De novo Migraine with Aura in the Third Trimester of Pregnancy: A Case Report and Literature review

Background: Among all headache disorders, migraine has the highest prevalence during gestation. The majority of migraineurs experience improvement during pregnancy, but a few may experience migraine for the first time. This poses a diagnostic challenge in the differential diagnosis between primary and life-threatening secondary headache disorders. Because pregnancy itself is an independent risk factor for secondary headache disorders, it is mandatory to exclude these conditions in order to diagnose migraine. There is a large body of literature about pre-existing migraine course during pregnancy and its link with adverse pregnancy outcomes, but there are no studies examining these aspects among women with new-onset migraine during pregnancy. Case report. A 31-year-old female at 33 weeks of gestation (gravida 2, para 2) was referred to the neurologist eds disturbances, which were followed by pressing severe headache, rated as 8 out of 10 on a numeric rating scale and accompanied by dizziness. The headache lasted for one day, and dizziness continued to the following day. The patient was investigated for a secondary headache disorder, but laboratory and neuroimaging results were unremarkable. A migraine with aura was diagnosed. The patient was advised to keep a consistent sleep schedule, maintain regular low physical activity, eat regularly and take magnesium supplementation. The patient was informed about a safe treatment approach in case of an acute attack. At 40 weeks of gestation the patient delivered female newborn, weighing 3750g, with Apgar scores of 8 and 9 (due to a nuchal cord). The postpartum period was uneventful. During the subsequent 4 years, the patient did not experience any recurrent migraine attacks and had no pregnancies. Conclusion. In order to diagnose a migraine during pregnancy, exclusion of secondary headache disorders is mandatory. Pregnant migraineur should be regularly monitored for adverse birth outcomes. It is essential to educate patients, provide information about the safe treatment of migraine attacks, and explain nonpharmacological prevention and supplementation benefits.


Introduction
According to the latest study of the Global Burden of Disease, a migraine is the second highest cause of years lived with disability for both genders and the first among young women [1]. Among all headache disorders, a migraine, followed by a tension-type headache (TTH), has the highest prevalence during gestation [2], and it is estimated to be around 20% [3].
The majority of migraineurs experience improvement during pregnancy [4]. However, for a few women, migraine, especially migraine with aura (MA), may occur for the first time during gestation [5]. It is thought that the mechanism leading to this phenomenon could be elevated oestrogen levels and/or the lack of oestrogen cycling, which are believed to reduce the threshold for cortical spreading depression [6]. Clinical features of a new-onset migraine may resemble secondary headaches caused by life-threatening conditions and especially those attributed to vascular disorders [7]. More so, pregnancy and migraine, especially MA, are risk factors for preeclampsia, cerebral venous thrombosis, transient ischemic attack (TIA) and stroke [8,9]. For this reason, health care workers often face difficulties diagnosing migraine, as well as predicting its course. While there is little data on a new-onset migraine during pregnancy, we report a description of a patient with de novo migraine with aura in late pregnancy and provide a literature review.

Case report
A 31-year-old female at 33 weeks of gestation (gravida 2, para 2) was referred to the neurologist with a history of two headache episodes, which she experienced for the first time in her life. Episodes occurred spontaneously, without any apparent trigger, seven and four days ago, respectively. During the episodes the patient experienced visual, sensory and speech disturbances. The visual symptom was defined as gradually increasing bilateral flickering in the right visual field, which lasted thirty minutes. In the next fifteen minutes, the patient experienced difficulties of word finding, followed by fifteen minutes of gradually spreading numbness in the right hand and right cheek. Ten minutes after the numbness ended, the patient developed a right-sided headache, which later spread to both sides of the head. Headache was pressing in quality, rated as 8 out of 10 on a numeric rating scale and accompanied by dizziness and balance loss. Neither vomiting nor photo/phonophobia was present. Ibuprofen 300 mg and acetaminophen 500 mg were partially effective: the headache lasted for one day, and dizziness continued for two days. After the second attack, the patient complained of a remaining discomfort on the right side of the head. Her past medical history was unsignificant.
Physical examination showed tachycardia (102 bpm) and normotension (111/76 mmHg). Neurological examination and fundoscopy was unremarkable with the exception of mild and inconsistent right hypoesthesia of face and right hand. No pathologies were identified during gynaecological examination. Complete blood count, venous glucose and urinalysis were normal, elevated D-dimer level (600 mcg/L, normal values < 250 mcg/L) was interpreted as physiological change during pregnancy. Because of the new-onset headache, subjective sensory deficit and elevated D-dimer levels, it was decided to perform 1, 5 T brain magnetic resonance imaging with angiography (MRI/MRA) without contrast enhancement in order to exclude the acute cerebrovascular pathology. No acute ischemia, haemorrhage, and no changes in intracranial arteries, cerebral veins or sinuses were found. Mild cerebellar tonsillar ectopia of 4 mm and left maxillary sinus retention cyst were incidental findings.
Migraine with typical aura according to the International Classification of Headache Disorders, 3rd edition (ICHD III) criteria was diagnosed (table 1).
The patient was advised to keep a consistent sleep schedule, maintain low physical activity, eat regularly, and take 600 mg of magnesium citrate a day (for 1-2 months) for migraine prophylaxis. Treatment for acute migraine attack was proposed: to take 1 g of paracetamol as soon as flickering starts. If necessary, the dose can be repeated when the headache continues.
There were no complications during the rest of the pregnancy and at 40 weeks of gestation the patient had spontaneous vaginal delivery. Female newborn, weighing 3750g, with Apgar scores of 8 and 9 (due to a nuchal cord) was delivered. The patient and newborn were discharged 3 days later. The postpartum period was uneventful.
Migraine with aura subsided with no further recurrence over a 4-year follow-up period. During this period, the patient had no pregnancies.

Discussion
Acute onset headache, especially when associated with other neurological symptoms, causes anxiety to the pregnant female and requires an urgent evaluation by the doctor. One of these occasions may be a new-onset migraine during gestation. New-onset MA (table 1) is more frequent than de novo cases of migraine without aura (MO) [4,10].
A new-onset MO affects from 1 up to 10% and MA from 10.7 up to 14% of pregnant women [10]. Since there are no biomarkers or specific imaging findings, the diagnosis of migraine mainly relies on the history. Due to less experience with neurological disorders, this task becomes even more difficult for the obstetrician/gynaecologist, who consults pregnant women with an acute headache. A migraine mimics many life-threatening headache disorders [11], which leads to the conclusion that in order to prevent possible harm to the mother or offspring, any severe new-onset headache during gestation demands an urgent and accurate exclusion of secondary headache disorders (SHDs) (table 2). Transient focal symptoms associated with aura may resemble vascular disorder, such as TIA. To complicate the matter, TIAs may present with headache [9], and migraine aura can occur without an accompanying headache [11]. The focal deficits are typically sudden and occur all at once in TIA, however in migraine aura, focal symptoms in most cases gradually spread from one modality to another [11]. The presence of positive rather than negative symptoms supports a diagnosis of migraine aura [12]. Nevertheless, MA is by far the most common disorder underlying transient focal symptoms among pregnant women [9]. Overall, detailed history taking and neurologic examination can lead to more accurate predictions of the underlying causes and prevent unnecessary interventions.
There is no high evidence data on the typical time of the occurrence of de novo migraine or on its course after and during the pregnancy. Therefore, it could be a subject for the future studies.
The occurrence of SHDs ranges from 14.3 to 52.6% of all pregnant women presenting with an acute headache [10,18,19]. Altogether, these studies suggest that hypertensive disorders, such as preeclampsia [18] and infections (most commonly viral infections and sinusitis) [4] are the most common causes of SHDs. It is important to emphasize that the hypercoagulable state caused by pregnancy [2,10] and migraine [20] are independent risk factors for preeclampsia, cerebral venous thrombosis, TIA and stroke [8,9]. Two retrospective studies reported that specific clinical findings, so-called "red flags" (Table 3) [4,18], should alarm doctors to investigate for the underlying cause of SHD.
The majority of cerebrovascular disorders have overlapping presentations but distinctive imaging. This is where the medical team faces another obstacle since pregnancy limits the use of neuroimaging techniques. MRI would be the preferred method. However, head computed tomography is faster and considered safe for the foetus, given its low ionization dose (<1 rad) [21]. Contrast Table 1. Clinical features and criteria of migraine with aura [11]

ICHD-III diagnostic criteria Migraine headache features
A. At least two attacks fulfilling criteria B and C B. One or more of the following fully reversible aura symptoms: visual, sensory, speech and/or language, motor, brainstem, retinal C. At least three of the following six characteristics: 1. at least one aura symptom spreads gradually over ≥ 5 minutes 2. two or more aura symptoms occur in succession 3. each individual aura symptom lasts 5-60 minutes 4. at least one aura symptom is unilateral 5. at least one aura symptom is positive 6. the aura is accompanied, or followed within 60 minutes, by headache D. Not better accounted for by another ICHD-3 diagnosis.  materials should be avoided unless absolutely necessary [22]. Examination of our patient raised suspicion that secondary headache disorder was the underlying cause of the headache. The patient's history and examination revealed two red-flags: lack of a history of primary headaches and abnormal neurologic examination (sensory deficit). Hence, head MRI/MRA without contrast enhancement was performed to identify possible intracranial pathology. After excluding SHDs, clinical features of the headache can help differentiate between primary headache disorders and are usually enough to diagnose them. In our case headache characteristics resembled TTH rather than a typical migraine.
However, full clinical picture should be evaluated. According to the ICHD III, migraine aura is sometimes associated with a headache that does not fulfill criteria provided in Table 1, but this is still regarded as a migraine headache because of its relation to the aura [11]. In other cases, migraine aura may occur without headache. A migraine itself rather than its treatment is also associated with an increased risk of adverse perinatal outcomes. A systematic study confirmed that migraineurs have an increased risk of preterm birth and low birth weight baby by 1.72-fold and 1.8-fold respectively, compared to nonmigraineurs [3]. However, there is a hypothesis that low birth weight may be the consequence of comorbid conditions rather than the migraine itself [23]. Pregnant migraineurs also have an increased risk of preeclampsia, need for the Caesarean section, gestational hypertension [3], placental abruption [24], and even stroke [25]. Unfortunately, there is no data reporting a link between new-onset migraine and adverse pregnancy outcomes.
After diagnosing migraine, doctors face another challenge posed by the limited use of drugs in migraine management during pregnancy. Migraine must be treated adequately since it majorly interferes with daily activities. Treatment may reduce migraine-related presenteeism, absenteeism and improve both physical and mental health during and after delivery. Moreover, vomiting can lead to dehydration and electrolyte imbalances [6]. An abortive treatment for migraine includes acetaminophen, nonsteroidal anti-inflammatory drugs (during second trimester only) as first-line or triptans as second-line choices, and a rule, as with all acute medications during pregnancy, follows: treatment should be used for the shortest period possible to minimize any potential risk [26,27]. Acute and preventative treatment, such as peripheral nerve blocks with lidocaine or ropivacaine is considered safe [28]. However, safety of supraorbital nerve stimulator and transcranial magnetic stimulators has not been formally studied [6]. Antiemetic drugs (metoclopramide as firstline) can be used to relieve symptoms and aid in faster absorption of abortive oral medications [26]. Nonpharmacologic preventative measures are the most important, given the teratogenicity of the majority of migraine therapeutics. Lifestyle and behavioral modifications include regular physical activity, proper hydration, sleep hygiene, avoidance of fasting and certain foods, such as chocolate, red wine, excessive caffeine (abrupt discontinuation should also be avoided) [29]. Regular relaxation training and biofeedback can be helpful [30], and the effect can be enhanced if used in combination with pharmacologic treatment [31]. There is a lack of evidence to determine magnesium supplementation effectiveness in preventing migraines [32]. Preventive pharmacologic treatment, such as propranolol (first-line), amitriptyline and coenzyme Q10 (second-line), are considered safe [6].

Conclusions
A new-onset severe headache during pregnancy requires urgent evaluation to exclude threatening secondary causes, and this is mandatory in order to diagnose a primary headache disorder. A migraine is the most common primary headache among pregnant women. Pregnancy may require closer surveillance for adverse birth outcomes. The symptoms that might signify this need to be explained, and the attendance at regular antenatal checks encouraged. Nonpharmacological preventive measures remain the cornerstone method in preventing the recurrence of migraine. There are too few studies investigating de novo migraine during pregnancy, and there are none that analyse different pregnancy outcomes depending on which new-onset migraine subgroup (MA or MO) occurred.