Comparative Study of Dietary and Immunological Management of Refractory Epilepsy in Children
Comparative Study of Dietary and Immunological Management of Refractory Epilepsy in Children
1. Comparison of the efficacy of Rituximab and ketogenic diet in controlling refractory
 seizures versus the traditional lines as corticosteroid and trace elements.

 2. Improving the management of children with refractory seizures
1. Definition of refractory epilepsy

 A task force of the International League Against Epilepsy proposed that drug-resistant
 epilepsy be defined as failure of adequate trials of two tolerated and appropriately
 chosen and used antiseizure drug schedules (whether as monotherapies or in combination)
 to achieve sustained seizure freedom (1)

 . This requires application of the intervention at adequate strength/dosage for a
 sufficient length of time (2)..Terms refractory" intractable", drug-resistant"
 pharmaco-resistant" have been used interchangeably in several documented literature in
 different time periods (3). The first antiseizure drug fails in 20 to 40 percent of
 children with epilepsy; lack of efficacy and side effects contribute to treatment
 failure (4)

 Epidemiology About 10-20 % children with epilepsy develop drug refractory epilepsy
 (5).In a systematic review of 35 observational studies that included over 13,000
 patients with epilepsy and 3900 patients with drug resistant epilepsy( DRE), the pooled
 prevalence of (DRE) was 30 percent, and the pooled incidence proportion was 15 percent
 (6).

 Risk factors

 - A high number of seizures prior to diagnosis and treatment

 - Genetic or inherited syndromes, for both generalized and localization-related
 epilepsy, have a better prognosis than symptomatic/cryptogenic epilepsy in both
 pediatric and adult populations (7).

 -  Localization-related epilepsy underlies more than half of the cases of DRE in
 children (8,9).

 -  Other findings more variably associated with the risk of DRE include a presentation
 with status epilepticus , a longer duration of epilepsy , a family history of
 epilepsy , a history of febrile convulsions , abnormal ( ELECTROENCEPHALOGRAM ) EEG
 findings . An abnormal neurologic examination and/or developmental delays (10,11).

 -  Some pediatric studies have found that seizure onset in later childhood or
 adolescence appears to be more likely to be associated with DRE than seizures with
 onset between the ages of 5 and 10 years (12).

 Causes (13,14 ) Epilepsy syndromes

 Infancy

 • Epilepsy of infancy with migrating focal seizures

 -  West syndrome

 -  Dravet syndrome

 -  Doose syndrome

 Childhood

 -  Lennox-Gastaut syndrome

 -  Epileptic encephalopathy with continuous spike and wave during sleep

 Metabolic

 • Pyridoxine dependent epilepsy

 • Biotinidase biosynthesis deficiency

 • Organic acidemia

 • Urea cycle disorders

 • Non-ketotic hyperglycinemia

 -  Aminoacidopathies

 -  Mitochondrial disorders including Alpers syndrome

 -  Hashimoto encephalopathy

 Structural Abnormality

 • Malformations: Neuronal migration defects and neural tube defects

 • Neurocutaneous syndromes

 ,

 Infectious/Inflammatory:

 ,

 • Hypoxic ischemic encephalopathy,

 • Rasmussen encephalitis

 -  Stroke

 -  Tumors

 -  Mesial temporal sclerosis

 Autoimmune epilepsies

 : N-methyl-D-aspartate receptor(NMDAR),

 Connective tissue disorders

 • Systemic lupus erythematosus,

 • Wegener's granulomatosis

 -  , sarcoidsosis,

 -  celiac disease,

 -  Crohn's disease,

 -  Behcet's

 -  Sjorgren's syndrome,

 EVALUATION

 A- History and presentation :

 The approach depends upon age of onset, accurate description: pre-ictal, ictal,
 postictal events, precipitating events, seizure types, evolution relation to fever,
 previous history of febrile seizures (simple/complex), associated non-epileptic events,
 intake of (ANTI EPILPTIC DRUGS )AEDs with dose, developmental history, sleep history,
 detailed birth and peri-/antenatal history etc.

 B-Clinical examination depends upon anthropometry, syndromic facial dysmorphism,
 neurocutaneous features and detailed neurological and systemic assessment

 C- Pseudo-refractoriness indicates a condition in which seizures persist because the
 condition has not been adequately treated. The most common causes of pseudo refractory
 epilepsy include

 1. Inappropriate diagnosis

 -Cardiogenic (arrhythmias) and vasovagal events (syncope)

 -  Parasomnias

 -  Movement disorders (paroxysmal dyskinesias, cataplexy)

 -  Psychogenic nonepileptic seizure (PNES) can mimic epileptic seizures. , do not
 respond to antiseizure drug therapy.

 While not without limitations, video-EEG monitoring is the gold standard test for the
 diagnosis of PNES

 2. Bad compliance ; Missed dose

 3. Incorrect drug An incorrect diagnosis of seizure classification leading to incorrect
 drug choice It is not uncommon for diopathic generalized epilepsy syndromes to be
 unrecognized and inappropriately treated with antiseizure drugs that are more
 appropriate to localization-related epilepsy .

 4. Inadequate dosage

 5. Inadequate frequency

 6. Enzyme induction, especially if more than one antiepilptic drug AED or other medication
 is used

 7. Inadequate anticonvulsant therapy

 D-Investigation for the patients include;

 1-EEG Routine EEG is a must for the clinical diagnosis of epilepsy and associated syndrome.

 For the majority of patients with epilepsy, routine EEG is sufficient to classify seizure
 type and to start treatment But for refractory epilepsy ( RE) and a doubtful seizure,
 video-EEG monitoring is the best diagnostic tool available. 2-Drug level monitor 3-Serum
 electrolyte, serum glucose 4-MRI brain ; High-resolution MRI helps in isolating the cause of
 focal epilepsies and to predict long-term outcome and spontaneous remission in patients. In
 some cases, follow-up MRI reveals an etiology for epilepsy (such as cerebral neoplasm,
 autoimmune encephalitis) that was not seen on the initial study and requires specific
 therapies in addition to antiseizure drugs . 5- Metabolic Work up Arterial blood gas (ABG )
 Serum ammonia ,lactate Tandem mass screening 6-Genetic Testing as karyotyping , gene sequence
 ,-Fundus examination The presence of features like dysmorphism, growth retardation,
 intellectual disability and hypotonia may indicate an underlying genetic syndrome, 7-CSF
 culture, analysis • Lumbar puncture of infectious process 8-vascuilitis panel Complete blood
 cell count Erythrocyte sedimentation rate CRP ( C REACTIVE PROTEIN ) VWF Ag (VON WILLEBRAND
 FACTOR) C 3, 4 (COMPLEMENT 3, 4) Antinuclear AB (ANTIBODY) Antiphospholipid AB Antineutrophil
 cytoplasmic AB Anti-DNA AB 9-autoimmune encephalitis (Hashimotos ) antithyroid peroxidase AB,
 anti-TSH receptor AB Anti-NMDA-R AB Anti-MOG AB (if CNS demyelination) abdominal ultrasound
 and -MRI abdomen;To detect ovarian teratoma as in autoimmune encephalitis

 F-Practice recommendations for AED trial:

 1. Optimise the dose of each AED by increasing the dose incrementally. If the maximum dose
 is ineffective introduce a second AED while continuing on the first. If seizure control
 is achieved, consider tapering the first AED. The advice to "start low and go slow" is
 appropriate 2. If one or two AEDs are ineffective, rational polytherapy should be
 explored. 3. Consider using AEDs with different mechanisms of action 4. Avoid using an
 AED that may worsen or provoke seizures Carbamazepine (CBZ), Oxcarbazepine (OXC),
 Phenytoin (PHT), Vigabatrin (VGB) and Tiagabine (TGB) may worsen myoclonus and absence
 seizures

 -  Gabapentin (GBP) and Lamotrigine (LTG) may worsen myoclonus (Benzodiazepines given
 intravenously may worsen tonic seizures but may be very useful in treating
 Lennox-Gastaut and does not contraindicate their use

 Background A-Immunotherapy

 Evidence that the immune system is involved in the pathogenesis of epilepsy
 particularly, medically refractory epilepsy, has given rise to the use of adjunctive
 immunotherapy to slow or change the epileptogenic process.

 -  The presumed immune therapeutic mechanism (ACTH, corticosteroids, plasmapheresis
 human immunoglobulin G, rituximab, azathioprine, and cyclophosphamide) is the
 removal of various neuroimmunological mechanisms involved. However, new models
 suggest suppression of endogenous brain agent's proconvulsant (neuropeptides) There
 is limited data of these treatments outside of specific epileptic encephalopathies
 such as West syndrome, Rasmussen encephalitis, Landau Kleffner and specific
 antibody mediated encephalitis such as anti NMDA encephalitis a) Corticosteroids:
 Their immunological mechanisms are inhibition diapedesis and therefore infiltration
 of lymphocytes to the injured areas, attenuating production of inflammatory humoral
 mediators (IL-2) and inhibition of leukocyte function (helper T lymphocytes mainly)
 as well as endothelial cells.

 Dose:

 Methylprednisolone 30 mg /kg /day for 5 days up to 1 gm /day ,pulsed monthly for 6
 months (15).

 b) Plasmapheresis: the activity of auto-Abs can be modulated by treatment with IVIGs and
 by plasma treatment, which consists of the mechanical removal of Abs (16)

 c) Human immunoglobulin G:

 . IgGIV inhibits activation of innate cells, suppression of the production of
 proinflammatory cytokines, and soluble factors as tumor necrosis factor and interleukins
 induced by this factor. In endothelial cells and macrophages, suggesting a mechanism
 antiepileptic Dose:400 mg.kg /day for 5 days

 D--Rituximab:

 Rituximab, a chimeric monoclonal antibody that binds to CD20, was the first monoclonal
 antibody to be approved for clinical use in the therapy of cancer. It is approved for
 use against indolent B-cell non-Hodgkin's lymphoma (NHL), although its use has expanded
 significantly beyond that indication to virtually any CD20-positive NHL, and more
 recently into other areas such as autoimmune disorders

 ) Rituximab targets CD20, a transmembrane protein present on virtually all B cells from
 the stage at which they become committed to B-cell development until it is downregulated
 when they differentiate into antibody-secreting plasma cells (17) Numerous review
 articles whose primary focus is the action of rituximab in the treatment of RA, systemic
 lupus erythematosus (SLE) and other autoimmune diseases were published in 2006. Although
 there is a clear consensus that substantial clinical benefits are associated with
 rituximab therapy, the exact mechanism(s) by which the B-cell depletion promoted by
 rituximab ameliorates autoimmune disease activity remains an area of active
 discussion.(18, 19) The most likely mechanisms have naturally centered on the pathogenic
 role of B cells in autoimmune disease: these include the potential of B cells to give
 rise to plasma cells that secrete autoantibodies as well as the ability of
 autoantigen-specific B cells to present antigens to autoreactive T cells, which leads to
 T-cell activation, cytokine release and inflammation. In certain cases the results of
 clinical trials have demonstrated moderate correlations between reduction of
 autoantibody levels and lessening of disease symptoms, which has emphasized the role of
 autoantibodies in disease pathology. In other studies such correlations have not been
 observed, which has led investigators to favor B cell-T cell interactions as the most
 important in the etiology of tissue injury in autoimmune diseases.

 (20 ,21)

 B-Dietary Therapy

 1. ketogenic diet rationale; The common element of these different approaches is variable
 reduction in the amount of carbohydrate with appropriate increase in fat.

 Diets that produce a state of ketosis are referred to as ''ketogenic" When deprived of
 glucose through restriction of carbohydrate intake, the human body begins metabolizing
 fat.In doing so, ketone bodies (acetoacetate, acetone, and hydroxybutyrate) are produced
 . (22).

 KDT is associated with increased mitochondrial biogenesis, oxidative phosphorylation,
 enhanced gamma-aminobutyric acid (GABA) levels, reduced neuronal excitability and
 firing, and stabilized synaptic function (23)

 Indicated Dietary therapy has been reported as effective in the treatment of seizures
 associated with glucose transporter 1 deficiency, pyruvate dehydrogenase deficiency,
 infantile spasms, absence epilepsy, myoclonic atonic epilepsy (Doose syndrome), Dravet
 syndrome, tuberous sclerosis complex, mitochondrial disorders, Lennox-Gastaut syndrome,
 Sturge-Weber syndrome, and Rett syndrome (24) Results from the randomized control trial
 indicated that 38% of children had more than 50% reduction in seizure frequency, and 7%
 had more than 90% reduction in seizure frequency three months after starting classic
 ketogenic diet. Retrospective studies reported a higher rate of seizure control (25).

 Contraindications Absolute contraindications for the use of diet therapy include
 carnitine deficiency (primary), carnitine palmitoyltransferase (CPT) I OR II deficiency,
 carnitine translocase deficiency, β-oxidation defects, pyruvate carboxylase deficiency,
 and porphyria.

 2. trace elements and antioxidants; The equilibrium of trace elements is essential for a
 healthy nervous system due to their key roles in activation of specific enzyme in many
 pathways of the central nervous system function metabolism

 -  Essential trace elements that include zinc, copper, magnesium, and selenium might
 play a role in the pathogenesis of seizures because of their possible influence on
 synaptogenesis, their actions on ligand- and voltage-gated ion channels, their
 effects on membrane lipid peroxidation and turnover of some neurotransmitters, and
 their roles in immunity (26)

 Antioxidative defense mechanisms are important pathways involving trace elements. The
 accumulation of free radicals may lead to seizures and increases the risk o f their
 recurrence, because oxidative stress produces peroxidated membrane lipids and damages the
 cells

 . Glutathione peroxidase (GPx) and superoxide dismutase (SOD) are two major enzymes that are
 involved in antioxidative defense mechanisms.

 Selenium (Se), zinc (Zn), and copper (Cu) are important trace elements that participate in
 the structure of these enzymes patients with intractable epilepsy had significantly decreased
 levels of serum Se and Zn in comparison to the controlled group(27)
Inclusion Criteria:

 -  1-Age 1 month up to 17 years 2-Both male and female 3-Epileptic patient on two
 tolerated and appropriately chosen and used antiepilptic drugs with no response

 Exclusion Criteria:

 -  1-Neonate 2-Epieptic patient on monotherapy 3-Conditions mimic epilepsy 4-Pseudo
 refractioness 5-Absolute contraindications for the use of diet therapy include
 carnitine deficiency (primary), carnitine palmitoyltransferase (CPT) I OR II
 deficiency, carnitine translocase deficiency, β-oxidation defects, pyruvate
 carboxylase deficiency, and porphyria 6-Contraindication for Rituximab:

 1. Hypersensitivity to any component, murine proteins. b. Heart failure c. Active
 infection