phenylalanine is often present in those with DS (114). There seems to be a difficulty in converting phenylalanine into tyrosine in DS, probably because the activity of phenylalanine hydroxylase is impaired in the liver of those with DS (115). Phenylketonuria, which can also cause mental retardation, is caused by a deficiency of hepatic phenylalanine hydroxylase and reduces the conversion of phenylalanine into tyrosine, and is often controlled by reducing consumption of high phenylalanine foods (113). There is a case report where improvements where noted in a DS patient who went on a low phenylalanine diet (116).

Serine Seizures are a symptom associated with serine deficiency (117,118), which is peculiar since serine levels tend to rise during some seizures. A study involving epileptic mice found that the serine protease neuropsin was significantly elevated and concluded that neuropsin inhibitors may be useful to treat epilepsy (119).

One study found a significant plasma deficit of serine for those with DS compared those with non-DS mental retardation (109).

Superoxide Dismutase A two-year study found that superoxide dismutase levels rose in epileptic children who took either valproate or carbamazine monotherapy (120). An Asian study found “a greatly high concentration of EC-SOD, albeit not statistically significant” in epileptic children (121).

It is well recognized that superoxide dismutase levels are abnormally high in those with DS (73,89,122).

Tryptophan Tryptophan levels are reduced in cerebrospinal fluid and plasma in people with seizure disorders (123,124); one reason may be hypercatabolism of tryptophan (125). An open trial with tryptophan supplementation found improvement in epileptics as well as an increase in blood serotonin levels (126). Prusinski & Stepien-Barcikowska reported temporary improvement using tryptophan on children with Lennox-Gastaut syndrome (127). Anti-epileptic drugs tend to decrease tryptophan levels (117), "while those epileptic patients who respond to vagus nerve stimulation tend to have increases in tryptophan levels” (122).

“There appears to be an abnormality of tryptophan metabolism in Down’s syndrome” (14,35). Infants with DS have been shown to improve muscle tone by taking tryptophan supplementation (128).

Because of the vast amounts and forms of nutrients (especially non-essential ones), no paper can possibly review all the peer-reviewed literature to determine all the possible nutritional similarities which may exist for individuals with DS and epilepsy. Furthermore, the efficacy of multi-nutrients in DS alone, though advocated by some (i.e. 14,53,129,130), has been discounted by others (i.e.131-133). {It should be understood that those who have discounted it, rarely (if ever) tried to precisely replicate the formulas that the advocates of nutrition actually use (129)}. Irrespective of that controversy, a review of the nutrients/metabolic end-products shown above suggests that many of the nutritional similarities in DS and epilepsy and the high combined prevalence of these disorders may not be coincidental.

Some of the nutrients which tend to be lower in both disorders include vitamin A, vitamin B1, folate, vitamin B12, vitamin C, iron, magnesium, manganese, selenium, zinc, carnitine, carnosine, choline, and possibly serine. Excess amounts of copper, cysteine, and superoxide dismutase are also sometimes encountered in both disorders. Disorders of metabolism involving vitamin B6, vitamin D, calcium, and tryptophan may play a role, as opposed to simply being a matter of deficiency or excess.

The overexpression of the 21st chromosome seems to increase epilepsy in non-ethnically oriental children with DS. The previously cited reports suggest that the prevailing belief that people with DS are about 5 or so times as likely to develop seizures (i.e. 134), understates the joint prevalence--it appears that by age 40-50, people with DS are 15-30 times more likely to develop epilepsy than the general public. The presence of epilepsy and mental retardation appears to increase the severity of pyschopathology (135). Brodtkorb found that there is a causal relationship with mental retardation and epilepsy when they co-exist and that the pathogenic period of the underlying brain disorder and the time of seizure onset, may be separated by many years (136).

There is some evidence that nonconvulsive status epilepticus may be a cause of mental retardation (137). Nutrients (such as carnosine, selenium, vitamin E) seem to help protect the brain and may reduce the probability of seizures related to aging in this population. Both humans with DS and mice with segmental trisomy 16 (Ts65Dn, which have been used as a model for DS) experience a significant deterioration of cholinergic neurons as they age (138), which is probably one of the reasons why there is an increase in epilepsy as people with DS age. Selected nutritional supplementation may help reduce this.

While it is true that not all with DS or epilepsy have the same nutritional needs, it does appear that there is a tendency towards similarities in nutritional profiles. Health professionals may wish to look at each of these nutrients if they wish to customize a nutritional program for their patients with both disorders.

The presence of trisomy 21 alters overall metabolism enough to account for at least some of the nutritional differences for individuals with DS. Since DS is associated with metabolic disturbances of many types and is associated with higher incidences of epilepsy, it seems reasonable to conclude that nutritional deficiencies common to both disorders may be playing a significant role in seizure development. Cross comparison studies of the two populations, including a group with both DS and epilepsy, seems to be indicated.

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