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 Table of Contents  
Year : 2015  |  Volume : 52  |  Issue : 4  |  Page : 264-269

Migraine comorbidity in patients with multiple sclerosis

1 Department of Neurology, Ain Shams University, Cairo, Egypt
2 Department of Neurology, Helwan University, Cairo, Egypt

Date of Submission01-May-2015
Date of Acceptance20-Jun-2015
Date of Web Publication27-Nov-2015

Correspondence Address:
Lobna M El-Nabil
Department of Neurology, Ain Shams University, 11539 Cairo
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1110-1083.170659

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Migraine headache is a common feature in multiple sclerosis (MS) patients, with variable prevalence among studies. It can influence the diagnosis, radiological evaluation, treatment, and quality of life of these patients.
The aim of the study was to assess the frequency and severity of migraine in a sample of Egyptian patients with MS and to study the clinical and radiological characteristics in those patients.
Patients and methods
We studied 55 patients with MS. They were subjected to full clinical and neurological assessment, including the diagnosis of migraine. Migraine diagnosis was made using a questionnaire based on criteria proposed by the International Classification of Headache Disorders, 2nd ed. Neurological impairment was evaluated with the Multiple Sclerosis Severity Scale; migraine severity evaluation was made using the Migraine Disability Assessment Scale. MRI of the brain and spinal cord was also performed.
Migraine headache was present in 19 (34.5%) patients. Our results indicate that the majority of patients with coexisting migraine and MS develop migraine years earlier. There was no statistically significant difference between patients with migraine and those without with respect to the age at onset of MS, duration of illness, annual relapse rate, Expanded Disability Status Scale, and Multiple Sclerosis Severity Scale. However, midbrain periaqueductal affection in MRI was more prevalent among MS patients with migraine.
Migraine is comorbid in patients with MS. The exact etiology and pathogenesis of these two seemingly disparate disorders has not been completely understood.

Keywords: migraine, migraine disability assessment scale, multiple sclerosis, multiple sclerosis severity scale

How to cite this article:
El-Nabil LM, Ashraf G, Abdulghani KO, Nasef A, Abdulghani MO. Migraine comorbidity in patients with multiple sclerosis. Egypt J Neurol Psychiatry Neurosurg 2015;52:264-9

How to cite this URL:
El-Nabil LM, Ashraf G, Abdulghani KO, Nasef A, Abdulghani MO. Migraine comorbidity in patients with multiple sclerosis. Egypt J Neurol Psychiatry Neurosurg [serial online] 2015 [cited 2023 Nov 29];52:264-9. Available from: http://www.ejnpn.eg.net/text.asp?2015/52/4/264/170659

  Introduction Top

Migraine is a chronic neurological disorder characterized by recurrent, moderate-to-severe headache often in association with a number of autonomic nervous system symptoms. Typically, the headache is pulsating in nature, lasting from 4 to 72 h. Associated symptoms may include photophobia, phonophobia, nausea, and vomiting. Pain is generally aggravated by physical activity, poor sleep, and hypoglycemia. Up to one-third of people with migraine headaches report an aura that can be a transient visual, sensory, language, or motor disturbance that signals that the headache will soon occur. Occasionally an aura can occur with little or no headache following it [1] .

Multiple sclerosis (MS) symptoms at presentation vary individually and are unpredictable. Although headache is not generally regarded as a symptom of MS, migraine headache commonly affects patients with MS. Up to two-thirds of MS patients complain of headache, and the majority of MS patients with a headache have migraine [2] .

Several reports have documented that migraine headaches may occur during exacerbation of symptoms, and may even herald the onset of relapse in MS. Recently, it was reported that patients with MS, diagnosed according to the revised McDonald criteria, had an initial presentation of worsening migraine headache. These cases returned to the remission stage, after steroid therapy, without obvious neurological sequel and with the headache significantly improved [3] .

  Aim Top

The aim of the study was to assess the frequency and severity of migraine in a sample of Egyptian patients with MS and to study the clinical and radiological characteristics in those patients.

  Patients and methods Top

This was a cross-sectional study conducted on 55 consecutive patients diagnosed as having MS according to the revised McDonald criteria [4] who were recruited from the Neurology Department of Ain Shams University Hospitals. Because the study was designed to assess migraine headache in relapsing remittent MS patients, patients with secondary MS and other types of headache were excluded. The patients were subjected to the following clinical and imaging evaluations:

  1. Thorough medical history taking, stressing on age at onset of MS, duration of illness, current therapy, yearly exacerbation rate, age at onset of migraine headache and its relation to MS control medications;
  2. Migraine diagnosis using a questionnaire based on criteria proposed by the International Classification of Headache Disorders, 2nd ed. [5] ;
  3. Neurological disability evaluation by means of Kurtzke's Expanded Disability Status Scale (EDSS) [6] ;
  4. Multiple Sclerosis Severity Scale (MSS) using disability and disease duration to rate disease severity [7] ;
  5. Migraine severity evaluation using the Migraine Disability Assessment Scale (MIDAS) in which a score of 5 or higher is considered an indicator of disability (range 0-21) [8] ; and
  6. MRI of the brain and spinal cord using a Signa 1.5 T MRI Machine (GE Medical Systems, Waukesha, Wisconsin, USA).

MRI protocol of the brain included axial, sagittal, and coronal T1-weighted and T2-weighted images, as well as fluid attenuation inversion recovery images. Postcontrast T1 sequence was also included to exclude recent relapse. MRI of the spinal cord included axial and sagittal T1, T2, and fluid attenuation inversion recovery images before contrast injection and with postcontrast axial and sagittal T1.

Statistical analysis

Data collection was done using Microsoft Office Excel 2010. The statistical data analysis was performed using IBM SPSS (version 19, Armonk, New York, USA). Descriptive analysis for the nominal and categorical data included frequency and percentage, whereas that for the parametric data included mean and SD. For the nonparametric variables median and interquartile descriptive statistics were used. Tests for correlation included the χ2 , one-sample T test, independent sample T test, Wilcoxon test, and the Mann-Whitney test. Significance level was considered at P value less than 0.05, and high significance was considered at P value less than 0.01.

  Results Top

Fifty-five MS patients were studied, of whom 44 were female patients representing 80% of the sample with a mean age of 31.1 ± 7.9 years.

Mean age at the time of MS illness was 25.7 ± 6.9 years and the mean duration of MS illness was 4.3 ± 3.2 years. The annual relapse rate was 2.1 ± 1.2. The mean EDSS of the whole sample was 2.8 ± 1.4, whereas the MSS mean was 5.2 ± 2.5.

Out of 36 (65.5%) patients on single treatment, 25 (45.5%) were on monthly 1 g intravenous methylprednisolone, nine (16.3%) were on disease-modified therapies (DMTs) - three patients on Gilenya Basel, Switzerland, four on Rebif Darmstadt, Germany, one on Betaferon Berlin, Germany, and one patients on Avonex Cambridge: Massachusetts, USA - in addition to a single patient on cyclophosphamide single intravenous dose per month, and another one on oral prednisone. In contrast, 19 (34.5%) patients were on combined treatments: eight (14.5%) were on methyl prednisone plus DMT, six (10.9%) were on methylprednisolone plus azathioprine, four (7.3%) were on methylprednisolone plus cyclophosphamide, and one (1.8%) was on combined prednisone and methylprednisolone.

Regarding brain lesions, 49 (89.1%) patients had periventricular lesions, 47 (85.5%) had juxtacortical lesions, 24 (43.6%) had corona radiate lesions, 24 (43.6%) had callosal lesions, nine (16.4%) had centrum semiovale lesions, five (9.1%) had midbrain periaqueductal lesions, and 15 (27.2%) had other infratentorial lesions.

Twenty-four (43.6%) patients had spinal cord lesions: 20 (36.3%) patients had cervical cord lesions, two (3.6%) had dorsal cord lesions, and two (3.6%) had combined lesions.

The sample was further classified into two groups according to the presence of headache. Out of 55 patients with MS, 36 (65.5%) patients did not suffer from migraine (group A), whereas the remaining 19 (34.5%) had migraine (group B).

In group A, 30 (83.3%) patients were female. In group B, 14 (73.7%) patients were female. The detailed clinical characteristics are summarized in [Table 1]. There was no statistically significant difference between the two groups regarding distribution of gender, age at onset of MS, duration of illness, annual relapse rate, EDSS, and MSS.
Table 1 Correlation between the clinical characteristics of patients in the two groups

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In group A, 30 (83.3%) patients were on monthly intravenous methylprednisolone, nine (25%) were on DMT, five (13.9%) were on cyclophosphamide monthly dose, two (5.6%) were on oral azathioprine, and none were on oral prednisone. In group B, 14 (73.7%) patients were on monthly intravenous methylprednisolone, seven (36.8%) were on DMT, four (21.1%) were on oral azathioprines, two (10.5%) were on oral prednisone, and one (5.3%) was on monthly cyclophosphamide. There was no statistically significant difference regarding the type of medications used between the two groups, except for oral prednisone, which was used in only two (10.5%) patients in group B ([Table 2]).
Table 2 Medications used among the two groups

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Regarding MRI findings, midbrain periaqueductal affection was significantly prevalent among patients with migraine ([Figure 1] and [Figure 2]).
Figure 1 MRI findings in the two groups. MS, multiple sclerosis

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Figure 2 Brain MRI of a 23-year-old patient having migraine comorbid with relapsing remittent multiple sclerosis, showing periaqueductal hyperintense lesions (arrows) appearing in both (a) fluid attenuation inversion recovery and (b) T2-weighted images

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On the basis of migraine headache onset in relation to the first appearance of MS symptoms, group B was further subdivided into three subgroups. Group B1 included 12 (63.2%) patients who had migraine onset before MS onset; seven (58.3%) of them were female. Group B2 included four (21%) patients who had simultaneous onset of both illnesses; all of them were female. Group B3 included three (15.8%) patients who had started to suffer from migraine after being diagnosed with MS; all of them were female. There was no statistically significant difference between the three subgroups with respect to patient age, sex, onset of migraine, age at onset of MS, duration of MS illness, and MS annual relapse ([Table 3]).
Table 3 Correlation of clinical characteristics between the subgroups of multiple sclerosis patients with migraine

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There was a statistically significant correlation between the occurrences of severe migraine attack before MS relapse in patients who developed migraine headache for the first time simultaneously with MS presentation ([Table 4]). In contrast, there was no statistically significant difference between the three groups in terms of MIDAS (P = 0.1; [Table 5]).
Table 4 Correlation between onset of migraine headache in relation to multiple sclerosis relapse

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Table 5 Correlation between migraine severity and initiation of multiple sclerosis medications

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As for the effect of MS medications on migraine characters, there was a highly significant correlation between initiation of DMT and increase in migraine severity ([Table 5]). However, there was no significant correlation between the frequency of migraine attacks and initiation of MS medications.

  Discussion Top

MS is a chronic inflammatory disorder of the brain and spinal cord. It is characterized by episodes of focal neurological dysfunction due to widespread microglial activation, and inflammatory demyelination associated with extensive and chronic neurodegeneration, the clinical correlate of which is progressive accumulation of disability [9] . It was once thought to be a 'painless' disease, but research has shown that pain with its different causes is a significant problem among individuals with MS [10] .

Migraine prevalence is about 5-14.5% of the general population worldwide [11] . Its exact etiology and pathogenesis are still subject to research; experimental and clinical data have implied that cortical and subcortical factors initiate the migraine attack, especially the trigeminovascular system [12],[13] .

In MS, headaches generally and migraine particularly can influence the diagnosis, radiological evaluation, treatment, and quality of life of patients. Similarities in symptomatology between cases of MS and migraine presenting with headache may lead to a misdiagnosis. Moreover, MRI findings that can be found in migraine patients without other neurological symptoms or signs may cause some diagnostic puzzlement and patient apprehensiveness.

Studies addressing the pathophysiology of these comorbid conditions have not found a clear link yet, but brainstem lesions and inflammatory processes have been proposed. Several reports have documented that migraine headaches may occur during exacerbation of symptoms and may even herald the onset of relapse in MS. Management of de-novo or treatment-induced headache in MS patients is fairly straightforward if the physician is aware of the problem [14] .

Our study showed that migraine headache was experienced by 34.5% of our sample, which is a higher than that of the general population. This result is quite similar to those of several other studies on the prevalence of migraine headache among MS patients, which ranges from 21 to 35%, or even goes up to 61%, which is more than two-fold higher than that of the general population [15],[16],[17],[18] . However, although some studies showed that relapsing remitting MS (RRMS) could correlate with migraines, this issue could not be confirmed in other studies, which may be due to the different methodologies adopted for the diagnosis of migraine headache or higher prevalence of migraine in their control groups [19],[20] .

It is hypothesized that those who have migraine comorbid with MS develop migraine at a younger age than MS [21] . This was the case in our study with more than 60% of patients experiencing migraine headache at a younger age before the onset of MS symptoms. In contrast, 21% had their first migraine headache with onset of MS symptoms or during the first attack, and 15.8% developed migraine after being diagnosed with MS.

It has been hypothesized that changes in cytokine expression during migraine attacks may predispose to autoimmune disease in the central nervous system (CNS), or to increased permeability of the blood-brain barrier, exposing CNS to the action of T cells secondary to migraine. This might explain why headaches occur at a younger age in MS patients [22] .

No MS patients with migraine recalled occurrence of aura before their attacks in our study, which is consistent with the findings of D'Amico et al. [23] . However, other studies concluded that migraine with aura has a stronger association with MS and might provide evidence for the cortical spreading depression theory for provocation of immune response against CNS due to increased blood-brain barrier permeability [3] .

There have been several reports about the relationship between migraine headache and onset of MS relapse. Many patients reported worsening of their migraine headache upon MS flair-ups [24] . This is consistent with our findings, especially in patients who had migraine headache simultaneous with MS onset. Tabby et al. [25] reported that migraine headache worsening in MS patients correlated with MS exacerbations.

Of the patients whose headaches were frequently to always severe, 85% also reported that their headaches were worse during MS exacerbations, especially migraine with aura. Conversely, only 11% of patients who never or rarely experienced severe headaches had worsening upon MS flare-ups, which could uphold the conclusion that severe migraine headache attacks especially in migrainous MS patients should direct attention to the possibility of new relapse.

Our two groups of patients did not show significant difference in the annual relapse rate of MS, EDSS, or MSS. There are multiple studies on MS disease burden in the migrainous MS patients with conflicting results [23],[24] . These studies reported that those with and without headache did not differ in terms of illness duration or disability. However, a survey conducted among the members of the MS patients in France found that EDSS was significantly lower for migraineurs, which could be due to the inclusion of progressive MS in their population [26] .

In our study, MS patients with migraine showed statistically significant midbrain periaqueductal hyperintense lesions. Periaqueductal gray matter (PAG) modulates pain through the descending system and exerts an antinociceptive effect to the peripheral afferent system, as white matter hyperintensities are believed to consist of gliosis and local loss of myelin. Therefore, worsening migraine followed by an episode of focal neurological deficit could be explained by the involvement of the periaqueductal gray matter because of its role in the initiation or modulation of migraine headache, which could explain the occurrence of migraine associated with worsening of MS relapses [23],[27] .

Our migraine patients showed little to moderate disability caused by their headaches. Headache presence and severity has clinical implications in patients with MS. Research on this topic found that more than half of the cases reported pain so intense that the patients had to rest until the pain had subsided, further hampering patient functioning. This observation is strikingly similar to the estimates of disability in chronic migraine sufferers, of whom more than 50% experience severe impairment during headaches [19],[25] .

Unfortunately, several treatments exacerbate headaches in patients with MS, particularly those with migraine. The role of MS-specific therapies, such as interferon β (IFN-β), in exacerbating pre-existing or triggering de-novo headaches has been emphasized. Among patients complaining of migraine with IFN-β treatment, only 15% reported an onset after the IFN-β initiation, whereas the majority had worsening of a pre-existing migraine. The worsening of migraine induced by IFN-β was mostly independent from the familiar flu-like symptoms, as they had been using IFN-β for years before this complaint. Moreover, the flu-like symptoms disappear within the first three months from starting IFN-β in more than 80% of cases. In addition, the headache characteristics are quite different from those of migraine [21],[23] .

In our study group, patients on DMT, mainly INF-β, showed increase in the severity of migraine headache after initiation of treatment, unlike those who were not on INF-β. This could be due to changes in cytokine levels induced by INF-β, especially IL-5, IL-6, and IL-10 [28],[29] .

  Conclusion Top

Headache inquiry in the examination of all patients with MS can be of great value. MS patients experiencing migraine attacks especially if changed in character should be evaluated for MS relapse, so that a tailored therapeutic approach can be implemented.

Long-term studies should be conducted to determine whether treating headaches promptly and aggressively affects the clinical course of MS and the level of patient functioning.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2]

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]

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