Immunoglobulin And Effective Treatments Of Epilepsy

Published Date: 02 Nov 2017

Omar Garcia

Biochemistry 362-1

[email protected]

Introduction

Immunoglobulin are glycoproteins involved with immune response of different organism in order to eliminate any foreign substances, which can cause infections and diseases. They are also known to be antibodies produced by the immune system, and can act as an enzyme. The group of proteins are part of a larger group of protective proteins with an addition of like lymphocyte antigen-recognizing receptors found in our nervous system. There are more protective proteins such as blood clotting protein, such example as fibrin and thrombin. Immunoglobulin is important in biochemistry, it discuss basic structure and chains and variable region sequences of amino acids can vary in different class of immunoglobulin. Immunoglobulin classes can have different effects on a patient of their immune response from any particular organisms invading. Immunoglobulin are antibodies responsible for fighting off any infections either bacterial or viral, can impact from infants to adult different diseases and different reaction of the body responsiveness.

There is no absolute proof efficiency of IVIg can cure epilepsy, but it considered to be an effective treatment when it comes to improvement, and a safe add-on medication for epilepsy patients. There has been studies on cerebrospinal fluid IgG concentration before and after IVIg treatment of epilepsy, concluded IVIg preparation crosses blood CSF barrier allowing increase of IgG concentration to reach the brain and act centrally. Studies show immunogenetic mechanism plays a role for triggering and maintaining epilepsy.

Seizure epilepsy are most common neurological disorders affecting millions of children and adults worldwide. Scientist hypothesized that some form of epilepsy could have an autoimmune component, in which association of antibodies is directed towards antigens on neuronal cell surface. Often disorder is located mainly at the temporal lobe, and at some point it involvement with cortex in which can cause severe memory impairment and disturbance of mood. As years pass by there has been significant increase of temporal lobe disorders, very often temporal lobe seizure occurred. The temporal lobe has an association with antibodies to molecules on neuronal membranes, the molecules contain extracellular domains that allows antibodies to bind. A perfect method for measuring the level of antibodies is the demonstration of immunoglobulin G in short terms IgG, which binds to cell surface that has been transfected with complementary deoxyribonucleic acid for targeting molecules.

Antibodies may target the following voltage gated potassium channel complex, along with a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, or y-amino butyric acid receptor (Irani et al., 2010). The complex of VGKC antibodies are measured by immunoprecipitation of VGKC Kv1 subunits soluble detergent from brain tissue of an animal rabbit and is labeled by I-dendrotoxin in which can be found in toxins of a snake, and will bind to Kv1.1, 1.2, and 1.6. The associated molecules that were so far identified are LGI1 and CASPR2, a large significant number of patient with limbic encephalitis and temporal lobe epilepsy reported having antibodies to LGI1. The male patients are greatly affected then females, having their disease onset is older the age of 50 years old.

Many patients reported having high complex VGKC antibodies found to have faciobrachial dystonic seizure in short terms FBDS, within the development of temporal lobe seizures along with other features of limbic encephalitis (Lai et al., 2010). There has been cases main specific target was LGI1in which one had contactin-2 antibodies and two additional antibodies of CASPR2. Patients with FBDS tend to experience seizures a median of 50 attack per day. Identifying FBDS as a seizure hallmark complex of VGKC antibody disease mediated is a clinically important.

There are other antibodies that target patients with limbic encephalitis and or temporal lobe seizures are referred to GABA receptor and the AMPA receptor. Antibodies that are present at the extracellular region of GABA receptor reports 15 patients having refractory temporal lobe seizures as well as limbic dysfunction. There were cases of 7 patients diagnosed with tumors, out of those 7 only 5 were small cell lung cancer. Many patients that received immunotherapy, with tumor treatment results showed neurologic improvement in contrast to those untreated patients.

The results of patients who has limbic encephalitis with appropriate antibodies toward the AMPA receptor, the number of seizure is significally decreased. Studies show that only three of ten patients had seizures as early symptom, and only one patient had seizures after a relapse (Lai et al., 2009). There are more experimental test to be performed on patients with seizure epilepsy, and again seizure epilepsy is present at the temporal lobe of the human brain that controls behavior, and memory.

Research Design & Methods:

Immunoglobulin & effective treatments of epilepsy:

Steroids: Steroids are also known as corticosteroids, and glucocorticoids. They are taken either orally or injected into patients. Steroids exert important anti-inflammatory & immunosuppressive effects, and will most likely have long term side effects.

Immunoglobulin (Ig): Immunoglobulin are large glycoprotein that are secreted from the plasma cells in vertebrates and are well known as antibodies in the immune system. Different class of immunoglobulin are IgA, IgD, IgE, IgG, & IgM.

Specific aim 1. Determine the effects of immunoglobulin and steroid treatment together to combat seizure epilepsy.

Rationale: In order to determine effectiveness of steroids & immunoglobulin together, they must suggest dosage of three to five consecutive infusion of 0.4g/kg/day (Bien et al., 2005). This must proceed monthly does of 0.4/kg/day over a course of one through five consecutive days for human adults, and may vary for children.

Anticipated preliminary results:

It�s expected that there will be a large reduction of seizure greater than 52%, and less than 23% remission were reported in the 368 patients in which have been treated with (IVIG). There has been reports of a decrease in frequency and severity of seizure in children with epilepsy whom were treated with Ig. Steroids has been known to treat not only epilepsy, but also to rescue developmental regression. Steroids can have short and long term side effects, such as irritability, weight gain, hypertension, infection, gastric irritation, and Cushing�s syndrome. Long term effects can include osteoporosis, impairment of growth, and adrenal suppression.

Immunoglobulin treatment has impacted beneficial effects on epileptic seizures, and reports show a decrease of frequency and severity on children with epileptic seizure treated with Ig for recurrent upper respiratory tract infections. The overall mean seizure reduction is 52% and a 23% remission reported out of 368 patients, whom has been treated with intravenous IVIG Ig administration. Other studies included 43 patients with different types of epilepsies and out of those 43 patients only 18 were controlled with different doses of IVIG a responder and non-responder ratio was significantly higher in treated group. The only differences shown in these studies was the statically significant subgroup of patients with partial epilepsies, not full (van Rijckevorsel-Harmant et al., 1994).

Further research has been conducted and results were reported the population of patients with IS and or LGS, LKS, and CSWS with epilepsies, RE and other types of paraneoplastic and nonparaneoplastic autoimmune encephalitis is officially defined as limbic encephalitis. Intravenous Ig could have an immunorestorative effect when alteration of kinetics of expression of disease related autoAbs (Dietrich et al., 1992). The effect of clinical IVIG is directly correlated due to alteration of immunologic and inflammation markers, but their interpretation is equivocal and interferences variety factors can�t be ruled out. It�s strongly recommended to use a combination of IVIG with steroids as a first line therapy in late onset RE for adults, and as a third line therapy RE in childhood onset. Studies show it�s highly recommended to start dosage within three to five consecutive infusion of 0.4g/kg/ a day and with a continuous monthly dosage of 0.4-2.0g/kg distributed over one thru five days (Bien et al., 2005).

There are other types of epilepsies in their pathogenetic role of immune mediated mechanism is less clear, and all other studies with IVIG demonstrates a beneficial effect in a substantial percentage of pharmacoresistant patients which supports experimental evidence of role played by inflammatory and immunological mechanism in seizure epilepsy. A published guidelines of the European federation of neurological societies included information related to drug resistant epilepsy of childhood, and among the 12 neurological disorders where IVIG is administrated. The recommended dosage is somewhat similar to the one for RE which involves taking 0.4g/kg for 5 days at a 4 week intervals every month. Treatments are effective, with a side effect of a headache occurred in 30% of patients. In rare cases a 4% of patients were reported with severe side effect which includes thrombosis of the jugular vein, allergic reaction, and retrosternal pressure leading to discontinued treatment. There were no significant changes in blood work, but it�s mandatory for monitoring of laboratory findings.

Many researchers ask if applying steroids with IVIGs could be a possible treatment in epilepsy syndrome, or worst case scenario probable cause of autoimmune disease. Due to multiple questions regarding IVIG treatment for epilepsy, it would be crucial to carefully evaluate dosage and administration interval on adults and children patients. This experiment show great results and could possibly be a ground break cure for seizure epilepsy, although there are downsides of IVIG and steroids causing severe damages to patients in which these treatments are not for all patients.

At 1942 the first report use of steroids in epilepsy was based on observations of individual patients with epilepsy had provoking seizures with an increase water intake and administration of antidiuretic hormones in short terms ADH. Eight years pass by six patients were reported, they were treated with adrenocorticotropic hormone in short term ACTH hoping to seek treatment that produce metabolic effects similar to ketogenic diet. By in taking ACTH is not known to be a true mechanism, but had a positive effect on 4 of the 6 children with seizure epilepsy (Klein & Livingston, 1950). The use of steroids for treatment of epilepsy includes ACTH, prednisolone, prednisone and hydrocortisone. ACTH is not categorized as a steroid rather it�s a 39 amino acid polypeptide secreted from anterior pituitary gland, and releases a stimulate the adrenal gland for a production of glucosteroid cortisol. Steroids are useful and releases anti-inflammatory and immunosuppressive effect, but will cause short and long term side effects. Short term effect includes weight gain, irritability, glucose intolerance, hypertension, gastric irritation, common infection and Cushing�s syndrome. Long term effect poses a greater and permanent effect on patients which may include growth impairment, osteoporosis, and adrenal suppressant.

Steroid could possibly benefit throughout variety of childhood epilepsy, but evidence to support this treatment is variably dependent with patients on the syndrome and it very limited in most situation. Steroids has been reported in the treatment of nonconvulsive status epilepticus known as NCSE. The only drawback is evaluating the condition to be treated at the outset, it may be beneficial not a guarantee. NCSE patient�s shows behavioral changes and responsiveness compared to baseline, with EEG alteration activity showing continuous epileptic discharges. The use of steroids to treat NCSE can result in beneficial effect on clinical state and EEG. The use of steroids in drug resistant epilepsies bring variable benefit, but in some patients they were marked heterogeneous and positive effect lasted only a short amount time in most cases.

Many people has debated the mechanism of steroids in the treatment of epilepsies. Many has hypothesized immunosuppressant and anti-inflammatory effect, and the suppression of corticotropin releasing hormone known as CRH level in the central nervous system are thought to have anticonvulsant action with a decreasing neuronal excitability. Researchers proposed a study that steroids may have a direct effect on y- amino butyric acid known as GABAA receptors and possibly enhancing action of neurosteroids. Many has reported ACTH to be more effective treatment for epilepsy instead of steroids, probably due to less direct effect through activation of central melanocortin receptors (Vigevano & Cilio, 2009).

A compound related to neurosteroid allopregnanolone and a positive allosteric modulator of GABA receptors is known as Ganaxolone was evaluated in epilepsy. Ganaxolone and steroids both has similar effect on the central nervous system, the only exception is not the peripheral side effects. The use of steroids has been somewhat effective towards treating difficult epilepsies in order to reduce seizures, and stopping the developmental progression.

Abstract