Tuberous sclerosis complex (TSC) is a multisystem genetic disorder with variable phenotypic expression. Epilepsy is the most common neurological complication and up to 80%-90% of the individuals with TSC suffer from epilepsy at some point in their lifetime. Developmental delay, intellectual impairment, autism, behavioral problems, and neuropsychiatric disorders occur commonly in individuals with TSC and may be associated with poorly controlled epilepsy.1 In this paper we reported a case report of TSC, focusing on the patient's clinical symptom, surgical aspects and neuropathology through a comprehensive analysis.
A 6-year-old, right-handed boy with TSC was referred for consideration of surgery. Seizures began at 80 days of age with infantile spasms. Typically, seizure onset was characterized by raised two hands to ears seeming to hear some “voices”, vocalization, followed by eye deviation to the right, tonic stiffening of both arms, right arm flexed, left arm extended, extension of both legs, and finally he would fall to the ground. After seizure, he could speak words immediately. In some seizures, there was also clonic jerking of the left arm and leg and alteration of awareness. Seizures were unresponsive to phenobarbital, phenytoin, carbamazepine, valproate, oxcarbazepine and lamotrigine. He continued to exhibit recurrent seizures at a frequency of 7–8/month.
In the neonatal period several depigmented macules were noted on the face and back, and a diagnosis of TSC was made. Family history was negative. His development was globally delayed, and he was nonverbal and satisfied the diagnostic criteria for autism. The boy's intellectual function at 6-year-old was in the range of severe intellectual impairment.
On examination, he had multiple depigmented macules, a shagreen patch and periungal fibromas on his face and back. Neurological examination was normal. CT head scans at age of 80 days demonstrated a large right frontal calcified tuber. MRI at 6-year of age demonstrated multiple tubers and subependymal lesions. Large calcified tubers and narrowed gyri were seen in the right superior frontal gyrus (Figure 1A). Interictal fluorodeoxyglucose and positron emission tomography (FDG-PET) showed multiple areas of hypometabolism, especially on the right frontal lobe (Figure 1B). Interictal EEG delineated generalized slowing and right central frontal and temporal spikes. Ictal EEG demonstrated the epileptogenic zone probably located on the right superior frontal gyri included the tuberous lesion.
A right frontal lobe lesionectomy and corticoectomy under electrocorticography (ECoG) monitoring and neuronavigation guidance was performed. Neuropatholoy demonstrated the lost of the normal neuronal lamination order and calcification, gliosis, astrocytes proliferation, dysmorphic neurons like balloon cells had been found under a microscope. Dysmorphic neurons, balloon cells and proliferation of astrocytes were present in the tuber (Figure 2A). Immunohistichemical studies proved that cytoplasm of balloon cells were positive for both TSC1 (Hamartin) and TSC2 (Tuberin) (Figure 2B). The boy was seizure-free after operation (Engel Ia) at one year follow-up. However, the intellectual impairment, autism and behavioral problems showed no improvement.
The estimated frequency of tuberous sclerosis complex in the general population is said to be one in 10 000. Many findings regarded as highly specific to TSC are not apparent until late childhood or adulthood, so the true prevalence of TSC may be as high as one in 6800.2 About 60% of patients have no family history and are thought to represent sporadic mutations.3 Present evidence suggests that TSC are due to a developmental disorder of neurogenesis and neuronal migration, abnormalities of neuronal migration, cellular differentiation and excessive cellular proliferation.4 Seizures are often resistant to antiepileptic drugs and may have a negative impact on the child's neurocognitive development.5
The surgical treatment of intractable epilepsy has gained significant interest in recent years. However, how to identify the primary epileptogenic tuber or region is a precondition to ensure the surgical approach appropriately and effectively. Presurgical evaluation comprises video-EEG, MRI of the brain with fluid-attenuated inversion recovery (FLAIR) sequences, interictal FDG-PET and neuropsychological testing. According to the results of recently published series, the best surgical outcome is for: (1) patients with single seizure type or with a single tuber; (2) patients with multiple tubers and one large, calcified cortical tuber with interictal EEG revealing predominant focal spikes corresponding to the lesion; (3) patients with convergent clinical and imaging data (seizure semiology, MRI, PET and ictal EEG).6 In our case, comparing the factors that influenced surgical outcome mentioned above, it was coherence of conditions 2 and 3.
The product of the TSC1 gene is known as “hamartin”. The protein encoded by the TSC2 gene is “tuberin”. TSC1 and TSC2 function as tumor suppressor genes.7 Recent data also suggest that both genes play a role in cortical differentiation and growth control. Dabora SL et al described a more severe outcome of tuberous sclerosis complex in patients with TSC2 gene mutations compared with those with a mutated TSC1 gene.8 They had a higher frequency of seizures, greater number of subependymal nodules and cortical tubers, more severe kidney involvement, presence of retinal hamartomas, more severe facial angiofibromas and mental retardation. In this case, the right frontal tuber is firm (dystrophic calcification) and pale combined with dysmorphic gyri. The dysmorphic gyri in which the cortex/white matter junction had become blurred, similar to changes noted in severe cortical dysplasia (focal cotical dysplasia with balloon cells, FCD IIb).
In TSC patients with concordant clinical EEG and imaging data, single stage surgery is safe and effective. Best outcome is usually achieved when a single epileptogenic tuber is safely removed with associated areas of ECoG abnormalities. Long-term follow-up will determine whether only a single stage surgery could improve seizure control and development outcome in children with TSC. However, just as in our reported case, most children with TSC have multiple potentially epileptogenic tubers, and a multistage surgical approach in selected patients should be a reasonable way to control the intractable epilepsy in patients with TSC.9,10
1. Connolly MB, Hendson G, Steinbok P. Tuberous sclerosis complex: a review of the management of epilepsy with emphasis on surgical aspects. Childs Nerv Syst 2006; 22: 896–908.
2. Ahlsen G, Gillberg C, Lindblom R, Gillberg C. Tuberous sclerosis in Western Sweden. A population study of cases with early childhood onset. Arch Neurol 1994; 51: 76–81.
3. Jozwiak J, Jozwiak S, Wlodarski P. Possible mechanisms of disease development in tuberous sclerosis. Lancet Oncol 2008; 9: 73–79.
4. Curatolo P, Bombardieri R, Cerminara C. Current management for epilepsy in tuberous sclerosis complex. Curr Opin Neurol 2006; 19: 119–123.
5. Curatolo P, Bombardieri R, Verdecchia M, Seri S. Intractable seizures in tuberous sclerosis complex: from molecular pathogenesis to the rationale for treatment. J Child Neurol 2005; 20: 318–325.
6. Romanelli P, Verdecchia M, Rodas R, Seri S, Curatolo P. Epilepsy surgery for tuberous sclerosis. Pediatric Neurol 2004; 31: 239–247.
7. Green AJ, Smith M, Yates JR. Loss of heterozygosity on chromosome 16p13.3 in hamartomas from tuberous sclerosis patients. Nature Genet 1994; 6: 193–196.
8. Dabora SL, JoŸwiak S, Franz DN, Roberts PS, Nieto A, Chung J, et al. Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs. Am J Hum Genet 2001; 68: 64–80.
9. Weiner HL, Ferraris BA, LaJoie J, Miles D, Devinsky O. Epilepsy surgery for children with tuberous sclerosis complex. J Child Neurol 2004; 19: 687–689.
10. Weiner HL, Carlson C, Ridgway EB, Zaroff CM, Miles D, LaJoie J, et al. Epilepsy surgery in young children with tuberous sclerosis: results of a novel approach. Pediatrics 2006; 117: 1494–1502.