Management of Headache in People with Multiple Sclerosis

Multiple sclerosis (MS), a chronic and often debilitating neurologic disease, affects >2 million people worldwide.^1,2 Symptoms of MS include not only motor and sensory neurologic deficits but also painful manifestations such as Lhermitte sign, neuralgias, temporomandibular joint pain, muscle spasms, restless legs syndrome, and headaches.³ Clinical diagnosis of MS occurs by means of the 2017 McDonald criteria.^4,5

Headaches are extremely common in MS, with prevalence estimated between 35.5% and 70% of people with MS.^6-9 The disease-modifying therapies (DMTs) are essential to prevent disease progression and recurrence of MS demyelination, but these DMTs can worsen preexisting headaches or lead to headaches as a side effect.⁷ The headaches experienced by people with MS are heterogenous: migraines are the most common, followed by tension-type headaches,^1,6 and, much more rarely, cluster headaches.² Migraines, which are characterized by recurrent headaches lasting anywhere from 4 to 72 hours, are often a presenting symptom of MS. They are associated with nausea, vomiting, photophobia, phonophobia, and auras (reversible focal neurologic symptoms such as visual disturbances or speech dysfunction),⁸ and are often found in people with MS who have cortical or brainstem lesions.⁶

With the high prevalence of headaches in people with MS, understanding the availability of both abortive and preventative therapies for headache is integral to patient care. Headaches have been associated with decreased quality of life and life expectancy in people with MS.^1,6 Therefore, use of headache-targeted medications such as antiepileptics, Β-blockers, calcium channel blockers, botulinum toxin injections, and calcitonin gene-related peptide (CGRP) antagonists—as well as lifestyle changes such as stress avoidance and sleep hygiene—along with cotreatment of MS can improve patients’ lives.¹

Epidemiology and Pathophysiology of Headache

Headaches occur in ≈50% of the global population, with increased prevalence in women. The most common form of headache is tension headache, followed by migraine.¹ People with MS are more commonly female, and both MS and headaches result in dramatic reductions in disability-adjusted life-years.⁹ The 2 conditions are commonly comorbid, with headaches estimated to occur in up to two-thirds of people with MS.^6,7,10-12 Migraines occur in 27% to 30% of people with MS across multiple studies,^1,6 and tension-type headaches are estimated to occur in 20% to 38% of individuals with MS. Migraines with aura are more common than migraines without aura in people with MS.⁶ Other forms of primary headache in people with MS include cranial neuralgias, with trigeminal neuralgia prevalence increasing with age similarly to that in the general population, and glossopharyngeal neuralgia, occurring much less commonly.⁶ Of particular diagnostic importance is trigeminal neuralgia, because it can be an early presenting symptom of MS, and MS should be considered and excluded in a young adult presenting with this cranial neuralgia.⁶

People with MS also commonly have secondary headaches. The DMTs used to treat MS can lead to new-onset headaches as well as worsening of preexisting headaches. For instance, in previous studies, interferon-Β (IFN-Β) has been estimated to trigger new headaches in 70% to 75% of cases.^1,13 Other secondary causes of headaches in MS include cerebral vein thrombosis, cervical or cranial trauma, infection, psychiatric disorders, and medication overuse headaches (although these are not necessarily related to having MS itself).²

Headaches have been linked with various other autoimmune disorders besides MS.¹ Headaches in autoimmune conditions may arise from ischemia and inflammation of the trigeminal nucleus.¹ Migraines are thought to arise from aberrant nociceptive signaling within the trigeminal neuralgia by vasoactive and inflammatory mediators such as CGRP.^14-16 There are multiple studies exploring the relationship between the pathophysiology of migraine headaches and MS, although the association between the two is unclear. Migraines have been suggested to be part of the prodromal state in individuals who later develop MS.²

Multiple retrospective analyses have presented evidence to suggest that lesions in the brainstem contribute to increased risk of headache. One retrospective analysis showed evidence that periaqueductal gray (PAG) matter lesions of the midbrain increase the risk of comorbid migraine by 4-fold, tension-type headache by 2.5-fold, and mixed headache by almost 3-fold.¹⁷ Another retrospective analysis showed that not only PAG lesions, but also lesions of the red nucleus and substantia nigra, may be implicated in migraine pathophysiology.¹⁸

Concurrence of Migraine and MS

After MS diagnosis, screening for concurrent migraine is a necessity. The exact link between MS and migraine remains elusive, but there are shared contributing factors including sex, age, and associated psychological factors.

In people reporting new or worsening headaches, it is important to rule out secondary causes (eg, infection, venous sinus thrombosis, trauma, medication overuse, somatoform disorders), and, although a rare presentation, consider MS exacerbation as a possible etiology.² There can be diagnostic confusion between an episode of migraine with aura vs an MS relapse.² Focal neurologic symptoms that are unilateral, fully reversible, predominantly positive sensory symptoms (possibly also including language, motor, and retinal and brainstem symptoms) that develop gradually over 5 minutes and last <60 minutes support an attack of migraine with aura rather than an MS exacerbation.² Migraine headache typically develops within 60 minutes after the onset of the aura or during the aura, but this is not always the case.² Visual aura consisting of positive phenomena of scintillations, flashing lights, spots, and wavy lines is more consistent with migraine, in contrast to the negative visual symptoms of vision loss, decreased color perception, and decreased visual acuity that typically accompany MS-related optic neuritis.²

Clinicians should be cautious of overdiagnosing MS in people with migraine, as white matter lesions are common to both conditions. White matter lesions are seen on MRI in 29% to 73% of people with migraine, and occur more commonly in migraineurs with aura, given the microvascular alterations associated with cortical spreading depression.² Clues that the lesions are representative of MS include contrast enhancement and spinal cord lesions.⁹ Nevertheless, it is prudent to consider a new MS exacerbation in a person with worsening migraine, with special attention to the PAG on imaging.¹⁹

Multiple hypotheses have been posed in an attempt to explain the connection between MS and migraines. One theory is that the headaches of MS are attributable to the geography of demyelinating lesions. MS lesions in the PAG midbrain area are associated with increased headache incidence, and electrical stimulation of this area has been shown to cause migraine-like attacks.^9,13 Another possible explanation is that inflammation-mediated cortical demyelination can facilitate the cortical spreading of migraines.¹ Alternatively, migraines themselves may lead to increased permeability of the blood–brain barrier, exposing myelin to T cells and enabling the autoimmune demyelination associated with MS.^9,13 No widely accepted pathobiologic theory fully explains the concurrence of migraines and MS.

MS DMTs

MS management is complex. Alongside a plethora of DMT options, medication selection for people with concurrent headaches and MS is further complicated by the consideration that DMTs may exacerbate preexisting headaches, and this is especially true for people with migraine. It is prudent to obtain a headache history, particularly with respect to frequency and severity, prior to starting a DMT to avoid agents that may cause or exacerbate headaches.

Certain DMTs are well-known to have the adverse effect of headache: in particular, the interferon class. IFN-Β1a was associated with headache in 71% of participants in the PRISMS trial (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis), and IFN-Β1b fared no better in other studies.⁹ This suggests a class effect of interferons, rather than a subtype-specific adverse effect. IFN-related headaches are typically either migraines (50%) or tension-type (50%).⁹ One theory posits that IFN-Β results in headache by inciting neuronal excitability in the neocortical pyramidal neurons and disrupting the cytokine milieu, specifically by a Th2 shift to an anti-inflammatory profile.^9,13 Despite its associated decrement to quality of life, most people using IFN treatment do not discontinue because of headache.⁹

Fingolimod, the first oral therapy for relapsing-remitting MS, had headache reported in 25% of the treatment group vs 23% in the placebo group, suggesting that prevalence of headache in MS may have been more to blame.¹² However, as in IFN treatment, headaches induced by fingolimod were more likely to be new persistent headaches.⁹ Both IFN-Β and fingolimod induce interleukin-10 production, and interleukin-10 has been shown to be increased during migraine attacks.⁹ Likewise, direct and indirect anti–B-cell therapies (eg, rituximab, ocrelizumab, ofatumumab, ublituximab, cladribine) result in increased interleukin-10 levels upon B-cell reconstitution, and one systematic review including 9 randomized controlled trials with these therapies found a trend toward headache. However, on subgroup analysis, only cladribine had a significant association with increased incidence of headache.⁹ Thus, whereas MS therapies may result in increased levels of interleukin-10, this is likely not the single mechanistic pathway by which DMT-associated headache is induced.

The anti-α4 integrin monoclonal antibody natalizumab also has been shown to be associated with headache, with headache occurring in 38% of people being treated with natalizumab vs 33% of people receiving placebo.⁹ However, headaches induced by natalizumab typically occur as part of an infusion-related reaction within the first 2 hours after administration.¹² Another study found no exacerbation of comorbid migraines in people receiving natalizumab.¹²

Glatiramer acetate, teriflunomide, and dimethyl fumarate have not been reported to have major association with headache.^1,13 Headaches may be more attributable to the increased prevalence in MS rather than a therapeutic adverse effect of these particular DMTs. Ultimately, obtaining an adequate headache history before initiating a DMT and monitoring for exacerbation of headache in people with comorbid headache disorders will help optimize therapy and minimize DMT discontinuation. People with comorbid headache disorders, particularly migraine, likely would benefit from comanagement with a headache specialist.

Previous Treatment and New Therapeutics for Migraine Management in MS

Once a headache disorder has been diagnosed appropriately in a person with MS, the same general tenets apply to its treatment as in the general population. Both pharmacologic and nonpharmacologic measures can be used to facilitate optimal response. Starting preventative pharmacologic therapy should be considered in people who have 6 or more headache days per month with at least some impairment on 4 of these days or severe impairment on 3 of these days.¹ By using a combination of pharmacologic and nonpharmacologic approaches, such as cognitive-behavioral therapy, biofeedback, and meditation, to decrease the frequency and severity of headaches, quality of life can be improved and disability reduced.¹ The major classes of medications traditionally used for migraine prevention include antiepileptics, antidepressants, Β-blockers, calcium channel antagonists, nonsteroidal anti-inflammatory drugs, and angiotensin-converting enzyme inhibitors.¹ For chronic migraine, botulinum toxin can also be used. In 2018, the first medication with a migraine-specific target—the anti-CGRP receptor monoclonal antibody erenumab—was approved. This was revolutionary, as previous therapies relied on off-label use. Further development of other CGRP-targeted therapies ensued, as shown in Figure 1.

Multiple drug classes for migraine treatment act by means of decreasing excitatory signaling within the brain. The antiepileptic class includes topiramate, gabapentin, and valproic acid. Topiramate functions primarily through blockage of voltage-gated sodium and calcium channels, but also acts at multiple other receptors. It is believed to exert its antimigraine effect by acting as an antagonist at the AMPA/kainate subtype of glutamate receptors, thereby decreasing excitatory signaling. Both gabapentin and valproate enhance GABA concentrations in the brain, acting as proinhibitory medications; gabapentin blocks voltage-gated calcium channels, and valproate blocks voltage-gated sodium channels. The antidepressant amitriptyline is thought to decrease migraine by inhibiting both norepinephrine and serotonin reuptake, similarly leading to a reduction in excitatory activity. Β-blockers, such as propranolol, help decrease norepinephrine release and synthesis, which lead to reduced adrenergic tone. Calcium channel blockers, including verapamil and nimodipine, are thought to be effective particularly in ceasing cortical spreading depression through inhibition of serotonin release. Angiotensin-converting enzyme inhibitors are effective through modulation of calcium and potassium channels.¹

For people with MS and concurrent chronic migraine, Botox, an onabotulinum toxin, is an option that is commonly used when other therapies fail or are insufficient at headache reduction. Botox is thought to reduce trigeminal-triggered pain by inhibiting the release of pain peptides, substance P, bradykinin, glutamate, and CGRP.¹

CGRP-specific antimigraine therapies are used for both abortive and preventive treatment of episodic and chronic migraine headaches. There are 2 mechanisms of action: small-molecule inhibition of the CGRP receptor and monoclonal antibodies. The small-molecule inhibitors of the CGRP receptor include the Food and Drug Administration–approved atogepant, ubrogepant, and rimegepant as well as olcegepant, telcagepant, and zavegepant. The Food and Drug Administration–approved monoclonal antibodies include eptinezumab, erenumab, fremanezumab, and galcanezumab.²⁰ There are limited data on the safety and use of these agents in people with MS on DMT. However, CGRP monoclonal antibodies may serve a role in reducing autoimmune inflammation within the central nervous system, which may prove a beneficial secondary effect.^1,7 One case series reported only mild to moderate adverse events (eg, urinary tract infections, sinus infections, upper respiratory tract infections) with the use of CGRP monoclonal antibodies in MS.²¹ At this juncture, there is no clear evidence supporting or contradicting the use of these therapies for people with MS; the immunomodulatory effects of these agents may raise concern in clinicians treating the immunologic sequelae of MS.

Conclusion

Given the relatively high concurrence of headache and MS, it is imperative for the clinician to be up to date on the diagnosis and management of common headache disorders. People with MS frequently have primary headache disorders, with the most prevalent being migraine, followed by tension-type, and, more rarely, cluster headache. Secondary causes should be considered and ruled out as appropriate. Although DMTs are central to treatment of MS, some can worsen preexisting headaches or lead to headaches as a side effect. Therefore, knowledge of therapeutic agents in the headache abortive and preventative categories will not only help to treat the headache disorder, but may also aid in DMT compliance. Older therapeutic options can be trialed for migraine, but there have been many developments in headache pharmacotherapy. Particularly revolutionary has been the development of the anti-CGRP class, which has primary indication for the treatment of migraine rather than off-label indication. There remains limited evidence supporting the use of the CGRP class—particularly the monoclonal antibodies—in people with MS on DMT. However, there is no clear evidence to suggest against their use if necessary, and they should be considered as a therapeutic option. Overall, headache treatment in MS requires a combination of clinical repertoire and flexibility.