TS is considered to be a rare neurological illness, although increasingly high rates of prevalence are being reported in current studies. The condition is seldom diagnosed, due to ignorance of its existence and characteristics . Until very recently, TS was only recognized as such for the most severe cases, in which there was an important degree of functional limitation and very evident coprolalia. Although this situation is changing, TS is still considered an uncommon disease.
Few clinical studies have been made with children, because, in addition to the normal difficulties arising in this kind of study (with adults), legal considerations must be borne in mind, due to the logical necessity to protect minors. Nevertheless, such studies are clearly needed .
TS is a neurological illness, and its physiopathological and inherited alterations, as well as aggravating environmental factors, are increasingly well understood . Effective treatment is provided by dopamine post-synaptic D2 receptor-inhibiting neuroleptic agents [34, 35]. Other types of medication, such as anti-epileptic drugs, have also been applied, although the evidence of their effectiveness is less apparent [36, 37]. However, the control of TS symptoms provided by the latter kind of treatment is only partial, and side effects such as sedation and dysphoria are common, as are others that are potentially very serious (tardive dyskinesia, arrhythmia or sudden death) [20, 38, 39]. In view of these considerations, many other forms of treatment have been studied, of varying nature and effectiveness; these include drugs that act on the central nervous system, botulinum toxin, acupuncture, plasmapheresis, conventional neurosurgery and, more recently, deep brain stimulation [40–45]. This diversity suggests that the illness is, as yet, poorly controlled, especially in the most severe cases.
The possibility of a complementary treatment with magnesium and vitamin B6 would represent an important improvement in controlling the illness, by reducing the need for neuroleptic drugs and other medication; it would also reduce the amount and severity of side effects.
The alternative therapy proposed in this paper is based on theoretical principles, but also on specific communications and on a prior study, on which the present protocol is based .
In clinical terms, magnesium deficiency is related to neuromuscular hyperexcitability, and may give rise to convulsions, chorea and athetoid movements. It has also been related to biochemical and genetic alterations that may provoke the symptoms evidenced by children with TS .
The enzyme kynureninase requires the presence of both magnesium and pyridoxal phosphate, and so in cases of hypomagnesemia there are high levels of kynurenines in the blood – which is the case with TS. Abnormally high levels of kynurenines provoke anxiety, an increased release of noradrenaline, locomotory hyperactivity, tics, increases in quinolinic acid, heightened sexual activity among females, reduced levels of serotonin and blocking of the GABA receptors. Therefore, this enzyme has been related to the presence of tics, anxiety and coprolalia-copropraxia .
A deficit of magnesium reduces the activity of vitamin B6, by inhibiting the activity of the alkaline phosphatase required to achieve its active form in the tissues, pyridoxal phosphate. A deficit of vitamin B6 activity has been related with raised levels of kynurenines, spasmodic movements, abnormal movements of the head, hyperirritability, increased sympathetic stimulation and heightened sensitivity to glucocorticoids. The symptoms worsen in situations of stress and with the administration of catecolamines and glucocorticoids .
Magnesium deficit increases NMDA receptor activity, producing greater neural excitability. In consequence, there is heightened anxiety and orofacial tardive dyskinesia, an increased release of dopamine, more defensive behaviour and greater modulation of serotonin receptors. Furthermore, other symptoms may be affected, such as migraine, which is more frequent among patients with TS .
This situation also raises the levels of substance P, and is associated with defensive behaviour, heightened response to stress and to allergenic phenomena.
It should be noted, however, that to date no clinical trials have been published corroborating this hypothesis . In view of the fact that current treatment with neuroleptic medication only achieves partial effectiveness and may cause severe side effects, we believe there is reason to carry out clinical trials with the proposed, less aggressive, substances .
The composition of multivitamin and mineral compounds is very diverse, but from a theoretical standpoint, taking into account their pharmacological properties and following the hypothesis set out above, we consider that clinical trials should be focused firstly on the administration of magnesium and vitamin B6. Both substances present a wide therapeutic margin and have very few side effects; moreover, they are authorized for similar indications among children and have a long history of therapeutic use.
Magnesium ions are fundamentally intracellular or located in the bones, with only 1% being extracellular; in consequence, magnesium levels in plasma do not accurately reflect the content in the body. Traditionally, it has been used intravenously to treat severe nutritional deficit, as an antiarrhythmic agent and in cases of eclampsia-preeclampsia. Orally-administered magnesium has been used as a nutritional supplement. It can be given to children. It is contraindicated in cases of acute or chronic decompensated renal insufficiency, myasthenia gravis, diabetic coma and Cushing's disease. The recommended physiological dose is 0.2–0.5 mEq/kg/day .
Vitamin B6 (pyroxidine) is a hydrosoluble vitamin with a wide therapeutic margin. In clinical and pharmacological trials, it has been shown to have interesting properties, participating in oxidative deamination, transamination and decarboxylation; it also participates in the decarboxylation of glutamic acid to GABA, from DOPA to dopamine and from 5-hydroxytrytophan to seratonin. It presents anti-convulsant properties and seems to exercise a neuroprotective and antitoxic effect. It can be administered to children, and has been authorized for use to treat children with alterations in character, language and behaviour; learning difficulties; delayed learning to walk; convulsive illnesses; intoxication of the central nervous system; trembling; and Parkinson's disease. The dosage provided may vary widely, as renal elimination ensures its toxicity is minimal .
As the activity of magnesium is a consequence of its ion fraction, it is mainly intracellular and bears little correlation with the magnesium in serum. We do not believe clinical conclusions can be drawn from the measuring of magnesium levels in serum . In the same way, determining the levels of vitamin B6 in serum would not be useful, in view of the fact that the problem lies in the activity deficit .
The statistical parameters to be used in this protocol are derived from the above-mentioned prior study carried out by our research group; this was a phase II clinical trials of the effectiveness and safety of the treatment in question. It was useful for pre-determining the degree of improvement that could be expected among the experimental group and, therefore, the minimum sample size needed, together with the mean and standard deviation values measured on the YGTSS.
This prior study showed that the treatment produced a significant decrease in the YGTSS score, with no side effects. Nevertheless, this was a pilot study, with methodological limitations that we seek to overcome in the present protocol .
In turn, the methodological instrument that will be used was also developed in a previous study of ours, namely the YGTSS translated into Spanish, adapted and validated for the local population .
The population chosen for this study is deliberately restricted, being limited to children aged 7–14 years, which is the age group in which clinical exacerbation, in theory, is greatest. By this limitation, we seek to obtain a population group of very homogeneous characteristics and, at the same time, one presenting severe symptoms, defined as a high score on the YGTSS (≥40).
It may be difficult to recruit the necessary numbers of patients for the sample size envisaged, given the nature of the clinical condition, the relative rarity of its diagnosis and the fact that children are involved. We hope to overcome this difficulty by expanding the geographic scope of the study and the number of medical personnel involved in recruiting suitable patients.
The follow-up period of three months is based on the natural course of the illness, with exacerbations and remissions lasting approximately this length of time. We believe that if the patient enters the study at the onset of a period of exacerbation, the YGTSS score will be high and it will be easier to identify significant differences, with the symptoms being controlled to a greater extent, and more quickly, among the experimental group than among the control group.
The reason for performing a PET on the experimental group before and after the administration of the medication is to objectify the dopaminergic activity within the basal nuclei and in the prefrontal cortex, as well as to reveal any alterations occurring in these areas as a result of the medication administered. However, these images are of low specificity and might not enable clear-cut conclusions to be drawn. Nevertheless, it seems reasonable to attempt to support the results of the clinical evaluation with these alternative, objective data. Be that as it may, these images will be of use as a basis for subsequent studies [15, 16].
It is also important to assess the repercussions on family life (which tends to be greatly impaired in severe cases) of an improvement in the control of TS symptoms among children. The PGWBI reflects psychological well-being (or otherwise); it is based on theories of evaluation of the domestic environment and is an appropriate means of determining the distortion produced by TS within the household [30, 32]. We have no doubt that a direct correlation will be found between the children's symptoms and the psychological well-being within the family home.
The joint application of these three measurement methods, namely the objectification of tics and incapacity, the assessment of metabolic changes in the circuits of the basal ganglia and of the cortex, and the evaluation of stress within the family, will enable us to reach an objective judgement as to the effectiveness of the treatment being tested.
In summary, treatment for TS continues to present important shortcomings and further clinical trials are necessary in this respect, especially among children.