Abnormal Axial Diffusivity in the Deep Gray Nuclei and Dorsal Brain Stem in Infantile Spasm Treated with Vigabatrin

Abstract

SUMMARY:We evaluated the DTI changes in the deep gray nuclei and dorsal brain stem, which demonstrated abnormal T2 and/or diffusion signal intensity, in 6 patients with infantile spasm treated with vigabatrin compared with 6 age-matched controls. Regions of interest were placed in the globi pallidi, thalami, and dorsal brain stem; FA, trace, D ʈ , and D Ќ were measured. Patients on vigabatrin had significantly lower FA in both globi pallidi (P ϭ .01) and the dorsal brain stem (P Ͻ .01), significantly lower trace in both globi pallidi (P ϭ .01) and the thalami (P ϭ .02 and .01 for right and left, respectively), and significantly lower D ʈ in both globi pallidi (P Յ .01), the thalami (P Ͻ .01), and the dorsal brain stem (P ϭ .03). There were no significant differences in D Ќ of the globi pallidi, thalami, or dorsal brain stem in patients compared with controls. The findings suggest that axonal changes play a greater role in the observed abnormal signal intensity, with lesser contribution from myelin changes.ABBREVIATIONS: D ʈ ϭ axial diffusivity; D Ќ ϭ radial diffusivity; DB ϭ dorsal brain stem; DTI ϭ diffusion tensor imaging; FA ϭ fractional anisotropy; GABA ϭ ␥-aminobutyric acid; GP ϭ globi pallidi; ICC ϭ intraclass correlation coefficient; IS ϭ infantile spasm; L ϭ left; MRI ϭ MR imaging; R ϭ right; Thal ϭ thalami; TSC ϭ tuberous sclerosis complex; VGB ϭ vigabatrin; VGB-Pt ϭ patients on vigabatrin therapy with abnormal T2 and/or diffusion signal intensity on MR imaging V igabatrin is a structural analog of GABA, which irreversibly inhibits GABA-transaminase, increasing brain levels of GABA. Vigabatrin has been used to treat infantile spasms and refractory complex partial seizures, and clinical trials have shown that vigabatrin may provide rapid reduction in seizure frequency and has allowed some patients to become seizurefree.1 Vigabatrin was generally reported as a well-tolerated drug; however, visual disturbances, manifested as visual blurring and constriction of visual fields, were noted in some patients treated with vigabatrin. In addition, animal studies have raised concerns that prolonged administration of vigabatrin induced intramyelin edema. [2][3][4] Recently, human studies have described reversible MR imaging abnormalities characterized by T2-weighted hyperintensities and/or restricted diffusion in the globi pallidi, thalami, dorsal pons, and midbrain in approximately 20%-30% of patients with infantile spasm. 5-7Young age and high dose appeared to be risk factors for the development of these reversible changes in the deep gray nuclei and brain stem. [5][6][7] The underlying microstructural changes responsible for the T2 and diffusion changes in the human brain are unknown. However, on the basis of animal studies, we postulated that the abnormal T2 signal intensity and diffusion restriction in the deep gray nuclei and dorsal brain stem were related to intramyelin edema.DTI can be used to indirectly evaluate the integrity of the axonal microenvironment by assessing the diffusion of water molecules and i...

In-vivo multi-exponential T2, magnetization transfer and quantitative histology in a rat model of intramyelinic edema

“…In humans, vigabatrin has been associated with reversible T 2 hyperintensity in pediatric patients (Dill et al, 2013; Dracopoulos et al, 2010; Pearl et al, 2009), but lack of imaging specificity has left the microanatomical basis for these observations unknown. Dracopoulos et al (2010) found a decrease in the apparent diffusion coefficient (ADC) of water corresponding to regions of T 2 hyperintensity, which is consistent with IME (Karaarslan and Arslan, 2008; Righini et al, 2003), but Simao et al (2011) found a directional dependence to the ADC change which led to the postulate that it resulted from axonal rather than myelinic sources. More recently, it has also been suggested that some observed T 2 changes could correspond to physiologic rather than potentially pathologic changes (Aguilera-Albesa et al, 2012).…”

Cerebral Diffusion Tensor MR Tractography in Tuberous Sclerosis Complex: Correlation with Neurologic Severity and Tract-Based Spatial Statistical Analysis

“…14 The lower axial diffusivity in the tuberous sclerosis complex group suggested poor integrity of axons. 35,36 Moreover, because FA is known to positively correlate with axial diffusivity, 37 our result of a decrease in both FA and axial diffusivity was reasonable.…”

Vigabatrin as First-Line Treatment for Infantile Spasms Not Related to Tuberous Sclerosis Complex

“…[19][20][21] Also, vigabatrin -related magnetic resonance imaging changes are seen in 22%-32% of children treated for infantile spasms, and although these changes are mostly asymptomatic and typically resolve even when vigabatrin is continued, there is concern that the changes reflect a medication-related neurotoxicity. 19,22,23 For patients who do not have a complete resolution of clinical spasms and electrographic hypsarrhythmia when treated with vigabatrin for 2 weeks, we prescribe a 6-week course of synthetic ACTH (Synacthen) intramuscularly on alternate days as a second-line agent. This rigorous protocol of using vigabatrin as the first-line drug for the first 2 weeks, followed by high-dose ACTH in those children who fail to have both a clinical resolution of spasms and an EEG resolution of hypsarrhythmia leads to seizure control in 96% of patients.…”