History and Physical
A 12-year-old girl presents with episodic recurrent headaches since 10 years of age, which are throbbing in quality, 8/10 in intensity. The headaches are accompanied by phonophobia, photophobia, nausea, and vomiting, and sometimes a preceding visual aura. Episodes last 2 to 4 hours, with no obvious trigger, and improve with pain relievers or a short nap. Patient has no relevant prior medical history, no known exposure to trauma or toxins, no mood disorders, and good school performance. Family history: mother and maternal grandmother report similar headache episodes. Grandmother has cognitive impairment. Two maternal uncles have a history of stroke. Clinical examination: vital signs and height appropriate for age, neurological examination normal. Basic labs are negative for systemic abnormalities. Given the frequency of symptoms, migraine with aura was initially diagnosed and patient was treated with cyproheptadine, flunarizine, and topiramate, with minimal improvement.
Diagnostic Workup
Brain MRI reveals frontoinsular cortical atrophy and bilateral symmetric T2 hyperintense signal in the subcortical and periventricular white matter with extension to internal and external capsules ( Fig. 7.1 ).
Oligosymptomatic CADASIL with nonspecific hyperintensities in white matter. (A and B) Brain MRI, axial FLAIR, shows mild insular atrophy ( arrowheads ) with confluent bilateral hyperintensity of periventricular white matter ( arrows ) extending into internal and external capsules. CADASIL , Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; FLAIR , fluid-attenuated inversion recovery.
Metabolic studies are normal: lactic acid, pyruvate, ammonium, creatine phosphokinase (CPK), carnitine, acylcarnitine, adrenal and pituitary hormones, lysosomal enzymes, very long chain fatty acids in blood, amino acids in blood and urine, organic acids and acylglycines in urine. Other studies including EEG, auditory and visual evoked potentials, and peripheral nerve conduction velocity are also normal.
Patient continues to experience headaches of variable frequency, some preceded by facial sensory symptoms. At 15 years of age, following an episode of prolonged headache, she presents with hemiparesis and right hemihypoesthesia. Extensive workup excludes vascular, metabolic, inflammatory, cardiac, and mitochondrial diseases.
Repeat brain MRI shows progression of confluent hyperintensities in the subcortical white matter, with predominance in the temporal poles and posterior periventricular regions, and additional lesions in the optic pathway, thalami, and pontine tegmentum. A small left thalamic lesion shows restricted diffusion indicative of an early acute lacunar infarct. MRI angiography is normal ( Fig. 7.2 ).
Follow-up CADASIL with acute lacunar infarction. (A and B) Brain MRI, axial FLAIR, shows progression of confluent hyperintensities in periventricular white matter, with subcortical predominance in anterior temporal ( white arrowheads ) and parietal lobes ( black arrowheads ), and additional lesions in the optic radiations, thalami, and pons. (C) Axial DWI and (D) ADC show restricted diffusion in the left thalamus corresponding to an acute lacunar infarction ( arrows ). (E) MR angiography is normal. ADC , Apparent diffusion coefficient; CADASIL , cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; DWI , diffusion-weighted imaging; FLAIR , fluid-attenuated inversion recovery.
Genetic testing confirms NOTCH3 gene mutation in both the patient and mother.
Clinical Differential Diagnosis
Numerous pathologies in children are associated with recurrent headaches and stroke, including primary and secondary CNS vasculitis, SWS, moyamoya syndrome, and mitochondrial diseases (MELAS).
White matter abnormalities can be seen with migraine ( Fig. 7.3 ), demyelinating diseases, leukodystrophies, and metabolic diseases (homocystinuria, Fabry disease).
Migraine. Brain MRI, axial FLAIR, shows scattered small hyperintense foci throughout the subcortical white matter. FLAIR , Fluid-attenuated inversion recovery.
Imaging Differential Diagnosis
Many diseases can affect white matter in pediatrics, but few involve the temporal subcortical white matter. The differential diagnosis includes congenital cytomegalovirus (CMV) infection ( Fig. 7.4 ), Alexander disease, megalencephalic leukoencephalopathy, and congenital muscular dystrophies ( Fig. 7.5 ).
