Language Disturbances as a Side Effect of Prophylactic Treatment of Migraine
Dr. Paola Sarchielli, Neurologic Clinic, Department of Medical and Surgical Specialties and Public Health, University of Perugia, Policlinico Silvestrini, Via Sant'Andrea delle Fratte, 06156 Perugia, Italy.
Background.— Language disturbances have been previously described as word-finding difficulties in epileptic patients. These disturbances have been recently reported in migraineurs in treatment with topiramate but they have never been defined and assessed in these patients with the aid of neuropsychological testing.
Objective.— To verify the occurrence of language disturbances as a side effect of topiramate treatment in episodic and chronic migraine patients.
Methods— Language disturbances were recorded on the basis of spontaneous reports of 30 migraine patients treated with topiramate and 2 control groups (20 patients treated with other prophylactic drugs and 20 patients without prophylactic treatment) and were explored with neuropsychological tests. Psychiatric comorbidity was assessed using Zung Anxiety and Depression Scales.
Results.— Language disturbances were referred by 26.7% (n = 8) of patients during topiramate treatment but by none of the patients in the 2 control groups. All patients in the topiramate group had a worse performance on all tests compared to patients of the 2 control groups. Moreover, in the topiramate group, patients with referred language disturbances had higher scores for all neuropsychological test variables, indicative of aworse performance. Some language functions (Trail Making Tests A and B) seemed to be influenced by the concomitant presence of psychiatric comorbidities, particularly anxiety and depression.
Conclusion.— It can be hypothesized that a disorder such as migraine, which involves numerous cortical and subcortical circuits implicated in the transmission and behavioral and emotional processing of pain, represents a facilitated substrate for the occurrence of language disturbances due to topiramate. This could be the expression of a more generalized impairment of cognitive processing. These aspects should be investigated in prospective studies involving larger migraine patient samples.
trail making test-A
trail making test-B
phonemic verbal fluency
semantic verbal fluency
Cognitive complaints have been reported as a side effect of topiramate treatment in epileptic patients and also in research carried out on healthy volunteers. These complaints have been investigated in some studies with neuropsychological testing and include impaired concentration and memory, slowed thinking, and language disturbances.1-9
Cognitive side effects have also been recorded in studies aimed at investigating the efficacy and tolerability of topiramate in migraine prophylaxis, but they have never been defined and assessed with the aid of neuropsychological testing. Mathew et al.10 showed cognitive slowing in 11% of patients treated with topiramate at dosages ranging from 25 to 200 mg, administered as monotherapy for the prophylactic treatment of episodic migraine or add-on therapy for chronic migraine (CM). Diener et al.11 found impaired concentration in 4% and 12% of patients affected by episodic migraine treated with topiramate at dosages of 100 and 200 mg/day, respectively. Cognitive effects were also reported by Rothrock et al.12 in patients with CM treated with topiramate 100 mg/day. In a recent, randomized controlled trial, impaired memory was referred from 9.3%, 7%, and 12.4% of patients treated with 50, 100, and 200 mg/day topiramate for migraine prophylactic treatment, and impaired concentration from 2.5%, 4%, and 9.7% of patients in the 3 treatment groups, respectively.13 The authors described language disturbances as a side effect of topiramate treatment in 5.9% of cases at dosages of 50 mg/day, 7.9% at 100 mg/day, and 12.4% at 200 mg/day. In this trial, as in previous studies, cognitive side effects, including language disturbances, seemed to be dose-dependent, generally resolved over time, often after adjustment of the dosage and, less frequently, led to discontinuation of the drug.
Based on the above evidence, the present study was aimed at verifying the occurrence of referred language disturbances as an adverse event of treatment with topiramate in migraine patients compared with patients treated with other prophylactic drugs or patients without prophylactic treatment. The impact of topiramate on language functions was then explored with neuropsychological tests. The relationship of language disturbances with drug dosages, headache frequency or chronicity as well as the occurrence of neuropsychological disturbances were also investigated.
Patients.— The study protocol was approved by the Ethics Committee of the Azienda of Umbria and all patients and controls gave their written consent to the study.
Thirty migraine patients treated with topiramate as prophylactic agent, attending the Headache Center of the University of Perugia, were enrolled in the period January–October 2005. Four of them suffered from episodic migraine, the remaining 26 (85.7%) complained of CM (n = 17) or medication-overuse headache (MOH) (n = 9), according to the current International Classification of Headache Disorders (ICHD)-II Criteria and the revision of CM and MOH definitions reported in the Appendix.14-16 Topiramate was chosen as a preventive drug for these patients after previous attempts with other antimigraine prophylactic drugs resulted in only a partial response in terms of reduction in frequency and intensity of attacks.
To verify whether language disturbances were specifically related to topiramate treatment, we assessed 2 control groups in the same time period. The first group included 20 migraine patients treated with other prophylactic drugs but not antiepileptics, and the second group, 20 migraine patients without prophylactic treatment. Patients in the untreated group attended for the first time our Headache Center and had not yet started preventive treatment. Patients in both control groups shared similar clinical characteristics with migraine patients treated with topiramate in terms of gender, age, age at headache onset, duration of headache, and frequency and intensity of migraine attacks at the time of assessment (Table 1). Preventive treatments used by patients following other prophylactic drug treatment were: amitriptyline (n = 12), propranolol (n = 3), paroxetine (n = 2), pizotifen (n = 1), and amitriptyline + propranolol (n = 2).
Table 1.—. Demographic and Clinical Details of the Three Patient Groups
| Females||27 (90%)||18 (90%)||18 (90%)|
| Males||3 (10%)||2 (10%)||2 (10%)|
| Age (years)||40.0 ± 10.5||39.0 ± 9.5||38.9 ± 9.6|
| Education (years)||13.2 ± 3.1||13.0 ± 2.8||13.2 ± 2.9|
| Age at headache onset (years)||14.3 ± 5.2||14.5 ± 4.4||13.4 ± 3.1|
| Frequency of attacks||20.4 ± 4.8||20.0 ± 4.9||19.8 ± 4.7|
|Distribution of diagnoses according to ICHD-II|
| MWoA||3 (10%)||2 (10%)||2 (10%)|
| MWoA + MWA||1 (3.3%)||1 (5%)||1 (5%)|
| CM||17 (56.7%)||11 (55%)||11 (55%)|
| MOH||9 (30%)||6 (30%)||6 (30%)|
The patient group that received no medication was chosen as an additional control group because it did not suffer from the potential placebo cognitive effect of the control group taking nonantiepileptic prophylactic medications, and therefore could furnish information on the neuropsychological profile of migraine patients in the other 2 treatment groups, based on similar characteristics at baseline in terms of duration, intensity, and frequency of attacks.
Language Disturbance Assessment and Neuropsychological Testing.— Patients in the group treated with topiramate and those treated with other prophylactic drugs were questioned about the occurrence of side effects due to treatment. In particular, language disturbances were recorded on the basis of spontaneous patient reports and were confirmed by clinical evaluation. The language disturbances referred spontaneously by patients were arbitrarily classified as mild (not interfering with daily routine activity and not requiring reduction of the drug dosage), moderate (partially interfering with daily routine activity and requiring a lowering of the dosage), and severe (strongly interfering with daily routine activity and requiring drug withdrawal).
Patients in the topiramate group and in the 2 control groups underwent neuropsychological tests. Since cognitive dysfunction has been well documented during migraine attacks, neuropsychological testing was performed in the headache-free period, even in patients with CM. Neuropsychological tests included: the Trail Making Tests (TMT-A and TMT-B), which explores attention and visuo-motor tracking abilities and problem-solving; and the Controlled OralWord Association Test, which measures phonemic verbal fluency (the subject is invited to produce as many words beginning with the letters F, A, and S as possible within a minute for each letter: PVF-F, PVF-A, PVF-S), and semantic verbal fluency (the subject is invited to name as many flowers, animals, and cities as possible within a minute for each category-SVF-F, SVF-A, SVF-C). Although subtests imply different cognitive components, both need verbal initiative ability to perform the tasks: a Denomination Test, which is a timed task of denomination of stimuli presented in a sensorial modality (visual), which involves different cognitive components, first of all the perceptive identification of the stimulus.
Zung Anxiety and Depression scales were also administered to patients in the 3 groups to verify the occurrence of psychiatric comorbidities.
Statistical Analysis.— Fisher test was used to compare percentages among patient groups. Continuous variables of the 3 patient groups, expressed as mean ± 2SD, were compared using ANOVA and Least Significant Difference (LSD) Test as post-hoc analysis.
Factorial ANOVA was applied to verify the contribution of the following variables to the value and significance of F in ANOVA: type of prophylactic treatment, anxiety and depression occurrence, headache frequency, number of days with headache per month, headache duration, as well as drug overuse. Correlations between the age of patients (years), duration of headache (years), frequency of headache, and values of neuropsychological variables for each patient group were calculated using Spearman rank correlation test. Values of P < .05 were considered as minimum levels of significance.
At the time of enrollment, patients in the topiramate group had used the drug for at least 3 months (duration of prophylactic treatment: 3–6 months, mean ±2SD, 4.2 ± 0.73). The same was true for patients taking other prophylactic drugs (duration of prophylactic treatment: 3–7 months, mean ± 2SD, 4.6 ± 0.87). For all patients in the group treated with topiramate, the initial dosage of 25 mg/day was slowly increased according to the current titration scheme (25 mg/week) to reach the dosages currently recommended for the prophylactic treatment of migraine. Dosages used at the time of assessment were 200 mg/day (1 patient), 150 mg/day (1), 100 mg/day (10), and 75 mg/day (18). Patients treated with 75 mg/day could not increase the dosage because of the occurrence of unpleasant side effects, including cognitive disturbances (in particular, difficulty of concentration).
In both the topiramate group and the group treated with other preventive drugs, prophylactic treatment induced a significant decrease in the frequency of headache and the conversion of chronic forms to an episodic pattern in 70% and 75% of cases, respectively. Among the CM forms, which persisted despite prophylactic treatment, MOH represented 10% of patients treated with topiramate and 15% ofpatients treated with other prophylactic drugs.
In this latter group of patients, only 4 patients (20%) complained of side effects, consisting primarily of somnolence and weight gain, and none of the patients referred language disturbances. Fifteen patients (50%) in the topiramate treatment group spontaneously complained of 1 or more side effects, which were all mild or moderate in intensity (Table 2). In the same group, in particular, language disturbances were referred by 8 patients (7 females and 1 male, 26.7%), alone (1 patient, 3.33%) or in association with other side effects by 7 patients (6 females and 1 male, 23.3%). They occurred within the first month, during the titration period, and were present at the time of enrollment, were of mild severity in the majority of patients (only 1 patient judged them of moderate severity), and in all cases did not require a further adjustment of dosages or discontinuation of the drug.
Table 2.—. Side Effects (No. of Patients and Relative%) Referred by Patients in the Topiramate and Other Prophylactic Treatment Groups
|Paresthesias||12 (40.0%)||0 (0.0%)|
|Weight loss||9 (30.0%)||0 (0.0%)|
|Weight gain||0 (0.0%)||2 (10.0%)|
|Language disturbances||8 (26.7%)||0 (0.0%)|
|Emotional lability||4 (13.3%)||0 (0.0%)|
|Fatigue||3 (10.0%)||1 (5.0%)|
|Dysgeusia||2 (6.7%)||0 (0.0%)|
|Difficulty of concentration||2 (6.7%)||0 (0.0%)|
|Somnolence||0 (0.0%)||2 (10.0%)|
|Constipation||0 (0.0%)||1 (5.0%)|
|Dry mouth||0 (0.0%)||1 (5.0%)|
Language disturbances were variably described by the above patients: a difficulty of word finding, and as in previous reports a slowing of verbal expression, a change of 1 word with another with the same meaning, a need to search for the right word, the production of nonexistent words deriving from the fusion of 2 words, or an occasional difficulty in object denomination.
Comparison of the variables of neuropsychological tests revealed a worse performance in the TMT-B (corresponding to a longer execution time) for the topiramate group compared with the 2 control groups. In contrast, values of TMT-A, although higher in the topiramate patient group, did not differ significantly from those of the other patient groups. In the Controlled Oral Word Association Test, a statistically significant difference emerged among the mean values of 2 categories of semantic verbal fluency (flowers and cities) of the 3 patient groups, with the lowest number of words produced by patients in the topiramate group. Values of phonemic verbal fluency categories, although lower in the topiramate group, were not statistically different from those of the 2 treated and untreated control groups (Table 3). No differences emerged among groups for mean values of the Denomination Test.
Table 3.—. Mean Values (±2 SD) of Neuropsychological Tests Administered to Patients Treated With Topiramate, With Other Prophylactic Drugs, and Patients Untreated With Prophylactic Drugs
|Trail making test|
| TMT-A||36.6 ± 15.7||31.3 ± 6.3||31.3 ± 6.3||n.s.||T vs OP: n.s.|
|T vs U: n.s.|
| TMT-B||103.6 ± 43.8||70.9 ± 16.0||79.2 ± 28.9||F = 5.77||T vs OP: P < .001|
|P < .005||T vs U: P < .01|
|Controlled oral word association test|
| PVF-F||9.0 ± 2.5||9.7 ± 1.8||9.3 ± 1.8||n.s.||T vs OP: n.s.|
|T vs U: n.s.|
| PVF-A||7.5 ± 2.4||8.9 ± 2.2||8.1 ± 1.5||F = 2.51||T vs OP: P < .03|
|P < .08||T vs U: n.s.|
| PVF-S||9.2 ± 3.4||10.4 ± 2.4||10.6 ± 1.4||n.s||T vs OP: n.s.|
|T vs U: n.s.|
| SVF-F||9.1 ± 1.7||13.2 ± 2.6||11.4 ± 1.9||F = 18.14||T vs OP: P < .0001|
|P < .00001||T vs U: P < .001|
| SVF-A||12.1 ± 3.2||13.7 ± 3.5||13.9 ± 2.1||n.s||T vs OP: n.s.|
|T vs U: n.s.|
| SVF-C||14.2 ± 3.8||17.1 ± 3.5||17.0 ± 3.0||n.s.||T vs OP: P < .01|
|T vs U: P < .01|
|Denomination test||39.2 ± 1.5||39.7 ± 0.7||39.6 ± 0.9||n.s.||T vs OP: n.s.|
|T vs U: n.s.|
No effect emerged for gender, education, headache frequency, number of days with headache per month, headache duration, drug dosage, and concomitant overuse of symptomatic drugs on the mean values of neuropsychological tests considered as dependent variables in ANOVA. Moreover, no significant correlations emerged between age of patients, frequency of attacks, duration of both headache and prophylactic treatment, and values of neuropsychological tests. However, comparison between the values of neuropsychological tests of patients referring and not referring language disturbances in the topiramate group showed a significant difference for bothTMT-A and TMT-B subtests. A significantly lower number of denominations also emerged in patients in the former group. The mean values of all phonemic and semantic categories did not differ significantly between patients with referred language disturbances and those without in the topiramate group (Table 4). However, even in patients not referring language disturbances, the values of all neuropsychological variables indicated a worse performance than those of the two control groups.
Table 4.—. Mean Values (±2 SD) of Neuropsychological Tests Administered to Patients Treated With Topiramate Referring and Not Referring Language Disturbances
|Trail making test|
| TMT-A||55.6 ± 21.7||30.3 ± 5.5||F = 18.6|
|P < .0004|
| TMT-B||138.6 ± 61.4||92.0 ± 30.7||F = 5.18|
|P < .03|
|Controlled oral word association test|
| PVF-F||9.4 ± 3.2||8.9 ± 2.4||n.s.|
| PVF-A||7.0 ± 4.3||7.7 ± 1.5||n.s.|
| PVF-S||10.2 ± 4.7||8.9 ± 3.1||n.s.|
| SVF-F||9.4 ± 1.5||9.0 ± 1.8||n.s.|
| SVF-A||11.4 ± 3.9||12.4 ± 3.0||n.s.|
| SVF-C||13.6 ± 5.1||14.4 ± 3.5||n.s.|
|Denomination test||37.6 ± 1.8||39.7 ± 1.0||F = 10.91|
|P < .003|
From the evaluation of Zung Anxiety and Depression scales at the time of patient assessment, the concomitant presence of psychiatric comorbidity in patients treated with topiramate were: for anxiety alone, 15%; for depression alone, 20%; and for anxiety + depression, 35%.The relative percentages of patients following other prophylactic treatments were 10%, 30%, and 25%, respectively. Lower percentages of anxiety alone (5%), depression alone (15%), and anxiety + depression (25%) were found in patients without prophylactic treatment. FactorialANOVAverified the influence of the concomitant occurrence of anxiety and depression on some neuropsychological tests independently of treatment effect. In particular, the occurrence of anxiety seemed to negatively influence in all patient groups the performance of TMT-A and TMTB subtests (β value: −0.44, P < .0007; and −0.5, .0001, respectively), and the occurrence of depression on the values of SVF-F and SVF-C (β value: 0.25, P < .02; and < .28, < .02, respectively). Because the percentages of concomitant neuropsychological disturbances did not significantly differ from those calculated before starting prophylactic treatment between the topiramate and other prophylactic drug patient groups, pretreatment differences in concomitant psychiatric disturbances and topiramate-induced mood changes could not have influenced the differences in abnormalities of speech tests. Moreover, no significant influence on worsening neuropsychological test scoring was detected due to the presence of side effects, such as fatigue and difficulty of concentration, complained of by 10% and 6.7%, respectively, of patients in the topiramate group.
Language disturbances, such as word-finding difficulties, have been described in epileptic patients treated with topiramate.8,9 Although similar language disturbances have been reported for migraine patients treated with the same drug, neuropsychological analysis of these alterations has never been performed.11-13 In the present study, we found language disturbances in about 27% of migraine patients treated with topiramate. The definitions given by patients for describing language disturbances were more complex than the simple word-finding difficulty reported in previous studies. Language disturbances referred by patients were confirmed by clinical evaluation and neuropsychological tests. Alteration of these tests exploring not only language function but also attention, visuomotor tracking abilities, psychomotor speed, shortterm memory, and cognitive flexibility suggested the involvement of wider cognitive processes.
The mechanism through which topiramate influences language functions is unknown. Studies that have investigated these aspects in epileptic patients hypothesized, on the basis of electroencephalographic recordings, greater occurrence in patients with epileptogenic foci in left posterior temporal areas.13 Alternatively, an asymmetry of neurotransmitter systems has been hypothesized to explain the greater susceptibility of language areas even in the absence of an epileptogenic focus. This can be particularly relevant to antiepileptic drugs containing sulfhydryl residues, such as topiramate and zonisamide.8,17,18
In our study, no relationship was found between the occurrence of language disturbances and the dosage of topiramate, nor did language disturbances appear to be associated with the duration and clinical characteristics of the headache or presence of abuse of symptomatic drugs. In the same group, certain language functions seemed to be influenced by the concomitant presence of psychiatric comorbidities, particularly anxiety (TMT-A andTMT-B) and depression, as emerged from factorial ANOVA. It should be emphasized that patients with neuropsychological disturbances are more prone to refer side effects due to treatment. In particular, a positive history of previous and current psychiatric comorbidities represents a risk factor for cognitive side effects as a consequence of topiramate treatment.5
In our study, only 2 of 6 tests in the Controlled Oral Word Association Test achieved a statistically significant difference among the study groups: the response for semantic verbal fluency letters F and C, with fewer words produced by patients in the topiramate group. Lower values were also found for semantic verbal fluency for letter A in the same group, but they did not differ statistically from those of the other 2 patient groups. One hypothesis to explain the lower values for semantic verbal fluency of letter Fand to a lesser extent letter C, observed in all patient groups and more accentuated in the topiramate groups, could be attributed to lesser knowledge and usage of nouns in the categories of flowers and cities, perhaps due to cultural reasons, even though these values did not seem to be influenced by the level of education.
Values of phonemic verbal fluency were also slightly but not significantly lower in the patients given topiramate, suggesting that the ability to generate words in response to letters F, C, and A is less compromised than that of semantic verbal fluency for the same letters and is not influenced by the frequency of words beginning with these letters in the Italian language. The discrepancy between phonemic and semantic fluency resultsmaybe due to the greater difficulty in recalling words within specific categories compared to that of generating words using specific letters as stimuli. This difficulty seemed to be further compromised by topiramate treatment.
It remains to be clarified if the subtle language disturbances referred by migraine patients treated with topiramate specifically express a disturbance of language areas or rather reflect a wider impairment of cognitive processing. Based on our results, it can be hypothesized that a functional disturbance of cognitive areas, in particular those related to language, could be present in migraineurs independently of topiramate treatment. This is suggested by the values calculated for all neuropsychological tests, which exceeded those assumed as normal in clinical practice, in all patient groups including those without prophylactic treatment.
Topiramate could also further impair cognitive functioning, and in particular language performance, in relation to its mechanism of action. This might involve a direct action on non-N-methyl-d-aspartate glutamate receptors, modification of several receptorgated and voltage-sensitive ion channels, including voltage-activated Na+ and Ca2+ channels and, in particular, potentiation of γ-aminobutyric acid (GABA)-mediated inhibition by facilitating the action of GABA receptors.19,20 The knowledge of neuronal circuits and brain areas involved in neuropsychological tests used in the present study can also be helpful to understand the effects of topiramate on language function in some migraineurs.
It should be emphasized that some brain areas activated during neuropsychological testing while exploring language performance, such as the right anterior cingulate, posterior cingulate, cerebellum, thalamus, insula, prefrontal cortex, and temporal lobes are also involved in the emotional elaboration of pain during spontaneous migraine attacks.21,22 Adisorder such as migraine, which involves numerous cortical and subcortical circuits implicated in pain processing and in the behavioral and emotional processing of pain, may represent a facilitated substrate for the occurrence of language disturbances, which can be interpreted as an expression of a more generalized impairment of cognitive processing. This aspect has been scarcely evaluated in patients affected by migraine. The available literature on this point has been far from conclusive, and reports of cognitive testing in adult migraineurs and controls have yielded inconsistent results. Until now, no studies have specifically focused on aspects related to language.23-29 Future prospective studies exploring these aspects should be conducted involving migraine patients treated not only with topiramate but also with other antiepileptic drugs. Studies comparing the prevalence of topiramate-induced speech disturbances in epileptic patients and in migraineurs should also be performed, with particular regard to patients with CM.
Patients in our open label study were aware of the drug prescribed and were able to familiarize themselves with the potential side effects. This could explain the magnification of these effects not only in the topiramate group but also in the other patient groups following nonepileptic prophylactic treatment. For the patients given topiramate, information on potential adverse events, including cognitive disturbances before beginning treatment, could explain in particular why 18 of 30 patients had to stop at 75 mg and why the percentages of unpleasant side effects recorded were higher than those reported in placebo-controlled studies aimed at verifying the efficacy of this antiepileptic drug for migraine.
Moreover, our patient group treated with topiramate, although not different from the other 2 groups in terms of days with headache per month and severity of attacks, may represent a “more recalcitrant” subgroup of migraine patients, and additionally, a “more severe” migraine patient group due to refractoriness to other migraine prophylactic treatment. To avoid this potential bias, which did not allow us to exclude a greater cognitive deficit at baseline, future studies should benefit from the random assignment of equivalent patients to separate treatment groups in a placebo-controlled design. Future studies, in particular, can be relevant to confirm the observations of the present preliminary study in a small topiramate-treated patient group that dose, duration, and phenotype of headache do not predict the occurrence of language disturbances. Functional magnetic resonance imaging studies could also be promoted in both migraineurs and epileptic patients, aimed at exploring the different aspects of cognitive processing and language function.
Acknowledgments: The authors express their gratitude to John A. Toomey for editing the English and Marisa M. Morson for technical assistance.
Conflict of Interest: None.