**3. Epilepsy in tuberous sclerosis complex**

Epilepsy was once included in tuberous sclerosis triad along with mental retardation and adenoma sebaceum (Provenzale, 1991). Although removed from the diagnostic criteria, epilepsy remains a dominant feature in tuberous sclerosis, covering up to 60% - 90% of TSC cases. Genetic factors play important contributions in the manifestation of epilepsy in TSC. It has recently been described that inactivation of *TSC2* causes more severe epilepsy phenotype than inactivation of *TSC1* in a mouse model of tuberous sclerosis and suggested that the difference in phenotype may be related to the degree to which *TSC1* and *TSC2*  inactivation causes abnormal mTOR activation (Zheng, 2010).

Based on clinical features alone, TSC patients may experience a wide variety of ictal symptoms. Two syndromes are usually noted: infantile spasms (Christophea et al., 2000), which then evolve into partial or mixed epilepsies (Dabora et al., 2001) and partial seizures, typically starting later in childhood. The high incidence of infantile spasms in TSC has long been emphasized. Infantile spasms have been reported to be the presenting symptoms in up to 69% of patients with TSC. Infantile spasms in TSC usually have their onset between 4 to 6 months of age (Curatolo et al., 2001 and Fukushima et al 2001). TSC has been found in 7%– 25% of infants with symptomatic West syndrome. West syndrome classically consists of the clinical-electroencephalographic triad of spasms (the seizure type), hypsarrhythmia and mental deficiencies. The main types of spasms (flexor, extensor, mixed) may occur in infant with TSC, but focal features such as head turning, nystagmus, tonic eye deviation or unilateral limb movement differentiate them from classical infantile spasms. Partial seizures predominate with the increasing age (Curatolo, 2001 and Jambeque et al., 1991).

Location of tubers on MRI often correlates with EEG discharges. Tubers consist of dysplastic neurons and glial cells that distort the normal cortical architecture, causing them to be highly epileptogenic (Christopher et al., 2000). Jambaque and collegues found that an initial presentation with infantile spasms, refractory seizures and mental retardation or behaviour

Definite TSC Either two major features or one major plus two minor

Possible TSC Either one major features or two or more minor features

a. Multiple Endocrine Neoplasia type I (MEN-I) in which multiple angiofibromas, confetti-like hypopigmented macules, and multiple gingival papules are also seen. b. Hypopigmented macules in TSC resemble nevus anemicus and nevus depigmentosus. c. Renal Carcinoma may also be caused by mutations within VHL (cause VHL disease) or MET (cause HPRC) genes, although with different pathologic findings. The renal cell carcinomas in TSC are morphologically heterogenous, including clear cell, papillary, and chromophobic tumors. VHL patients almost exclusively develop clear cell

carcinoma, while HPRC patients develop almost exclusively papillary tumors.

Epilepsy was once included in tuberous sclerosis triad along with mental retardation and adenoma sebaceum (Provenzale, 1991). Although removed from the diagnostic criteria, epilepsy remains a dominant feature in tuberous sclerosis, covering up to 60% - 90% of TSC cases. Genetic factors play important contributions in the manifestation of epilepsy in TSC. It has recently been described that inactivation of *TSC2* causes more severe epilepsy phenotype than inactivation of *TSC1* in a mouse model of tuberous sclerosis and suggested that the difference in phenotype may be related to the degree to which *TSC1* and *TSC2* 

Based on clinical features alone, TSC patients may experience a wide variety of ictal symptoms. Two syndromes are usually noted: infantile spasms (Christophea et al., 2000), which then evolve into partial or mixed epilepsies (Dabora et al., 2001) and partial seizures, typically starting later in childhood. The high incidence of infantile spasms in TSC has long been emphasized. Infantile spasms have been reported to be the presenting symptoms in up to 69% of patients with TSC. Infantile spasms in TSC usually have their onset between 4 to 6 months of age (Curatolo et al., 2001 and Fukushima et al 2001). TSC has been found in 7%– 25% of infants with symptomatic West syndrome. West syndrome classically consists of the clinical-electroencephalographic triad of spasms (the seizure type), hypsarrhythmia and mental deficiencies. The main types of spasms (flexor, extensor, mixed) may occur in infant with TSC, but focal features such as head turning, nystagmus, tonic eye deviation or unilateral limb movement differentiate them from classical infantile spasms. Partial seizures

predominate with the increasing age (Curatolo, 2001 and Jambeque et al., 1991).

Location of tubers on MRI often correlates with EEG discharges. Tubers consist of dysplastic neurons and glial cells that distort the normal cortical architecture, causing them to be highly epileptogenic (Christopher et al., 2000). Jambaque and collegues found that an initial presentation with infantile spasms, refractory seizures and mental retardation or behaviour

Table 2. Clinical Diagnosis of TSC. There are several differential diagnosis of TSC :

features

Probable TSC One major plus one minor features

Clinical Diagnosis Characteristic

**3. Epilepsy in tuberous sclerosis complex** 

inactivation causes abnormal mTOR activation (Zheng, 2010).

disorder were all more likely in children with greater numbers of cortical tubers. The classic interictal EEG pattern of patients with epileptic spasm is hypsarrhythmia. Hypsarrhythmia was originally defined by Gibbs and Gibbs in 1950 as completely chaotic and disorganized background pattern consisting of high amplitude slow waves and spikes that are asynchronous, non-rhythmic and variable in duration and topography. The spikes usually alternate randomly between focal, multifocal and generalized discharges at different moments within a brief record. It is most pronounced in slow-wave sleep. Ictal recordings of spasms can demonstrate a focal increase in spikes and polyspikes at the onset, with an abrupt generalized slow followed by electro decrement or generalized lower amplitude fast activity coincident with the spasm itself. Curatolo has theorized the following sequence of events. Electrographic onset of spasms is more common from the posterior temporal and occipital regions than from other locations. Subsequent partial seizures tend to arise from the frontal or anterior temporal regions.

Drug selection should be tailored to both clinical and EEG attributes observed. Antiepileptic drug monotherapy is used whenever possible. Vigabatrin may be especially effective for infantile spasms in patients with TSC, with some series reporting complete control occurring in about 95% of patients (Aicardi, 1996 and Hancock, 1999). Vigabatrin produces its antiepileptic effect by irreversibly inhibiting the enzyme GABA-aminotransferase. This results in increased brain and spinal fluid concentration of the inhibitory neurotransmitter GABA. Unfortunately, recent reports of visual-field constriction associated with vigabatrin therapy may limit its use and may prevent from becoming an approved treatment in United States and other countries (Krauss et al., 1998). Other evidence from randomized controlled studies includes using ACTH and corticosteroids for infantile spasms. Chronic use of benzodiazepines and barbiturates should be avoided if possible owing to their cognitive and behavioural adverse effects. Other medications useful to treat seizures in TSC include lamotrigine, felbamate, topiramate, carbamazepine and levetiracetam. When anticonvulsant options have been exhausted, alternative treatment such as ketogenic diet may be tried. If severely disabling seizures are present with consistent electroclinical and imaging data suggesting a confined area of seizure onset, surgical treatment should be considered. The most common surgical procedures offered to TSC patient include topectomies, gyrectomies or wider lobar resection as well as multiple subpial transection. Vagal nerve stimulation is a surgical option restricted to TSC patients with intractable epilepsy who fail to meet the criteria for resective surgery.

#### **4. Molecular diagnosis of tuberous sclerosis complex**

Despite the comprehensive criteria for clinical diagnosis of TSC, molecular analyses of both causing genes remain of importance. Mutation analysis in TSC patients is useful 1) to confirm a clinical diagnosis of TSC, especially in young patients in whom many clinical features have yet to develop, 2) in families with sporadic cases of TSC, mutation analysis may provide reassurance that the rest of the family members do not carry the mutation. However, such testing does not provide complete reassurance in regard to the possibility of having the second child with TSC, even when the parents do not appear to carry the mutation, and 3) to perform prenatal diagnosis, in families with either a child or a parent with a known mutation.

Tuberous Sclerosis Complex 17

\*R/C = Reported/Concluded. "Reported Pathogenicity" refers to the pathogenicity as published by the authors in the original paper or as submitted to the LOVD-TSC database if the data has not been published. "Concluded Pathogenicity" refers to the pathogenicity that the curators of the database have assigned to the variant. (Personal Communication with the LOVD-TSC Database Curator; Dr. Rosemary Ekong). "-" = no known pathogenicity; "-?" = probably no pathogenicity; "+" = pathogenic; "+?" =

In *TSC1*, the most prevalent types of variations found are substitution (49.8%) followed by deletion (34.4%). Of 468 unique variations reported in *TSC1*, 73.5% (344) had their pathogenicity determined. In *TSC2*, the most prevalent types of variations found are also substitution (68.7%) followed by deletion (16.9%). Of 1222 unique variations reported in *TSC2*, only less than half (48%) had their pathogenicity determined. Different gene sizes of *TSC1* and *TSC2* may explain the fact that more variations occurred in *TSC2* than in *TSC1.*

probably pathogenic; "?" = unknown pathogenicity.

Table 4. *TSC2* sequence variations and their pathogenicity.

Substitution Insertion Deletion DuplicationInsertion /


Deletion **Total** 

Types

Pathogenicity (R/C)\*
