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

Discussion

We found significantly reduced trace and significantly reduced D_‖ in the globi pallidi and thalami, but no significant elevation in D_⊥. Animal studies suggested that a reduction in D_‖ could be related to an abnormality in the axonal structure rather than abnormal myelin. Beaulieu et al¹² studied wallerian degeneration of the frog sciatic nerve and observed that most axons had either collapsed or were degraded and permeated with amorphous granular material instead of containing normal neurofilaments and mitochondria. The authors attributed the reduction in D_‖ to breakdown of the longitudinal axonal structure. They also observed an increase in D_⊥, which was attributed to breakdown of myelin by macrophages, hence loss of the distinction of intra- and extra-axonal water environments. Song et al⁸ examined the optic nerve serially by using DTI following ischemia and observed a reduction in D_‖ 3 days after ischemia without concurrent detectable changes in D_⊥. The reduction in D_‖ correlated with histologic findings of axonal degeneration with no detectable evidence of demyelination. The elevation of D_⊥ was observed 5 days after ischemia, and this correlated with histologic findings of myelin degeneration.

Our findings of significantly reduced D_‖ suggested that derangement in axonal structure might play a dominant role in the observed DTI changes in the deep gray nuclei and dorsal brain stem. This is contrary to the findings described in animals that have been exposed to vigabatrin. A randomized placebo-control study of 108 dogs given vigabatrin for ≤12 weeks demonstrated myelin vacuolation in the thalamus, hypothalamus, and fornix on histology 4–5 weeks after treatment.⁴ The ages of the dogs were not stated. MR imaging changes were present in these animals several weeks after histologic changes. There was increased T2 signal intensity in the hypothalamus 4 weeks after treatment and in the thalamus and fornix 7 weeks after treatment. The MR imaging signal intensity increased with the duration of the treatment and normalized 16 weeks after the drug was discontinued.⁴

Myelin vacuolation has been reported in the myelinated white matter tracts of mice exposed to vigabatrin.² Further study of rats that have been treated with vigabatrin showed lesions in the cerebellar white matter and increased T2 relaxation on MR imaging, which correlated with microvacuolation on postmortem examination.³ At the time of vigabatrin administration, these rats were 4 weeks of age and myelination was expected to have been completed at that point in time. Increased T2 relaxation on MR imaging was also seen in the cerebral cortex, thalamus, and hippocampus, which correlated with reactive astrocytes and, in more severe cases, microglial proliferation and microvacuoles.³

Besides myelin microvacuolation, animal studies have also found other histologic abnormalities in immature animals exposed to vigabatrin. Sidhu et al¹³ examined immature rats from 12 to 16 days of age exposed to clinically comparable doses of vigabatrin (15–50 mg/kg/day) and demonstrated axonal degeneration and glial cell death in the white matter and reactive astrogliosis in the frontal cortex. However, they did not detect myelin vacuolation. Qiao et al¹⁴ studied the long-term effects of vigabatrin administration on the immature rat brain. At the end of 2 weeks of vigabatrin administration, they found abnormal signal intensity on T2 and diffusion-weighted imaging and observed microvacuolation, dying cells, and swollen axons in the corpus callosum. Two weeks after cessation of vigabatrin administration, there was no abnormal signal intensity on MR imaging, but the T2 relaxation time remained elevated in the hypothalamus and the reduction of the myelination reversed partially.¹⁴ In explants of rat cerebellum exposed to vigabatrin, there was no evidence of intramyelin edema or primary demyelination, but degenerating myelinated fibers and astrocytic gliosis were seen on electron microscopy.¹⁵ It is possible that axonal swelling, axonal degeneration, reactive astrogliosis, or an as-yet-unknown factor may have, in part, contributed to the significantly reduced D_‖ in the deep gray nuclei and dorsal brain stem in our patients.

Immature animals were more likely to demonstrate histologic findings other than myelin vacuolation, such as axonal swelling, axonal degeneration, and astrocytic gliosis¹⁵ compared with myelin-mature animals. Previous studies have shown that children younger than 2 years of age were more likely to demonstrate abnormal signal intensity in the deep gray nuclei and dorsal brain stem compared with older children or adults when exposed to vigabatrin.^5,7,16 The observed abnormal signal intensity in the deep gray nuclei and dorsal brain stem in infants with relatively immature myelin exposed to vigabatrin may not be related to myelin vacuolation—hence, the lack of significant alteration of D_⊥in the globi pallidi, thalami, and dorsal brain stem in our cohort of patients.

In studies involving animal models, the question often remains as to whether the findings are generalizable to humans. To date, there has been 1 postmortem case of a child with a history of hypoxic injury due to prematurity who received vigabatrin at 9 months of age for the treatment of infantile spasm.¹⁷ This child underwent vigabatrin treatment for 3 days, and 9 days later underwent vigabatrin treatment for a total of 11 days before dying of bronchopneumonia. Postmortem findings demonstrated microglial activation in the white matter and the CA1 sector of the hippocampus as well as the presence of large vacuoles within the myelin in the brain stem and white matter associated with the globi pallidi, dentate nucleus, and white matter of some cerebellar folia. There was no evidence of reactive astrocytes, reactive microglia, or damaged axons associated with the vacuoles. It is not known whether both myelin vacuolation and axonal changes could occur in infants exposed to vigabatrin or whether myelin vacuolation represents early changes and axonal changes developed later. The observed reduced D_‖ in this study may be related to the longer exposure to vigabatrin because the mean duration of vigabatrin exposure in our patients was 74.5 days. Further longitudinal studies are needed to determine if DTI indices of D_‖ and D_⊥ alter during the course of vigabatrin treatment.