Neuroimaging and clinical features in type II (late-onset) Alexander disease

Abstract

Objective: To describe the imaging and clinical features in type II (late-onset) Alexander disease (AxD). Methods:We retrospectively identified all cases of type II AxD evaluated at Mayo Clinic, Rochester from January 1996 to February 2012. Clinical and neuroimaging data abstracted from the record included age at onset of symptoms, age at diagnosis, first symptom, neurologic symptoms, physical/neurologic findings on examination, genetic testing and/or biopsy (if performed), and MRI findings.Results: Thirteen patients with type II AxD were identified. Median age at onset was 38 years (range: 12-63). Five patients were female. Eleven of 13 patients had atrophy of the medulla while all 13 had medullary T2 hyperintensity. In 7 patients, these brainstem regions showed patchy enhancement. Five subjects had T2 signal change in the middle cerebellar peduncle, with associated contrast enhancement in 4 subjects. Eleven of 12 patients with T2 fluid-attenuated inversion recovery (FLAIR) imaging had pial FLAIR signal change in the medulla. Nine of 12 patients with spinal cord imaging had cord atrophy, and 3 of 9 of these evaluated with contrast had cervical cord enhancement.Conclusions: Our study confirms prior reports of atrophy and signal change of the medulla and spinal cord in late-onset AxD. We expand on previous imaging studies by identifying middle cerebellar peduncle and pial FLAIR signal changes as important diagnostic clues. Variable patchy enhancement may occur in regions of T2 hyperintensity, leading to diagnostic uncertainty. In addition, we demonstrate that previously emphasized clinical features such as palatal tremor may not be common. We affirm that age at onset predicts clinical phenotype and imaging findings. Alexander disease (AxD) 1 is a leukodystrophy that is pathologically characterized by the presence of Rosenthal fibers. Mutations in the glial fibrillary acidic protein (GFAP) gene cause AxD. Traditionally, AxD has been categorized into infantile, juvenile, and adult forms according to the age at onset.3 MRI criteria for the infantile variant consist of frontal white matter changes; a periventricular rim with high T1 and low T2 signal; T2 hyperintensity (herein referred to as signal abnormality) involving the basal ganglia, thalamus, and brainstem; and contrast enhancement of particular gray and white matter structures (ventricular lining, periventricular rim of tissue, white matter of the frontal lobes, optic chiasm, fornix, basal ganglia, thalamus, dentate nucleus, and brainstem). 4 Imaging and clinical features of late-onset AxD have been less frequently described. Available studies suggest that the clinical and radiologic presentation differs significantly from infantile-onset cases.5-11 Adult-onset cases appear to have less cerebral white matter involvement. Medullary and spinal cord atrophy occurs in most, but often with a mixture of additional findings that may present diagnostic challenges. 5,12 In a review of more than 215 cases of AxD, AxD was divided into 2 groups: type I was char...

Prominent cognitive decline and behavioural disturbance in late-onset Alexander disease

“…Here, we report two patients with adult-onset AxD, who developed early and Cognitive decline and behavioural problems have generally not been highlighted as features of adult-onset AxD in large case series [1][2][3], although a Japanese study reported behavioural abnormalities and cognitive impairment in 2/12 patients [5]. Our two cases suggest that cognitive decline and behavioural disturbance may be prominent and early features of adult-onset AxD, and that…”

“…An adult-onset form of the disease is being increasingly recognised, and presents commonly with progressive ataxia, bulbar and pyramidal features, and dysautonomia [1][2][3].…”

Quantitative Evaluation of Brain Stem Atrophy Using Magnetic Resonance Imaging in Adult Patients with Alexander Disease

“…On the other hand, types 2 and 3 show various symptoms such as muscle weakness, spastic paralysis, ataxia, a bulbar or pseudobulbar sign, and autonomic dysfunction, and it is difficult to suspect AxD solely based on clinical symptoms. The characteristic findings of brain MRI are signal abnormalities or atrophy of the medulla oblongata and/or cervical cord [5,6,7,8], reported as a tadpole appearance [7]. However, there is no quantitative standard for assessment of the findings, and it is typical for evaluation to be solely based on clinicians' visual impression.…”

Incidental diagnosis of an asymptomatic adult-onset Alexander disease by brain magnetic resonance imaging for preoperative evaluation

“…Although diagnostic MRI criteria for infantile AD have been defined by van der van der Knaap et al [4], recent studies suggest that the radiologic presentation of AOAD significantly differs from infantile-onset cases [5,6]. AOAD cases appear to have less cerebral white matter involvement.…”