Effect of Adding Lamotrigine to Sodium Valproate in Childhood Epilepsy: Clinicolabratory Study

Study Overview
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Brief Summary
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Epilepsy is one of the most common serious chronic brain disorders of childhood. The causes of epilepsy include :acquired brain damage, altered metabolic states, inborn brain malformations, and genetic causes. At present, antiepileptic drugs (AEDs) are the first line therapy for resistant epilepsy (RE) , and the second line is surgery , and vagus nerve stimulation . Sodium valproate (SV) is a first line anti epileptic drug that can be applied to various seizure types in children . SV has anticonvulsant activity through regulation of neuronal pathways . It has a molecular structure similar to neurotransmitter γ aminobutyric acid (GABA) resulting in GABA synergism , A serious adverse effect of the valproic acid (VPA) : is its effect on liver function with resultant drug-induced hepatotoxicity, hyperammonemia . Lamotrigine (LTG) is a second generation AED . LTG belongs to the sodium channel blocking class of antiseizure medications (ASMs). Lamortigine side effects include severe rash, fever, lymphadenopathy, hepatic dysfunction, blood disorder,and disseminated intravascular coagulation and Stevens-Johnson syndrome (SJS) . the aim : Evaluation of the efficacy and safety of adding lamotrigine to sodium valproate in epileptic children not responding to SV alone for 6 months. Moreover, the investigators will evaluate the effects of this addition ,appearance of side effects,laboratory evaluation and EEG changes 50 epileptic patients receive SV for 6 months without complete remission for participants, the investigators will add lamotrigine for 6 months.

Detailed Description
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Epilepsy is one of the most common serious chronic brain disorders of childhood. It is characterized by recurrent seizures that can cause motor, sensory, cognitive, psychic, or autonomic disturbances. It has a negative impact on 0.6% of the population in developed countries and 1.6% in developing countries . The causes of epilepsy include :acquired brain damage, altered metabolic states, inborn brain malformations, and genetic causes .. At present, antiepileptic drugs (AEDs) are the first line therapy for resistant epilepsy (RE) , and the second line is surgery , and vagus nerve stimulation . Although the treatment for RE has been continuously updated, the exploration of high efficacy AED combinations is still ongoing . Sodium valproate (SV) is a first line anti epileptic drug that can be applied to various seizure types in children . SV has anticonvulsant activity through regulation of neuronal pathways . It has a molecular structure similar to neurotransmitter γ aminobutyric acid (GABA) resulting in GABA synergism , A serious adverse effect of the valproic acid (VPA) : is its effect on liver function with resultant drug-induced hepatotoxicity, hyperammonemia . Lamotrigine (LTG) is a second generation AED , and also has the function of resisting depression and stabilizing mood . It is applicable for children and adolescents with various seizure types and syndromes due to its good anticonvulsant, tolerance, broad spectrum activity, and safety . LTG belongs to the sodium channel blocking class of antiseizure medications (ASMs). Lamortigine side effects include severe rash, fever, lymphadenopathy, hepatic dysfunction, blood disorder,and disseminated intravascular coagulation and Stevens-Johnson syndrome (SJS) has also been mentioned as a rare hypersensitivity reaction . The aim : Evaluation of the efficacy and safety of adding lamotrigine to sodium valproate in epileptic children not responding to SV alone for 6 months. Moreover, the investigators will evaluate the effects of this addition ,appearance of side effects,laboratory evaluation and EEG changes 50 epileptic patients receive SV for 6 months without complete remission for participants, Investigators will add lamotrigine for 6 months. Setting: single -center study with outpatient from University Children's Hospital , Faculty of Medicine , Assuit University Design of this study :- Cross -sectional interventional. Selected patient for this study will receive additional treatment of LTG with SV for 6 month . Doses of the drugs: Sodium valproate : 30 mg / kg / day , maximum dose 1500mg / day . LTG will be initiated at a daily dose of 0.5 mg/kg for 2 weeks in two divided doses, followed by 1.0 mg/kg/day for an additional 2 weeks,followed by 1.5mg/kg/day for additional 2weeks Thereafter, doses will be increased in 0.5mg/kg/day increments every 2weeks until intolerable adverse effects occurred, or a maximum dose of 3mg/kg/day will be reached . The outcome measures : The outcome measures will be . 1.Clinical measures: -patient will be clinically examined For side effects(body weight ,muscle weakness ,ataxia , hair loss). - The seizure frequency before and after adding lamotrigine. the investigators will exclude patient with allergy to LTG after the first 2 weeks of treatment. 2- Laboratory measures :- -Serum concentration of lamotrigine at the end of study . - The incidence of adverse reactions will be assessed by lab tests as 1. liver function tests. 2.serum ammonia 3. coagulation function 4. complete blood count. 3-Neurophysological evaluation:-EEG will be done at the beginning and end of the study. Inclusion criteria : 1. Male or female, ages 2 - 12years. 2 . 50 epileptic children on sodium valproate for 6 months without complete remission. Exclusion Criteria: Subjects will be excluded if any of the following criteria are met:- Suspected other neurological disorders . Allergic to LTG. Liver dysfunction. kidney dysfunction . Not cooperating with this study

Official Title
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Effect of Adding Lamotrigine to Sodium Valproate in Childhood Epilepsy: Clinicolabratory Study

Conditions
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Epilepsy, Lamotrigine, Sodium Valproate Adverse Reaction

Intervention / Treatment
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* Drug: Sodium Valproate 500 Mg Prolonged-Release Oral Tablet
* Drug: Lamotrigine
* Device: E.E.G


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, ages 2 - 12years. 50 epileptic children on sodium valproate for 6 months without complete remission. Exclusion Criteria: other neurological disorders . Allergic to LTG. Liver dysfunction. kidney dysfunction . Not cooperating with this study

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: 50 epileptic patients receive SV for 6 months , for whom add lamotrigine for 6 month<br>50 epileptic patients receive SV for 6 months at dose 30 mg.kg.day, for whom add lamotrigine for 6 month at dose 0.5 mg.kg.day then add 0.5 mg.kg.day every 2 weeks | Drug: Sodium Valproate 500 Mg Prolonged-Release Oral Tablet<br>* sodium valproate tablet30 mg / kg / day , maximum 1500mg / day . LTG :<br>Drug: Lamotrigine<br>* lamotrigine tablet 0.5 mg/kg for 2 weeks in two divided doses , increased in 0.5mg/kg/day increments every 2weeks .<br>Device: E.E.G<br>* device recording of brain activity. During this painless test, small sensors are attached to the scalp to pick up the electrical signals produced by the brain. These signals are recorded by a machine and are looked at by a doctoris<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Weight | Weight in kilogramme will be measured in 50 participants | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| liver function tests | blood tests that measure different enzymes, proteins, and other substances made by the liver.The liver function tests typically include alanine transaminase (ALT) and aspartate transaminase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), serum bilirubin, prothrombin time (PT), the international normalized ratio (INR), total protein and albuminALT. 7 to 55 units per liter (U/L) AST. 8 to 48 U/L. ALP. 40 to 129 U/L. Albumin. 3.5 to 5.0 grams per deciliter (g/dL) Total protein. 6.3 to 7.9 g/dL. Bilirubin. 0.1 to 1.2 milligrams per deciliter (mg/dL) GGT. 8 to 61 U/L. LD. 122 to 222 U/L. | 6months | 
| serum ammonia. | An ammonia test measures the amount of ammonia in the blood , Ammonia level normal range is usually : 170-340 mcg/dL in new-borns, 70-135 mcg/dL in children , Ammonia Colorimetric Assay Kit will be used for assessment of serum ammonia levels | 6months | 
| complete blood count | complete blood count, or CBC, is a blood test that measures many different parts and features of blood, including red blood cells, white blood cells, and platelets | 6 months | 
| E.E.G | E.E.G power in alpha band ,device recording of brain activity. During this painless test, small sensors are attached to the scalp to pick up the electrical signals produced by the brain. These signals are recorded by a machine and are looked at by a doctorisThe most commonly studied waveforms include delta (0.5 to 4Hz); theta (4 to 7Hz); alpha (8 to 12Hz); sigma (12 to 16Hz) and beta (13 to 30Hz). In addition, there are other waveforms such as infra slow oscillations (ISO) (less than 0.5Hz) and high-frequency oscillations (HFOs) (greater than 30Hz) which are outside the conventional bandwidth of clinical EEG but have recently found clinical importance with the adven | 6months | 
| Serum concentration of LTG | The serum concentration should be interpreted in the context of the patient's clinical response and may provide useful information in patients showing poor response, noncompliance, or adverse effects, particularly when lamotrigine is coadministered with other epileptic drugs. | 6 months |