Refractory epilepsy

In parallel with the identification of distinct transporters for GABA there has been continued interest in the development of selective blockers of these transporters and the therapeutic potential that could result from prolonging the action of synaptically released GABA. It has been known for a long time that certain pro-drugs of nipecotic add (e.g. nipecotic acid ethyl ester) are able to cross the blood-brain barrier and are effective anticonvulsants in experimental models of epilepsy. More recently, several different systemically active lipophillic compounds have been described that act selectively on GAT-1, GAT-2 or GAT-3 (Fig. 11.4). Of these, tiagabine (gabitiil), a derivative of nipecotic acid that acts preferentially on GAT -1, has proved clinically useful in cases of refractory epilepsy. 

French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs II treatment of refractory epilepsy, report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology 2005 62 1261-1273. 

Tolerance may occur which means that the effect of some AEDs may wear off with time (benzodiazepines, barbiturates, vigabatrin). There are exceptional cases where refractory epilepsy escapes... 

Control of increased seizure activity in patients with refractory epilepsy who are on stable regimens of anticonvulsants Rectal Gel 0.2 mg/kg may be repeated in 4-12 hr. 

Lapierre YD, Browne M, Horn E, et al Treatment of major affective disorder with fluvoxamine. J Clin Psychiatry 48 65-68, 1987 Lapierre YD, Ravindran AV, Bakish D Dysthymia and serotonin. Int Clin Psychopharmacol 8 (suppl 2) 87-90, 1993 Lapin 1, Oxenkrug G Intensification of the central serotonergic process as a possible determinant of thymoleptic effect. Lancet 1 132-136, 1969 Larkin JG, McKee PJ, Blacklaw J, et al Nimodipine in refractory epilepsy a placebo-controlled, add-on study. Epilepsy Res 9 71-77, 1991 Larsson LI, Rehfeld JF Localization and molecular heterogeneity of cholecystokinin in the central and peripheral nervous system. Brain Res 165 201-218, 1979 Laruelle M, Abi-Dargham A, Casanova M, et al Selective abnormality of prefrontal serotonergic receptors in schizophrenia a post mortem study. Arch Gen Psychiatry 50 810-818, 1993... 

It is 1,5 benzodiazepine with a chemical structure slightly different from that of diazepam and clonazepam. This change in structure results in less sedative and psychomotor retardation. Though introduced as an anxiolytic it has been found to be useful in treatment of patients with refractory epilepsy. 

Jawad S, Yuen WC, Peck AW, et al. Lamotrigine single-dose pharmacokinetics and initial 1 week experience in refractory epilepsy. Epilepsy Res 1987 1(3) 194-201. 

Of 63 children with refractory epilepsy given add-on clobazam (mean dosage 0.8 mg/kg/day) and followed for 15-64 months, 15 (24%) had to discontinue treatment owing to adverse effects, which included severe aggressive outbursts, hyperactivity, insomnia, and depression with suicidal ideation (6). Likewise, there were behavioral or mood problems in 38 of 119 children taking clobazam... 

The authors commented that although paradoxical reactions to benzodiazepines are rare, they should be considered in cases of refractory epilepsy. 

Brodtkorb E, Aamo T, Henriksen O, Lossius R. Rectal diazepam pitfalls of excessive use in refractory epilepsy. Epilepsy Res 1999 35(2) 123—33. 

Withdrawal of anticonvulsants with favorable mood stabilization properties, such as carbamazepine, has often been associated with acute psychosis (45,46). Moreover, the phenomenon of forced normalization, by which complete seizure freedom in a patient with previous refractory epilepsy can lead to a psychotic state, may also contribute to the apparent association between drugs and psychosis (47). 

A 5-year-old girl with refractory epilepsy treated with a ketogenic diet was given levetiracetam 250 mg bd (25 mg/kg/day). She had a history of mild mental retardation and was receiving special education. Two weeks later she started to have visual hallucinations, became agitated, bit relatives, and could not sleep. Levetiracetam was withdrawn and her symptoms resolved within 24 hours and did not recur. 

Pinfo A, Sander JW. Levefiracefam a new fherapeufic opfion for refractory epilepsy. Inf J Clin Pracf. 2003 57(7) 6f6-2f. 

Datta PK, Crawford PM. Refractory epilepsy treatment with new antiepileptic drugs. Seizure 2000 9(l) 51-7. 

Cilio MR, Kartashov AI, Vigevano F. The long-term use of felbamate in children with severe refractory epilepsy. Epilepsy Res 2001 47(l-2) l-7. 

Doherty K, Gates JR, Penovich P, Moriarty M. Gabapentin in a medically refractory epilepsy population seizure response and unusual side effects. Epilepsia 1995 36(Suppl 4) 71. 

Watts AD, Herrick lA, McLachlan RS, Craen RA, Gelb AW. The effect of sevoflurane and isoflurane anesthesia on interictal spike activity among patients with refractory epilepsy. Anesth Analg 1999 89(5) 1275-81. 

The efficacy and tolerability of levetiracetam 1-4 g/day as add-on treatment for refractory epilepsy have been studied in 29 patients with refractory epilepsy (8). The most common adverse events were somnolence and weakness, the frequency and severity of which increased with increasing doses. 

In a pooled analysis of safety data from double-bUnd, placebo-controUed add-on trials of levetiracetam (1-3 g/ day) in adults with refractory partial seizures, adverse events occurring in at least 3% of patients and with at least 3% higher incidence in the active treatment group were tiredness (14 versus 10%), somnolence (15 versus 10%), dizziness (9 versus 4%), and common cold or upper respiratory tract infections (13 versus 7%) (11). The proportions of patients requiring withdrawal of treatment or dosage reduction owing to adverse events were 15% with levetiracetam and 12% with placebo. The efficacy and tolerability of levetiracetam monotherapy in refractory partial seizures have been studied in a double-blind, pla-cebo-controUed study in 286 patients (12). Adverse events that were more common with levetiracetam and that occurred in more than 5% of cases included weakness, infection, and somnolence. Of 181 patients who took levetiracetam, 36 completed the study compared with only 10 of 105 who took placebo. The tolerability and efficacy of levetiracetam, 2 or 4 g/day, as add-on therapy have been studied in 119 patients with refractory epilepsy (13). Somnolence was the most common reason for withdrawal and occurred more often with levetiracetam than placebo, as did weakness. Somnolence was more common with the higher dose, which was not more effective than... 

Four patients with refractory epilepsy taking carbamaze-pine were given added levetiracetam and developed central nervons system effects (ataxia, diplopia, nystagmns) suggestive of carbamazepine toxicity (18). Rednction in the dose of carbamazepine resolved the symptoms in three cases. Carbamazepine and carbamazepine-epoxide blood concentrations were not altered dnring levetiracetam co-medication. Thns, a pharmacodjmamic interaction between carbamazepine and levetiracetam is likely. 

Grant R, Shorvon SD. Efficacy and tolerability of 1000-4000 mg per day of levetiracetam as add-on therapy in patients with refractory epilepsy. Epilepsy Res 2000 42(2-3) 89-95. 

Krakow K, Walker M, Otoul C, Sander JW. Long-term continuation of levetiracetam in patients with refractory epilepsy. Neurology 2001 56(12) 1772-4. 

Betts T, Waegemans T, Crawford P. A multicentre, double-bUnd, randomized, parallel group study to evaluate the tolerabiUty and efficacy of two oral doses of levetiracetam, 2000 mg daily and 4000 mg daily, without titration in patients with refractory epilepsy. Seizure 2000 9(2) 80-7. 

The adverse effects of remacemide have been stndied in 40 patients with refractory epilepsy randomized to... 

The efficacy, safety, and pharmacokinetics of adjunctive remacemide have been investigated in a randomized, double-blind, placebo-controlled, crossover study in 28 adult patients with refractory epilepsy (5). The mean plasma carbamazepine concentration increased by about 15%. Three patients withdrew owing to adverse events (two remacemide, one placebo). Adverse events that occurred more often with remacemide than placebo included dyspepsia, dizziness, abnormal gait, diplopia, abnormal vision, somnolence, chest pain, and fatigue. 

Richens A, Mawer G, Crawford P, Harrison B. A placebo-controUed, double-blind cross-over trial of adjunctive one month remacemide hydrochloride treatment in patients with refractory epilepsy. Seizure 2000 9(8) 537 3. 

Devinsky O, Vazquez B, Faught E, Leppik IE, Pellock JM, Schachter S, Alderfer V, Holdich TA. A double-blind, placebo-controUed study of remacemide hydrochloride in patients with refractory epilepsy following pre-surgical assessment. Seizure 2002 ll(6) 371-6. 

The effects of tiagabine have been studied in a 4-month, single-blind study in 52 children over the age of 2 years with different syndromes of refractory epilepsy (5). Adverse events, mostly mild to moderate, were reported by 39% of the children during the single-blind placebo period and by 83% of the children during tiagabine treatment. The events predominantly affected the nervous system weakness (19%), nervousness (19%), dizziness (17%), and somnolence (17%) were the most common. One child had hallucinations that responded to dosage reduction. Only three children withdrew because of adverse events. 

Uldall P, Bulteau C, Pedersen SA, Dulac O, Lyby K. Tiagabine adjunctive therapy in children with refractory epilepsy a single-blind dose escalating study. Epilepsy Res 2000 42(2-3) 159-68. 

The efficacy and tolerability of topiramate have been studied in 170 patients with refractory epilepsy (7). The most common adverse effects resulting in withdrawal were fatigue, weight loss, irritability, paresthesia, depression, and headache. Three patients developed renal calculi but continued therapy. 

Abou-Khalil B. Topiramate in the long-term management of refractory epilepsy. Topiramate YOL Study Group. Epilepsia 2000 41(Suppl l) S72-6. 

Stephen LJ, Sills GJ, Brodie MJ. Topiramate in refractory epilepsy a prospective observational study. Epilepsia 2000 41(8) 977-80. 

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