Clinical FeaturesNeurologyWomen’s Health

Migraine in Women

Introduction: Migraine is a neurological disorder characterised by recurrent bouts of severe headaches with autonomic and neurological symptoms. Scientific advances in recent decades have provided us with a clear understanding of the pathophysiology of migraine and enabled the development of migraine specific acute and preventative therapies. Migraine occurs in 10-12% of the population and there is a 3:1 female to male ratio. It is particularly common, in women of all ages, and female preponderance begins around the time of the menarche. The World Health Organisation Global Burden of Disease study ranked migraine as the 2nd leading cause of disability and the leading cause in women under the age of 50 years.

Diagnosis: The International Headache Society has standardised the diagnosis of migraine using universally accepted diagnostic criteria (ICHD3) and these guidelines have provided us with a uniform approach to diagnosis in clinical practice (Fig 1,2,3,4).

Migraine Without Aura: 1.1

A. At least 5 attacks fulfilling criteria B-D

B. Headache attacks lasting 4-72 hours (untreated or unsuccessfully treated)

C. Headache has > 2 of the following characteristics 1. Unilateral Location

2. Pulsating Quality

3. Moderate or severe pain intensity

4. Aggravated by or causing avoidance of routine physical activity.

D. During Headache > 1 of the following.

1. Nausea and or vomiting

2. Photophobia and Phonophobia

E. Not better accounted for by another ICHD-3 diagnosis

Fig: 1

Migraine With Typical Aura: 1.2.1

A. At least 2 attacks fulfilling B and C

B. Aura of visual, sensory and /or speech /language symptoms, each fully reversible, but no motor, brainstem or retinal symptoms.

C. > 2 of the following 4 characteristics

1. > aura symptom spreads gradually over 5 minutes and /or > 2 symptoms occur in succession.

2. Each individual aura symptom lasts 5-60 minutes

3. > 1 aura symptom is unilateral

4. Aura accompanied by or followed in < 60 minutes by headache

D. Not better accounted for by another ICHD-3 diagnosis, and TIA excluded.

Fig: 2

Chronic Migraine: 1.3

A. Headache (TTH-like and /or Migraine-like on >15 d/mo for > 3 month and fulfilling criteria B and C.

B. In a patient who has had > 5 attacks of fulfilling criteria B-D For 1.1 Migraine Without Aura and /or criteria B and C for 1.2 Migraine With Aura

C. On > 8 d/month for > 3 month fulfilling any of the following:

1. Criteria C and D for Migraine Without Aura

2. Criteria B and C for Migraine With Aura

3. Believed by the patient to be migraine at onset and relieved by a triptan or ergot derivative

D. Not better accounted for by another ICHD-3 diagnosis

Fig: 3

Hemiplegic Migraine: 1.2.3

A. Attacks fulfilling criteria for 1.2 Migraine With Aura and criterion B below.

B. Aura consists of both of the following

1. Fully reversible motor weakness

2. Fully reversible visual, sensory, and or speech / language symptoms

Fig: 4

Many migraine patients also experience other symptoms which are disabling but are not incorporated into the diagnostic guidelines. These symptoms vary and include vertigo, dizziness, cutaneous alloydynia, tiredness and psychomotor slowing.

The natural history of migraine in women is that it begins around the time of the menarche and early teenage years, peaks in the 30’s and declines rapidly in the post-menopausal years. The average patient gets 2-3 attacks per month and for 10% of sufferers migraine is a progressive disorder leading to Chronic Migraine (>15 days per month) at a time in life when individual demands and commitments are greatest.

Migraine and Women: Throughout a woman’s life hormonal factors have a significant influence in the threshold, susceptibility, risks, and management of migraine (Fig:5).

1. Migraine and the menstrual cycle

2. Migraine and the oral contraceptive

3. Migraine and Pregnancy

4. Migraine and HRT / Menopause

1. Migraine and Menstrual Cycle: Women are vulnerable to migraine attacks at the time of menses and less commonly around the time of ovulation. Attacks, however, are not exclusive to these times and many other migraines may occur either spontaneously or on exposure to a trigger (e.g. diet factors, alcohol, stress and lifestyle factors). Menstrual migraines most frequently occur between days -2 to + 3 of menses. Attacks are more likely to be migraine without aura and are longer in duration (> 72 hours). It is also considered more disabling and more difficult to treat. In the perimenstrual period, and to a lesser extent at the time of ovulation, oestrogen levels decline and fluctuate. This decline activates the trigeminovascular system resulting in an acute attack. Many patients are able to anticipate menstrual migraines enabling them to treat early, particularly with longer acting triptans (e.g. frovatriptan 2.5mg or naratriptan 2.5mg) with or without an NSAID (e.g. naproxyn 500mg).

2. Migraine and Oral Contraceptive: The combined oral contraceptives are ethinyloestradiol / progestogen preparations (COCP). The newer versions contain lower doses of the oestrogen component.

The combined pill is a risk factor for cardiovascular and cerebrovascular disease and careful consideration needs to be given when prescribing in migraine patients. Migraine With Aura is an independent risk factor for stroke as are the COCP, cigarette smoking and hypertension. This risk is accumulative and migraine patients need to be advised to stop smoking. The use of a headache diary is invaluable in this supervision as the pill is known to:

• Trigger headache and first attack of migraine without aura.

• Trigger aura symptoms for the first time in patients already diagnosed with migraine without aura.

• Worsen and increase the frequency of migraine in patients with an established diagnosis.

• It can improve migraine or in others it has no impact on the frequency, severity and duration attacks.

• Continuation of the pill without break through 3 cycles may prevent menstrual migraine attacks.

In patients with an established diagnosis of Migraine With Aura the combined pill is contraindicated and patients who develop aura symptoms after commencing the COCP need to discontinue the pill immediately due to stroke risk. The headache diary will identify those patients in whom the COCP worsens their migraine and for whom it must be stopped or is contraindicated in the first place. The diary, paradoxically, will also demonstrate those patients in whom the COCP has benefited their migraine and reduced the frequency of attacks.

The protestrogen-only-preparations are an alternative in women for whom the COCP is contraindicated. The POP’s are safe and do not trigger or worsen migraine.

3. Migraine and Pregnancy: Pregnancy is a positive time for migraine patients and up to 60- 70% of migraneurs improve during pregnancy, particularly after the first trimester, with many achieving a remission. This is due to the sustained high levels of oestrogen, which no longer fluctuate, providing a preventative benefit to triggering attacks. After childbirth the migraine pattern tends to re-emerge within the first month. Breast-feeding may delay the re-emergence in the puerperium.

7% of women, however, experience their first migraine attack during pregnancy and women who present with new onset headache may have other causes such as cerebral venous thrombosis (CVS), preeclampsia or subarachnoid haemorrhage.

Many of the acute and preventative therapies are contraindicated during pregnancy due to their potential for harm. These include the triptans, paracetamol / codeine preparations, topiramate, sodium valproate and the latest preventative therapies the CGRP monoclonal anti-body antagonists. Patients are limited to the use of simple analgesics such as paracetamol combined with metoclopramide for the treatments of acute attacks.

4. Migraine HRT and the menopause: The perimenopausal years frequently sees a rise in the frequency and disability of migraine attacks with many women progressing to chronic migraine (> 15 headache days per month) along with the vasomotor symptoms of the menopause. This can be a very challenging time and it is due to the fluctuating and erratic oestrogen levels during this time.

The use of hormone replacement therapy (HRT) is NOT contraindicated in either Migraine With Aura or Without Aura . Oestrogen replacement therapy administered transdermally (with progestogen) in physiological doses can be very efficacious as a preventative migraine therapy and also for the troublesome menopausal vasomotor symptoms.

The natural history of history of migraine is that migraine prevalence goes into a rapid decline after the menopause. It is rare, but not unheard of, for the elderly to continue to complain of migraine in their advancing years.

Management of Migraine: The guiding principles in the management and treatment of migraine are outlined in fig:6.

1. Use of a Headache Diary.

3. Preventative Therapies.

4. Non Drug Therapies.Fig:61.Use of a Headache Diary: Migraine is a recurrent disorder and a headache diary is a useful guide and aid memoir in chronicling the frequency, severity, duration and impact of attacks. It helps identify trigger factors and

2. Acute Therapies.evaluate the efficacy of acute and preventative therapies.

1. Acute Therapies: One third of migraine patients can effectively manage their acute attacks with over-the-counter simple analgesics such as soluble aspirin, paracetamol or ibuprofen. Prescribed medications, the triptans, are now the gold standard in the management of the acute attack and these include: sumatriptan, zolmitriptan, almotriptan, eletriptan, frovatriptan and naratriptan. Ideally patients should get meaningful relief from their headache and most bothersome symptoms within 2 hours. These medications can be combined with anti-nausea medication and NSAIDS (e.g. naproxyn) which may enhance efficacy. Acute therapies which provide no relief within 4 hours are deemed to be lacking in efficacy. Compound analgesics (e.g. paracetamol / codeine, tramadol) should be avoided or prescribed with caution due to risk of developing Medication-Overuse- Headache.

Newer treatments, the small molecule ‘’gepants’’, CGRP antagonists, are on the horizon and soon to be approved. They will add to armamentarium for the treatment of acute attacks and also as a preventative therapy.

2. Preventative Therapies: Preventative therapies are indicated when patients experience 4 or more migraine days per months, and are poor responders to acute therapies. The conventional preventative therapies are listed in fig:7

1. B-blockers: propranolol, metoprolol, atenolol.

2. Anti-depressants: amitriptyline, venlafaxine.

3. Anti-epileptics: topiramate, sodium valproate.

4. Anti-hypertensives: candesartan.

5. Flunarizine.

6. Pizotifen.7. Botulinun Toxin.

Fig: 7The benchmark in evaluating the efficacy of preventative therapies is the achievement of at least a 50% reduction in the frequency of headaches in 50% of patients. To determine this end point patients need to remain on their medication for 3 months before a determination is made. Many patients in clinical practice discontinue their preventative therapy within weeks either due to side-effects or a perceived lack of efficacy.

New Preventative Therapies: C.G.R.P. (Calcitonin Gene Related Peptides) Monoclonal Antibody Antagonists:

The CGRP monoclonal antibody antagonists are the first specifically developed migraine preventative therapies targeting the underlying mechanisms of migraine (Fig:8).

1. Erenumab 70mg or140mg s.c monthly injection.

2. Fremanezumab 225mg s.c monthly or 3 monthly

3. Galcanezumab s.c monthly

4. Eptinezumab 100mg or 300mg IV every 3 months (awaiting approval)

Erenumab, fremanezumab and galcanezumab are approved by the HSE on the Hi-Tech hub for patients who have Chronic Migraine (>15 headache days per month) and have failed to benefit from 3 previously prescribed conventional preventative therapies. They are licenced for patients aged between 18 and 65 years. In clinical trials benefits and efficacy are seen within 1 week and 25% of patients achieve up to 75% reduction in the frequency of headaches.

Conclusions: Migraine is a common disabling disorder which significantly impacts on the quality of life of women at pivotal times throughout their adult lives. In the past, it has traditionally been underdiagnosed and undertreated. Many patients have fatalistic expectations regarding the management of migraine as they have had to endure migraine attacks for many years. Others may have witnessed a family member such as a parent or aunt or uncle suffer and endure a similar fate.

Today we are much better at diagnosing, understanding and treating migraine. Migraine specific acute and preventative are now available enabling us to better manage migraine. On going research is developing additional treatments (small molecule ‘gpants’ and ditans) which will further advance our ability to manage migraine and improve the quality of life for many migraneurs.

Written by Dr Edward M. O’ Sullivan, Clinical Director Headache Migraine Clinic Department of Neurology Cork University HospitalGeneral Practitioner in Cork, Medical advisor to the Migraine Association of Ireland

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