MRI Characterization and Longitudinal Study of Focal Cerebellar Lesions in a Young Tuberous Sclerosis Cohort

Discussion

We found that cerebellar tubers were present in 24.1% of our 145 pediatric and young adult TSC cohort, similar to the percentage in a recent report of one-third of 27 patients with TSC having cerebellar abnormalities on MR imaging.⁷ Our imaging features of cerebellar tubers were similar to those in previous reports with predominantly wedge-shaped lesions that are hyperintense on T2 and hypo- or isointense on T1.⁷ Prior work reports that cerebellar tubers (3%–92%) are more likely to enhance than cortical tubers (3%–4%).^7,11 This difference may result from impaired blood-brain barrier function near areas with inflammation and cortical disorganization.¹² In our cohort, 51% of the cerebellar tubers enhanced, often in a “zebralike” pattern⁴; this frequency and pattern are similar to those in prior reports. The zebralike pattern may reflect the underlying cerebellar anatomy with interposed cerebellar CSF-filled sulci between the neuronal elements (Fig 3). Nine tubers demonstrated a change in enhancement pattern with time, and this evolving pattern may contribute to the widely differing frequencies (3%–92%) among reports.^7,11

Traditionally, tubers were considered stable lesions resulting from abnormal cortical migration during early fetal development. Recently, however, a few case reports and studies document the dynamic nature of a small percentage of tubers.¹³ One report documented 2 patients with cystlike tubers that increased in size and number with time.¹³ In our cohort, 52% of cerebellar tubers changed in some manner when longitudinally studied, supporting the dynamic nature of the infratentorial tubers. In patients with multiple cerebellar tubers, some of the tubers changed while others remained static; while in others, several tubers changed in parallel. The pathologic specimens of the resected cystlike tuber demonstrated the typical giant or balloon cells with a disorganized cortex; however, the subcortical white matter showed more striking fiber depletion and gliosis than in supratentorial tubers.¹³ The pathogenesis of the change in these cystlike tubers is still unknown; possibilities include disordered migration, tuber degeneration, accelerated astroglial apoptosis, or a combination of these processes.¹³ A spectrum of degenerative changes may occur in all cortical tubers, with cystlike tubers representing a subset undergoing more rapid changes.¹³ We lack the radiologic-pathologic correlation of cerebellar tubers but suspect a similar process as occurs in the supratentorial cystlike tubers. Previously resected cerebellar tubers have shown abnormal neuronal migration, gliosis, calcification, and folial atrophy with similar pathology as is seen in the supratentorial lesions¹⁰; this pathology is reflected in the MR imaging appearances.

Although supratentorial cortical tubers are considered responsible for the neurologic and often epileptic manifestations of TSC, many tubers appear epileptically inactive and seizures may arise from the cortex surrounding the tuber.¹⁴ Similarly, cerebellar symptoms are not clearly associated with cerebellar tubers.^7,15 A correlation between autism and posterior fossa tubers was found in 1 study, while others correlated autistic symptoms (social isolation, stereotypical behavior, and communication and developmental problems) with right-sided tubers.^4,16,17 However, other studies correlated autism in TSC with temporal lobe tubers^18,19 and left temporal lobe epileptiform foci.²⁰ Future studies should examine the relationship between cerebellar lesions, the severity of phenotype, and cognitive behavioral function, controlling for the effects of epilepsy and cerebral tuber burden.

The reported incidence of cerebellar atrophy varies from 4% to 13% in patients with TSC.^5,7,15 Additionally, is this atrophy reflecting a primary aberrant neuronal developmental process or rather the sequela of seizures or other associated destructive processes? The similarities in the pathologic cerebellar tuber specimens to the supratentorial tuber specimens may be indicative of a similar primary abnormal developmental process.¹⁰ In our cohort, the presence of cerebellar tubers and the presence of global cerebellar atrophy were associated. Cerebellar tubers tend to calcify more frequently than cortical tubers. Moreover, 54% of the cerebellar tubers in our cohort were at least partially calcified, with associated retraction deformity in 85%. The cerebellar calcification may be a manifestation of the end stage of the abnormal neuronal organization,¹² and the high frequency of tuber calcification and retraction may account for the associated focal atrophy previously reported.⁵ Similarly, the global cerebellar atrophy may reflect underlying abnormal gliosis or treatment-related effects.

To date, the literature is mixed on whether cerebellar tubers are associated with more phenotypically severe TSC. A relationship between a certain subtype of cortical tubers “type C” and a more severe phenotype has been suggested, with the “type C” tubers corresponding to the previously described cystlike tuber type.²¹ Clinically, these patients had difficult-to-control and more frequent seizures as well as lower intelligence quotient scores,²¹ and they also had a larger cortical tuber burden, a higher percentage of the TSC2 gene mutation, and a higher occurrence of SGAs.²¹ There was, however, no significant difference detected in the percentage of cerebellar lesions among the 3 cortical tuber groups, again raising questions of whether cerebellar lesions and SGAs are related and whether either are indicative of a more severe disease subset. Cerebellar tubers are not reported to occur in the absence of cortical tubers, and patients with cerebral and cerebellar tubers have significantly more global cortical lesions than patients without cerebellar tubers.⁵ In a future study, we would like to correlate our findings in the cerebellum with our cohort's supratentorial cortical tuber burden and clinical phenotype.

There are limitations to our study, including the retrospective nature, the limited follow-up examinations available for some of our patients, and the potential for bias, because our epilepsy center is a large TSC referral center and may, therefore, have a TSC patient population with a more severe phenotype than average. We also recognize that if, in fact, the presence of cerebellar lesions is associated with more phenotypically severe TSC, then our reported incidence of lesion change could be an overestimate because these patients could have undergone more frequent scanning because of their more active disease.