Need of Immediate Drug Reduction after Epilepsy Surgery – A Prospective Observational Study
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.266282
Source of Support: None, Conflict of Interest: None
Keywords: Clobazam, drug tapering, GABA receptors
Nearly 50 million people suffer from epilepsy worldwide, and about one-third of them are drug refractory. Epilepsy surgery has been proven to be the best treatment possible in the drug refractory epilepsy (DRE) both in adults and children.[2–5] Temporal lobectomy (TL) and hemispherotomy (HS) are associated with high chances of seizure freedom in appropriately selected cases.,,,,,,, After successful epilepsy surgery, most epileptologists prefer to start tapering the drugs at 1 year after getting a normal electroencephalogram (EEG) in adults and at 6 months in children. Overall, one-third of patients are free from drugs, one-third continue to have drugs to control seizures, and one-third have persisting seizures.
Perioperative tailoring of drugs is not infrequent and depends upon many factors. This includes continuing seizures, ammonia levels, and electrolytes. Data on this topic are limited in the literature. In our experience, patients of HS often go into prolonged drowsiness after surgery needing perioperative tapering of drugs, while patients of TL continue to have same dosages and drugs. Our objective was to compare immediate drug alterations in HS and TL patients, and provide a hypothesis regarding the difference.
A prospective analysis of cases performed between January 2011 to December 2016 at a single tertiary care center for treating epilepsy. Ethical clearance was taken from the institutional review board and informed consent was taken from each patient. Patients with DRE undergoing either HS or TL of any age group were included in the study. All patients were preoperatively worked up by the senior neurologist and discussed in the an epilepsy surgery conference comprising of neurologists, neurosurgeons, neuroradiologists, and nuclear medicine specialists. Patients of TL comprised either of mesial temporal sclerosis ± focal cortical dysplasia, ganglioglioma, or dysembryoplastic neuroepithelial tumor. Patients of HS comprised of Rasmussen's encephalitis, hemimegalencephaly, or post-infarct/meningitis encephalomalacia. All patients underwent a long-term scalp video EEG monitoring on 10/20 system, an epilepsy protocol magnetic resonance imaging (MRI) comprising of 1 mm thickness, 0 mm gap, T1-weighted sagittal 3D, and T2-FLAIR sequences reconstructed in axial and coronal sequences and arterial spin labeling sequences. Patients also underwent positron emission tomography (PET), single photon emission computed tomography (SPECT), and magnetoencephalography (MEG), whenever required. Temporal plus epilepsy or bilateral hemispheric pathologies were excluded from the study.
All surgeries were performed by the same experienced neurosurgeon. And postoperative computed tomography (CT) scans were obtained for all patients. We monitor drug levels of phenytoin, valproate, and carbamazepine both preoperatively and postoperatively for all patients in the perioperative period. The postoperative drug tapering was started at one year for adults, and at six months for children. However, in the events of hyperammonemia- the valproate and/or topiramate was tapered early, for prolonged drowsiness - CLB was tapered early, and for behavioral problems - levetiracetam was tapered early. In the events of repeated or increased seizures we performed MRI under epilepsy protocol to see completeness of disconnection/resection, started EEG monitoring, and stepped up the anticonvulsants based on the drug levels.
The objective was to compare the drug alterations in perioperative period (within 3 days of surgery) and at 1 year, and seizure freedom using the International League Against Epilepsy Scale at 1 year. The objective was to compare the intelligence quotient (IQ) on the Binet–Kamat Intelligence Quotient/Wechsler Adult Intelligence Scale.
Data was collected through the computerized patient record system of hospital on an excel sheet and analyzed using the SPSS 20.0 software. Comparison between the two groups for categorical variables was done using the Chi-square test and comparison of means was done using the analysis of variance (ANOVA) test.
A total of 71 patients (38 HS and 33 TL) were included with a mean age of 16.93 ± 11.88 years (TL – 25.69 ± 1.91, HS – 9.31 ± 0.95). Males were 46 and females were 25. The frequency of seizures was 4.36 ± 0.88/day (TL – 0.97 ± 0.32, HS – 7.31 ± 1.47). The age of seizure onset was 85.98 ± 13.65 months (TL – 168.6 ± 26.8, HS – 35.98 ± 6.79). IQ was low in 26 (HS) and in 15 (TL) patients. All patients were conscious and alert before the surgeries.
The number of drugs in the preoperative period was 3.55 ± 0.13. These were higher in HS group (HS – 4.03 ± 0.19, TL – 3 ± 1.07) with a P value of 0.002. Postoperatively, immediate drug reduction (clobazam – CLB) was needed in 3/38 patients in HS group, while none were required in the TL group.
Drug dosages reduction
Immediate need of dosage reduction was necessary in 23/38 (60.52%) patients in HS group, and in 2/33 (6%) patients in TL group. This was found statistically significant (P < 0.001). The common drug to have reduction was CLB, with a reduction in 21/27 (77.7%) patients. Mean reduction of CLB dosage was 41.21 ± 4.01% from the preoperative dose. [Table 1] shows the number of patients and percent reduction of different drugs that were reduced.
In two patients of HS group, a new drug in the perioperative period had to be added. For one patient carbamazepine had to be substituted for valproate due to raised ammonia levels, and in other patient CLB had to be substituted for levetiracetam due to behavioral issues. There was no drug addition in the TL group.
In four patients of HS group, dosages of drugs had to be increased. In three patients, levetiracetam was increased for reduction of CLB, and in one patient valproate was increased in lieu of levetiracetam reduction. There were no dosage increases in TL group.
About 64/71 (90.1%) patients achieved Class I outcome at 1-year postoperative time point (TL – 90.9% and HS – 89.47%). There was no significant difference between the two outcomes, P value 0.4. No patient had seizures due to drug alterations.
At 1 year, 33/38 (86.84%) patients of HS group and 29/33 (87.8%) of TL group had tapering of drugs. There was no statistical difference between the two groups.
IQ was measured using the Binet–Kamat test in children (33 in HS and 5 in TL) and the Wechsler Adult Intelligence Scale in adults (5 in HS and 28 in TL). The preoperative IQ in HS patients was 50 ± 15 and in TL patients was 80 ± 27. After 1 year, IQ was not found to be altered in both the groups.
TL and HS are the two most successful epilepsy surgeries, giving 70–80% of seizure freedom., Patients undergoing these surgeries are on polytherapy. Benzodiazepines, including CLB, are a frequent member of the drug regime in these patients. CLB is 1,5-benzodiazepine with a half-life of 37.5 hours. Apart from its anticonvulsant properties, it has anxiolytic and sedative activity, albeit lesser than diazepam, lorazepam, and clonazepam. The receptor of CLB is a ligand gated gamma-aminobutyric acid-A (GABA-A) receptor. CLB typically has two α, two β, and one γ subunits. The α1 subunit mediates the sedative effect. Though CLB has been the Food and Drug Administration (FDA) approved only as an adjunctive therapy in Lennox–Gastaut syndrome in >2 years of age, it has been used in many epilepsy types, including as a monotherapy.,
Generally, these drugs are continued in the postoperative period for minimum 1 year, and then tapered gradually on an individual basis depending upon the EEG status, side effects of drugs, need for patient to drive, and neurologist preference.
A significant subset of patients develop tolerance to CLB, which is on an average 36%, but may range from 0–86%. Approximately 9% of patients have to discontinue the treatment due to tolerance to the therapy. We compared two groups of patients – one of HS and other of TL since both groups have similar seizure freedom of use approx 80% of seizure freedom, and have CLB as an adjunctive therapy, albeit significant difference in the demographic profiles like age, seizure frequency, cognition, extensive epileptogenic zone, and degree of brain handling during the surgery.
HS and TL are two highly effective surgeries.,,,, Post-HS, the seizures go off abruptly and the patients often go into prolonged sedation. This may be due to either of loss of cortical drive from one hemisphere over the reticular activating system, GABA receptor denervation hypersensitivity, or action of drugs only on the remaining hemisphere. Since the CLB receptors have tolerance activity and drugs are preoperatively in good levels the remaining receptors postoperatively in the normal brain may get sensitive to the existent drug level. Post-denervation GABA receptor hypersensitivity is well known with animal experiments., The results of this analysis show that the CLB has to be decreased in 60.52% patients of HS compared to only 6% of TL patients. This is highly significant (P < 0.0001). Similarly, CLB had to be stopped in three patients of HS, while none were rquired to stop for TL patients. It was reduced in 77.7% of patients taking it, with a mean dose reduction of 41.21%.
We found no difference in the IQ levels pre- and postoperatively. This may be explained by short follow-up of 1 year in our study. This has been shown in prior studies. A longer follow-up may show improvement in the IQ scores.
There were several limitations in the study. First, molecular analysis of GABA receptors on the abnormal and normal hemispheres could have been done to prove the hypothesis of increased action of CLB on the remaining active hemisphere. Second, the TL and HS groups were different demographically. However, since TL and HS surgeries have similar seizure outcomes, they were compared to remove the confounding factor of seizure control after surgery. Third, it was an observational study based on the individualized need of the patients. Therefore, a randomized controlled trial for HS patients in which one group has CLB and other group without CLB can be a more scientifically strong study.
The benzodiazepine drugs have to be reduced in the perioperative period in most of the hemispherotomy patients, compared to none of the temporal lobectomies. This may be due to the loss of half of cortical excitatory activity upon reticular activating system after HS, denervation hypersensitivity of GABA receptors, or drug action only on the remaining hemisphere. More research needs to be done in the perioperative epilepsy drug management area.
This work was funded by the Centre of Excellence for Epilepsy, a collaborative project between the National Brain Research Centre, Manesar, India and All India Institute of Medical Sciences, New Delhi, India funded by the Department of Biotechnology, Ministry of Science & Technology, Government of India [Grant: BT/01/COE/09/08].
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Authors affirm that the work described is consistent with the journal's guidelines for ethical publication.
The work was presented as a poster in the AOEC Bali 2018.
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