Original Research

Might Calcium Disorders Cause or Contribute to Myoclonic Seizures in Epileptics?

By R. Thiel, Ph.D., Naturopath

Center for Natural Health Research, Down Syndrome-Epilepsy Foundation

1036 W. Grand Avenue, Grover Beach, CA 93433

Thiel R. Might disorders of calcium cause or contribute to myoclonic seizres? Accepted for publication by Medical Hypotheses, November 17, 2005

Abstract: Epilepsy is not rare, yet since many epileptic conditions are considered to be idiopathic, the related seizures are usually considered to be of unknown origin. It does appear that different types of seizures are caused by differing mechanisms. This paper discusses scattered case reports involving problems with calcium, the thyroid, and/or the parathyroid glands concurrent with seizures that support the position that calcium control mechanisms may have been involved in causing seizures in those patients. This paper hypothesizes that calcium levels, which are controlled by various mechanisms in the body, can cause, or at least contribute to, myoclonic (jerk) seizures, as well as to possibly infantile spasms. As these conditions are difficult to treat medically, this paper suggests that nutritional interventions, such as supplemental calcium and vitamin D, might well be considered as an option as a first-line treatment in those with these types of epileptic disorders. The nutritional recommendations also would apply for those who have seizures concurrent with Down syndrome.

Introduction

Epilepsy is not rare, yet since many epileptic conditions are considered to be idiopathic, the related seizures are usually considered to be of unknown origin [1]. Electrical discharge is involved, “In partial seizures, the excess neuronal discharge is contained within one region of the cerebral cortex. In generalized seizures, the discharge bilaterally and diffusely involves the cerebral cortex” [1].

While many lay people seem to consider that “grand mal” (generalized tonic-clonic) seizures are the only type, those with epilepsy can suffer from a variety of types of seizures. Simple partial seizures (like myoclonic) have motor, sensory, or psychomotor involvement, but without loss of consciousness [1]. Thus, it appears that differing mechanisms cause different types of seizures.

“Myoclonic seizures are brief lightening like jerks of a limb or several limbs, or the trunk. They may be repetitive leading to tonic-clonic seizures” [1]. Those with infantile spasms also tend to have myoclonic seizures.

This paper will focus on some calcium-related mechanisms that may be associated with myoclonic seizures.

Observation and Hypothesis Development

While working with a child with both Down Syndrome (DS) and Lennox-Gastaut Syndrome (LGS), this investigator noticed that variations in his nutritional regimen (ketogenic diet with supplements), specifically supplements that were related to calcium changed the frequency of myoclonic seizures he was experiencing; this investigator also noted a similar pattern in a non-DS adult with myoclonic seizures. For the DS child, supplements related to calcium had no discernable affect on the other types of seizures (LGS is an intractable form of epilepsy with multiple types of seizures). Those with DS are much more likely than the general public to suffer from seizure disorders [2], plus have a higher incidence of thyroid disorders than the general public [3].

One hormone produced by the thyroid gland is calcitonin. Calcitonin is a neurotransmitter and is involved in calcium regulation as it acts as mild hormone to retain calcium in the bones [4]. This investigator supported the thyroid gland by using a product that contained small amounts of kelp (a source of iodine which has been used for thousands of years to treat thyroid problems [5]), l-tyrosine (an amino acid necessary for the production of most thyroid hormones [4]), and bovine thyroid glandular (a thyroxine-free, enzyme source [6,7])—variations in this type of regimen have been used to help those who are either hypothyroid or hyperthyroid, normalize various symptoms associated with thyroid dysfunction [7].

The parathyroid hormone helps insure that there is sufficient calcium in the blood [4]. Some early researchers have suspected problems in calcium metabolism, and current researchers have suggested the possibly of impaired parathyroid hormone production, in those with DS as they tend to have low bone mass [8,9]. In this particular case, the parathyroid was supported nutritionally with vitamin D and a bovine parathyroid glandular (enzyme source [6,7]).

Varying amounts of calcium and magnesium were also used, and it was noted that too much magnesium seemed to increase the incidence of myoclonic seizures.

The results were inconsistent at first, but the trend was towards less myoclonic seizures. After making a variety of changes (primarily in adjusting dosages), no myoclonic seizures have been observed by the parents for over three years. The non-DS myoclonic epileptic was helped as well on a similar regimen sans the ketogenic diet.

These experiences led this investigator to consider that there may be a relationship between calcium control mechanisms and myoclonic seizures. Hence the question, might calcium disorders cause or contribute to myoclonic seizures?

Calcium and Related Mechanisms

From a physiological perspective, it is logical that calcium supplementation may be indicated when myoclonic seizures are encountered. For “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 nerve impulses in the peripheral nerves” [4].

Since calcitonin and the parathyroid hormone affect serum calcium concentrations, is it not possible that problems in the production of either can lead to limited tetantic contractions?

Johns Hopkins’ researcher JM Freeman (M.D.) has found, “Significant changes in important body chemicals such as calcium and magnesium can cause seizures; so can a lack of certain vitamins. These chemical changes may provoke a disturbance in the brain, or a single seizure, by influencing the thresholds for firing...Calcium is a very important mineral for the normal functioning of brain cells, and low levels of calcium (hypocalcemia) can cause seizures. Hypocalcemia can be a consequence of severe kidney disease when too much calcium escapes from the kidney into the urine. It may also, but rarely, be caused by a hormonal problem that has the same effects...A deficiency of magnesium, a mineral that interacts with calcium, may cause low blood calcium and, thus, seizures” [10]. Interestingly, with a ketogenic diet, “a calcium supplement must be taken every day to be nutritionally complete” [11].

Other researchers have been coming to the conclusion that calcium-related nutrients and/or calcium-control mechanisms play a role in seizures.

Takeda et al concluded that there is growing evidence that elevated extra-cellular calcium levels and homeostatic calcium control mechanisms may be factors in developing acquired epilepsy (epilepsy that occurred after an injury) [12]. Similarly, after doing a study involving injury-induced epilepsy, Raza et al noted, “It is important to evaluate the possible functional consequences of altered CA 2+ dynamics in epileptogenesis…The ability of the neuron to restore CA 2+ loads to resting [CA 2+] is regulated by CA 2+ homeostatic mechanisms. Increased or prolonged entry of extracellular CA 2+ could contribute to the altered CA 2+ homeostatic mechanisms in epilepsy” [13] (note that cellular calcium levels tend to be inversely correlated with extra-cellular calcium levels). Thus, it does not seem unreasonable to conclude that those without injury could have seizures caused by calcium problems.

Interestingly, a study by Hamed et al found that those that were on long-term anticonvulsant medications had higher levels of calcium than non-medicated controls [14]. This might suggest that one of the reasons that some of these medications are continued long-term is that for some people, they somehow increase the retention of calcium, which may account for some of their anticonvulsant effects.

Hirose et al noted, “some forms of juvenile myoclonic epilepsy can result from mutations of a Ca 2+ channel. This line of evidence suggests the involvement of channels expressed in the brain in the pathogenesis of certain types of epilepsy ” [15]. While Kamp et al noted, “Ca 2+ influx into excitable cells is a prerequisite for neurotransmitter release and regulated exocytosis. Within the group of ten cloned voltage-gated Ca 2+ channels, the Ca(v)2.3-containing E-type Ca 2+ channels are involved in various physiological processes, such as neurotransmitter release and exocytosis together with other voltage-gated Ca 2+ channels of the Ca(v)1, Ca(v)2 and Ca(v)3 subfamily…the interaction of Ca(v)2.3 with the EF-hand motif containing protein EFHC1 is involved in the aetiology and pathogenesis of juvenile myoclonic epilepsy ” [16]. Kamp et al, properly concluded, “However, E-type Ca 2+ channels also exhibit several subunit-specific features, most of which still remain poorly understood ” [16].

While they are not fully understood, it seems apparent that calcium control mechanisms play some role in myoclonic seizures [15,16].

Other Reports

There are other scattered hints that parathyroid problems, hypocalcemia, and/or vitamin D problems appear in some cases of those with myoclonic or related seizures.

Gunn and Gaffney reported that, “Mutations in the calcium-sensing receptor gene (CaSR) may result in disorders of calcium homeostasis manifesting as familial benign hypocalciuric hypercalcaemia (FBHH), neonatal severe hyperparathyroidism (NSHPT) or autosomal dominant hypocalcaemia with hypercalciuria (ADHH)… The ADHH condition may result in asymptomatic hypocalcaemia…and a minority experience seizures in infancy which can recur into adulthood ” [17].

A case report from the Netherlands involving a woman with tetany and myoclonic epilepsy found that she had hypoparathyroidism and was successfully treated with calcium and vitamin D [18].

One case report from Poland involving pseudohypoparathyroidism found tetantic seizures as a component, and that supplementation with calcium and an active form of vitamin D3 was effective [19]. Another case report found myoclonic seizures concurrent with vitamin D resistance and parathyroid problems [20]. A study by Hatun et al found that the majority of infants with vitamin D deficiency present with seizures [21].

There is also a case report of myoclonic-seizures in a hyperthyroid adult, who on more than one occasion was seizure-free when taking anti-thyroid medications, but who experienced these seizures during the times he chose to be off anti-thyroid medications [22]. Though the study does not discuss it, it may be that there was an overproduction of calcitonin during these periods of hyperthyroidism that may indirectly account for these seizures, especially since calcitonin only works for short durations [1]. There was also another case report of a hyperthyroid individual whose seizures stopped once he became euthyroid [23].

Even in generalized seizures, Natelson et al reported, “Epileptics are generally mildly hypocalcemic, especially in the period before the seizure…Stress, which releases epinephrine and corticotropin, results in high serum citrate concentration, which probably contributes to decreased serum [Ca2+] just before a seizure” [24].

Interestingly, it is reported that long-term treatment of epileptic children with various anticonvulsant medications, raised TSH and diminished T3 and T4 [25]. While that study did not specifically address calcitonin, it is reasonable to conclude that calcitonin levels would have been lowered as well. Other studies have found that long-term use of certain anticonvulsant medications tended to impair at least a portion of thyroid function [26-28].

Discussion

Myoclonic seizures tend to be resistant to drug therapies [1]. It is possible that since many anti-epileptic medications impair thyroid function and/or somehow result in increased calcium levels, perhaps a partial reason for their occasional success with myoclonic seizures is the partial suppression of the thyroid hormone calcitonin which results in an increase of serum calcium levels.

On the more negative side, Otoom and Al-Hadidi have shown that there are scattered reports that the anti-convuslant medications phenobarbital, carbamazepine, valproate, lamotrigine, gabapentin, and vigabatrin can cause or induce myoclonic seizures in epileptics who had not been experiencing those types of seizures [29]. It is possible this occurs because some anticonvulsant medications can reduce vitamin D levels [30]. Other researchers have thus suggested supplemental vitamin D when taking certain anticonvulsant medications [31].

Myoclonic seizures can have an appearance of a limited tetantic contraction associated with insufficient calcium levels. It is important to note that others, while not specifically discussing myoclonic seizures, have also suggested that somehow increasing calcium levels should be looked at for the treatment of epileptics [10,32]. Hence, it may be wise to consider nutritional interventions that affect calcium levels as a first-line treatment

Currently, this is rarely the case. Even though, “Some antiepileptic drugs could also worsen some types of seizures” [33] and it is known that “Other therapies can be efficient in refractory epilepsies: steroids, vague nerve stimulation, ketogenic diet and surgery” [33], nutritional therapies (especially outside the ketogenic diet) seem to be often overlooked. It should be noted that it is theoretically possible that for some types of seizures that calcium could be contraindicated.

Yet it is not unheard of that nutrition should be considered as a first-line for intractable forms of epilepsy, as others have sometimes advocated it [34] (though this investigator appears to be the first advocating supplemental calcium, vitamin D, etc. as first-line nutrients, as well as first to advise nutrients specifically for myoclonic seizures). One of the reasons that nutrition should be considered as a front-line therapy is that it is low risk [34].

Consumption, for example, of calcium-containing foods and/or calcium-containing supplements is so safe that although calcium can react with some medications, “(o)verdosage has not been reported with calcium supplements” [35]. This investigator, however, would prefer forms other than calcium carbonate as “calcium carbonate may cause gastrointestinal side reactions such as constipation, bloating, gas and flatulence. Prolonged use of large doses of calcium carbonate—greater than 12 grams daily (about 5 grams of elemental calcium—may lead to milk-alkali syndrome, nephrocalcinosis and renal insufficiency” [35]. The individuals in the two cases that this investigator mentioned in this paper always took less than 1 gram of calcium per day and never used calcium carbonate. Although there are some theoretical concerns involving excess vitamin D, this investigator almost never advises more than 900 i.u. of vitamin D per day. “Typically, chronic ingestion of 50,000 to 100,000 IU/day of vitamin D is required to produce hypercalcemia” [35], and since this investigator is not aware of others advising vitamin D in that high range, reasonable amounts of vitamin D should be safe for nearly everyone with myoclonic seizures. This investigator always recommended less than 400mg of magnesium per day, which is also considered safe for all except those with renal failure or specific hypersensitivity [35]. The other substances this investigator used are also considered safe and have been consumed by humans for centuries [e.g. 36].

It should be noted that although many of the nutritional approaches mentioned in this paper have been used clinically for decades and some fell out of common medical usage some years ago, they are currently still recommended by some medical experts [36].

Although scattered case reports, of themselves, are not necessarily conclusive, one of the purposes of having case reports published is to gain insight that may help improve the knowledge of similar, or even seemingly different, conditions. In all probability, the literature (beyond simply case reports) seems to support the idea that localized, nearly instantaneous, reductions in serum calcium levels may cause, or at least contribute to, myoclonic seizures. If this hypothesis is correct, it would suggest that looking at calcium, and other related control mechanisms, would continue to make sense for researchers in this field.

This investigator agrees with the conclusion of other epileptic researchers that we are getting closer to the time when “this extremely common, and debilitating, neurological disorder will be solved” [37]. But this investigator also believes that nutrition may play a greater role [2] than some others in this field suggest (some others tend to be more focused on genetic involvement [e.g. 37,38]). This is not to say that genetics play no role, but that more people may be helped sooner if nutritional interventions were considered now, as opposed to waiting for certain genetic solutions which are not likely to be used clinically until sometime in the distant future.

In this paper, no specific quantitative recommendation for each possible substance that could affect calcium levels have been made beyond discussing some upper limits. The reason is that the amount needed appears to vary by individual (as well as size in the case of children). But irrespective of the quantities, it does appear reasonable to conclude that calcium control mechanisms can play a causal role in myoclonic seizures AND THAT CALCIUM AND OTHER NUTRIENTS SHOULD BE CONSIDERED AS POSSIBLE FRONT-LINE THERAPIES FOR THESE HARD TO TREAT MYOCLONIC SEIZURES.

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