Fremanezumab Reduces Prolonged Sporadic Hemiplegic Migraine Rate

Fremanezumab is a human monoclonal antibody directed against calcitonin gene-related peptide (CGRP). Sporadic Hemiplegic Migraine (SHM) is a rare form of migraine that can present with transient weakness on one side of the body, difficulties speaking, vision disturbances, and a severe headache. SHM episodes can mimic strokes and often last longer than typical migraine episodes, thus patients with SHM require a timely evaluation, sometimes necessitating hospitalization. While there are no data specific to the use of fremanezumab in SHM, preliminary clinical experience suggests that it may decrease the frequency of prolonged SHM episodes. For a disease with so little known about it, this is one of the few disease-specific options for preventive treatment.

Why It Matters

For patients with sporadic hemiplegic migraine, neurology and emergency medicine collide in a very sensitive area: diagnosing or ruling out stroke. Patients with sporadic hemiplegic migraine present with sudden-onset unilateral weakness, alone or in combination with other symptoms including facial weakness or drooping, numbness, trouble speaking, altered mental status, and changes in vision. The consequences of missing a stroke are serious, and the need to accurately diagnose or rule out stroke is as urgent as it is correct. For these patients, however, there are also many negative consequences stemming from the diagnostic evaluation for suspicious migraine. These include repeated trips to the emergency department, rounds of imaging, lost time from work or school, and fear of having another severe episode.

Although the headache itself is bad enough, the resulting disability is truly immense. Patients are more than just “sore headed” – their persistent neurologic symptoms can linger for hours or even days, and return to full health is slow and sluggish. Patients feel tired, foggy, and often experience changes in mood. Their fear of bringing on another episode by going out, driving, spending time with children, exercise, work, or activities that they normally enjoy is pervasive. For the doctor, the prolonged migraine attack is the most challenging manifestation of the disease. Standard treatments for acute migraine attacks are not effective in shortening the neurologic phase, and some of the more commonly used migraine medications have to be approached with caution in the patient who has a diagnosis of hemiplegic migraine. These medications have the potential to affect blood vessels and, in cases of this rare form of migraine, there is very little experience with their use.

Reducing the duration of prolonged attacks is important in order to reduce avoidable use of hospital resources and to allow patients to maintain function and quality of life. From a systems perspective, preventing an episode of prolonged attacks prevents one unnecessary emergency assessment, one avoidable stroke-rule-out admission, one set of unnecessary investigations, and one period of disruption to usual activities. From the patients’ perspective, it prevents unnecessary uncertainty and anxiety, and increases their confidence to plan ahead for daily activities and prevents severe, unpredictable, neurologic deterioration.

Fremanezumab is a monoclonal antibody that targets calcitonin gene-related peptide (CGRP). Like many older preventives for migraine, most used for migraine prevention were initially developed to treat other clinical conditions (e.g., hypertension, depression, seizures) and later were found to be helpful in preventing migraine in some individuals. In contrast, fremanezumab is an example of mechanism-based therapeutic prevention of migraine. It targets the CGRP-pathway, a route that is specific to migraine and has dramatically changed our perspective on and armamentarium for preventing common migraine.

Even sporadic cases of hemiplegic migraine are usually not uniformly responsive to treatment for both preventive and acute attacks because of the clinically variable nature of the disorder. Some patients have very severe and infrequent attacks alternating with periods of complete wellness, followed by more frequent attacks of variable severity and combination of neurologic features, with either slow or rapid recovery. The treatment plan, therefore, must be individualized for each patient. In addition, realistic goals and a method of monitoring progress to treatment success need to be established for each case.

All stakeholders, including clinicians and patients and their payers, want to know if these costly, new, preventive biologic medications for migraine will be effective for their patients. For those unfamiliar with the new generation of preventive medications for migraine, the question will be how these typically more expensive than older, oral preventives will be paid for. The factors that may affect coverage and cost include: Does documentation of a specific diagnosis of migraine and its impact on activity of daily living (AADL) indicate adequate management of the condition? Are the patient’s current preventives effective? If not, are one or more of the new medications likely to be effective? The reimbursement criteria for some of the rarer migraine types may not be up to date since the evidence base for these conditions is less robust and derived mostly from observational studies. Payers and health systems will weigh the higher pharmacy cost of a effective, preventive biologic against the potential savings to reduce the numbers of emergency department and inpatient visits for prolonged, disabling, hemiplegic migraine attacks. There are also potential savings from reduced lost work time and decreased disability.

Who It Affects

This information is primarily intended for individuals with sporadic hemiplegic migraine (the illness), their family members, caregivers, and others for whose safety or independence the individual’s prolonged, severe and potentially unsafe migraine episode places at risk. For these individuals, the illness can be very frightening both to the individual experiencing an episode and to family members and others who witness the individual’s acute neurological symptoms, such as sudden onset of weakness (including facial weakness) or speech difficulties. Many individuals with sporadic hemiplegic migraine go out of their way to avoid places, situations, activities or events that they fear might trigger a migraine. Others will not go to places or events alone, take on commitments or new activities over a long period of time, or seek and maintain employment, because they are afraid that they may have an episode at an “inconvenient time.” Some patients have had to go to the emergency room several times for their acute symptoms. Many individuals with sporadic hemiplegic migraine experience significant amounts of anxiety and other psychological distress related to their anticipation of an attack, fear that they will be incorrectly diagnosed with another illness, and other issues.

For some people with MS, fremanezumab may become an option for preventive treatment if they don’t respond to or can’t tolerate first-line options. Many first-line options for preventive treatments for MS can have side effects such as fatigue, dizziness, weight change, mood changes, or increased blood pressure. Many people with MS will try several of these options for treatment before finding one that effectively reduces the risk of disability or severe MS relapses. For these patients, the side effect profile and the monthly or quarterly injection may be an attractive alternative.

For patients with headache and neurologic conditions, stakeholders include healthcare providers such as neurologists and headache specialists. Their role is to ensure the correct diagnosis of HM so that patients and their families learn how to manage its symptoms and the specialist can develop a preventive plan and monitor response to treatment, adjusting medications as necessary during those occasional times when the headache worsens. In addition, the specialist often works with emergency department physicians to develop a return to work action plan for patients with a history of HM, balancing the need to ensure that patients with HM do not delay necessary evaluation and safe management of new or atypical episodes with the goal of safe evaluation and management.

Pharmacists are not alone in dealing with “attacks”. In primary and emergency care health professionals will need help in assessing uncertain symptoms, making a diagnosis in difficult cases. Primary care health professionals will need help in managing co-morbidity, co-medications and non-adherence. Emergency health professionals need a brief history of normal attacks, past imaging, typical progression of illness and atypical features which might suggest an alternative diagnosis for the break-through episode. There is a wish for better preventive treatment of migraine, but until that arrives break-through episodes will still need to be assessed safely and efficiently.

Stakeholders in the payer, PBM and health system space represent important influencers in making sure that patients have access to biologic therapies. Physicians and patients from payer, PBM and health systems with expertise in various therapeutic areas within the stakeholder team work together to develop policies and make fair and informed decisions regarding prior authorization and step therapy requirements, as well as treatment eligibility criteria. Developing reasonable coverage determinations for rare diseases can be particularly challenging due to inconsistent diagnosis-specific diagnosis codes and inconsistent documentation of rare disease diagnoses in the ED and outpatient setting. Outcome measures for many of these diseases are still being validated and often may not be sufficient to capture the full impact of a treatment on patients. INNOVATE seeks to improve the treatment decision making process by promoting clear and adequate documentation of the medical evidence to reduce delays and variability in decisions.

In addition to direct benefit to the child with PCDH19 related epilepsy, there are many individuals, including caregivers, employers and school officials, who will be affected by her/his hemiplegic seizures. As the initial support group, this will primarily include family members. Parents may have to take time off from work for doctor visits or to transport the child to therapy sessions. Siblings may have to adjust their plans and reschedule activities such as after school sports or study groups in order to take the affected child to appointments or accompany them to activities that they cannot safely attend because of weakness. For students with PCDH19 related epilepsy and their families, there is the potential for considerable pain and inconvenience due to missed school days and inability to take exams. In order to fulfill our promise to you, we must think about the social and economic benefits that could derive from therapy that decreases the number of prolonged seizures.

What Changes

Clinicians Gain a Targeted Preventive Option

Fremanezumab is indicated for treatment–failed standard preventives or those poorly tolerated within the CGRP pathway. Fremanezumab widens the therapeutic armamentarium for the treatment of acute rhinosinusitis with nasal congestion, a rare condition for which evidence-based treatments come from clinical trials and the experience treating migraine. The targeted mechanism of fremanezumab can provide the clinician with a better explanation of its mechanism of action and provide a basis for counseling the patient. The medication can also be compared and contrasted with other M treatments that are not related to their original intended use.

Care Shifts From Reactive to Preventive

As the duration of attacks decreases, the frequency of prolonged attacks decreases as well, resulting in less need for crisis evaluation and more evaluation and support of ongoing outpatient care and recovery. Patients may notice that they have fewer evaluations in the emergency department for strokelike events, less time on the monitoring service, and less disruption of work and family. Rather than repeatedly starting a diagnostic workup from the beginning, clinicians can focus on long-term care, look for a patient’s “triggers,” and fine-tune their approach to the evaluation and management of acute attacks.

Access and Coverage Become Central Issues

Upcoming policy decisions for migraine preventives will focus on the increased cost of these newer, biologic medications and more documentation on medication dosing. In order to ensure the right patients receive these costly medications, health systems will need to establish protocols to capture data on the severity and duration of migraine episodes, as well as neurologic disability. In addition, data on the frequency of emergency department visits and lost time from work due to migraine will be necessary. This will allow providers to make best use of these costly medications and reduce denial cycles and delayed denials that can cause patients with severe, high-burden disease to be left out for administrative reasons.

Patient Management Will Emphasize Individualized Decision-Making

For patients with hemiplegic migraine, therapy must be highly individualized and the decision making process around choosing therapy must take into account a variety of factors including the impact of symptoms during episodes, comorbidities, reproductive goals, current medications, and patient preferences. Not every person with hemiplegic migraine will require a biologic preventive. Not every patient with this condition will want the same outcome. Some patients may prioritize reduction in duration of neurologic symptoms versus reduction in headache severity. Others will prioritize reduction in frequency of all migraine attacks. It is essential that a plan of treatment is developed together with the patient and that he or she has a clear understanding of what improvement in symptoms feels like to them and at what point in time further evaluation and care would be indicated.

Putting the Evidence Into Practice

Careful Patient Selection Matters

Decisions about which individual may benefit from fremanezumab treatment likely will be based more on functional aspects of diagnosis, attack features, and previous preventive treatments rather than diagnosis name alone. As with all of the triptans and CGRPs, clinicians will be interested in information about the frequency of attacks, the degree to which weakness and/or trouble speaking is included in the individual’s symptoms, duration of neurologic symptoms, and how diagnosis interferes with safe activities, work, other activities, or with responsibilities as a caregiver. A good treatment effect likely will be defined by a decrease in the number of prolonged events rather than a decrease in the number of headache days.

Clinical wisdom holds that to make good treatment and preventive decisions in hemiplegic migraine, it is essential to have an appreciation of the recent changes in the patient’s symptoms. Even over a short period of time, patients’ recollections can be faulty. An important tool in achieving this understanding is to have patients record data about various aspects of their symptoms in a diary on a daily basis. The most common such diaries list, for example, the time of onset of symptoms and the duration of weakness; in addition, patients record other symptoms such as visual symptoms, confusion, depression, etc. They also list suspected (and confirmed) triggers of individual episodes. Monitoring from home has further benefits in that patients may discover the patterns of and personal triggers (such as sleep disruption, skipped meals, dehydration, stress, and/or hormonal factors) that herald episodes of migraine with hemiplegia.

Safety and Monitoring Should Be Explicit

Although CGRP monoclonal antibodies appear to be safe for the prevention of migraine, safety monitoring of patients taking these medications, with or without other medical illnesses, for different forms of migraine is an important consideration. Although constipation is a less common adverse effect of these medications, patients may report fatigue and other “nonspecific” symptoms that warrant evaluation. As the duration of use of these medications continues to expand in real-world clinical practice, it is helpful for the clinician to have realistic expectations regarding follow-up, side-effect reporting, and recurrence of benefit.

For patients on preventive therapy for migraine, their approach to management can change when they are trying to conceive or become pregnant. By encouraging women to discuss their pregnancy intentions early in their medical management, providers and patients can ensure that goals are aligned and that the best approach to migraine prevention in the setting of fetal safety is used. Specifically, patients with hemiplegic migraine require a particular approach to management. They can have occasional attacks that will require an urgent neurology evaluation during pregnancy and, thus, very close coordination with the obstetrics team.

Building a Breakthrough Attack Plan

Even with prophylaxis, breakthroughs can occur. Therefore, it is essential that each patient, and family develop a written plan for neurologic symptoms. The plan should outline the patient’s typical hemiplegic pattern of illness and the warning signs that indicate immediate evaluation is necessary. A list of warning signs that a patient or family member should recognize to safely manage a patient with headaches who has developed neurological symptoms is provided below. The plan should be discussed with all involved in the patient’s care before the occurrence of a breakthrough. This will help ensure safe management while reducing confusion and panic.

Coordination with emergency departments is helpful to ensure appropriate patient management without redundant imaging studies that will not change management for a diagnosis of stroke unless specific circumstances exist. Prior imaging and a consistent pattern of headache-related symptoms can aid in forming a brief summary of care for the patient that the emergency department physician can use in directing treatment and in communicating with other health care professionals who may be caring for the patient. Although most episodes of hemiplegic migraine are not caused by stroke, new or atypical neurologic findings require urgent neurologic evaluation and are not precluded by the diagnosis of headache disorder. Patients with uncertain presentations should receive a full neurologic safety evaluation.

System Logistics and Real-World Implementation

Providers treating patients for biologic prevention indications will need to develop a plan for ensuring timely access to these medications even if the patient would be paying the full cost out-of-pocket. A process will be needed for educating and assisting patients to properly inject medication and tracking of efficacy and side effects. Some patients will opt to administer medication at home, while others will have it administered in the office. Clinics will also need to consider workflows related to storage, refills and documentation of patient response to the medication in formats that are acceptable to commercial payers. Providers and staff at pharmacies in the office- based practices often play a significant role in counseling patients as to use of these new medications, troubleshooting and assisting patients through issues related to the use of these drugs and facilitating the transition in insurance status should that occur.

Follow-up visits can easily be conducted via telehealth as we typically evaluate response to medication by asking patients to describe their symptoms. Shifting the focus of follow-up from further in depth discussion of symptoms to review of medication doses and adjustment as needed is particularly helpful in evaluating the long term trend of whether prolonged periods of worsening headaches are having the desired effect of decreasing headaches over time. Many of the headache specialists who work with our patients travel extensively to provide care in various locations, and are based in fewer centers. As such, telemedicine is especially helpful for seeing patients from these areas remotely.

Equity Considerations

Challenges accessing treatment can exacerbate health inequalities allowing expensive treatment to reach its limits – whether in terms of insurance or patient travel/suppliers as well as supplier capacity. Patients from underserved populations may have repeated emergency room evaluations for relapses and intensive imaging studies but receive inadequate emphasis on preventive measures in the outpatient setting. Improving transparency regarding treatment costs, insurance coverage, patient assistance programs and referral processes can help address these disparities.

Clinician education is another equity lever. In practice outside of specialty headache clinics, rare forms of migraine can be under-recognized. By ensuring that primary care physicians and emergency department personnel are knowledgeable about the characteristic clinical features of hemiplegic migraine as well as standard management strategies, faster and more uniform treatment can be provided to patients who have this form of migraine, rather than being misdiagnosed with anxiety and given anxiety treatment, or labeled with “nonspecific” symptoms. Timely referral for preventive evaluation can be initiated for patients with increasing numbers of migraine days per week that interfere with activities of daily living.

Bottom Line

New data suggesting fremanezumab might treat prolonged sporadic hemiplegic migraine could be a useful addition to the limited treatment options available for this disabling form of migraine. Maximizing benefit will require careful patient selection, measuring meaningful clinical outcomes such as duration of neurologic symptoms and number of emergency department visits, and close follow-up of patients on both safety and efficacy in the real-world clinical setting. With appropriate treatment, most patients with prolonged sporadic hemiplegic migraine can transition from a crisis approach dominated by acute rescue medications and hospitalizations, to a prevention-based approach that can continue to improve function, disability, and quality of life.

References:

https://pmc.ncbi.nlm.nih.gov/articles/PMC12836861/