Abstract
The aim of this study was to assess the proportion of subjects with transformed migraine (TM) who have 15 or more migraine days per month as a function of duration of chronic daily headache (CDH) in an adolescent sample. CDH is a syndrome characterized by 15 or more headache days per month. In specialty care, TM is the most common type of CDH. Most adults who meet criteria for TM do not meet the International Headache Society (IHS) criteria for chronic migraine (CM). TM criteria require 15 or more headache days per month (not necessarily migraine), with a current or past history of migraine. CM requires 15 or more migraine days per month. As TM develops, attack frequency increases and the number of migraine features diminishes. If this observation is correct, individuals who meet criteria for TM but not CM may be at a later stage in the evolution of the disease, compared with those who meet criteria for CM. We reviewed charts of 267 adolescents (13-17 years) seen in a headache centre, to identify 117 with TM. We divide subjects with TM into those with recent onset (1 year) vs. longer duration (>1 year) and examined the number of migraine days per month and demographic features. We modelled predictors of CM (>15 migraine days per month) using logistic regression. Of 117 adolescents with TM, 55 (47%) had recent-onset (<1 year) and 62 (53%) had long-duration TM. Those with recent-onset TM were much more likely also to meet criteria for CM (74.5% vs. 25.8%, P < 0.001). This was verified in the TM with medication overuse subgroup (recent onset 66.7%, vs. long duration 37%, P = 0.01) and in the TM without medication overuse subgroup (62.2% vs. 19.2%, P = 0.001). Modelling the dichotomous outcome of CM (>15 days of migraine/month) in logistic regression, CM was predicted by recent onset of CDH, recent onset of migraine (<36 months), and younger ages (15 years), but not gender or use of migraine preventive drugs or medication overuse. Among adolescents with TM, CM is more likely in individuals who are young, whose episodic headache began recently, and with CDH of recent onset. These findings suggest that early in the process of transformation, migraine is more frequent, and that as CDH evolves, fewer typical attacks of IHS migraine occur.
Introduction
Clinical observation and epidemiological studies suggest that in a subset of individuals with migraine, attacks increase in frequency over time (1–3). The best approach to diagnosing these individuals remains controversial. Many clinicians diagnose these patients with chronic daily headache (CDH) or, more specifically, transformed migraine (TM) (4), terms not used by the International Classification of Headache Disorders (ICHD-2, 2004) (5). Several studies have reported difficulties using the ICHD-1988 (6) in the classification of subjects with CDH (7, 8). As a consequence, alternative approaches to classification of these patients have emerged (9). Of these proposals, the Silberstein-Lipton (S-L) criteria (4) have been widely used (10–12).
The ICHD-2 addresses several of the criticisms directed to the first edition (5). While the ICHD-1 defined only one of the forms of primary CDH, the ICHD-2 provides criteria for all four types of long-duration (>4 h), primary CDH [chronic migraine (CM), chronic tension-type headache (CTTH), new daily persistent headache, hemicrania continua]. The ICHD-2 criteria use the term CM, while the S-L criteria use the term TM to describe related disorders. While TM requires 15 or more days of headache (not necessarily migraine) per month and one of three possible links with migraine, CM is defined by 15 or more migraine days per month (Table 1). For individuals who meet criteria for TM but not CM, classification remains controversial.
Diagnostic criteria for transformed migraine according the Silberstein and Lipton criteria, and for chronic migraine, according the second edition of the International Classification of Headache Disorders (ICHD-2)
We recently compared the S-L and the ICHD-2 criteria in the classification of CDH in adults. We concluded that, for subjects with TM according to the S-L system, the ICHD-2 criteria are still complex and difficult to use and require multiple diagnoses (13). Very few patients with TM in the S-L system met the International Headache Society (IHS) criteria for CM.
While the ICHD-2 criteria have been explored in adults with CDH (13), they have not been assessed in adolescents. In this study we selected adolescents who meet criteria for TM and explore the proportion that meet also criteria for CM.
In most patients with TM, as attack frequency increases, the number of migraine features diminishes during the transformation period (1–3, 11). If CM represents an earlier stage of the disease, with more frequent migraine features, we predicted that more adolescents with TM would also meet criteria for CM, compared with adults. We also hypothesize that as the duration of CDH (interval from the onset of CDH to the current assessment), and duration of migraine (interval from the onset of migraine to the current assessment) increase, the proportion of patients with TM who meet criteria for CM will decline. To test these hypotheses, we examined a group of 117 adolescents who met criteria for TM, to contrast those who did and did not also meet criteria for CM.
Methods
We reviewed charts of 267 adolescents (13–17 years) seen in a headache centre, to identify 117 with TM. All subjects were assessed using standardized intake forms and headache calendars for at least 3 months. We collected information on the intensity of pain (4-point scale), frequency of pain at the time of the first visit (current) and at onset, location of pain, quality of pain, duration of headache, premonitory features, aura, associated symptoms, and relationship between pain and physical activity.
Relevant information was transferred to a standardized form that included the defining features required by the ICHD-2 (8), as well as the S-L diagnostic criteria (6).
We divided subjects with TM into those with recent onset (<1 year) vs. longer duration (≥1 year) and examined the number of migraine days per month and demographic features. We then reviewed the classification using both sets of criteria.
Table 1 summarizes the two sets of criteria we used in the current study. There are several differences between these systems. In brief, the ICHD-2 classifies CM as a complication of migraine in those cases where the headaches fulfil criteria for migraine in more than 15 days a month, and medication overuse is not present. If medication overuse is present, probable CM with probable medication overuse is the diagnosis. This system is considerably different from the S-L system, which classifies TM in two situations: first, a primary CDH develops in a person with a previous history of headaches; second, one of the three following links with migraine are satisfied: (i) a prior history of IHS migraine; (ii) a period of escalating headache frequency; (iii) concurrent superimposed attacks of migraine that fulfil the IHS criteria. Medication overuse is defined, in the S-L system, by the use of specific amounts of medication.
Data were summarized using frequency counts and descriptive statistics. We predicted CM (>15 migraine days per month) as a dichotomous outcome with time of onset of CDH, beginning of episodic headache, age, and use of preventive medication as predictor variables, using logistic regression. The dependent variable (migraine days) was defined by reviewing features of individual attacks in headache diaries. The independent variables were defined as follows: (i) time since onset of CDH was obtained by subtracting self-reported time of onset of CDH from the time of presentation, in months. The variable was arbitrarily dichotomized in recent onset of CDH (<1 year) or longer duration CDH (≥1 year); (ii) time since onset of migraine. The variable was defined as migraine of recent onset (<3 years) or longer duration (≥3 years); (iii) patient's age at the time of assessment (≤15 or > 15 years); (iv) gender; (v) use of preventive medications.
Multivariate logistic regression was used to estimate the odds ratio for each explanatory variable. Continuous independent variables were evaluated for non-linearity using squared and higher order terms. Backwards stepwise maximum-likelihood estimation was used to arrive at a parsimonious model. Analyses were performed using Stata (Intercooled Stata 6.0 for Windows, College Station, TX, USA).
Results
We assessed 117 adolescents with TM, 62 (52.9%) female, ages ranging from 13 to 17 years (mean = 15.9, SD = 1.1). The majority (66.7%) were not overusing medication. All the patients diagnosed as TM fulfilled criterion C1 (history of episodic migraine) and criterion C3 (some of the current attacks fulfil criteria for migraine), and 84 (71.7%) also fulfilled criterion C2 (history of transformation).
Overall, they reported episodic migraine beginning 50.8 (SD = 20.8) months, and CDH beginning 15.8 (8.3) months before their initial visit to the clinic. TM sufferers had a mean of 27.7 (8.3) days of headache per month, most not fulfilling criteria for migraine (Table 2).
Baseline demographic and headache features
The chronic migraine group is a subset of the transformed migraine group. CM+, Probable chronic migraine with probable medication overuse; CM–, chronic migraine (without medication overuse); TM+, transformed migraine with medication overuse; TM–, Transformed migraine without medication overuse.
ICHD-2 criteria for CM or probable CM with probable medication overuse (more than 15 days of migraine per month) were met by 68 (58.1%) participants. Of these patients, 19 (27.9%) were overusing medication. Overall, they reported episodic migraine beginning 40.1 (SD = 20.5) and CDH beginning 9 (7.5) months before their initial assessment. They had a mean of 23.1 (7.0) days of headache per month, and 19.1 (3.7) migraine days per month (Table 2).
Of the 117 TM sufferers, 55 (47%) had recent onset of TM (£1 year) and 62 (53%) had TM of long duration (>1 year). The recent-onset cases were much more likely to have more than 15 days of migraine per month (74.5% vs. 25.8%, P < 0.001) (Fig. 1). This was also verified in the TM with medication overuse subgroup (recent onset 66.7%, vs. long duration 37%, P = 0.01) and in the TM without medication overuse subgroup (62.2% vs. 19.2%, P = 0.001).
Proportion of subjects with transformed migraine with more than 15 days of migraine per month. ▪, Recent onset; □, long duration + A1. TM, Transformed migraine; TM–, transformed migraine without medication overuse; TM+, transformed migraine with medication overuse. ∗P < 0.001; ∗∗P = 0.01; ∗∗∗P ≤ 0.001.
We used logistical regression to identify predictors of the presence of CM (>15 days of migraine/month) among all TM sufferers (Table 3). CM was predicted by recent onset of CDH (within 1 year, P < 0.0001), recent onset of migraine (within 3 years, P < 0.05), and age ≤ 15 years (P < 0.0001). Gender and current use of preventive medication were not significant. Separately modelling TM+, CM was predicted by recent onset of CDH (P < 0.0001), and recent onset of migraine (P < 0.05) CM was not predicted by current age (although the P-value was 0.07), gender, or use of migraine preventive drugs. For TM–, CM was predicted by resent onset of CDH (P < 0.0001), and younger ages (0.0049).
Logistic regression model used to predict chronic migraine.
We found that all R 2 values were low (<0.75). We concluded that the variables used in this model were independent of each other and that multicolinearity was not a problem. In our model, for TM overall, the final R 2 for the equation was 62.01% (per cent of the variance in our dependent variable – diagnosis of CM – that was explained by the model).
Discussion
Among adolescents with TM, the majority (58.1%) could be classified as CM, according to the ICHD-2 criteria. Even among those overusing medication, most had more than 15 days of migraine per month. These findings contrast with our recent study using the same methods to assess the classification of CDH in adults. Using the S-L criteria, of the 158 adults with TM without overuse, we found that just nine (5.6%) met ICHD-2004 criteria for CM. Most subjects were classified using both migraine and CTTH diagnoses, because they had less than 15 days of migraine per month, but a large number of attacks resembling tension-type headache (13).
Further, among adolescents, the number of migraine attacks per month was a function of time since onset of migraine, time since onset of CDH (the more recent, the higher the chance of having more than 15 migraine days per month), and of age (younger participants had a higher chance of having more than 15 days of migraine per month). The groups were well balanced and the results remained significant after adjusting for other covariates.
To explain these findings, we suggest that in adolescents, when the process of transformation begins, migraine attacks increase in frequency. Later, as CDH evolves, migraine features become less prominent. Therefore, fewer attacks meet the criteria for migraine (14–16). In the process of transformation, as the frequency increases, the intensity of pain and number of associated symptoms decrease. The attacks come to resemble tension-type headache attacks much of the time, with attacks of full-blown migraine superimposed. These data support the concept of transformation.
Our data are consistent with prior results (17–19). In a recent study on behalf of the Pediatric Committee of the American Headache Society, Koenig et al. showed that, in adolescents with CDH, nearly one-quarter of patients reported two separate headache types with distinguishing characteristics. ‘Baseline’ headache was present 27.3 ± 4.1 days per month with a mean pain intensity of 5.9 ± 2.1 on a 10-point scale. Superimposed episodic headache occurred 4.7 ± 3.8 days per month with a mean pain intensity of 8.4 ± 1.4; these headaches were more often accompanied by other migrainous symptoms. After running logistic regression models to control for pain intensity, the authors concluded that these two headache types represent a single syndrome, where the headaches in many cases become worse and gather migrainous features (17). In a study on the natural history of CDH, Spierings et al. (18) assessed 258 subjects. While 22% of them had daily headaches from the onset, 78% initially experienced intermittent headaches. Of the patients with initially intermittent headaches, just 19% experienced an abrupt transition into CDH, while 81% experienced a gradual one, meaning that a transformation period could be detected. In the patients with gradual transition, the transition of the initial, intermittent headaches into daily headaches took an average of 10.7 years. Finally, a recent study assessing CDH in India found that TM accounted for 82.4% of the cases. Transformation was reported most of the time (89.4%) and it was gradual (19).
Caution is recommended in interpreting this study. First, results were derived from a clinic-based study where the influence of referral bias is difficult to assess. Second, undetected confounders (depression and other comorbid disorders) may have influenced the results. It is possible that some of them may also be associated with the number of headache days per month and were not modelled. Third, recent onset of TM (<1 year) and migraine of recent onset (<36 months) were arbitrarily defined. There is no evidence that the cut-offs used in this study are the most appropriate or that it reflects generally accepted clinical definition. Fourth, it is possible that the subtype of migraine at baseline was also of importance in predicting the number of migraine days after developing TM. While most of our patients had migraine without aura (74.6%), due to the retrospective nature of our data, we elected not to model the subtype of migraine as an independent variable. Furthermore, information on the other subtypes of migraine at baseline (childhood periodic syndromes, retinal migraine, etc.) could not be obtained. Finally, though our data suggest the existence of the transformation period in subjects with CDH, it is possible that participants in the recent-onset group had more severe headaches, and this was the reason for the higher frequency of migraine attacks. Because disability was not measured, we cannot exclude this hypothesis.
This study also has several strengths. Throughout the study period, standardized questionnaires and headache calendars were used. To be included in this study, patients had to have at least three consecutive months of CDH, and daily headache calendars were collected. Semistructured forms collected information on health-status, and acute and preventive medication.
We conclude that a significant proportion of adolescents with CDH have more than 15 days of migraine per month. We observed further that the number of migraine days per month was inversely related with the length of time the patient had CDH, length of time they had of migraine, and age of the patient. These findings suggest that early in the process of transformation, migraine is more frequent, and that as CDH evolves, fewer typical attacks of IHS migraine occur. An alternative hypothesis is that CDH in adolescents represents a different disorder than in adults, because most adults with CDH do not transform as adolescents but rather as adults (1, 8). Further research is warranted to test the alternative hypothesis.