A 23-year-old woman who has recently graduated from university, has been applying for a job for 5 months but has not succeeded. She is depressed and according to her family has lost her self esteem. She presents to you with five episodes of headache during the past 2 months. Each episode begins with yawning, sensitivity to light, and a depressed mood that is followed by the gradual onset of neck pain that spreads to the occipital region and eventually to the retro-orbital region on the right side. The pain becomes incapacitating over a period of 1 to 2 hours and is associated with nausea and sensitivity to light and sound. With two of the episodes, she had jagged lines in her vision for 15 minutes as the neck pain was beginning; with all the episodes, she had severe fatigue and difficulty concentrating and finding words. The headache last approximately 24 hours, and, after resolution, she has several hours of residual neck soreness, fatigue, and depressed mood. How will you evaluate and treat this patient?
Sounds like migraine. She is the right age, gender and has depression and anxiety about getting a job. What else can this be associated with? Migraine may be associated with increased risks of several other disorders, including asthma, stroke, anxiety and depression, and other pain disorders. When she was 10 years old she suffered from nightmares, headaches with vomiting and her work at school suffered. She was withdrawn from school for 2 months, her paediatrician diagnosed anxiety, she was sent to visit her grandmother in the village. There, a faith healer prayed over her, her father encouraged her to ride horses at the farm and she gradually became better and returned home and joined school again. The headaches did not recur until now.
Plan of management.
Management should include establishing an accurate diagnosis, identifying and modifying potential exacerbating factors (including medications), developing a plan for the treatment of acute attacks, and determining whether preventive therapy is warranted.
A complete physical examination is warranted including a careful neurological examination. Since this is her initial presentation as an adult, examine the optic fundi and even though there are no indications that it anything but migraine do imaging studies for an intracranial lesion. It is not necessary to do cranial imaging every time she has a headache unless a new neurological symptom or sign develops. Keep an eye on her blood pressure. Lab tests should include a complete blood picture, tests for renal and liver functions and blood sugars at least. These do not need to be repeated for every episode of headache.
Why isn’t migraine just a bad headache? A migraine may be associated with a stroke especially in the older patients and those with diabetes and hypertension hence needs to be distinguished as a migraine from a sentinel headache preceding a subarachnoid hemorrhage or a hemorrhagic stroke.
A variety of premonitory symptoms may occur hours before the headache begins and postdromal symptoms may last for hours after the headache ends. Yawning, mood change, light sensitivity, neck pain, and fatigue are common premonitory symptoms that may persist during and after the headache.
There may be an aura.
Aura symptoms may include visual disturbances (e.g., wavy lines or bright or dark spots), other sensory changes (e.g., numbness or tingling), language dysfunction, and vertigo.
Cutaneous allodynia (the experience of normal touch as uncomfortable) is also a common component of a migraine attack. Patients may not recognize or spontaneously report these symptoms, but when asked to record them, they can often identify the onset of an attack several hours before a headache occurs and realize that the disabling features of an attack often outlast the headache.
Some presumed triggers of migraine may be manifestations of the premonitory phase of a migraine attack; food, light, sound, and odor triggers that are identified by patients may in some cases be early symptoms of gastrointestinal and sensory sensitivity that are part of the attack.
What happens to the brain during a migraine attack?
The diverse and highly variable symptoms of migraine reflect complex alterations in the functioning of the nervous system. Changes in the activity of multiple brain regions during migraine attacks have been visualized with functional imaging techniques and quantified with the use of clinical electrophysiological techniques. These studies reveal activation of the hypothalamus, thalamus, brain stem, and cortex corresponding with various symptoms of a migraine attack, including those occurring before and after headache.
Although migraine is associated with intracranial vasodilation a cross sectional study was done and magnetic resonance angiography of intracranial and extracranial arteries in patients with spontaneous migraine without aura was carried out. (The Lancet Neurology. Volume 12, Issue 5, May 2013, Pages 454-461) Migraine pain was not accompanied by extracranial arterial dilatation, and by only slight intracranial dilatation. It is now clear that constriction of blood vessels is not a required mechanism of therapies for migraine.12 Although migraine is associated with an increased relative risk of stroke and cardiovascular disease,14,15 the mechanisms underlying this association remain uncertain, and it is exceedingly rare for cerebral ischemia or infarction to occur during a migraine attack. Future migraine research should focus on the peripheral and central pain pathways rather than simple arterial dilatation.
Diagnosis of migraine. Don’t mistake a migraine for cervical pain or sinus infection.
Migraine headache is characteristically severe, unilateral, and throbbing, it may also be moderate, bilateral, and constant in quality. The features of migraine other than headache, particularly sensitivity to light and sound, nausea, and interference with the ability to function, may be more useful in diagnosis than the character of the headache. Other common migraine symptoms, including aura, cognitive dysfunction, dizziness, and fatigue, may lead physicians to order brain imaging, yet this is generally unnecessary if symptoms have a gradual onset and are transient. Neck pain is another common symptom of migraine, but it is frequently misinterpreted as a manifestation of a disorder in the cervical spine, often leading to unnecessary scans of this region. Patients or physicians frequently believe that migraine is related to sinus disease, whereas the majority of patients who receive a diagnosis of “sinus headache” in fact have migraine.
Lifestyle changes which may help.
- Don’t skip a meal.
- Get regular sleep at your usual time.
- Don’t drink too much caffeine.
- Do regular exercises.
- You may need extra medicines before, during and after menstrual periods.
Medicines which make a migraine worse.
Many medicines make migraines worse or trigger them. They include oral contraceptives, postmenopausal hormone therapy, nasal decongestants, selective serotonin-reuptake inhibitor antidepressants, and proton-pump inhibitors. In some patients, the frequency and severity of attacks can be dramatically reduced by adjusting or discontinuing these medications. In addition, regular use of analgesic medications, particularly opioids and barbiturate–caffeine–analgesic combinations, can increase migraine frequency and severity, even when taken only once or twice a week. This exacerbation cannot be explained simply by tolerance, dependence, or addiction but rather is a direct adverse effect on migraine. Withdrawing the frequently used medication can result in marked improvement, but this may require substantial time and effort, and in some patients, inpatient treatment is needed.
How will you abort an acute migraine attack?
- Triptans such as almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan and zolmitriptan will provide relief by 2 hours and the patient is usually free of the headache in 24 hours. Nasal or subcutaneous delivery is more effective than oral. Don’t prescribe to any one with coronary artery disease.
- Ergots also provide pain relief in 2 hours and can be used as a nasal spray or subcutaneous injection and is often used for refractory migraine.
- Acetaminophen (paracetamol) will provide pain relief in 19% of patients. Use with an antiemetic like prochlorperazine (Stemetil) or chlorpromazine (Phenergan), metoclopramide (maxolon).
- NSAIDs like aspirin, diclofenac, ibuprofen, ketorolac and naproxen will also provide relief in 2 hours in 20-40% of patients. Use with triptans.
- Combinations of acetaminophen-aspirin and caffeine or naproxen and sumatriptan may also provide pain relief in 2 hours in 20% of patients.
- Single pulse TMS (transcranial magnetic stimulation) through a handheld device will also work in about 20% of patients.
- CGRP (calcitonin gene-related peptide) receptor antagonists are under investigation. These are remigepant, ubrogepant,
- A review of three trials evaluating valproate products (divalproex sodium, sodium valproate, and valproic acid) at doses ranging from 500 to 1500 mg daily for migraine prevention found that valproate was significantly more effective than placebo as measured by the number of patients experiencing a ≥50 percent reduction in migraine frequency in adults.
- Intravenous valproate. The utility of IV valproate for the treatment of acute migraine in children is not established, and the existing evidence is limited and retrospective
- Anti-inflammatory drugs, and antiemetic agents individually or in combination) should be taken as early as possible after the onset of a migraine attack.
- Preventive therapies (e.g., beta-blockers, candesartan, tricyclic antidepressants, and anticonvulsant agents as well as botulinum toxin for chronic migraine) should be considered on the basis of the frequency and severity of attacks, response to medications for acute migraine, and coexisting conditions.
- Recent clinical trials support the efficacy of new therapies targeting calcitonin gene–related peptide (CGRP) for the treatment of acute migraine and for migraine prevention. The CGRP is a therapeutic target in migraine because of its hypothesized role in mediating trigeminovascular pain transmission and the vasodilatory component of neurogenic inflammation. The US Food and Drug Administration (FDA) approved the CGRP antagonists erenumab, fremanezumab, and galcanezumab in 2018 and eptinezumab in 2020 for migraine prevention.
In clinical practice, a substantial percentage of patients report dissatisfaction with triptans because of a slow or incomplete response. For some, the addition of a nonsteroidal antiinflammatory drug (NSAID) (including nonprescription preparations), or taking one of these medications independently, can be effective.
Multiple ergotamine preparations are available, and intravenous dihydroergotamine in particular is a mainstay of treatment for refractory migraine in urgent care or inpatient settings. Intranasal, subcutaneous injectable, rectal suppository, or other non-oral preparations of therapies for acute migraine may be able to achieve therapeutic levels more quickly than oral preparations and are indicated if nausea and vomiting are a feature of migraine attacks.
Be careful with triptans. The primary concern with frequent triptan use is not safety but rather the potential development of medication-overuse headache, which the ICHD, third edition, defines as more than 10 days per month of triptan use in a person who has 15 or more days of headache per month.
When are you going to initiate preventive therapy in a patient?
There is no evidence supporting a specific “threshold” migraine frequency for which preventive therapy is clearly warranted, although it is generally agreed that preventive therapy should be considered if migraine occurs at least once per week or on 4 or more days per month. Preventive therapy may also be tried in the following situations:
- Frequent or long lasting migraine headaches
- Migraine attacks that cause significant disability or diminished quality of life despite appropriate acute treatment
- Contraindication to acute therapies
- Failure of acute therapy
- Serious adverse effects of acute therapies
- Risk of medication overuse headache
- Menstrual migraine
All currently available preventive medication therapies for migraine were initially developed for other indications and have been secondarily adopted as treatments for migraine. Antihypertensive agents (e.g., beta-adrenergic blockers and candesartan), anticonvulsant agents (e.g., topiramate and divalproex sodium), and tricyclic antidepressants (e.g., amitriptyline and nortriptyline) are standard preventive therapies for migraine. For some patients, these agents can be highly effective, although the average difference in headache days per month between preventive therapies and placebo has been small in clinical trials. Adverse effects are common for most of the preventive therapies, and patients often report an initial response that “wears off” despite increasing doses. Adherence to treatment is generally poor.
OnabotulinumtoxinA is a Food and Drug Administration (FDA)–approved therapy for the prevention of chronic migraine, defined as headache occurring on more than 15 days per month, with migraine features on at least 8 of those days. There is limited evidence to support the use of nonprescription agents — including coenzyme Q10, riboflavin, magnesium, melatonin, and petasites (Petasites are a genus of flowering plants in the sunflower family, Asteraceae) — but these agents are nonetheless widely used because of their acceptable side-effect profile.
Preventive migraine therapy also is indicated to reduce the risk of neurologic damage and/or impairment in the presence of uncommon migraine conditions including:
- Hemiplegic migraine
- Migraine with brainstem aura
- Persistent aura without infarction
- Migrainous infarction
Which preventive therapy to choose? For patients with hypertension, a beta-blocker or candesartan may be warranted; for those with insomnia, a tricyclic antidepressant may be considered; and for patients who are obese, topiramate may be appropriate.
How to use beta blockers.
- Propranolol in two divided doses starting at 40 mg daily; dose range 40 to 160 mg daily
- Metoprolol in two divided doses starting at 50 mg daily; dose range 50 to 200 mg daily
- Nadolol starting at 20 mg once a day; dose range 20 to 240 mg daily
- Atenolol starting at 25 mg daily; dose range 25 to 100 mg once daily
For calcium channel blockers verapamil appears to be popular, flunarizine, nimodipine and nifedipine are also used. Tolerance tends to develop.
Of the ACEi/ARBs lisinopril appears to be more effective.
The tricyclic antidepressants most commonly used for migraine prevention include amitriptyline, nortriptyline, doxepin, and protriptyline. Amitriptyline is the only tricyclic that has proven efficacy for migraine; there are insufficient data regarding the other tricyclics The tricyclic antidepressant amitriptyline (starting dose 10 mg at bedtime, dosage range 20 to 50 mg at bedtime) was effective for migraine prevention in four trials. In other trials, the serotonin-norepinephrine reuptake inhibitor venlafaxine (starting at 37.5 mg once a day, dosage range 75 to 150 mg once a day) was also effective as prevention for migraine.
A 2012 guideline from the AAN concluded that topiramate and sodium valproate are established as effective for migraine prevention, while evidence is insufficient to determine the effectiveness of gabapentin.
Topiramate — Several placebo-controlled studies, a systematic review, and a meta-analysis have found that topiramate is effective preventive therapy for migraine. Significant reductions in migraine frequency occurred within the first month at topiramate doses of 100 and 200 mg/day.
The young woman described in the vignette has migraine with and without aura. If her neurologic examination is normal, there is no indication for an imaging study, given that she has had multiple episodes of typical duration with complete resolution of symptoms between episodes and no “red flags,” such as an abrupt onset of symptoms, fever, concurrent clinically significant illness, or persistent headache between attacks. Many practitioners reflexively order an imaging study when attacks include neurologic symptoms in addition to headache, but such symptoms are characteristic of migraine. Current medications should be reviewed as possible exacerbating factors. Consistency of lifestyle factors (diet, caffeine intake, sleep, and exercise) should be encouraged, and a strategy for the treatment of acute attacks with triptans, NSAIDs, antiemetics, or a combination of these agents should be developed, with an emphasis on treating as early as possible after migraine onset. The frequency and severity of migraine attacks should be monitored to assess whether preventive therapy may be indicated; options include a beta-blocker, candesartan, a tricyclic antidepressant, an anticonvulsant (topiramate or divalproex sodium), or onabotulinumtoxinA (if headache occurs ≥15 days per month). This choice should be informed by coexisting conditions and potential adverse effects. Paper or electronic symptom diaries can be very helpful in assessing the clinical course of migraine and the response to therapies. If pharmacologic therapies are ineffective or have unacceptable side effects, neuromodulation approaches should be considered.