Seizure control is the first step toward rehabilitation
Social Mpccti of the problem:
1. the ptrionalttj adjustment compares favorably with (he adjustment nude by diabetics
2. the u-ork edjuamtnt i> excellent, 7 J percent of patients with epifepiy are employed
3. rf itiJf of the ptrfomjaft of employed cpilcptks does not diviiit from that of normals with fctpect to absenteeism or frequency rate of injuries
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4. of the KttfJHpfoytJ, according to one report, "68*3fc given (Ucful medical and psycho-topical «udy tan be expected to be restored to employment,"
5iai Drt Ai* NV 4. F«d, Sr-untY A<cy Offict V«jrii.Q±l RrJ.iinliijiinft. W.iri . O.C . I'M*.
5. higher schoaimg is accomplished just a satisfactortly by those who 9re nholastnally qualified as by students without seiiures,
Mimlrr. J E.. am! R»|<hrr|, T A: Am-J.Pfyrhm Jflr V.r>,
6. marr/age is as feasible for rhe epileptic as for the patients with diabetes for in stance.
Me outturn in "Routine" "DtfliSklt" Cwei Of Eprlepf)
» Mesantoin is effective in Grand M*l, Jackson ian and Psychomotor seizure* 1 * It ¡1 also useful in controlling focal seizures. • High dosages of Mesantoin (1.0 Gm in divided doses) can be administered daily during dosage buildup if certain points are considered 1 Each Me&antoin tablet awttiflj 0.1 Cm. (iVjgr ) methyl-phenyi-ethyb fbopm dosaoe fftOCCDUftl hydantoin (see chart).
High doses of Moanroin do not produce cp¡gastric distress, belching or flatulence
1 In "drug résistant" tases of epdepsy, a large number of patients ha ve responded to Mesamoin3* This holds ♦rue for patients who have not responded to phénobarbital, diphenyl-hydantoin sodium, or to a combinai ion of Ihese drugs.
Drowsmc« following Mesantoin therapy usual ly subsides as the drug » laken over a Jong period. Many ptqntráiu use ihe ooset of drowsine» « rhc limiting factor in dosage 1 No évidence to date has sbown ihat Meuntoin has any to*ic effects on the liver ■ Mesarte m does not cause gum hyperplasia
> Blood exam mations as retotnmended at smtable întcrvals s inte in a fe* instantes, blood dyserasias have been reponed following M cunto ¡n therapy.
A booklet "Mesaatoia - Dü->»£c Adjintmoit *nd Swlc Elíorij, wirh .Inu^r rrjttnwn, inJe frictions, cnmhjnation drujî thrrapy anJ (heraprutk pKCtuliou — li availajitr «m rHjucu
Sandoz Pharmaceuticals imviíjo; OF lA^JDOZ ' 'I.U.- ' w o* tí. ¡wr I < .I- rr STXUT '■ * YOflK I' ¥.
Merritt and Putnam, had also been highly influential. Himworth considered that such models would be useful for determining relative efficacy, dosage and the value of certain combinations—a prediction that has been realized at least in part. On the clinical side, the arbitrariness of therapy was recognized. Himwich also noted that:
experience teaches in many instances a combination of antiepileptic drugs works better than any single one. At present we do not possess a rational basis either for the mixtures used or the dosages employed . . . plus ga change.
Mention was also made of the dangers of sudden withdrawal of barbiturate, clearly recognized at the time, especially in barbiturate addiction.
Mesantoin (methyl hydantoin, methphenytoin) was introduced into practice in 1945 (Fig. 3) and was the first of the phenytoin analogues to achieve wide usage. Mesantoin is N-methylated at position 3 in the hydantoin ring and has an ethyl group substitution in place of the phenyl group at position 5. This provides a broader spectrum of activity in animal models but also a lower therapeutic index. By 1949, observations from various series were being reported, often of patients who were treatment failures with dilantin. Excellent results were claimed, few side-effects and indeed stimulatory properties to counteract drug-induced somnolence. However, the first reports too of aplastic anaemia, pancytopenia and fatal skin reactions were also being made—a fact which did not stop the manufacturers Sandoz widely advertising its use (in the pages of Epilepsia) for routine cases of epilepsy as late as 1955. There were many reports of its value in the epilepsy literature reviews from 1945 onwards. The largest series of patients was of Kozol  and
Fig. 3 Contemporary advertisement from Epilepsia for mesantoin.
Loscalzo . In the first, 200 patients were treated for periods ranging between 2 months and 4 years. Seventy per cent had grand mal seizures and about half were taking mesantoin alone. Of the patients, 132 (66%) experienced a great reduction in seizures, and 43 (22%) had some benefit. Only 12% were reported to have no change in seizures. Loscalzo  reported similar findings in a series of224 patients treated for 1-7 years. Complete control in grand mal seizures was obtained in 305 and partial control in another 52%. Psychomotor seizures did nearly as well, but mesantoin was noted in this series, as in others, to be ineffective in petit mal. General toxicity was thought to be less with mesantoin than with phenytoin. Loscalzo  reported sedation in 16%, skin rash with fever and lymphadenopathy in 9% and gum hyperplasia in 3%. Hirsutism and skin pigmentation were rare. However, Abbot and Schwab  found a fall in the leucocyte count below 2500 in 23% of 79 treated patients and in view of this and the relatively high number of fatalities linked to mesantoin therapy due to exfoliative dermatitis, aplastic anaemia, pancytopenia and hepatic failure, recommended that the drug should be considered contraindicated in therapy in all but exceptional cases.
i\fiu...u fill it linimi far the rlouri »1 petit ninl llirru^h rr*lH»»nt wnh IWwnr. lU' ' 1"m irMV ncnr Jr nllrVid I ---- I «iJiaeitMUl hi ■
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| - |, . . -I taxing tran iU • ■ I. ■ ■ ■■ i itw > '" «nH*lrtT in IH " ' ' T' w^rtn]tH«it L'ip* linn iJlv.li.iirtfci "1 lllr J»U"I p.jh.lr* ill yi fin «n I Onlj Til prowl ' ■■' to . 'n-v ii' i. i^^mwii, I el mfiu ibiv wiF..lrl I: " n'MUrn flMT ■1 >1 - i II .it. vbrn I'».!" J:FH: » n- ili-.i m m.irfjr TriUtw i» tfl V"'inll in 4 cerium prqpuiliiii of pejfhfiamlar , (i.. . ■ Mm. U m* 1i l iW*nim ¿rTAlufH I-'J I I* kMBtm I-"" *' TfiHIThi Null" CfaLtl^iT. tllinnra.
Fig. 4 Contemporary advertisement from Epilepsia for Tridione. A fantasy of new horizons and care-free life. There is no mention of the risks of idiosyncratic reaction.
Trimethadione was synthesized in 1944 by Spielman  in his search for drugs with analgesic properties. Its anticonvulsant effects in animals were reported in the same year , and in human subjects by 1946 [53-57]. It was licensed for therapy in 1946 (Fig. 4). It was recognized immediately that the drug was particularly effective in petit mal. Again, it was frequently the subject of the Epilepsia reviews. Perlstein and Andelman  for instance reported that 11 out of 14 patients with petit mal were greatly improved, and three out of seven with grand mal. Lennox  reported dramatic results in 166 patients with the petit mal triad, of whom >80% improvement was noted in 63 % in petit mal, 64% of astatic attacks and 70% of myoclonic jerks. Worldwide acceptance of Tridione was very rapid and faster than with phenytoin—perhaps because there was no alternative therapy—and as Lennox wrote in 1960 'Workers had a repetition of the thrill experienced with Dilantin only 7 years before' , Lennox estimated that amongst his 131 patients with petit mal, the annual mean rate of attacks fell from 3500 per year to about 1500 on Tridione—which assuming 100000 patients in the USA, was a reduction of over 200 million attacks a year. Tridione given IV controlled status in 16 out of 17 cases in one series . Trimethadione is metabolized to dimethadione in the liver and in chronic therapy the ratio of trimethadione to dimethadione is 1:20 and it is likely that the effects of the drug are due largely to the active metabolite. The major side-effect of Tridione is hemeralopia — a visual disturbance which is manifest by a glare when going into a brightly lit environment. Objects look indistinct and colours faded. When severe, the effect is that of a blinding snowstorm. The symptoms were recognized to appear within a few days of initiating therapy and wear off within 8-10 weeks of stopping therapy. The mechanism is obscure, although thought at the time to be retinal in origin . This curious effect is rare in younger children. Rash also occurs in 14% of patients, and other more minor gastric and neurological side-effects are common. Interestingly, seizures were also reported in the earliest literature to be markedly exacerbated in some patients. The rosy picture of medical progress was clouded however by reports of nephrotic syndrome , renal failure, fatal dermatitis and fatal blood dyscrasia , The nephrotic syndrome was usually reversible, although two fatalities had been recorded by 1957 . In 1947, within a year of the introduction of the drug, two deaths from aplastic anaemia were reported—and by 1957, a further 11 had been recorded . Davis and Lennox  found neutropenia (white count less than2500/cm3) in 6.3% of 222 patients. In Davidoff's series, six out of the 75 patients experienced severe blood reactions , Indeed, the jury in a coroner's court in London in 1948 were of the opinion that the drug should be scheduled as a poison. Some side-effects were not recognized in this period, including the unique precipitation of a myasthenic syndrome. By far the most serious omission though was surely the failure to recognize the very strong teratogenic effects of the oxalolidine diones (trimethadione and paradione). Trimethadione results in significant congenital deformity, growth retardation, and/or mental retardation in 30-5 0 % of exposed fetuses—and yet this fact was completely overlooked until 1970. One shudders to contemplate the numbers of adolescent and young adult girls that must have been treated for petit mal over these years, and the tragic unrecognized consequences. To paraphrase Lennox, was this drug worth that risk?
Section 1 Introduction
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Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...