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Table 10.4 Seizure Prevention or Prophylaxis Using Phenytoin

Author/Year/ Country/Study Design/PEDro/N Methods Outcome
Dikmen et al. (1991) USA RCT PEDro=6 NInitial=244, NFinal=124 Population: Head Injury; Phenytoin Group (n=104): Mean Age=30.9yr; Gender: Male=82, Female=22; Median GCS=11. Placebo Group (n=101): Mean Age=32.9yr; Gender: Male=70, Female=31; Median GCS=9. Treatment: Patients were randomized to receive phenytoin (prophylactic medication) or a placebo for 1yr. Patients were then observed for another 1yr while unmedicated. Outcome Measure: Halstead–Reitan Neuropsychological Test Battery, Katz Adjustment Scale, Sickness Impact Profile.
  1. From 1 to 12mo, more participants in the treatment group stopped receiving their assigned drug (p<0.01) due to idiosyncratic reactions and requests.
  2. Those severely injured (GCS≤8) and receiving phenytoin did more poorly on most neuropsychological measures than controls determined by the overall rank-sum type test at 1mo (p<0.05). No significant differences were found at 1yr.
  3. No significant differences in neuropsychological performance were found between groups for patients with moderate injuries (GCS≥9) at 1mo or 1yr.
  4. Changes in neuropsychological measures from 12 to 24mo showed that phenytoin had a small but negative widespread cognitive effect as evidenced by the overall rank-sum type test (p<0.05).
Temkin et al. (1990) USA RCT PEDro=6 NInitial=404, NFinal=123 Population: TBI; Phenytoin Group (n=208): Mean Age=34yr; Gender: Male=162, Female=46; GCS ≤10=125. Placebo Group (n=196): Mean Age=34yr; Gender: Male=147, Female=49; GCS ≤10=131. Treatment: Participants were randomized to either the phenytoin (n=208) or placebo group (n=196). Phenytoin group received an initial dose of 20 mg/kg intravenously, then serum levels were maintained at 3–6 µmol/l. Treatment started within 24hr of injury and continued for 1yr. Follow up at 2yr. Outcome Measure: Occurrence of early (<1wk) and late (>8d) seizures.
  1. Cumulative early seizure rates were 3.6% in the phenytoin group and 14.2% in the control group (p<0.001); phenytoin was associated with a decrease of 73% in the risk of early seizures.
  2. Late seizure occurrence (day 8 to 2yr) did not differ significantly between the treatment and control groups (27.5% vs 21.2%, p>0.2).
  3. More participants in the phenytoin group stopped taking the drug between day 8 and 1yr, mainly due to idiosyncratic reactions or requests (103 vs 67).
Young et al. (1983) USA RCT PEDro=6 N=244 Population: TBI; Phenytoin Group (n=136): Mean Age=24.4yr; Gender: Male=110, Female=26. Placebo Group (n=108): Mean Age=25.8yr; Gender: Male=91, Female=71. Treatment: Patients were administered phenytoin (serum concentration10-20µg/ml) or placebo, starting within 24hr of injury. Outcome Measure: Occurrence of early seizures (≤1wk of injury).
  1. Five in the phenytoin group and 4 in the control group had early seizures (p=0.75).
  2. Mean time from injury to early seizure in the treatment and control group was 3.2 and 4.5d, respectively (p=0.41).
Young et al. (1983) USA RCT PEDro=6 NInitial=214, NFinal=179 Population: TBI; Phenytoin Group (n=105): Mean Age=24.1yr; Gender: Male=84, Female=21. Placebo Group (n=74): Mean Age=26.3yr; Gender: Male=61, Female=13. Treatment: Participants treated with phenytoin (serum concentration 10-20µg/ml) or placebo starting within 24hr of injury. Treated duration 18mo. Patients were switched to phenobarbital if there was a hypersensitivity to phenytoin (n=20). Outcome Measure: Occurrence of late (>7d post injury) seizures.
  1. Late seizures occurred in 11 (12.9%) of the phenytoin group, 2 (10%) of the phenobarbital group, and 8 (10.8%) of controls.
  2. There were no significant differences between groups in the percentage of late seizures (p=0.75).
McQueen et al. (1983) United Kingdom RCT PEDro=7 N=164 Population: TBI; Phenytoin Group (n=84): Gender: Male=67, Female=17; Age Range: 5-15yr=29, 16-65yr=55. Placebo Group (n=80): Gender: Male=63, Female=17; Age Range: 5-15yr=14, 16-65yr=66. Treatment: Patients received either phenytoin or placebo for 1yr. Phenytoin administration for adults was 300mg and for children 5mg/kg. Follow-up continued for 2yr. Outcome Measure: Occurrence of seizures.
  1. Only 48% of the treatment group had plasma levels greater than 40µmol/l.
  2. Nine percent of participants developed post-traumatic epilepsy within the first 2yr.
  3. At 1yr, 6 participants in the treatment group and 5 in the control group developed post-traumatic epilepsy.
  4. Eight participants in the treatment group and 7 in the control group developed seizures by 2yr.
Bhullar et al. (2014) USA Case Control N=93 Population: TBI, GCS=3-8; No Prophylaxis Group (n=43): Gender: Male=28, Female=15. Phenytoin Prophylaxis Group (n=50): Gender: Male=42, Female=8.Treatment: Medical records were reviewed and patients were divided into two groups: no prophylaxis and phenytoin prophylaxis. Outcome Measure: Occurrence of early (<7d post injury) seizures, length of stay (LOS), Glasgow Outcome Scale (GOS), modified Rankin Scale (mRS).
  1. There was no significant difference in the occurrence of early seizures between the no prophylaxis and phenytoin groups (2.3% versus 4.0%, p=1.0).
  2. The phenytoin group, compared to no prophylaxis, had longer hospital stays (36± 31 vs 25± 16d, p=0.03), and worse functional outcome at discharge (GOS, 2.9± 1.0 versus 3.4±1.1, p=0.01; mRS, 3.1± 1.5 versus 2.3±1.7, p=0.02).
Servit & Musil (1981) Czechoslovakia Cohort N=167 Population: TBI; Mean Age=30.6yr; Gender: Male=128, Female=39. Treatment: Participants in the treatment group (n=143) were administered phenytoin (160-240mg/d) and phenobarbital (20-60mg/d). The control group (n=24) was treated with conventional methods for 2yr. Outcome Measure: Occurrence of late seizures.
  1. Post-traumatic epilepsy occurred in 25% of the control and 2.1% of the treatment group (p<0.001).
PEDro=Physiotherapy Evidence Database rating scale score (Moseley et al., 2002).