Case History

CT is a 47-year-old female with complex past medical history (PMH) who initially presented with a 10-year history of headaches. Headaches were described as unilateral, right or left sided, throbbing, stabbing pain associated with photophobia, phonophobia, and nausea/vomiting. Patient also stated that initially headaches were intermittently associated with left eyelid droop. Over time however, headaches began to be associated with more frequent and severe symptoms of weakness and numbness, including facial weakness and numbness as well as hemiparesis, usually right side greater than left. Symptoms of weakness and numbness usually resolved after 1-2 hours. Patient had tried multiple medications and therapies for headache including prophylactic medications, such as supplements, amitriptyline, and topiramate; abortive medications, such as triptans and Lasmiditan; and other therapies, such as botulinum toxin injection, physical therapy, and cognitive behavioral therapy.

The patient also had a complex past medical history (PMH) of depression, anxiety, unilateral progressive hearing loss, vertigo, thyroid disease, asthma, and cataracts. Specifically, she had developed worsening vertigo and hearing loss over time for which she saw audiology and ENT and had been diagnosed with Meniere’s disease. Patient also had history of impairment of memory and concentration for which neuropsychiatric testing was obtained and revealed significant deficits with attention. The patient had a strong family history of migraines though no clear history of hemiplegic migraine.

Physical exam was unremarkable with normal neurologic exam except loss of hearing on the right. No other focal neurologic signs were present.

Case Differential/Work Up

Differential diagnosis included hemiplegic migraine, RCVS (reversible cerebral vasoconstriction syndrome), HaNDL (transient headache with neurological deficits and CSF lymphocytosis), Fahr’s disease, MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes), CADASIL (Cerebral Autosomal Dominant Arteriopathy with Sub-cortical Infarcts and Leukoencephalopathy), TIA, and epilepsy. Lab work was largely unremarkable, including CBC, CMP, ESR, TSH, and B12. EEG was obtained and normal. Multiple MRIs of the brain were obtained, all of which revealed stable gradient echo hypointensities in bilateral basal ganglia, likely representing calcification. It was later revealed that the patient’s son also had bilateral basal ganglia calcifications seen on CT head which had been obtained during workup for concussion. Whole genome sequencing was obtained and revealed a variant of unknown significance (VUS) in the CACNA1A gene in both the patient and her son, confirming likely diagnosis of familial hemiplegic migraine in the patient.

DISCUSSION

Hemiplegic migraine (HM) is a rare subtype of migraine with aura that characterized by attacks fulfilling criteria of migraine with aura along with transient, fully reversible motor weakness. Auras can consist of visual or sensory symptoms.1 Pathogenic mutations of three genes (CACNA1A, ATP1A2, and SCN1A) have been identified in patients with HM. These genes encode for protein subunits of neuronal channels involved in ion transportation. CACNA1A encodes for the main subunit of Ca,2.1 neuronal channels. CACNA1A mutations are responsible for familial HM type 1 and have also been associated episodic ataxia type 2 and spinocerebellar ataxia type 6. New mutations of the CACNA1A gene are being discovered in patients with HM and are associated with a spectrum of clinical phenotypes. 2,3,4,5,6 Our patient was found to have a VUS of the CACN1A gene in the setting of clinical history consistent with HM and other complex medical problems, including progressive unilateral hearing loss and cognitive decline. The patient and her son also had prominent bilateral basal ganglia gradient echo hypointensities on head imaging. The genetic mutation of CACNA1A found on their whole genome testing may represent another genetic/phenotypic variant of HM. For patients with history consistent with HM, genetic testing is a useful and informative tool to aid in diagnosis and management of these patients.

REFERENCES

1. Pelzer, N., Stam, A., Haan, J., Ferrari, M. and Terwindt, G., 2012. Familial and Sporadic Hemiplegic Migraine: Diagnosis and Treatment. Current Treatment Options in Neurology, 15(1), pp.13-27.

2. Pelzer, N., Haan, J., Stam, A., Vijfhuizen, L., Koelewijn, S., Smagge, A., de Vries, B., Ferrari, M., van den Maagdenberg, A. and Terwindt, G., 2018. Clinical spectrum of hemiplegic migraine and chances of finding a pathogenic mutation. Neurology, 90(7), pp.e575-e582.

3. Ducros, A., Denier, C., Joutel, A., Cecillon, M., Lescoat, C., Vahedi, K., Darcel, F., Vicaut, E., Bousser, M. and Tournier-Lasserve, E., 2001. The Clinical Spectrum of Familial Hemiplegic Migraine Associated with Mutations in a Neuronal Calcium Channel. New England Journal of Medicine, 345(1), pp.17-24.

4. Grieco, G., Gagliardi, S., Ricca, I., Pansarasa, O., Neri, M., Gualandi, F., Nappi, G., Ferlini, A. and Cereda, C., 2018. New CACNA1A deletions are associated to migraine phenotypes. The Journal of Headache and Pain, 19(1).

5. Ducros, A., 2014. Familial hemiplegic migraine: A model for the genetic studies of migraine. Cephalalgia, 34(13), pp.1035-1037.

6. Russell, M. and Ducros, A., 2011. Sporadic and familial hemiplegic migraine: pathophysiological mechanisms, clinical characteristics, diagnosis, and management. The Lancet Neurology, 10(5), pp.457-470.