Lasmiditan as a potential targeted therapy for vestibular migraine? A case study

Abstract

Background

Vestibular migraine (VM) is a common migraine subtype. Treatment options in the acute stage are limited.

Case

Here, we present the case of a 53-year-old woman experiencing frequent episodes of sensory aura, as well as vertigo and right-sided headaches lasting between 2 and 9 hours. The patient initially used rizatriptan as acute therapy, which reduced the headaches but not the vertigo. Only the use of lasmiditan led to a reduction in both the headache and the vertigo.

Conclusion

We hypothesize that in this patient, the vertigo was caused by vasoconstriction and that rizatriptan was unable to reverse this effect due to its selective binding to 5-HT1B receptors, which mediate vasoconstriction. As lasmiditan does not bind to 5-HT1B receptors, it should be evaluated as an option for the acute treatment of VM in larger cohorts.

Graphical abstract

This is a visual representation of the abstract.

Introduction

Vestibular migraine (VM) is a subtype of migraine in which vertigo constitutes the leading symptom. Affecting ∼3% of the population, it is among the most common causes of vertigo. ¹ Clinically, both central vertigo, characterized by symptoms such as upbeat nystagmus, and peripheral vestibular symptomatology can be observed. ² Headache, as the defining feature of migraine, may manifest differently in VM compared to typical migraine. Many patients describe a feeling of pressure, including in the skull and neck area. ¹

The pathophysiology of migraine is complex and not yet fully understood. It is generally accepted that irritation of the trigeminal nerve leads to the release of vasoactive neuropeptides, such as calcitonin gene-related peptide (CGRP). The resulting inflammation activates the nociceptive trigeminal system, producing pain. Contrary to previous assumptions, vasodilation appears not to play a significant role in migraine-associated headache. ³ In VM, not only can the clinical picture of the headache and the vertigo vary, but also the occurrence and severity of accompanying symptoms such as sensitivity to light, sensitivity to noise, and nausea. This raises the question of whether different pathomechanisms may be present that explain these symptoms. ¹ One mechanism could be cortical spreading depression, similar to that seen in the aura, which originates in the occipital cortex and potentially lasts for days. ⁴ As evidence for trigeminovascular mechanisms, a plasma extravasation in the inner ear could be triggered in mice, which the authors see as a possible explanation for vertigo and noise sensitivity in migraine. ⁵ In addition, there are indications that the vascular mechanisms of migraine can also be vasoconstrictive ⁶ and that the symptoms can manifest themselves as they can also occur due to an ischemia in the inner ear, namely through tinnitus, unilateral hearing loss, and vertigo. ⁷

Triptans, which act as 5-hydroxytryptamine (5-HT) receptor agonists, are used as migraine-specific treatments against headaches; however, there is limited evidence supporting their use in VM. ⁸ Moreover, because of their 5-HT1B receptor-stimulating vasoconstrictive effect, triptans are contraindicated in patients with vascular ischemia or during migraine aura. ⁹ For patients with VM involving a vasoconstrictive mechanism, triptans may thus offer only limited benefits or may even exacerbate symptoms.

To circumvent this issue, the selective 5-HT1F receptor agonist lasmiditan has been developed. This receptor is expressed on cell bodies of neurons in the trigeminal ganglion; its stimulation modulates neuropeptides, like CGRP, release. ¹⁰ Unlike triptans, lasmiditan does not stimulate the vasoconstrictive 5-HT1B receptor. ¹¹

Case

Since December 2024, an initially 53-year-old woman presented 3 times to our outpatient clinic due to episodes of vertigo and balance disturbances. Symptoms had been present since April 2024 and had worsened during the observation period, most likely due to increased stress relating to her workload and personal commitments. At the time of writing this report, she experienced vertigo episodes approximately twice weekly, lasting 2–9 hours. An aura of 5 minutes duration typically preceded these. The aura usually started with right-sided hearing loss, followed by blurred vision in the right eye, progressive hyperesthesia of the right facial region, and a rightward body tilt. Vertigo was usually associated with right-sided headaches of a dull character, worsening when moving. Apart from inactive ulcerative colitis and ankylosing spondylitis, there were no relevant pre-existing conditions. Magnetic resonance imaging examinations of the head in July 2024 and November 2024 showed a 6 × 7 × 9 mm, T2-weighted hyperintense lesion in the tectum and tegmentum of the midbrain, respectively, without changes over time. The lesions showed no uptake of gadolinium-based contrast agent and did not cause any disturbance in cerebral fluid circulation. The most likely differential diagnoses were low-grade glioma (LGG) or post-inflammatory changes. In addition, a 3 × 3 mm vestibular schwannoma was observed in the right internal auditory canal (Figure 1). These findings were considered insufficient to explain the symptoms presented here, and there was no indication for surgery.

Figure 1.

Magnetic resonance imaging (MRI) of a 53-year-old woman with vestibular migraine. (A) Axial contrast-enhanced T1-weighted image. The 3 × 3 mm hyperintensity in the right internal auditory canal (arrow) most likely represents a vestibular schwannoma. (B) Axial T2-weighted image. The 3 × 5 mm hyperintense lesion in the posterior region of the mesencephalon was suggestive of a low-grade glioma (arrow). The lesions were stable over the course of 4 months and considered non-explanatory for vestibular migraine.

Clinical neurological examinations during the presentations, including positional diagnostic maneuvers, were always without any pathology.

Betahistine did not improve symptoms. Two intratympanic glucocorticoid therapy sessions were performed before presenting at our hospital, based on a presumed diagnosis of Ménière's disease. These sessions had no effect. Ambulatory blood pressure monitoring showed elevated systolic values (150 mmHg), for which treatment with bisoprolol, the only long-term medication at the time, was initiated. This led to a marked reduction in headache frequency and severity. Vertigo episodes persisted during the attacks, albeit with lower intensities. She also regularly took magnesium, vitamin B2, and coenzyme Q10. 12.5 mg amitriptyline was initiated in 2025, and because it was not well tolerated by the patient, discontinued after 26 days. Due to the persistence of symptoms, the patient was started in 2025 on monoclonal antibody therapy with erenumab with proven effectiveness for VM, ¹² initially at 70 mg, later increased to 140 mg monthly. After 3 months, the attacks were reduced by half.

Since 2024, the patient has also been using various on-demand medications during VM seizures, which have led to similar results in at least 13 seizures: ibuprofen and dimenhydrinate helped only slightly against headaches and nausea. Thus, she tried rizatriptan 10 mg, which led to complete resolution of the headache but no improvement of vertigo. Then she took lasmiditan 50 mg, which resulted in complete relief from both headache and vertigo within 15 minutes of intake. As a side effect, she reported tiredness that made her unable to perform her professional duties. She reduced lasmiditan to 25 mg, which was still effective in treating headache and vertigo, and reduced the side effects.

Discussion

The patient described here presented with symptoms that were indicative of severe VM. In the absence of pathognomonic biomarkers, VM is diagnosed based on the following criteria: ¹³ at least five episodes with vestibular symptoms with moderate or severe intensity lasting between 5 minutes and 72 hours, history of migraine or current migraine, and migraine-like symptoms, such as headache, during at least 50% of vertigo episodes. The patient met all of these criteria. However, according to the diagnostic criteria, the symptoms must not be better accounted for by another diagnosis. ¹³ This is often difficult to assess, particularly in the case of differential diagnoses such as Ménière's disease or BPPV. In our case, the lack of response to betahistine and an intratympanic glucocorticoid injection without any effect argues against Ménière's disease, and we never found any evidence of BPPV in our clinical examinations. We therefore started with migraine prophylaxis^12,14 using flunarizine, amitriptyline, beta blockers, and erenumab. In addition, the patient took magnesium, Q10, and vitamin B2 in accordance with evidence-based practice. ¹⁵ This led to a reduction in symptoms, most successfully with erenumab.

Acute treatment with rizatriptan, a 5-HT1B/1D receptor agonist, with vasoconstrictive properties due to its affinity to 5-HT1B receptors, ¹¹ alleviated headache but did not alleviate vertigo. In contrast, lasmiditan—a selective 5-HT1F receptor agonist without affinity to 5-HT1B receptors—consistently resolved both headache and vertigo.

The pathomechanism underlying vertigo in VM is not fully understood, but there is some evidence that vasoconstrictive mechanisms contribute relevantly. ⁶ Moreover, our patient reported about regularly occurring right-sided hearing loss, tinnitus, rotational vertigo, and vestibular nystagmus during the attacks, which also suggests reversible vascular involvement. All these symptoms have been described to occur also after ischemic events in the inner ear. ¹⁶ We therefore hypothesize that the vertigo of this patient is, at least partly, caused by vasoconstriction. Due to the vasoconstrictive properties of the triptan used by the patient, this medication may not have adequately alleviated this symptom. Lasmiditan, on the contrary, may have been effective as it lacks vasoconstrictive activity (Figure 2).

Figure 2.

Schematic representation of the difference in the mechanism of action between lasmiditan and triptans. Both the triptans class and lasmiditan act on the 5-HT1 receptor. Triptans can stimulate the 5-HT1D receptor in neurons of the trigeminal ganglion (TG) and, since proven affinity exists, the 5-HT1F receptor on neurons. Stimulation of these receptors modulates the release of neuropeptides and thus counteracts migraine attacks. Unlike lasmiditan, triptans also act on the 5-HT1B receptors located in the smooth muscle of cerebral vessels and in the inner ear, and can lead to vasoconstriction.

Other mechanisms may also be involved in VM pathophysiology, ¹⁷ but in our view, none of them can adequately explain the different effects of rizatriptan and lasmiditan observed in this patient. Cortical spreading depression (CSD)6 is one of these mechanisms. It is an electrophysiological phenomenon that has often been associated with visual migraine aura, since the depolarization usually starts from the occipital regions. ¹⁸ In rat brains, it was shown that 5-HT stimulation by sumatriptan leads to a slower spread of CSD. ¹⁹ Whether the effect is mediated by specific 5-HT receptors is, to our best knowledge, not yet clear. Since the patient also reported a short-term visual aura problem, involvement of CSD cannot be ruled out. However, the hearing impairment and vertigo persisted in this patient, which is difficult to explain solely via CSD.

Another mechanism potentially associated with migraine is neural inflammation, caused by the release of neuropeptides. ²⁰ However, both triptans and lasmiditan have been shown to reduce neuropeptide release, and there is no evidence of a significant difference between the two types of medication in this regard. ²¹ A mechanism that is potentially involved specifically in VM is based on connections between nociceptive and vestibular signaling pathways. This involves reciprocal connections between the vestibular nucleus and, for example, the parabrachial nucleus, the raphe nucleus, or the locus coeruleus, which are regions potentially involved in the development of migraine headaches. ⁶ It is conceivable that when headaches develop and the activity of the abovementioned anatomical structures changes, the connections to the vestibular nucleus evoke disturbances, and vertigo develops. In the patient described here, it seems less likely that this mechanism is centrally involved, as the headaches are always preceded by hearing deficits. We cannot rule out that in other patients with VM, other pathomechanisms are associated with vertigo, and these patients may still substantially benefit from triptans.

The patient presented with imaging abnormalities, suggestive of a LGG and schwannoma, respectively. LGGs are rarely associated with headaches, ²² and vestibular schwannomas can cause vertigo. However, these symptoms are not known to be associated with migraine features,^23–25 which were the most prominent features in this patient, and the lesions were so small that they were considered asymptomatic.

In conclusion, this case highlights a compelling example of how individualized treatment approaches may benefit patients with VM. While rizatriptan, with its vasoconstrictive properties, failed to alleviate the vertigo, lasmiditan—notably free from vasoconstrictive effects—brought about a marked improvement. This suggests a promising direction for more tailored therapeutic strategies in managing VM symptoms.

Article highlights

• Lasmiditan reduces both vertigo and headache in a patient with VM.

• Rizatriptan was ineffective for vertigo despite headache relief.

• Lasmiditan may be effective in VM due to its non-vasoconstrictive mechanism.