Abstract
Introduction
Migraine with aura (MA) is a common condition; however, MA status is considered very rare. According to the 2004 International Classification of Headache Disorders, MA status is a condition of MA characterized by at least two auras per day for ≥5 consecutive days (1). Aura status generally resolves spontaneously. However, during the episodes patients are greatly debilitated. It is rare for a MA status to be the first time MA occurs. In fact, patients with MA status have usually had previous attacks of MA. The cause of MA status is unknown. We report two cases of MA status associated with a condition of hyperhomocysteinaemia.
Case reports
Patient 1
The patient was a 57-year-old man with a 45-year history of MA and a 3-year history of hypertension in treatment with ACE-inhibitors. He had a family history of MA. He usually complained of one to two MA attacks every month. The aura symptoms were characterized by scintillating scotomas lasting 10–15 min followed by paraesthesia starting in the left hand and gradually spreading to the perioral region on the left side of his face. The aura symptoms always lasted <1 h and were invariably followed by frontal pulsating headache accompanied by photophobia, phonophobia and nausea. He had been previously treated with amitriptyline, but the drug had been withdrawn due to side effects of drowsiness. Thereafter, the patient was treated with verapamil with no satisfactory effect on his headache. In the last few years he had been on cyclic treatment with flunarizine with satisfying control of his attacks. The pain phase responded to symptomatics drugs within <1 h. He presented to the emergency department because of a MA status with visual and paraesthesic symptoms, reporting that during the last 2 weeks he had experienced two to four attacks per day. The auras lasted between 20 and 40 min and were sometimes not followed by headache. Between the auras, the patient was without symptoms. After 5 days he had started a self-medication cycle with flunarizine, but did not observe any change in migraine occurrence. Blood pressure was in the normal range, computed tomography (CT) of the brain was normal, EEG showed bilateral temporo-occipital slow waves. Contrast transcranial Doppler sonography (TCD), performed at rest and after Valsalva manoeuvre to assess the possible presence of a right-to-left shunt, was normal. Laboratory analysis was performed and included blood chemistry, blood cell counts, erythrocyte sedimentation rate and coagulation panel. Coagulopathy work-up showed high fasting plasma homocysteine concentrations (35 µmol/l), heterozygosity for the 677C→T substitution polymorphism in the methylene tetrahydrofolate reductase (MTHFR)-encoding gene and heterozigosity for Factor V Leiden. Brain magnetic resonance imaging (MRI) with and without contrast showed multiple, small, bilateral, subcortical white matter hyperintensities on T2 images. Acetazolamide treatment (a carbonic anhydrase inhibitor which is thought to ameliorate ion channel function) and folic acid supplementation were started. The aura symptoms disappeared within a few days. In the 18-month follow-up period there have been no further episodes of MA status.
Patient 2
The second patient was a 28-year-old woman with a 3-year history of migraine with visual and sensory aura. She usually complained one attack of MA per month and more frequently she was bothered by scintillating scotomas and left-sided paraesthesia marching from the left hand to the arm, face and tongue lasting 15–40 min not followed by headache. She had been on oral contraceptives (Gestodene 75 µg/Ethinylestradiol 20 µg) for 1 year, during which time she had observed a slight worsening in headache frequency and severity. She had had a previous history of anorexia. At the time of observation her body mass index was 16.9 and she had normal cycles. She was experiencing MA status with visual symptoms and left-handed paraesthesia that had started 10 days previously. In the previous 10 days she had had three attacks of MA per day. Between the auras, the patient was without symptoms. A cerebral CT scan was normal, EEG showed bilateral occipital slow waves. Contrast TCD at rest and after Valsalva manoeuvre was normal, as was brain MRI. Laboratory analysis was performed and included blood chemistry, blood cell counts, erythrocyte sedimentation rate and coagulation panel. Coagulopathy work-up showed high fasting plasma homocysteine concentrations (24 µmol/l) and heterozygosity for the 677C→T substitution polymorphism in the MTHFR-encoding gene. Oral contraceptive treatment was discontinued. Folic acid supplementation was started. The patient was put on acetazolamide treatment but the drug had to be withdrawn because of side effects (drowsiness and bilateral paraesthesia). However, the attacks disappeared within a week. There was no return of MA status. Since that time the patient has reported sporadic occurrence of MA attacks. In the 10-month follow-up period there have been no further episodes of MA status.
Discussion
The relationship between the aura and the occurrence of pain in migraine is still not clear. Pathophysiological studies in migraine patients and in animal models of migraine headache have identified the trigeminovascular system, brainstem and cerebral cortex as structures which may have primary causative roles (2).
Case–control and population-based studies examining the relationship between two common MTHFR polymorphisms, C677T and A1298C, and migraine have provided conflicting results (3–7). Similarly, findings on the relationship between homocysteine levels and MA are equivocal (5–9). On the other hand, animal models suggest a relationship between hyperhomocysteinaemia and susceptibility to migraine. In a cat model of craniovascular pain Storer and Goadsby (10) demonstrated that the excitatory amino acid DL-homocysteic acid, a substance which mimics the effect of homocysteine on arteries, increases cell firing on trigeminal cells. In addition, increased homocysteine levels or reduced folate have been associated with disruption of endothelial function (10, 11), which may be relevant (i.e. altering brain ion homeostasis) to cortical spreading depression, a phenomenon thought to be involved in MA pathophysiology (2). Elevated plasma concentrations of homocysteine may occur either because of impaired metabolism of this amino acid as a result of genetic factors, or may be attributable to impaired blood levels of folate and vitamin B12. Elevated plasma concentrations of homocysteine have been observed in anorexia nervosa, most probably due to subclinical folate deficiency (12). In the cases reported here, a combination of genetic predisposition and intercurrent factors might have contributed to the hyperhomocysteinaemia. MA status is probably very rare and its cause and treatment are unknown (13). The cause of normal aura and MA status is presumably the same, but the patient is temporarily more vulnerable to pathophysiological migraine stimuli. The association between MA status and hyperhomocysteinaemia we observed might not be incidental.