G.A.B. Davies-Jones

7 Anticonvulsant drugs GENERAL TOPICS

Anticonvulsant osteopenia ( S E D- I O , 109; SEDA-8, 69)

As mentioned in previous volumes, signifi- cant reductions in serum calcium and phos- phate and an increase in serum alkaline phosphatase may be found in up to 50% of adult patients treated for epilepsy, and altera- tions in vitamin D metabolism are generally thought to account for the hypocaicemia and osteopenia. Weinstein et al (1 R) found that serum-ionized calcium levels in 109 ambulatory adult epileptic outpatients receiving chronic anticonvulsant drug therapy in Georgia, U.S.A., (with more than adequate exposure to sunlight) were decreased. Immunoreactive parathyroid hormone concentrations were in- creased while bone mineral content was re- duced. Hypocalcemia and osteopenia occurred in spite of normal mean levels of serum 25-OH- D and 1,25-(OH)2D, suggesting that the hypo- calcemia was independent of the effect of the drugs on vitamin D metabolism. Bone biopsies revealed increased osteoid but normal calcifica- tion front formation, accelerated mineraliza- tion rate and decreased mineralization lag-time indicative of increased skeletal turnover, rather than osteomalacia.

Anticonvuisants and cognitive function (SED-IO, 110; SEDA-8, 69; 44 R)

Anticonvulsants interfere with cognitive function, but carbamazepine had less effect than phenytoin on memory and other cognitive functions in patients with epilepsy of approxi- mately 6 years mean duration (2R).

Second-generation effects (SED-IO, 109; SEDA-9, 57)

Numerous studies have indicated an increase in the frequency of major and minor malfor-

Side Effects of Drugs Annual 10 M.N.G. Dukes, editor �9 Elsevier Science Publishers B.V., 1986

mations in children exposed to anticonvulsants in utero, especially to phenytoin. Craniofacial dysmorphic features are part of the fetal hydantoin syndrome. Such features may be apparent at birth, but Van Lang et al (3 R) now point out that even when the infant exposed to phenytoin in utero appears normal at birth and has normal external craniofacial measurements at 4 and 10 years of age, cephalometric analy- ses may demonstrate a pattern of reduced bony interorbital distance, maxillary size, mandibu- lar length, cranial base and skull size and a reduction in nose dimensions when compared with controls.

It has been suggested that anticonvulsants produce their teratogenic effects via folate defi- ciency (SED- 10, 109). Biale and Lewenthal (4 R) now report a prospective study which, when compared with their previous retrospective study, seems to support this assumption. The true answer awaits the findings of a large controlled prospective study.

INDIVIDUAL DRUGS

Carhamazepine (SED-IO, 113; SEDA-8, 72; SEDA-9, 58)

Carbamazepine can produce various invol- untary movement disorders (SED-10, 114), but recently Neglia et al (5 c) described 3 patients who either experienced the onset (1 case) or exacerbation of multiple motor tics and vocali- zations 2-4 weeks after starting carbamazepine treatment for control of suspected seizures. In 2 patients multiple motor tics and vocalizations were present during the EEG recordings and were not associated with paroxysmal dis- charges. None of the patients had signs of carbamazepine intoxication and all had serum carbamazepine levels within the therapeutic range. The motor tics did not resolve or return to pre-treatment frequency after stopping the carbamazepine. In an electro-oculographic evaluation of carbamazepine-associated side effects, Casazza et al (6 c) found that it pro- duced a reduction of pursuit gain, saccade frequency and velocity which were directly

54 Chapter 7 G.A.B. Davies-Jones

correlated with increasing blood levels within the range of 4.9-13.9 gg/mi. Reiss and O'Donnell (7 c) reported carbamazepine- induced mania in 2 ten-year-old boys, one with a complex-partial seizure disorder and the other with a primary affective disorder.

Hyponatremia is a well-recognized side effect of carbamazepine, associated with moderate or large doses. Lahr found the risk to be greater in the older patient and in the patient with high serum drug levels (8x). The hyponatremia (sodium level < t35 mmol/l) was established in 21.7% of patients taking the drug. Appleby (9 c) now reports the occurrence of hyponatre- mia in a 62-year-old woman after a very low dose (100 mg 3 times daily) for only 7 days. The hyponatremia resolved on stopping the drug but reappeared on rechallenge. The serum carbamazepine level was within the therapeutic range (5 and 6 mg/l, therapeutic range 3-13 mg/1). Carbamazepine may produce hypocalce- mia, hypophosphatemia elevated serum alkaline phosphatase and a reduction in serum 25-OH-D levels (10 c) (SED-10, 114). Hoikka et al (10 R) also found features of histological osteomalacia in 2 of 18 biopsies. Rajantie et al (11 R) confirmed lower serum calcium and 25-OH-D and higher alkaline phosphatase in 20 institu- tionalized mentally retarded children taking carbamazepine only as compared with 20 colleagues in the same institute on no treat- ment. Vitamin D supplements abolished the biochemical changes.

Bradley et al (12 c) reported profound carba- mazepine induced thrombocytopenia in a young Child taking 100 mg 3 times daily. The platelet count was 14,000 per mm 3 but returned to 239,000 per mm 3 5 days after stopping the drug. The first reported case of carbamazepine- induced hemolytic anemia was described by Stroink et al (13c). The patient was not taking any other drugs and the anemia appeared 20 days after the beginning of carbamazepine therapy. It resolved completely on stopping the drug. Carbamazepine can precipitate an illness identical to acute intermittent porphyria (SEDA-8, 72), and Rapeport et al (14R), in a study of the effect of carbamazepine on heme biosynthesis in male volunteers, found that carbamazepine is a porphyrinogenic drug which mimics the changes in enzyme activities and urinary porphyrin ester profile found in patients with latent acute intermittent porphy- ria.

Erythematous maculopapular rash and erythema multiforme, possibly immunologically induced, have been described in association

with carbamazepine therapy. Staughton et al (15 c) have recently reported the first case of toxic pustuloderma due to carbamazepine.

Interactions Carbamazepine is regarded as producing an insignificant and unpredictable change in serum phenytoin (SED-9, 92). Zielinski et al (16 a) now report elevation of plasma phenytoin concentration due to carba- mazepine. Jann et al (17 R) found plasma halo- peridol levels to be reduced by carbamazepine. In 2 patients on steady dOsages of haloperidol its plasma level dropped by 59% and 61% when carbamazepine was added. In a third patient, plasma haloperidol levels rose by 61% when carbamazepine was discontinued. In 2 of these patients, the plasma haioperidol changed slowly over 2-3 weeks. They attributed this effect of carbamazepine to hepatic enzyme induction. Carbamazepine- 10,11-epoxide is the major metabolite ofcarbamazepine which itself has anticonvulsant properties, and other an- tiepileptic drugs may increase its plasma con- centration (18R). Schoeman et al (18 R) found a positive correlation between side effects and plasma concentration of carbamazepine- 10,11- epoxide, whereas Riva et al (19 R) found no correlation between signs of neurological tox- icity and concentration of this metabolite. However, Patsolos et al (20 c) also describe a patient who showed a direct correlation between acute toxic side effects and high total and free carbamazepine-10,11-epoxide but it was not apparent whether clinical toxicity correlated better with free or total carbamazep- ine-10,1 l-epoxide levels. They felt that carba- mazepine-10,11-epoxide levels > 9 mmol/l were more often associated with side effects than lower values. They suggested that routine monitoring of carbamazepine levels might not be a totally reliable indicator of clinical toxicity in some patients and that routine monitoring of carbamazepine-10,11-epoxide might be necessary.

Two further cases of carbamazepine toxicity precipitated by erythromycin have been re- ported (21 c, 22c).

Cionazepam ( S ED- I O, 116)

O'Flaherty et al (23 c) describe a patient who developed choreoathetosis on completing the slow withdrawal of clonazepam over 9 days. This is the first report of choreoathetosis in relation to clonazepam.

Anticonvulsant drugs Chapter 7 55

Phenytoin (diphenylhydantoin) ( SED-IO, 111; SEDA-8, 58; SEDA-9, 71)

lymphoma of the jejunum developing 18 months after continuous phenytoin treatment.

Generalized myoclonus in response to touch due to phenytoin toxicity was described by Trauner (24 c) in a 1-month-old female child.

Phenytoin is known to cause a decrease in the serum levels of the thyroid hormones (SEDA-9, 71), but the patients remain euthy- roid. Kushnir et al (25 c) describe a patient who developed overt hypothyroidism associated with the characteristic changes in serum thyroxine and thyrotrophin as a result of phe- nytoin intoxication.

Phenytoin has rarely been associated with thrombocytopenia (SED-9, 95). Wong et al (26 c) describe a patient who developed sudden severe thrombocytopenia after 10 days of pro- phylactic phenytoin treatment. The patient had also been taking cimetidine for 2 months pre- viously and this is also known to cause throm- bocytopenia. The thrombocytopenia resolved rapidly on stopping the phenytoin and cimeti- dine.

Local skin and soft tissue reaction to intra- venous phenytoin was described in 9 patients by Kilarski et al (27c). In only 1 case was there evidence of infiltration of the drug into the tissues. The reaction to the injection consisted of a bluish discoloration of the surrounding tissue distal to the injection site'which appeared about 2 hours later. Six hours after the initial reaction the patients developed progressive erythema and edema which spread circumfer- entially from the injection site. In 3 patients vesicles and bullae developed at the site after 10 hours. Complete resolution of the symptoms took up to 3 weeks.

In a 3-year prospective study of patients taking phenytoin, Leppik et al (28 R) noted an erythematous morbilliform rash develop in 8.5% of 306 cases within 3 weeks of starting treatment. A striking seasonal incidence of the rash was noted. None of the 79 patients who received the initial dose during December to February developed the skin reaction whereas 13 (20.6%) of the 63 patients treated during June to August did. The periods from March to May and from September to November were associated with smaller incidence, 10% and 6.7% respectively, of the rash. The authors considered whether a photosensitivity phenom- enon or seasonal variation in immunological responses underlay this occurrence.

Malignant lymphoma can rarely be caused by phenytoin therapy. Recently Rubinstein et al (29 c) reported a case of isolated malignant

Interactions Phenytoin is known to increase serum warfarin levels. Levine and Sheppard (30 c) now describe a biphasic interaction of phenytoin and warfarin. Their patient's calcu- lated sensitivity to warfarin increased for the first 6 days after the addition of phenytoin and then declined to a level that was lower than that observed before phenytoin was begun. Freeman et al (31 c) reported that phenytoin caused a reduction in serum cyclosporin levels through increased oxidative metabolism brought about by enzyme induction.

Progabide

This recently introduced promising anti- convulsant drug has been associated with few, generally mild, side effects (SEDA-9, 60). Additional side effects lately reported have included nausea and vomiting, and dysarthria (32R).

Valproate semisodium (sodium valproate) (SED-IO, 114; SEDA-8, 70; SEDA-9, 59)

Hirose and Konda (33 c) observed a patient who developed intravascular hemolysis and pure marrow red cell aplasia while being treated with valproate which resolved on stopping the valproate and treatment with dexamethasone.

Powell-Jackson et al (34 R) and Jeavons (35 R) have reviewed the hepatotoxicity of valproate. Although it occurs in adults, it is commoner in children, a third of whom have had structural neurological disease. The characteristic histolo- gical lesion is microvesicular steatosis and cen- trilobular necrosis, but centrilobular necrosis may be the sole abnormality. The mechanism is probably a mixed hepatotoxic-idiosyncratic reaction. The condition can be reversed if valproate is stopped immediately when patients show gastrointestinal symptoms, drowsiness, lethargy, jaundice or change in seizure pattern. Felding and Rane (36 c) re- ported the case of a female neonate, whose mother had been treated throughout preg- nancy with valproic acid and phenytoin, who exhibited clinical evidence of hepatotoxicity confirmed by laboratory and histological changes of diffuse inflammatory reaction and focal necrosis. Whether this complication was due to either of these drugs or to the combina- tion is not known. Palm et al (37 c) report a case

56

of fatal hepatic failure in a woman on com- bined therapy with valproate and phenytoin where phenytoin intoxication was the first sign of liver damage induced by valproate.

There have been 14 reports of acute pancreati- tis due to valproic acid. This may be severe and 2 deaths have occurred from hemorrhagic pan- creatic necrosis. Complications have included pleural and pericardiai effusions, coagulopa- thy, pseudocyst, ascites, wound infection and pneumonia (38~).

Enuresis in children may be caused by sodium valproate (39r). The incidence varies between 1% and 7%. It is possibly secondary to the polydipsia as a result of the increased

Chapter 7 G.A.B. Davies-Jones

thirst due to valproate or perhaps as the result of the increased depth of sleep associated with valproate.

The role of valproate in the genesis of neural tube defects remains uncertain. Robert et al (40 ~) provide further data supporting this asso- ciation. A possible congenital dysmorphic syn- drome has again been reported in association with valproate therapy (41c).

Interactions Valproate displaces carbamazep- ine from protein binding and may inhibit the metabolism of carbamazepine-10,11-epoxide (42R). It also appears to inhibit the metabolism of ethosuximide (43~).

R E F E R E N C E S

1. Weinstein RS, Bryce GF, Sappington LJ et al (1984) Decreased serum ionised calcium and normal vitamin D metabolite levels with anticon- vulsant drug treatment. J. Clin. Endocrinol. Metab., 58, 1003.

2. Andrewes DG, Tomlinson L, Elwes RDC et al (1984) The influence of carbamazepine and pheny- toin on memory and other aspects of cognitive function in new referrals with epilepsy. Acta Neurol. Scand., 69, Suppl. 23.

3. Van Lang QCN, Tassinari MS, Keith DA et al (1984) Effect of in utero exposure to anticonvul- sants on craniofacial development and growth. J. Craniofac. Genet. Dev. Biol., 4, 115.

4. Biale Y, Lewenthal H (1984) Effect of folic acid supplementation on congenital malformations due to anticonvulsive drugs. Eur. J. Obstet. Gynecol. Reprod. Biol., 18, 211.

5. Neglia JP, Glaze DG, Zion TE (1984) Tics and vocalizations in children treated with carbamazep- ine. Pediatrics, 73, 841.

6. Casazza M, Alpini D, Berardi C et al (1984) Valutazione elettrooculografica degli effetti indesi- derati della carbamazepina. Boll. Lega ltal. Epillesia, 45-46, 375.

7. Reiss AL, O'Donnell DJ (1984) Carbamazepine induced mania in two children: case report. J. Clin. Psychiatry, 45, 272.

8. Lahr MB (1985) Hyponatraemia during carba- mazepine therapy. Clin. Pharmacol. Ther., 37, 693.

9. Appleby L (1984) Rapid development of hypo- natremia during low dose carbamazepine therapy. J. Neurol. Neurosurg. Psychiatry, 47, 1138.

10. Hoikka V, Alhava EM, Karjalainen P e t al (1984) Carbamazepine and bone mineral metab- olism. Acta Neurol. Scand., 69, 77.

11. Rajantie J, Lamberg-Allardt C, Wilska M (1984) Does carbamazepine treatment lead to a need of extra vitamin D in some mentally retarded children? Acta Paediatr. Scand., 73, 325.

12. Bradley JM, Sagraves R, Kimbrough AC

(1985) Carbamazepine induced thrombocytopenia in a young child. Clin. Pharm., 4, 221.

13. Stroink AR, Skillrud DM, Kiely JM (1984) Carbamazepine induced hemolytic anemia. Acta Haematol., 72, 346.

14. Rapeport WG, Connell JC, Thompson GG (1984) Effect of carbamazepine on haem biosynthe- sis in man. Eur. J. Clin. Invest., 14, 107.

15. Staughton RCD, Harper JI, Rowland Payne CME (1984) Toxic pustuloderma: a new entity? J. R. Soc. Med., 77, Suppl. 4, 6.

16. Zielinski JJ, Haidukewych D, Leheta BJ (1985) Carbamazepine phenytoin interaction: elevation of plasma phenytoin concentrations due to carba- mazepine comedication. Ther. Drug Monit., 7, 51.

17. Jann MW, Ereshefsky L, Saklad SR et al (1985) Effect of carbamazepine on plasma haloperidol levels. J. Clin. Psychopharmacol., 5, 106.

18. Schoemar~, JF, Elyas AA, Brett EM (1984) Correlation between plasma carbamazepine-10,1 l- epoxide concentration and drug side-effects in chil- dren with epilepsy. Dev. Med. Child Neurol., 26, 756.

19. Riva R, Contin M, Albani F et al (1984) Free and total plasma concentrations of carbamazepine and carbamazepine- 10,1 l-epoxide in epileptic patients: diurnal fluctuations and relationship with side effects. Ther. Drug Monit., 6, 408.

20. Patsolos PN, Stephenson T J, Krishna S et al (1985) Side effects induced by carbamazepine- 10,11-epoxide. Lancet, 2, 496.

21. Kessler JM (1985) Erythromycin-carbamazep- ine interaction. S. Afr. Med. J., 67, 1038.

22. Carranco E, Karens J, Co Set al (1985) Carba- mazepine toxicity induced by concurrent erythro- mycin therapy. Arch. Neurol., 42, 187.

23. O'Flaherty SO, Evans M, Epps A et al (1985) Med. J. Aust., 142, 453.

24. Trauner DA (1985) Stimulus-induced myoclo- nus and burst suppression on EEG: effects of phenytoin toxicity. Ann. Neurol., 17, 312.

Anticonvulsant drugs Chapter 7 57

25. Kushnir M, Weinstein R, Landau Bet al (1985) Hypothyroidism and phenytoin intoxication. Ann. Intern. Med., 102, 341.

26. Wong YY, Lichtor T, Brown FD (1985) Severe thrombocytopenia associated with phenytoin and cimetidine therapy. Surg. Neurol., 23, 169.

27. Kilarski DJ, Buchanan C, Von Behren L (1984) Soft tissue damage associated with intravenous phenytoin. N. Engl. J. Med., 311, 1186

28. Leppik IE, Lapora A, Loewenson R (1985) Seasonal incidence of phenytoin allergy unrelated to plasma levels. Arch. Neurol., 42, 120.

29. Rubinstein I, Langevitz P, Shibi G (1985) Isolated malignant lymphoma of the jejunum and long-term diphenylhydantoin therapy. Oncology, 42, 104.

30. Levine M, Sheppard I (1984) Biphasic interac- tion of phenytoin with warfarin. Clin. Pharm., 3, 200.

31. Freeman DJ, Laupacis A, Keown PA (1984) Evaluation of cyclosporin-phenytoin interaction with observations on cyclosporin metabolites. Br. J. Clin. Pharm., 18, 887.

32. Martinez-Lage JM, Bossi L, Morales G (1984) Progabide treatment in severe epilepsy: a double-blind cross-over trial versus placebo. Epilepsia, 25, 586.

33. Hirose Y, Konda S (1984) Depakene-induced intravascular hemolysis and pure red cell aplasia. Acta Haernatol. Jpn., 47, 1366.

34. Powell-Jackson PR, Tredger JM, Williams R

(1984) Hepatotoxicity to sodium valproate: a re- view. Gutt, 25, 673.

35. Jeavons PM (1984) Non-dose-related side effects of valproate. Epilepsia, 25, Suppl. 1, $50.

36. Felding I, Rane A (1984) Congenital liver dam- age after treatment of mother with valproic acid and phenytoin. Acta Paediatr. Scand., 73, 565.

37. Palm R, Silseth C, Alvan G (1984) Phenytoin intoxication as the first symptom of fatal liver damage induced by sodium valproate. Br. J. Clin. Pharmacol., 17, 597.

38. Wyllie E, Wyllie R, Cruse RP et al (1984) Pancreatitis associated with valproic acid therapy. Am. J. Dis. Child., 138, 912.

39. Choonara IA (1985) Sodium valproate and enuresis. Lancet, 1, 1276.

40. Robert E, L6fkvist E, Mauguiere F (1984) Valproate and spina bifida. Lancet, 2, 1392.

41. Diliberti JH, Farndon PA, Dennis NR (1984) The fetal valproate syndrome. Am. J. Med. Genet., 19, 473.

42. Levy RH, Moreland TA, Morselli PL et al (1984) Carbamazepine-valproic acid interaction in man and rhesus monkey. Epilepsia, 25, 338.

43. Pisani F, Narbone MC, Trunfio C (1984) Valproic acid-ethosuximide interaction: a pharma- cokinetic study. Epilepsia, 25, 229.

44. Reynolds EH, Trimble MR (1985) Adverse neuropsychiatric effects of anticonvulsant drugs. Drugs, 29, 570.