Abstract
Purpose:
To evaluate frequency of migraine, vasospasm (VS), family history (FH) of migraine, and family history of glaucoma (FHG) in different types of glaucoma in relation to age and stage of visual field loss (VFL) at diagnosis.
Methods:
A total of 2170 patients with glaucoma or ocular hypertension (OH) were interviewed by using standardized questions concerning FHG, age at diagnosis, and potential risk factors, including migraine and VS. Of 2027 patients providing information on migraine, 1244 had primary open-angle glaucoma (POAG), 140 normal tension glaucoma (NTG), 49 pigmentary glaucoma, 64 pseudoexfoliation glaucoma (PEX), 138 OH, and 218 primary angle closure glaucoma (PACG).
Results:
Of all patients, 13.7% reported migraine, 19.0% VS, 30.8% FH of migraine, and 40.3% FHG. Patients with FHG had a significantly higher frequency of migraine than patients without FHG (15.7% vs. 12.3%, P = 0.02). Migraine was significantly more frequent in NTG (21.4%) than POAG (13.1%; P = 0.01), PEX (7.8%; P = 0.02), and PACG (10.1%; P = 0.004). Compared to patients with POAG, patients with NTG had a 63.5% higher age-corrected probability for migraine (P = 0.007). There was no evidence for migraine or VS being prognostic factors regarding the extent of VFL at diagnosis. Migraine and VS were significantly more frequent in females.
Conclusions:
The higher frequency of migraine and VS in females could contribute to the female preponderance in NTG. Our findings suggest an association of NTG and migraine and a common, possibly polygenetic, vascular etiology of these two diseases both with familial predisposition.
Glaucoma is a multifactorial condition characterized by a progressive optic neuropathy and distinctive visual field loss. Normal tension glaucoma (NTG) differs from all other glaucomas, as it is the only condition with intraocular pressure (IOP) within the normal range of the population (10–20 mm Hg). This suggests that other risks factors apart from elevated IOP might play a particular role in NTG. Therefore, NTG is especially suitable to study IOP-independent risk factors. As in most complex diseases, the exact number of genes associated with the different glaucomas, their individual pathogenic contribution, and their specific ways of interaction with environmental susceptibilities remain largely unknown.
1,2 For NTG, a robust association has been found with
CDKN2BAS variants.
3 The further identification of risk factors that offer potential targets for treatment options is of particular importance.
There is a female preponderance in NTG.
4,5 Therefore, it is of interest which potential risk factors for glaucoma are more frequent in NTG than in other types of glaucoma and in females compared to males. Ischemia due to periodic vasoconstriction is considered as a potential risk factor for glaucomatous visual field damage,
6–8 making both migraine and vasospasm potential risk factors for glaucoma. The aim of this study was to prospectively evaluate (1) the frequency of migraine, vasospasm, family history of migraine, and family history of glaucoma in patients with different types of glaucoma and ocular hypertension (OH), and also, the frequency of migraine and vasospasm in female and male patients, and the association of migraine and vasospasm in patients with glaucoma or OH; (2) whether migraine and vasospasm are more frequent in patients with family history of glaucoma than in patients without family history of glaucoma; (3) whether there is any difference in the frequency of migraine or vasospasm in different types of glaucoma compared to NTG; (4) the age-related frequency of migraine and vasospasm in NTG and primary open-angle glaucoma (POAG); and finally, (5) the frequency of migraine and vasospasm in relation to stage of visual field loss at diagnosis in patients with POAG and NTG.
By means of a detailed questionnaire,
9,10 2170 glaucoma patients interviewed their siblings, children, parents, and relatives of mother and father (grandmothers, grandfathers, uncles, aunts) with 16 standardized questions. This resulted in information on family history of glaucoma in 12 groups of relatives for every patient. Results on family history of glaucoma and time of diagnosis from this cohort have been previously published.
10 Details concerning the questionnaire and interview procedure have been previously described by the authors.
10 The questionnaire used was designed for this study by the authors, as no such instrument was yet available. The original questionnaire (in German) has been published.
9 Patients were consecutively recruited at the glaucoma service of the University Eye Hospital Wuerzburg. All glaucoma patients coming to the glaucoma service and seen by EG during the time of the study were asked for participation.
The first part of the questionnaire was always completed by the same glaucoma specialist (EG) at the patient's visit, concerning type of glaucoma, age of the patient at diagnosis, and, for both eyes, the stage of visual field loss at diagnosis and maximal IOP, defined as the highest IOP ever measured. Concerning age at diagnosis, all patients were asked by the same glaucoma specialist at what age glaucoma had been diagnosed. This was verified from the medical records. If the answer was uncertain, the patient's ophthalmologist was contacted by telephone while the patient was still in the examination room. Thus, age at diagnosis was evaluated in a uniform way and, if necessary, confirmed from multiple sources. Many of the patients included had been under the care of the same glaucoma specialist (EG) for more than 30 years. This ensured a high reliability of diagnosis, especially in NTG.
For staging of visual field loss, the first available and reliable visual field was chosen to judge glaucomatous visual field loss at or close to the time of diagnosis. Goldmann perimetry and in addition, wherever feasible, computerized threshold determining perimetry of the central visual field had been performed at diagnosis with, for example, Octopus perimeter 201 or Octopus perimeter 500 (program 32 and/or 31, or G1; Interzeag, Schlieren, Switzerland), Humphrey perimeter (program 30-1 and/or 30-2; Zeiss, Jena, Germany), or Competer (Taberna Pro Medicum, Lueneburg, Germany). Due to the change in perimetric equipment over the past decades, for the study the glaucoma specialist staged visual fields at diagnosis in both eyes according to the classification of Aulhorn.
11 This ensured comparability between all perimetric results based on a descriptive staging method. The eye with more severe visual field loss was used for statistical evaluation. According to stage of visual field loss, patients were divided into two groups: with no or with beginning visual field loss (stages 0–II classification of Aulhorn) or with moderate to severe visual field loss (stages III–V).
The second part of the questionnaire contained the questions for the interviews of patients' relatives on history of glaucoma or OH. Patients received instructions in a uniform way by the same glaucoma expert on how to perform the interviews of their relatives before using the questionnaire. The patients took the questionnaire home to perform the interviews of their relatives and then returned the questionnaire by mail free of charge. Each relative was asked by the patient whether glaucoma or OH had been diagnosed or excluded by an ophthalmologist. Patients were instructed to read out the questions word by word. Answer categories were “yes/no/do not know.” Only “yes” or “no” answers were included in further evaluations. Family history of glaucoma or migraine was defined as glaucoma/OH or migraine in at least one first- or second-degree relative. Concerning siblings and children, patients were asked about the number of brothers and sisters/daughters and sons, and number of brothers and sisters still alive. It was asked whether one or more of the siblings/children had glaucoma or OH. Answer categories were “yes,” “no,” and “not known.” If the answer was “yes,” the number of affected brothers/sisters and daughters/sons was sought.
The third part of the questionnaire addressed the potential risk factors migraine, vasospasm, heart disease, blood pressure, and systemic medication. Information on diagnosis of migraine and vasospasm was established by directly questioning the patient about whether he/she suffered from migraine or vasospasm. This was done for all patients in a uniform way by the same ophthalmologist (EG) reading out the questions on the questionnaire. Patients were asked for an established diagnosis of migraine and about migraine headache characteristics according to the criteria of the International Headache Society.
12 Concerning vasospasm, patients were asked whether they suffered from “sudden episodes of cold and pale fingers.” A positive/negative answer signified presence/absence of vasospasm. For all patients reporting vasospastic symptoms, oral therapy with magnesium was advised, as this treatment has been recommended by several experts.
6,13 However, patients were informed about the lack of final evidence for benefit of magnesium therapy in this context from controlled studies, and the possibility that costs for this therapy might not be covered by insurance. They were informed about the expert opinions. Additional information on migraine and vasospasm was derived from patients' medical records. Patients reporting migraine symptoms in recent years were additionally referred to a neurologist for neurologic evaluation and therapeutic recommendations.
The study adhered to the tenets of the Declaration of Helsinki and written informed consent from participants was obtained.
We received 2170 questionnaires suitable for evaluation. Details on demographic and ophthalmologic data for these patients are shown in
Table 1. Of 2027 patients who provided a “yes” or “no” answer on migraine diagnosis, 1244 had POAG, 140 NTG, 49 pigmentary glaucoma (PG), 64 pseudoexfoliation glaucoma (PEX), 138 OH, and 218 primary angle closure glaucoma (PACG). One hundred seventy-four patients had other types of glaucoma, which are not evaluated here due to small sample sizes and are published separately.
14–16 A total of 2015 patients provided a “yes” or “no” answer regarding diagnosis of vasospasm.
Table 1 Demographic and Ophthalmologic Data of Study Patients*
Table 1 Demographic and Ophthalmologic Data of Study Patients*
In our study NTG was defined as glaucomatous optic neuropathy and visual field loss with maximal IOP up to diagnosis not exceeding 21 mm Hg. A small number of NTG patients had pressure spikes > 21 mm Hg in single measurements and these patients were therefore admitted for inpatient IOP monitoring including measurements at night. If the pressure spike could not be confirmed by repeated diurnal tension curves, patients remained in the diagnosis group of NTG. All patients with NTG received IOP-lowering therapy.
Fisher's exact test 2-sided, Mantel-Haenszel χ2 test, Cochran-Armitage trend test, and Cochran-Mantel-Haenszel statistics based on table scores were used for statistics. Due to the explorative nature of the analysis no adjustment of α error was performed. A P value ≤ 0.05 was considered statistically significant.
Of 2027 patients who answered the question on migraine, 13.7% (277) reported episodes of migraine. Family history of migraine was established in 30.8% of all patients answering the question on family history of migraine (347 of 1127 patients). Vasospasm was reported by 19.0% of patients (383 of 2015). Migraine and vasospasm were significantly more frequent in females with 18.1% (203 of 1120 female patients providing information on migraine) and 20.7% (232 of 1119 female patients providing information on vasospasm), respectively, than in males with 8.2% (70 of 859 of male patients providing information on migraine; P < 0.0001, Mantel-Haenszel χ2 test) and 16.7% (142 of 850 male patients providing information on vasospasm; P = 0.02, Mantel-Haenszel χ2 test), respectively.
Frequency of Migraine and Vasospasm in Patients With and Without Family History of Glaucoma
Frequency of Migraine in Different Types of Glaucoma Compared to Frequency of Migraine in NTG
Frequency of Vasospasm in Different Types of Glaucoma Compared to Frequency of Vasospasm in NTG
The frequency of migraine, assessed for the total patient cohort, decreased significantly with age (age < 30 years, 31.0%; 31–40 years, 27.3%; 41–50 years, 23.4%; 51–60 years, 20.8%; 61–70 years, 10.7%; 71–80 years, 8.1%; Cochran-Armitage trend test, P < 0.0001). This was found for male (Cochran-Armitage trend test, P < 0.0001) as well as female patients (Cochran-Armitage trend test, P < 0.0001).
Frequency of migraine in NTG and POAG patients in five age groups is shown in
Figure 1. Fifty percent of NTG patients aged 40 years and younger reported migraine. The frequency of migraine declined with increasing age in both NTG and POAG and reached a similar level in POAG and NTG patients older than 70 years.
The frequency of vasospasm, assessed for the total patient cohort, decreased significantly with age (age < 30 years, 34.5%; 31–40 years, 21.6%; 41–50 years, 20.0%; 51–60 years, 21.5%; 61–70 years, 15.5%; 71–80 years 17.8%; Cochran-Armitage trend test, P = 0.01). This age effect was significant in female (Cochran-Armitage trend test, P = 0.02) but not in male patients (Cochran-Armitage trend test, P = 0.3).
Frequency of vasospasm in NTG and POAG patients in five age groups is shown in
Figure 2. In NTG, frequency of vasospasm was highest in patients younger than 41 years, but in all other age groups there was no obvious trend in both NTG and POAG.
Frequency of Migraine and Vasospasm in NTG and POAG Patients With Different Stages of Visual Field Loss
One strength of this study was that assessment of family history of glaucoma and other risk factors was performed in different glaucomas in a uniform way, by one glaucoma specialist using the same methods. This approach allowed us to assess differences in risk factors between the glaucomas. No preselection of patients was performed, but all patients coming to the glaucoma clinic and seen by EG were asked consecutively for participation. The participation rate was very high, as most patients had been under the care of the glaucoma specialist (EG) for several decades. Only a small number of patients (approximately 10–15 patients) refused to participate in the study in the first place. Reported reasons for this were the fact that they had no living relatives, had been adopted, or there was uncertainty about paternity in the family. There was no charge for mailing the questionnaire, thus there was no financial reason not to return it. The number of unreturned questionnaires is unfortunately not available. However, the fact that the first and third part of the questionnaire were completed by the ophthalmologist at the time of the visit in the glaucoma clinic should have encouraged patients with and without migraine or vasospasm, and with and without family history of glaucoma, equally to complete and return the questionnaire. Patients had been informed that the additional information on family history from the study would also be used to complete their medical record and would therefore also be available in future patient care. This should have motivated patients with and without family history of glaucoma to return the questionnaire. Also, some questions concerned additional risk factors, such as low blood pressure, heart disease, or systemic medication, which again should have encouraged patients with and without migraine or vasospasm to complete and return the questionnaire.
The fact that all tasks were performed by only one glaucoma specialist is regarded as a particular strength of this study, allowing for high comparability between different glaucoma types. However, staging of the disease and questionnaire instructions by only one observer can theoretically also create a bias. Even if a selection, observer, or ascertainment bias of some extent cannot be excluded, this should equally affect all types of glaucoma, thus still allowing for comparison of, for example, frequency of migraine, vasospasm, and family history of glaucoma between the glaucoma types.
The diagnosis of migraine is currently based on patient history and there is no technical instrument to verify this diagnosis. Information on diagnosis of migraine or vasospasm was established by questioning of the patients in a uniform way by the same glaucoma expert and in addition confirmed from medical records of patients who had previously been evaluated by a neurologist. Patients with migraine symptoms in recent years were referred to a neurologist for evaluation and therapy. The diagnosis of vasospasm in this study was established by reported clinical symptoms and patients' medical records only—objective measurements such as nailfold videomicroscopy
13,46 could not be performed as part of this study focused on family history of glaucoma in a large patient cohort.
We thank all patients and their families for participation in this study. We thank Georg Burkard and Elmar Beck (Statistical Institute Anfomed, Möhrendorf) for support with the statistical analysis. These results were obtained and presented in part in the context of a medical thesis by Gwendolyn Gramer.
Supported by a research scholarship (Olympia Morata Programme) of the medical faculty of the University of Heidelberg (GG). For this study, printing of questionnaires, prepaid envelopes for mail return of questionnaires, and costs for statistical support by the statistical institute Anfomed were partly covered by Chibret, Germany (to EG). The authors alone are responsible for the content and writing of the paper. Gwendolyn Gramer participated as investigator in a clinical trial sponsored by Merck Serono.
Disclosure: G. Gramer, None; B.H.F. Weber, None; E. Gramer, None