Diagnostic Criteria
Suggestive Findings Alexander disease should be suspected in individuals with the following age-related clinical and brain MRI findings. Clinical Findings Neonates • Weak suck, feeding difficulties, hypotonia, and myoclonus • Progressive psychomotor impairment or developmental regression • Megalencephaly with frontal bossing Note: Though the terms megalencephaly and macrocephaly are sometimes used interchangeably, macrocephaly refers to head circumference that is more than two standard deviations above the mean adjusting for age and sex, whereas megalencephaly refers to increased volume of brain parenchyma. Macrocephaly – which reflects the size of intracranial contents as well as bone and scalp – may result from megalencephaly but also other medical issues, such as hydrocephalus or thickening of the skull. • Seizures • Occasional hydrocephalus secondary to aqueductal stenosis • CSF protein elevation Children • Developmental delay (slow attainment of developmental milestones or failure to achieve later milestones) • Seizures • Megalencephaly • Gradual loss of intellectual function • Regression after mild head injury or seizure • Dysarthria (in those children who attain speech) • Failure to thrive Juveniles • Developmental delay • Seizures • Bulbar/pseudobulbar signs with nasal speech, dysphagia, dysphonia • Failure to thrive • Intractable vomiting • Scoliosis • Autonomic dysfunction Adults • Bulbar/pseudobulbar signs • Pyramidal tract signs • Cerebellar signs • Dysautonomia • Sleep disturbance • Gait disturbance • Hemiparesis/hemiplegia or quadriparesis/quadriplegia • Diplopia or oculomotor abnormalities Brain MRI Findings Based on a multi-institutional retrospective survey of MRI studies of 217 individuals with leukoencephalopathy , it has been suggested that the presence of four of the five following criteria establishes an MRI-based diagnosis of Alexander disease, which can lead to targeted genetic testing: • Extensive cerebral white matter abnormalities with a frontal preponderance • Periventricular rim of decreased signal intensity on T2-weighted images and elevated signal intensity on T1-weighted images • Abnormalities of the basal ganglia and thalami that may include one or both of the following: • Swelling and increased signal intensity on T2-weighted images • Atrophy and increased/decreased signal intensity on T2-weighted images • Brain stem abnormalities, particularly involving the medulla and midbrain • Contrast enhancement of one or more of the following: ventricular lining, periventricular rim, frontal white matter, optic chiasm, fornix, basal ganglia, thalamus, dentate nucleus, and brain stem Table 1. Alexander Disease: MRI Features by Age of Presentation
