Zonisamide as treatment option in persistent migraine aura

Abstract

Persistent migraine aura without infarction is a rare but debilitating condition. Treatment options are mostly anecdotal and limited due to inefficacy and side effects. We present a 16-year-old female patient with triple X syndrome, having persistent aura symptoms for over 2 years, consisting of continuous visual and sensory sensations. Previous treatments with seven different migraine preventatives were not successful. The patient successfully responded to zonisamide against refractory prolonged aura and remained symptom-free under the ongoing treatment without any relevant side effects. Zonisamide may be considered a new and safe treatment option for patients with persistent migraine aura.

Background

According to the International Classification of Headache Disorders, third edition guidelines (ICHD-3), persistent aura without infarction (PMA) is defined as aura phenomena lasting for at least a week, supported by neuroimaging and excluding symptomatic aura.¹ A history of migraine with typical aura presentation is mandatory for the diagnosis. The neurological signs may continue for months or years.¹ Although this syndrome has a considerable impact on patients’ lives, it is still underdiagnosed and under-reported in the literature.

In the origin of aura phenomena, cortical spreading depression² and subsequent cerebral blood flow changes² might play a pivotal role. In neuroimaging studies investigating PMA, cerebral hypoperfusion, especially in the parieto-occipital region could be shown.² Several other theories comprising abnormal energy metabolism in the brain, altered magnesium levels in migraineurs, greater reactivity of N‐methyl‐D‐aspartate receptors to glutamate and loss of inhibitory gamma-aminobutyric acid (GABA)‐ergic interneurons are discussed.²

No randomised controlled trials, but a few case reports and reviews investigating PMA and its treatment options are available, implying that this is a rare condition and insufficiently investigated. So far, antiepileptic drugs (AEDs) like valproic acid³ or lamotrigine⁴ as well as intravenous furosemide⁵ have shown some effect on the symptoms.

Case presentation

We present the case of a 16-year-old female patient who was referred to our tertiary headache outpatient clinic in 2017 with a history of PMA since August 2016. A timeline of the patient’s clinical course and therapeutic attempts is shown in figure 1.

Figure 1.

Patient’s clinical course, including all therapeutic attempts from the first migraine headache with aura in 2012 until the last visit at our outpatient department in September 2019. Highlighted are the different medical treatments throughout the years and the hospitalizations.

She was diagnosed with a genetically confirmed triple X syndrome and treated with leuprolide acetate until the age of 12 years due to a precocious puberty. Otherwise, she developed clinically normally, including all milestones.

Her first migraine headache with aura was in 2012, at the age of 13 years, occurring simultaneously with her menarche. The migraine started with aura symptoms of hemihypesthesia, paraesthesia, scotoma and flickering light sensations spreading gradually, lasting for 20 min, followed by a pulsating, unilateral, severe headache with a duration of 2 days. The headache was accompanied by nausea, vomiting, photophobia and phonophobia, and withdrawal tendencies.

After that, she reported infrequent migraine headaches with similar symptomatology, fulfilling the ICHD-3 definition of episodic migraine with aura.

Her severe headaches were triggered by physical exertion, resulting in distinct visual aura phenomena as well as apractic and dysphasic disturbances, all of which were self-limiting. The headaches lasted <60 min, except two attacks, where the aura disappeared after 2 and 24 hours, respectively. During a migraine attack in August 2016, leading to hospitalization, the patient presented with a right-sided hemihypesthesia, global aphasia, homonymous hemianopsia and a severe migraine-like headache. Since then, the patient has experienced PMA symptoms such as macropsia and micropsia, photopsia, osmophobia and phonophobia, shooting pain in different body parts, high sleep requirement, tinnitus and photophobia. She constantly had to wear sunglasses. The migraine headaches occurred rarely, with a frequency of once every 3 months.

Investigations

Extensive imaging, electrophysiological and laboratory workup did not reveal any secondary causes. We performed an electroencephalogram, showing the left parieto-occipital slowing, thus being interpreted as unspecific pattern in migraine. Neuroimaging workup including diffusion-weighted MRI and intracranial and extracranial MR angiography, laboratory screenings for vasculitis, dysfunction in coagulation and hormonal abnormalities were all without pathological findings. Regular drug level monitoring was performed during subsequent treatments with AEDs.

Differential diagnosis

Family history regarding migraine was negative and there was no indication of motor weakness, excluding the differential diagnosis of sporadic or familial hemiplegic migraine. No evidence of febrile or epileptic seizures, neither clinically nor in the medical history, were found. As the symptoms observed were more extensive than the ones described in visual snow syndrome, (ie, macropsy, paraesthesia, osmophobia and phonophobia, and shooting pain in different body parts), we diagnosed her with PMA.

Treatment

At the beginning, the patient was able to treat the migraine attacks with non-steroidal anti-inflammatory drugs. In the course of her headache disorder, the frequency of attacks increased. As non-pharmacological approaches such as acupuncture did not yield any therapeutic effect, topiramate 100 mg/day was implemented. However, the patient experienced severe side effects such as, trouble finding words, behavioural changes and difficulties in concentration. Consequently, the treatment was stopped. At the time of her hospitalisation in August 2016, when the persistent migraine aura symptoms started, the patient was treated with lamotrigine 125 mg without success.

At her first visit to our headache clinic in 2017, we tried a methylprednisolone regime, starting with 80 mg/day of oral methylprednisolone and tapering the dose by a half every fifth day. As the treatment had almost no effect on the patient’s photophobia and phonophobia, the therapy was again changed to lamotrigine after 1 month. The dose of lamotrigine was slowly increased by 25 mg every 1–2 weeks until a daily dosage of 200 mg was reached. Due to ineffectiveness, the therapy was then switched to pregabalin. We started with 50 mg/day, divided into two single doses and slowly titrated up to a daily dose of 250 mg, which had no effect on the symptoms either. Furthermore, the patient noticed a depressive mood and after 1½ months, the therapy was stopped.

A trial and error of several other therapies followed, including valproic acid 1000 mg/day.

The regulatory provisions on administration of AEDs to women of childbearing age were observed. After 3 months, there was no significant alleviation of the aura symptoms, only a weight gain of 2 kg as side effect. A persistent visual aura triggered by optical stimuli and presenting as fortification spectrum still remained. At this point, the symptoms had started taking a great toll on the patient’s life. She was not able to continue with her education or obtain her driver’s licence. The therapy was changed from valproic acid to flunarizine 10 mg/day, causing dyskinesia in her toes. After 3 months, it was replaced by levetiracetam 500 mg/day which was slowly titrated up to 2 g/day within 6 weeks. In January 2018, the patient was hospitalised due to a status migrainosus. She received treatment with intravenous cortisone for 5 days.

One month after the hospitalisation, we discontinued the therapy with levetiracetam due to its ineffectiveness as well as side effects like weight gain. Next, we started a therapeutic attempt with dronabinol 2.5 mg, which also showed no response.

After having tried seven different treatment options, we started an off-label approach with zonisamide 50 mg/day in May 2018, increasing the dosage by 50 mg every week.

After 3 months, at a daily dose of 350 mg, the patient stated an easing of the paraesthesia and of her visual aura symptoms for the first time since the start of the PMA. As a side effect, a 4 kg weight loss was reported.

Outcome and follow-up

The further development turned out to be satisfactory. At the following visit, 6 months after the initiation of zonisamide, the patient reported a gradual improvement over the last few months and that she was now actually completely symptom-free and able to continue with her education. The therapeutic drug level was in the range between 27.81 μg/mL and 37.19 μg/mL.

At present, the patient has a pure menstrual migraine which responds to ibuprofen. She rarely has aura symptoms preceding her migraine headaches, and if so, they last for an hour at most.

Discussion

This is the first patient who is reported to have successfully responded to zonisamide in PMA and remained symptom-free under ongoing treatment on a stable dose of 350 mg/day without having relevant side effects.

To the best of our knowledge, only case studies of PMA have been described so far in the literature, and no randomised controlled trials. This might be due to its rarity and possible underdiagnosis; solid epidemiological data is lacking. The age of onset in these reports varied from 7 to 74 years and predominantly women were affected by this condition.⁶ Most of the published papers described the presenting symptoms, conducted investigations and different therapeutic approaches. These, however, were often frustrating.

Taking into account that PMA is highly disabling and has a considerable impact on the patient’s mental health and everyday life, there is an urgent need for treatment options.

AEDs have been implemented in clinical practice in the preventative treatment of migraines since the late 1980s. The European Headache Federation rates two AEDs with good evidence of efficacy: topiramate and sodium valproic acid. One negative aspect of AEDs is their range of adverse effects, including cognitive dysfunction, coordination disturbances, psychiatric effects as well as haematological and hepatic or pancreatic reactions.⁷

Zonisamide is one of the newer AEDs and its mechanism of action is not completely clarified. It potentially acts on voltage-gated sodium and calcium channels which are also expressed in the trigeminal ganglion and play a role in the calcitonin gene-related peptide mediation. Zonisamide has an impact on the GABA-ergic neuronal inhibition in increasing the seizure threshold.⁷

The efficacy, tolerance and safety of zonisamide in the prevention of migraine has been tested under controlled conditions in randomised and open-label design trials, showing no inferiority compared with topiramate^{8 9} or sodium valproic acid.¹⁰ However, we are aware of the fact that zonisamide is currently not listed as a first-line preventive treatment.

The triple X syndrome affects 1 in 1000 women, being the most common sex chromosome abnormality in women.¹¹ The majority is often undiagnosed due to mild symptoms. An association with delayed motor development, learning impairment as well as behavioural problems has been established.¹¹ Headache disorders, especially migraine, have not been reported pathognomonic for this syndrome. Due to the lack of scientific evidence, mere hypotheses can be made whether this chromosomal abnormality influences the severity of the migraine aura or the response to therapy.

The present case contributes to the rather sparse literature on this topic. Persistent migraine aura is a severely debilitating condition, making it all the more important to be able to offer patients treatment options for this difficult-to-treat condition.

Learning points.

• This is the first literature report of a patient with persistent aura without infarction treated with zonisamide. Besides lamotrigine and valproic acid, it could be a new and safe treatment option for patients with this condition.

• Persistent migraine aura is a severe condition and associated with a substantial burden, but still underdiagnosed.

• The underlying pathophysiology of persistent aura remains unclear. Further research, including neuroimaging, needs to be done to better perceive the condition and to develop adequate treatment guidelines.