• Topiramate;
  • Epilepsy;
  • Seizures;
  • Antiepileptic drugs;
  • Cognitive dysfunction;
  • Psychomotor slowing


  1. Top of page
  2. Abstract

Summary: Ideal antiepileptic drugs (AEDs) are designed to stop seizures with limited central nervous system (CNS) side effects. However, CNS-related treatment-emergent adverse events (TEAEs) often occur in patients receiving AEDs. Topiramate (TPM) is an AED proven to be safe and effective as adjunctive treatment for epilepsy patients with partial seizures. Double-blind, placebo-controlled, multicenter trials demonstrated potential effects on cognition. The P.A.D.S. (post-marketing antiepileptic drug survey) group, a cooperative group of 14 epilepsy centers that collaborate on obtaining data about new AEDs and devices, prospectively collected standardized data forms before and during treatment with TPM for epilepsy, and analyzed the postmarketing experience of CNS TEAEs with TPM. Our results from 701 treated patients show that cognitive complaints were the most common reason to discontinue TPM. The presence of complaints did have predictive value if the patient would discontinue TPM, although was not specific as to when discontinuation would occur. The spectrum of complaints in our open-label prospective multicenter postmarketing study was similar to those observed in controlled clinical trials. We were unable to demonstrate a specific population, dose titration, or concomitant AED that was at risk to discontinue treatment.  We conclude that most patients treated with TPM will continue therapy beyond 6 months. Cognitive complaints and not efficacy reflect the primary reason for discontinuing therapy. Psychomotor slowing was the most common complaint, yet most patients elect to continue treatment, with “better” or “much better” ratings of both seizure and global improvement during treatment.

The goal of epilepsy treatment is to make patients seizure free without intolerable medication side effects. All antiepileptic drugs (AEDs) have the potential to cause central nervous system (CNS) dysfunction. The risk appears greater with barbiturates and benzodiazepines, and increases when AEDs are used in combination or with higher serum concentrations (1). The cognitive ramifications of the newer AEDs require further elucidation. Topiramate (TPM) is a sulfamated monosaccharide structurally distinct from other AEDs. It has multiple mechanisms of action (2). TPM has been found to be safe and effective as adjunctive treatment for children or adults with refractory partial epilepsy in double-blind, placebo-controlled trials (3–7). TPM also is effective in the treatment of generalized tonic–clonic seizures (8–10). In prior controlled clinical trials, approximately 11% discontinued TPM treatment. The most common treatment-emergent adverse effects (TEAEs) associated with TPM were CNS related and included somnolence, psychomotor slowing, difficulty with memory, impaired concentration and attention, and speech and language problems (11). Long-term follow-up of patients suggests continued treatment efficacy without serious adverse events (12,13).

Clinical trials performed for registration purposes may not fully reflect the adverse event profile found in clinical practice (14,15). Typically, trial populations are homogeneous, refractory epilepsy patients taking one or two other AEDs, following standardized titration rates. Study designs of several months' duration are common with patients encouraged to continue treatment until termination. In order to obtain information about the behavior of new AEDs in clinical practice, the PADS group was formed. This group has been prospectively registering and following up patients treated with new AEDs since 1995. The prospective nature of this database distinguishes it from other similar attempts to obtain information from the clinic to detail the cognitive TEAEs by using TPM in a “real life” clinical setting. We analyzed our TPM results from the PADS group, highlighting patient subpopulations, risk factors, and patient profiles for those discontinuing treatment with TPM.


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  2. Abstract

Investigators at 14 U.S. epilepsy centers (Appendix) comprising the PADS study group prospectively followed up consecutive patients recommended for treatment with TPM for six months' duration following approval for marketing. Treatment decisions were not affected by the study. Patient selection and dosage regimens were left to the discretion of individual physicians. Standardized data forms were submitted for initial and follow-up visits and entered into a database. Follow-up information was compared with the initial/baseline evaluation. The initial form listed demographic information such as age, sex, duration of epilepsy, and current and previous drug therapy. Information about previous neuropsychiatric history (i.e., developmental delay, psychiatric illness, suicidal attempt/ideation) also was captured on the initial form. Patients' epilepsy was classified using all principal epilepsy classifications in accord with the International League Against Epilepsy, plus an additional designation for the Lennox–Gastaut syndrome. All adverse events were tabulated on a standardized data-retrieval form. Adverse-event terminology was based on World Health Organization Adverse Reaction Terminology (WHOART). Identification of cognitive TEAEs was based on subjective patient complaints and substantiated by the interpreting neurologist. Complaints identified as “cognitive” without additional clarification were categorized as “NOS” (not otherwise specified). Psychomotor slowing involved an alteration in the speed of mental processing. The degree of TEAEs was registered as mild, moderate, severe, or severe enough to require discontinuation. Efficacy and AE data were obtained from physician inquiry and serially entered in commercially available database software (Microsoft Access®) for computerized analysis. AEDs could be stopped for more than one reason, and more than one adverse reaction was possible to record. A 5-point scale of much better, better, no change, worse, or much worse was applied by the physician to assess both seizure control and global benefit. Seven hundred seventy-two patients initially completed forms of intent to initiate TPM, although 71 lacked follow-up forms for data analysis. These 71 patients included those with recent initiation and limited time to follow-up, those patients lost to follow-up, and those who did not begin drug as planned. Seven hundred one patients initiated treatment with TPM and had some follow-up information available. Patient characteristics are detailed in Table 1. Five hundred eight patients initiated between January 6, 1997, and May 5, 1998, and maintained TPM therapy for ≥6 months. Of 701 total patients, 285 discontinued TPM at some point during treatment with TPM, and 171 patients discontinued TPM within 6 months of treatment. Statistical analysis was performed using Fisher's Exact test and χ2 analysis. A p value of <0.05 was regarded as significant.

Table 1.  Patient demographics and characteristics
Patient characteristicsNumberRange
  1. AED, antiepileptic drug.

AGe (average) and range (yr)32.8(1–78)
Age at epilepsy onset (yr)11.7(0–69)
Duration of epilepsy21.1(0–78)
Any prior psychological diagnosis356 
Mental retardation185 
Seizure type  
 Complex partial475(67.8%)
 Secondarily generalized213(30.4%)
 Simple partial146(20.8%)
 Generalized tonic–clonic104(14.8%)
 Infantile spasms6(0.9%)
6-mo analysis508(72.5%)
Average number of concomitant AEDs (treated)2.0 
No. of failed AEDs (@ 6 mo) and range4.2(0–13)
Dose (@ 6 mo)/mg and range385(25–1700)
Mean dose titration/week (@ 6 mo)/mg  and range35.5(12–100)


  1. Top of page
  2. Abstract


Follow-up information was available for 701 patients. Patients had epilepsy for a mean of 21.1 years and previously were treated with a mean of 4.2 AEDs. Complex partial seizures were the most frequent seizure type. Patient demographics were comparable for those that continued and discontinued treatment. The study population and treatment typically reflected an epilepsy population and treatment representative of epilepsy patients seen at tertiary care centers. Most patients were aged 18–60 years, although 14% were younger than 18 years, and 3% were older than 60 years. Half of the patients had some neuropsychiatric diagnosis, whereas the largest subsets included 26.4% with mental retardation and 16.3% with depression.

Discontinuation rate

Patients who discontinued TPM were analyzed to determine CNS-related AEs significant enough to result in cessation of TPM therapy, as depicted in Fig. 1. Of the 285 (40.7%) patients who withdrew from treatment, 63 (22.1%) stopped for lack of efficacy, 135 (47.4%) stopped for AEs, 35 (12.3%) stopped for both, and 52 (18.2%) stopped for other reasons. Of 701 (24.2%) patients, 170 discontinued with TEAEs, 77 (11.0%) of 701 stopped because of cognitive side effects, 47 (6.7%) due to noncognitive side effects, and 46 (6.6%) due to TEAEs not specified. Of the 77 patients with cognitive side effects, 41 (5.8%) patients of 701 discontinued only because of cognitive adverse events.


Figure 1. Flow diagram of topiramate adjunctive antiepileptic drug therapy results.

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Of patients that discontinued TPM within 6 months of treatment initiation, mean length of treatment was 89 days. The cumulative rate of discontinuation is shown in the Kaplan–Meier curve in Fig. 2. The CNS-related side-effect profile for these with 6-month follow-up included psychomotor slowing, fatigue, unsteadiness, depression, slurred speech, sedation, irritability, behavioral changes and confusion, inappropriate laughter, and hallucinations, in order of descending frequency. The CNS-related TEAEs resulting in TPM discontinuation included cognitive complaints in 25 (32.5%) of 77, psychomotor slowing in 23 (29.9%) of 77, psychiatric complaints in 21 (27.3%) of 77, speech difficulties in five (6.5%) of 77, and confusion (specified) in three (3.9%) of 77.


Figure 2. Kaplan–Meier cumulative survival plot for time to stopping topiramate.

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Adverse events

A total of 290 (41.4%) of 701 patients registered a complaint of CNS-related dysfunction during least one point of the course of treatment. Only 17 (2.4%) of 701 were treated with TPM monotherapy. The AEs therefore reflect the effect of TPM combination therapy. Twenty-three patients had CNS-related side effects developing within the first month. Patients may have had more than one complaint. Psychomotor slowing was noted in 11 (47.8%) of 23, cognitive adverse events not otherwise specified occurred in nine (39.1%) of 23, dizziness in five (21.7%) of 23, ataxia in four (17.4%) of 23, behavioral changes in three (18.0%) of 23, diplopia in two (8.7%) of 23, and psychiatric in one (4.4%) of 23. The side effects of those continuing at 6 months showed that psychomotor slowing was the most common specified cognitive side effect in 23 (29.9%) of 77 of the subgroup discontinuing because of cognitive AEs. A previous report of history of neuropsychological dysfunction was not more frequent in patients with psychomotor slowing with TPM. Psychomotor slowing without a history of neuropsychological dysfunction occurred in 104 (29.9%) of 348, in 60 (32.4%) of 185 with mental retardation, in 53 (46.5%) of 114 patients with depression, and in 55 (41.7%) of 132 patients with other neuropsychological dysfunction. Some patients (66 of 701) were in more than one category of neuropsychological dysfunction. Psychosis occurred in six (0.85%) of 701 patients, necessitating discontinuation in three. Psychotic episodes occurred in seven (1.0%) patients. The post-marketing psychotic adverse events caused by topiramate have received independent scrutiny (16).

Risk factors

Specific risk factors for patients who discontinued TPM were evaluated. No specific seizure type was predisposed to discontinue TPM for CNS-related reasons (p ≥ 0.2). Dose titration was assessed. Patients using titration rates slower than 25 mg/week were significantly less likely to discontinue for cognitive reasons (p = 0.04). The mean total dose was 293 mg/day for patients discontinuing TPM, and 152 mg/day for those discontinuing because of cognitive TEAEs. Carbamazepine (CBZ) was the most common coadministered AED for those that discontinued, as well as for those continuing treatment with TPM. The average number of concomitant AEDs for patients discontinuing TPM was similar to those continuing TPM (1.9 vs. 2.0 AEDs). Twenty-four patients older than 60 years were analyzed, with seven (26.9%) discontinuing TPM. Of those who discontinued TPM, four (16%) of 24 did so for cognitive TEAEs. One hundred eighty-five (26%) patients had mental retardation. These patients were least likely to discontinue TPM because of CNS-related adverse effects, whereas 13 (2%) patients had baseline histories of suicide ideation or attempt and were most likely to discontinue treatment, although the results did not reach statistical significance (MR, p = 0.06; suicidal, p = 0.07). The presence of cognitive AEs was not predictive (p = 0.40) of when a patient was likely to discontinue TPM, but was significant in regard to whether discontinuation would occur (p = 0.002).

Patients Continuing

Of those continuing at 6 months, psychomotor slowing remained the most frequent side effect. Table 2 depicts the AE profile of patients continuing at 6 months of TPM treatment. Physician assessment of seizure ratings for patients with ≥6 months' treatment at the time of last follow-up assessment were classified as better or much better in 70.0%, 58.6%, and 71.4% of continuing patients remaining with Lennox–Gastaut syndrome, partial epilepsy, and generalized epilepsy, respectively. Global assessment ratings in patients continuing TPM treatment were ranked as better or much better in 53.3% of patients with Lennox–Gastaut syndrome, 50.6% of those partial epilepsy and complex partial seizures, and in 55.6% of those with generalized seizures.

Table 2.  Reasons for discontinuation of TPM
ReasonNumber of patient complaintsPercentage patient complaints
  • NOS, not otherwise specified; CNS, central nervous system; AE, adverse event.

  • a

     Symptoms <1% including nephrolithiasis, rash, hyperventilation, thrombocytopenia, myalgia, alopecia, alcoholism, another doctor's orders, pregnancy, nonspecified, surgery, unspecified toxicity, urinary retention.

  • b

     Symptoms <1% including hypertonia, LOC, insomnia, impotence, lethargy, multiple CNS AEs, paresthesias, somnolence, lobectomy.

 Cognitive, NOS258.8
 PM slowing238.1
 Psychological problems217.4
 Languate difficulties51.8
Loss of efficacy only6322.1
Adverse events, NOS4616.1
Patient decision144.9
Liver function test93.2
Change in weight/appetite93.2
Other non-CNSa186.3
Other CNSb113.9


  1. Top of page
  2. Abstract

Initial controlled studies of a new AED are often limited in relevance to the broader application used in clinical practice. Postmarketing surveillance is a necessary and important component of FDA-approved product-monitoring safety and TEAEs (17,18). Preclinical trials are typically shorter and conducted in a more controlled environment. Open-label study after approval allows different patient demographics and characteristics as well as treatment flexibility to optimize treatment response, similar to routine clinical practice. TPM is a potent broad-spectrum AED that is an effective treatment option for patients with partial as well as generalized epilepsy. At present, the primary question for TPM is its tolerability. Clinical trials and studies of health volunteers treated with TPM have emphasized a potential for cognitive TEAEs (3–10,13,19).

The spectrum of cognitive TEAEs seen in our study was similar to that of controlled clinical trials (5–10,20–25). The CNS-related dysfunction resulting in discontinuation of TPM therapy in our patient population also was similar. In our study, psychomotor slowing was the most common cognitive complaint. Psychomotor slowing is more likely to occur in polytherapy than during monotherapy (26). It is important to note that 290/701 (41.4%) of 701 patients reported cognitive TEAEs at any time during the course of treatment, yet only 41 (5.8%) of the 701 treated patients discontinued solely for that reason. In previous trials, most patients with CNS-related AEs including cognitive complaints no longer complained of them by their last visit (3,4,20). Similarly, of 290 patients with cognitive complaints, a much smaller percentage had similar complaints at 6-month follow-up evaluation.

Cognitive AEs were a significant reason for patients to discontinue TPM (p = 0.002), although patients did not necessarily discontinue because of cognitive TEAEs early in treatment. Patients who discontinued TPM because of cognitive AEs did so predominantly because of psychomotor slowing. Patients older than 60 years did not appear to be higher risk for discontinuation, although our sample size was small. Patients with depression had no higher risk to discontinue TPM for cognitive reasons when compared with patients with either mental retardation or with patients without any neuropsychiatric history. Patients with mental retardation had a trend toward lower discontinuation rates for cognitive reasons than did other populations without any neuropsychiatric history, whereas those with a history of suicidal ideation/attempt were at higher risk to discontinue treatment with TPM; the results were not significant.

Cognitive TEAEs have previously been seen with the first-generation AEDs prior to 1993 (27,28); however, well-controlled studies with the second-generation AEDs and cognitive function are limited. The study by Martin et al. (19) in healthy volunteers comparing gabapentin (GBP), lamotrigine (LTG), and TPM demonstrated impaired verbal memory, concentration, attention, and mental speed. However, high initial doses of 200 mg followed by rapid titration rates of 100 mg/week were used. Prior long-term open-label study of TPM on cognitive function has not shown functional decline over time (29,30). Comparing AEDs suggests that patients are more likely to discontinue TPM than GBP, LTG, or tiagabine (TGB) when discontinuation odds ratios were evaluated (31), although total dose achieved and rapid TPM titration rate limit current comparative clinical extrapolation.

Global assessments reported by the investigator remained favorable despite the CNS-related adverse events. Approximately 60% of patients remaining were reported as better or much better at 6 months regardless of the type of epilepsy. This is similar to 77% of TPM-treated patients having improvement at the end of the approximately 3-month double-blind phase in randomized trials (20). In controlled clinical trials, as in our clinical practice survey, TPM was most frequently administered as adjunctive therapy. In adjunctive clinical trials for intractable partial epilepsy, faster rates of dose titration, 100 mg/week (3–7), were used compared with 25–50 mg/week typically used in our clinical practice study. AEs have generally been noted to have a relationship to rapid dosing titration rates (4,25,32). Meador (33) compared 50-mg weekly increases with more rapid titration rates of 100 mg/week to obtain a 400-mg/day dose. Only mild to moderate changes in verbal memory and mental speed were seen in the 50-mg/week dosing group (33), in contrast to the severe cognitive changes seen with higher titration rates (19). Aldenkamp (34) reported visuomotor (psychomotor/mental slowing) and verbal memory impairment on separate tasks restricted to both end titration and the maintenance phase, despite low-dose escalations of 25 mg/week in patients treated for 8 weeks after titration with valproate (VPA) or TPM as first-line add-on therapy to CBZ in patients with partial epilepsy. In our study, dose escalation at <25 mg/week showed the lowest likelihood to discontinue for cognitive reasons (p = 0.04), though the number of patients in this group was small.

Patients who discontinued TPM were taking much lower doses than those used in clinical trials. There are several possible explanations for this. The first is that these patients discontinued before they had an opportunity to reach a higher dose. The second is that these patients were relatively less tolerant to TPM throughout treatment, and could never attain higher doses. Inability to achieve higher dose levels may be an early sign of TPM intolerance.

The current study has several design limitations. A substantial number of patients were taking polypharmacy using at least two drugs. Because some investigators have noted a relationship with concomitant AEDs and TEAEs, cognitive complaints might be reduced with monotherapy (25). The open-label method involved a heterogeneous patient population and had no control arm. Data acquisition also was limited by questionnaires, potential individual variation in terms used, and individual physician assessments that reflected patient complaint, and not necessarily cognitive AEs or TEAEs that were validated by formal neuropsychological testing. Hence the possibility of bias or overestimation of findings could exist. Nevertheless, our study demonstrated cognitive AEs similar to the spectrum of cognitive dysfunction observed in previous clinical trials. No specific population or concomitant AED denoted a significantly greater risk to discontinue treatment.

We conclude that TPM is a potent AED in our large postmarketing experience. CNS-related AEs were the most common in this study, similar to previous postmarketing experience (35). Although prior reports suggested that 20–25% of patients are intolerant to relatively low doses of TPM, very low-dose titration resulted in even less discontinuation of therapy in our clinical practice study. The treatment approach to CNS-related TEAEs with TPM may require slower titration rates, reduction of concomitant AEDs, or use of nonsedating combination therapy. Despite a report of psychomotor slowing or cognitive complaints, most patients will continue to take TPM for at least 6 months of treatment. The majority of patients demonstrated reduced seizures as well as global improvement despite cognitive TEAEs.


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  2. Abstract

The Postmarketing Antiepileptic Drug Survey Group

Blaise Bourgeois, M.D. Children's Hospital Boston, MA Lawerence Brown, M.D. Children's Hospital of Philadelphia Philadelphia, PA Robert Burgerman, M.D. Sacramento Comprehensive Epilepsy Sacramento, CA Mercedes Jacobson, M.D. Medical College of Pennsylvania Philadelphia, PA Giuseppe Erba, M.D. University of Rochester Rochester, NY Andres Kanner, M.D. Rush Presbyterian St. Luke's Medical Center Chicago, IL Joyce Liporace, M.D. Jefferson Comprehensive Epilepsy Center Philadelphia, PA Georgia Montouris, M.D. St. Lukes Comprehensive Epilepsy Center St. Louis, MO George Morris, M.D. Medical College of Wisconsin Milwaukee, WI Michael Privitera, M.D University of Cincinnati Cincinnati, OH Edward Faught, M.D. University of Alabama Birmingham, AL Jacqueline French, M.D. Hospital of the University of PA Philadelphia, PA Cynthia Harden, M.D. Cornell Comprehensive Epilepsy Center New York, NY William Rosenfield, M.D. St. Luke's Comprehensive Epilepsy Center St. Louis, MO William Tatum, IV, D.O. Tampa General Hospital Tampa, FL David Vossler, M.D. Swedish Medical Center Seattle, WA

Acknowledgment: We thank David G. Vossler, M.D., for his review of the manuscript, Josh Anderson for his help with the database, and Kelly Porrey for assistance with word processing. Support for the PADS study group was provided by educational grants from Novartis, Abbott, Ortho-McNeil, UCB Pharma, and Glaxo-Wellcome.


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