Abstract
There has always been an interest in brain imaging abnormalities in patients with migraines. Whereas various types of radiological findings have been described, there have only been a few reports of brain calcifications and their association with migraine. In particular, there have been no reports of a single family and its members having such findings. The clinical presentation of a mother and her only two daughters is discussed here who have strikingly similar migraine-like headaches as well as brain imaging showing brain calcifications in the basal ganglia and dentate nucleus of the cerebellum. We discuss the possible association with migraines in the light of previously noted similar cases of brain imaging.
Case reports
The mother, a 42-year-old, had had migraines since the age of 6 years. Headaches were holocranial, predominantly on the crown of the head, with variable fluctuating intensity from mild to severe, and were associated with photophobia and phonophobia especially when severe, as well as with nausea and occasional vomiting. Initially her headaches were episodic and then became daily during her teen years with daily use of aspirin and ibuprofen. After initiation of treatment with amitriptyline, her headache frequency improved to two or three episodes every week, lasting < 1 day and responsive to almotriptan. Her eldest daughter, now 20 years of age, had had very similar headaches that began at the age of 16 years, with identical intensity and associated symptoms, except that her headaches were less frequent and had an identifiable trigger of motion sickness. Her episodes were responsive to ibuprofen and sleep. She had tried topiramate and amitriptyline in the past but had stopped them due to side-effects and preferred not to use any prophylaxis. The second daughter, who was 17 years old, had also had very similar headaches, which had started a year earlier after a minor head trauma. Her headaches occurred less frequently, at the most once or twice a week and would last up to 2 h if untreated and would respond to ibuprofen and sleep as well. Her medical illnesses included biopsy-proven Crohn's disease and menstrual irregularities. Although all three members of the family met the criteria of migraine without aura, the mother had experienced one aura in her lifetime, which she described as seeing a beautiful kaleidoscope of colours. One of the mother's many siblings and her daughter had had similar headaches but no diagnosis of migraines had been made. She thought that one of her grandparents may also have had headaches, but was not sure. A pedigree is illustrated in Figure 1.
Pedigree chart showing family members involved and possible other relatives who have similar clinical symptoms of headaches but testing is not possible due to distance or death.
All three members of the family had computed tomography brain scans at different times as a part of a work-up during their initial evaluation of migraines and the scans showed strikingly similar distributions of high signal spots, which were presumed to be calcifications. These were evaluated via magnetic resonance imaging, which confirmed the presence of abnormal T1 bright signal in the basal ganglia, including globus pallidus, putamen and caudate. In addition, there was abnormal signal in the dentate nucleus regions of the cerebellum. These were markedly prominent in the daughters' scans, but could be seen clearly in the mother's imaging also (Figures 2–5).
Brain magnetic resonance imaging T1 images showing increased signal in the basal ganglia of 17-year-old daughter. Brain magnetic resonance imaging T1 images showing increased signal in the basal ganglia of 20-year-old daughter. Brain magnetic resonance imaging T1 images showing increased signal in the basal ganglia of 20-year-old daughter. Brain magnetic resonance imaging T1 images showing increased signal in the basal ganglia of 42-year-old mother.
Laboratory assessment was essentially normal, including a complete blood count, liver function tests, blood chemistry, urine analysis, calcium, ionized calcium, magnesium, phosphorus, serum electrophoresis, uric acid, C-reactive protein, erythrocyte sedimentation rate, thyroid-stimulating hormone, parathyroid hormone, vitamin B12, HIV, rheumatoid factor, lead level, ceruloplasmin, iron, ferritin, and urine metal screen. Antinuclear antibody was weakly positive with anti-double-stranded DNA antibody negative in both daughters. The vitamin D level in the 17-year-old daughter was low normal.
Discussion
Often, to rule out secondary causes of headaches, brain imaging is a typical component of the initial management (1). It is uncommon to find neuroimaging abnormalities in primary headaches (2) and, when present, these may either indicate a secondary cause of headaches or may suggest another coincidentally occurring syndrome (3,4). Migraines, in association with brain imaging abnormalities such as in our family, have been reported previously in the literature. They have generally been associated either with an atypical Sturge Weber syndrome (5) or with coeliac disease and folic acid deficiency (5,6) with primarily a parieto-occipital distribution of calcifications.
The pattern of imaging findings in our family is highly suggestive of idiopathic ferrocalcinosis, or recently better defined as bilateral striopallidodentate calcinosis (BSPDC). Other names have been used such as ‘brain calcinosis syndrome’, although that term has also included calcifications in other parts of the brain (7). Although much discussion has been held on trying to differentiate and characterize this radiological finding better and differentiate it from Fahr's ‘disease’, still little is understood about its cause and aetiology (8). It should be noted that the diagnosis of idiopathic calcinosis is made after ruling out most of the secondary causes.
These findings may present with or without symptoms, and the size and number of calcifications has correlated with the severity of symptoms (9). A recent attempt to accumulate a registry reviewed 99 such cases (10). Of these, 32 were asymptomatic, and amongst the symptomatic the most common symptoms were movement disorders, of which Parkinsonism was most frequent. Other symptoms were chorea, tremor, dystonia, athetosis, oro-facial dyskinesias, cognitive impairment, speech impairment, cerebellar impairment, psychiatric features, gait disorders, sensory changes and pain. The association with migraine has not been noted and there does not seem to be much literature on such a correlation.
Since BSPDC is not a common occurrence in migraine, one can argue that there could be multiple possible explanations for why our reported family has such findings. The first could be that BSPDC and migraine are completely separate syndromes and that they are occurring incidentally and independently of each other, and the reason why they are present in all members of our family is because they are independently autosomal dominant conditions. This argument does have weight as there are almost no reported cases of these two co-existing. Also, BSPDC does seem to have an autosomal dominant pattern since, when present, a significant number of family members seem to have the abnormal radiological finding, arguing against the previous concept that this was X-linked or recessive (8). Similarly, migraine studies showing higher incidence in monozygotic twins have supported a genetic aetiology, although the inheritance pattern is still not clear (11), (12).
The second possibility could be that the BSPDC in itself can cause migraine-like headaches and that previous case series were not large enough to capture this information. Support for this hypothesis comes from the occurrence of migraines in previously reported cases of brain calcifications due to other causes (5,6). A similar, and third possibility, is that there is a causal link in the opposite direction—that migraines may be causing the calcifications. Migraine as a risk factor for parenchymal brain lesions has been studied in a recent trial, and although it showed there is indeed an increased risk in certain populations, these brain abnormalities were primarily white matter lesions (13). The possibility that migraine caused these lesions in our patients seems less likely, as they are present also in both daughters, who have not had migraines as long as the mother.
Another possibility could be that BSPDC and migraines may share a similar chromosomal locus. More case reports and research may be needed to explore that relationship.
However, the similarities of expression of both these conditions in our patients are striking. The pathophysiology of basal ganglia calcifications, in general, is not clearly understood at this point, and while the radiological findings are mostly attributed to calcium deposits, mucopolysaccharides, traces of aluminum, arsenic, cobalt, copper, molybdenum, iron, lead, manganese, magnesium, phosphorus, silver, and zinc have also been noted (8,14). Reviewing what is known about the pathophysiology of migraines (1), there does not seem to be a common pathway.
Since this is the first report of the association of migraine with BSPDC, more cases would need to be accumulated and studied to confirm such an association. If so, perhaps this association will help identify a specific subtype of migraine that may have a unique course and treatment approach.