**1. Introduction**

10 Novel Aspects on Epilepsy

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TSC (OMIM#191100) is an autosomal dominant disorder characterized by a broad phenotypic spectrum including epilepsy, mental retardation, skin lesions and tumors in various organs. The broad phenotypic spectrum reflected the development of hamartomas in multiple organs throughout the body (Schwartz et al., 2008). The incidence of TSC has been reported to be 1 in approximately 6000 (Osborne et al., 1991). However, its true incidence is not known because of a number of undiagnosed cases consisting mostly of mildly affected or asymptomatic individuals (Osborne et al., 1991).

Two-thirds of TSC patients have sporadic mutations and only about one-thirds is familial. The genes in which abnormalities are found are called *TSC1* and *TSC2.* Both genes have been studied by multigenerational linkage analysis (Fryer et al., 1987 and Kandt et al., 1992). *TSC1* is located at position 9q34, and encodes a protein called hamartin, with an mRNA transcript of 8.6 kb containing 23 exons and encompassing 55 kb of DNA (van Slegtenhorst et al., 1997). *TSC2* is located at position 16p13.3, and encodes a protein called tuberin, with an mRNA transcript of 5.5 kb, containing 41 exons and encompassing 40 kb of DNA (Eur TS Consortium, 1993).

#### **2. Clinical diagnosis of tuberous sclerosis complex**

There are major and minor clinical features (Table 1) that enable clinicians to clinically diagnose TSC. The clinical diagnosis is made when two major features, or one major and two minor ones, can be shown (Table 2). Sometimes, an antenatal diagnosis can be made based on fetal ultrasound and MRI, which show cardiac and brain lesions (Roach et al., 1998).

Most patients are diagnosed in infancy or early childhood. A **definitive** diagnosis of TSC can be made when two major features or one major feature plus two minor features are demonstrated (Hyman, 2000 and Roach, 1998). Additional diagnostic categories include **probable** TSC when one major feature and one minor feature are present, and **possible** TSC when either one major feature or two or more minor features are present (Hyman, 2000 and Roach, 1998). However, as hamartomas are individually rare in the population without TSC, the presence of hamartomas in two different organ systems is considered by some clinicians to be sufficient for the diagnosis (O'Callaghan, 2000).

Tuberous Sclerosis Complex 13

95%

Features Description Diagnosis,

Occur in the third and fourth ventricular walls, but most are found in the lateral ventricular walls, near the sulcus terminalis, with their deeper parts embedded in the caudate or thalamus.

This type of tumor develops in approximately 15% of individuals with tuberous sclerosis. Typically, SEGAs do not occur in very young children, and the chance for their growth decreases after age 20.

Rhabdomyomas are benign tumors of striated muscle

Rare lung disease that results in a proliferation of disorderly smooth muscle growth (leiomyoma) throughout the bronchioles, alveolar septa, perivascular spaces, and lymphatics

Renal

angiomyolipoma is a benign neoplasm that may grow massive in TSC patients.

Subependymal nodule (Mennel et al., 2007)

SEGA (Mennel et al., 2007) (SEGAs)

Cardiac rhabdomyoma, single or multiple

Lymphangio myomatosis (Schwartz et al., 2007)

Renal angiomyolipom a (Schwartz et al., 2007)

location

MRI (brain)

Radiography (brain)

Echocardiography

Histologic (lung)

Histologic (kidneys)

Table 1. Major and Minor Features of Tuberous Sclerosis Complex.

Age of

Increases with the age of the patient

Child to adolescent

Grow during the second half of pregnancy and regress after birth

Adolescent to adult

Adolescent to adult

15%

90% (newborn) 20% (adult)

49%

80%

MAJOR FEATURES MINOR FEATURES

onset Prevalence Features Description Diagnosis,

Multiple, 1-2 mm white spots symmetrically distributed over extremities

Like AMLs, they are frequently multiple and bilateral. However, renal cysts are more likely to become symptomatic than AMLs. Polycystic kidney disease may also occur. It is a more severe, distinct entity with innumerable cysts that enlarge, replace renal parenchyma, and cause renal insufficiency and hypertension typically at an early age

Confettilike skin lesions (Mennel et al., 2007)

Multiple renal cysts (Inoue, 1998)

location

Histologic (skin) 2.8%

Histologic (kidney)

Prevalence

17% (children) 47% (adults)


74.5%

15.1%

97.2%

48.1%

Features Description Diagnosis,

Skin-colored or reddish nodules seen on the lateral nail groove, nail plate, or along the proximal nail folds; more commonly found on the toes than on the fingers

Leaf-shaped or polygonal white spots, enhanced by Wood's lamp examination; more common on the trunk and buttocks

Slightly elevated patch or plaque, usually found on the dorsal body surfaces, especially the lumbosacral area; its rough surface resembles an orange peel. Represents a connective tissue nevus, sometimes called collagenoma

Retinal hamartoma is a common finding in tuberous sclerosis, but the symptomatic changes of this lesion have rarely been described.

Cortical tubers are the most characteristic lesions of tuberous sclerosis at pathologic examination. Varying in size from millimeters to several centimeters, tubers are rounded or wartlike protrusions of single or adjacent gyri, very firm to touch and pale in color

lips

Red to pink papules with a smooth surface, symmetrically distributed over the centrofacial areas, sparing the upper

Facial angiofibromas or forehead plaque (Schwartz et al., 2007)

Non-traumatic ungula or periungual fibroma (Schwartz et al., 2007)

Hypomelanotic macules (three or more) (Schwartz et al., 2007)

Shagreen patch (connective tissue nevus) (Schwartz et al., 2007)

Multiple retinal nodular hamartomas (Xu et al., 1995)

Cortical tuber (Mennel et al., 2007)

location

Histologic (head)

Histologic (fingers and toes)

Histologic (skin)

Histologic (skin)

Ocular

MRI (brain)

Age of

Second to fifth year of life; more prominent with age

Puberty or soon after; more common with age

At birth or infancy Earliest cutaneous lesion appeared

Rare during infancy, tend to increase in size and number with age

(eyes) Infancy 9.7%

During fetus development

95%

MAJOR FEATURES MINOR FEATURES

onset Prevalence Features Description Diagnosis,

Dental pits are pits in the enamel of the permanent teeth. They occur more frequently in individuals with TSC than in people who do not have TSC.

These polyps are common and do not cause symptoms. Their distinctive appearance and distribution readily distinguish them from other types of rectal polyp and emphasize their importance as a potentially useful clinical marker of TSC

Most lesions are best seen on proton densityweighted images as bright spots.

These small fibrous nodules of the oral cavity are most commonly evident on the gingiva, especially in the anterior segment of the upper jaw but also on the buccal mucosa and dorsal surface of the tongue.

Homartomatous formation in other organs than the kidney.

Greyish or yellowish-white lesion in the back of the globe on the ophthalmic examination. A differential diagnosis for a calcified globe mass on a CT scan.

Multiple, randomly distributed pits in dental enamel (Mennel et al., 2007)

Hamartomatous rectal polyps (Young & Povey, 1998)

Cerebral white matter radial (Xu et al., 1996)

Gingival fibromas (Mennel et al., 2007)

Non-renal hamartoma (Mennel et al., 2007)

Retinal achromic patch (Mennel et al., 2007)

location

Histologic (rectum) 78%

MRI (brain) 15%

Oral (gums) 32%

CT Scan (eyes) 12%

Histologic ( Liver, spleen)

Direct inspection of the labial surfaces of the incisor and canine teeth

Prevalence

48 - 100%.


Table 1. Major and Minor Features of Tuberous Sclerosis Complex.

Tuberous Sclerosis Complex 15

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

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

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

the frontal or anterior temporal regions.

criteria for resective surgery.

with a known mutation.

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


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

