**7. Studies on therapeutics options for TSC**

At present, the management of TSC is symptomatic. Some of TSC manifestations have been subjected to drug therapies but they are still in the developmental stage (Yates et al., 2006). Table 5 summarized several drugs under investigation for their efficacy towards Tuberous Sclerosis Complex.

The discovery of mTOR (mammalian target of rapamycin) pathway upregulation in tuberous-sclerosis-associated tumours presents new possibilities for treatment strategies. A TSC mouse treated with rapamycin, also known as sirolimus, was found to have its learning and memory deficits improved (Ehninger et al., 2008).

Sirolimus is a macrolide antibiotic that acts as an mTOR kinase inhibitor. It is isolated from *Streptomyces hygroscopicus*. Sirolimus and its analogs have been shown to make the dysregulated mTOR pathway return to normal in cells that lack *TSC1* or *TSC2*. Several results from in-vitro or in-vivo animal studies suggest that sirolimus or its analogues might be effective in the treatment of various manifestations of tuberous sclerosis such as skin lesions (Rauktys et al., 2008), lymphangioleiomyomatosis (Goncharova et al., 2006 and Bissler et al., 2008), renal angiomyolipomas (Lee et al., 2006; Herry et al., 2007 and Wienecke et al., 2006), renal-cell carcinoma (Robb et al., 2007), subependymal giant-cell astrocytomas (Franz et al., 2006) or even polycystic kidney disease (Weimbs et al., 2006).

However, angiomyolipomas increased in volume after the therapy was discontinued, and some patients taking sirolimus experienced serious adverse events (Bissler et al., 2008; Herry et al., 2007 and Wienecke et al., 2006).

Recently, other classes of drugs have also been found to be possible therapeutic options for TSC. Interferon gamma and interferon alpha interact with mTOR, leading to deactivation of the translational repressor 4E-BP1, which could be beneficial for the treatment of tuberous sclerosis (Kaur et al., 2007). Other classes of drugs ranging from those which can alter amino acids metabolism, inhibit VEGF signalling and inhibit microtubules were also studied. Presence or absence of amino acids is an important regulator of mTOR pathway signalling (Avruch et al., 2006).

For example, L-asparaginase, a hydrolase enzyme and one of the most important agents used in multidrug chemotherapy for the treatment of cancer. It is mainly used to treat human leukemic cells in acute lymphoblastic leukemic. L-asparaginase has been found to


Table 5. Potential drugs under investigations for the therapy of TSC.

Tuberous Sclerosis Complex 23

reduce the levels of mTOR pathway's target p70 S6 kinase and 4EBP-1 (Iiboshi et al., 1999). The reduction indicates that L-Asparaginase can be a possible therapeutic option for TSC. VEGF is thought to play important role in the pathogenesis of TSC since tumors associated with TSC are vascular. *TSC2* has also been found to have association with increased levels of VEGF in cultured cells (Brogarolas et al., 2002). Since VEGF signalling is important in the TSC pathogenensis, combination of VEGF inhibitors with mTOR inhibitor analogs may

Sorafenib is one of VEGF inhibitors. It is an oral targeted kinase inhibitor that blocks VEGF-R. In TSC tumor preclinical study by Lee and colleagues, combination of Sorafenib and Sirolimus was found more effective than single agent (Lee et al., 2009). Other VEGF inhibitor is Sunitinib which also inhibit platelet derived VEGF-R. It is a receptor tyrosine kinase inhibitor. Bevacizumab, a recombinant humanised monoclonal antibody, is also a VEGF-R inhibitor. Both Sunitinib and Bevacizumab produce inhibitory effects to VEGF-R signalling

Fig. 2. Interaction of possible therapeutic options with various pathways in TSC pathogenesis (http://www.genome.jp/dbget-bin/www\_bget?map04150).

provide a promising treatment.

**8. Abbreviations** 

4E-BP1 : 4E Binding Protein 1

AML : angiomyolipoma DNA : deoxyribonucleidc acid EEG : Electroencephalography ERM : Exin-radixin-moesin

ACTH : adrenocorticotrophic hormone

pathway and may be useful for TSC treatment.

Table 5. Potential drugs under investigations for the therapy of TSC.

reduce the levels of mTOR pathway's target p70 S6 kinase and 4EBP-1 (Iiboshi et al., 1999). The reduction indicates that L-Asparaginase can be a possible therapeutic option for TSC.

VEGF is thought to play important role in the pathogenesis of TSC since tumors associated with TSC are vascular. *TSC2* has also been found to have association with increased levels of VEGF in cultured cells (Brogarolas et al., 2002). Since VEGF signalling is important in the TSC pathogenensis, combination of VEGF inhibitors with mTOR inhibitor analogs may provide a promising treatment.

Sorafenib is one of VEGF inhibitors. It is an oral targeted kinase inhibitor that blocks VEGF-R. In TSC tumor preclinical study by Lee and colleagues, combination of Sorafenib and Sirolimus was found more effective than single agent (Lee et al., 2009). Other VEGF inhibitor is Sunitinib which also inhibit platelet derived VEGF-R. It is a receptor tyrosine kinase inhibitor. Bevacizumab, a recombinant humanised monoclonal antibody, is also a VEGF-R inhibitor. Both Sunitinib and Bevacizumab produce inhibitory effects to VEGF-R signalling pathway and may be useful for TSC treatment.

Fig. 2. Interaction of possible therapeutic options with various pathways in TSC pathogenesis (http://www.genome.jp/dbget-bin/www\_bget?map04150).

#### **8. Abbreviations**


Tuberous Sclerosis Complex 25

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**3** 

**Daytime Sleepiness and Changes of** 

*I st Department of Neurology University Hospital of Medical Faculty,* 

It is well known, that patients with epilepsy suffer from excessive daytime sleepiness, fatigue and insufficient sleep. These problems are often overlooked or referred to epileptic seizures or antiepileptic drugs. It should be noticed, that patients with epilepsy suffer from sleep disorders more often than general population (Bazil 2003). Health outcome of patients with comorbidity of epilepsy and sleep disorders is worse as sleep disorders may aggravate epilepsy. Changes in amount and severity of epileptic seizures may lead to pharmacoresistency of epilepsy in patients with untreated sleep disorders. That is the reason why attention to quality of sleep and daytime vigility in patients with epilepsy should be payed. The cooperation of neurologist, pneumologist, somnologist and psychologist is very

Daytime sleepiness is defined as the inability to stay awake during waking episodes of the day. It results in unintended lapses into drowsiness or sleep. Sleepiness occurs mainly in boring situations. Sometimes it is associated with increase of total amnount of sleep without feeling of restoration. In most cases excessive daytime sleepiness (EDS) is a chronic symptom and it must occur for at least three months prior to diagnosis (ICSD-2, 2005). Excessive daytime sleepiness is often result of self-imposed sleep deprivation espetially in young people. More often it is effect of disturbed nocturnal sleep or misaligned circadian rhytms. It may be side effect of many often-used drugs, for example hypnotics or alcohol. Nocturnal sleep disturbances, which lead to EDS, should be carefully assessed and treated. In several conditions EDS is not an outcome of night-sleep loss and should be considered as primary hypersomnia of central origin. These hypersomnias according to ICSD-2 include narcolepsy with or without cataplexy, recurrent hypersomnia, idiopathic hypersomnia with or without long sleep time and hypersomnias due to different medical and neurological conditions. Narcolepsy with cataplexy is characretized with daytime sleepiness and unwanted episodes of sleep, which occur several times a day. The duration of episodes may vary from a few minutes to more than an hour, patients wake up refreshed. Cataplexy is paroxyzmal, abrupt and reversible loss of muscule tone often elicited with emotional experience. Manifestations of disociated REM sleep (sleep paralysis and hypnagogic halucinations) are also exposed (Chokverty, 1994). Narcolepsy without cataplexy is associated with snoozing in daytime, sleep paralysis and hypnagogic hallucinations may occur. Secondary narcolepsy may be caused by tumors of brain or multiple sclerosis, if

important in correct management of patients with epilepsy and sleep disorders.

**1. Introduction** 

 **Sleep in Patients with Epilepsy** 

Katarína Klobučníková and Branislav Kollár

*Comenius University,Bratislava,* 

*Slovak Republic* 

J.B., Ward, S., Green, A.J., Yates, J.R., Kwiatkowska, J., Henske, E.P., Short, M.P., Haines, J.H., Jozwiak, S. & Kwiatkowski, D.J. (1997). Identification of the tuberous sclerosis gene, *TSC1* on chromosome 9q34, *Science,* 277(5327):805-8.

