Pathophysiology and management of epilepsy

IV-Pharm.D, Pharmacotherapeutics-III, pathophysiology and treatment of epilepsy

1. PATHOPHYSIOLOGY & MANAGEMENT OF EPILEPSY T. SOUJANYA PHARM.D

2. DEFINITION: Epilepsy is a common neurological condition characterized by recurrent seizures (that usually occur unpredictably), loss of consciousness with or without body movements. It is derived from a Greek word Epi-upon, Leptos-seizures. It is also known as seizure disorder. Seizure is a phenomenon characterized by an excessive, hypersynchronous discharge of cortical neuronal activity (measured by EEG), featured by disturbances in consciousness, sensory motor systems, subjective well-being and objective behaviour.

3. EPIDEMIOLOGY: Incidence of epileptic seizures is around 50 cases per 1,00,000 of the population. Around 50 million people worldwide have epilepsy. Higher risk observed in extremes of age. Prevalence in European countries is 0.5%, prevalence in developing countries is higher due to parasitic illnesses like cysticercosis.

4. ETIOLOGY: In 20% cases cause can be determined, rest 72% are idiopathic (of unknown cause). Inherited/genetic causes: Single gene mutation (<2%), multiple genes + environmental factors, genetic disorders (down, dravet etc.), >200genes have the capability of causing epilepsy. Acquired causes: Head trauma, neurosurgery, cerebrovascular disease, infections (meningitis, influenza, toxoplasmosis, mumps, measles, syphilis), metabolic disorders (such as hypoglycemia and hypocalcemia), intracranial neoplasms. Congenital causes: Inborn error of metabolism. Withdrawal of drugs: Alcohol, benzodiazepines, barbiturates, antiepileptics. Drugs that induce seizures: Some of the antibiotics, antidiabetics, anesthetics, antimalarials, antispastics, antidepressants, antipsychotics, mood stabilizers.

5. PATHOPHYSIOLOGY: Neurons are inter-connected in a complex network. Each individual neuron is linked with hundreds of other neurons via synapses. Neurons discharge electrical current and neurotransmitters are released at synaptic levels and permits inter-communication. Neurotransmitters are of two types: Inhibitory neurotransmitters (INT) and Excitatory neurotransmitters (ENT). Inhibitory neurotransmitters (GABA): GABA (Gamma amino butyric acid) acts on ion channels and increases chloride outflow & decreases chances of action potential formation. Excitatory neurotransmitters (aspartate, glutamate): Aspartate and glutamate allows sodium and calcium influx which paves way for action potential formation.

6. CONTD… In this manner, information is conveyed, transmitted and processed throughout the CNS. Seizures occur due to the imbalance between the above inhibition and excitation. A normal neuron discharges repetitively at low baseline frequencies. If neurons are damaged, injured/suffer a chemical/metabolic insult, the changes in discharge pattern develops. During epilepsy, regular low frequency discharges are replaced by bursts of high frequency discharges followed by periods of inactivity. A single neuron discharging in an abnormal manner is usually not clinically significant. But when a whole population of neurons discharge synchronously in an abnormal manner, epileptic seizure is precipitated. This abnormal discharge may remain localized or it may spread to adjacent areas, recruiting more neurons as it expands.

7. CONTD… Abnormalities in ion channel (Na + , K + , Ca +2 ) or decreased INT activity/inactivation of INT activity Increased ENT activity Rhythmic & repetitive hypersynchronous discharge of neurons Seizures focus Seizures Repetitive seizures Epilepsy

8. Types of epilepsies including clinical manifestations: Based on International League Against Epilepsy (ILAE), they are classified into: Partial seizures (focal seizures) Generalized seizures

9. 1. PARTIAL/FOCAL SEIZURES (seizures begin locally): It is the most common type of seizures, localized to a neuronal system, limited to part of one cerebral hemisphere. Types of partial seizures include: a) Simple partial seizures (without impairment of consciousness): It is not associated with loss of consciousness. It is associated with motor signs (convulsive jerking, lip smacking), sensory and somatosensory signs (paresthesias, auras), autonomic signs (sweating, flushing, behavioural manifestations (dysphasia, structured hallucinations). b) Complex partial seizures (with impairment of consciousness): It is associated with impaired consciousness, impairment proceeds/follows seizures. It is also associated with purposeless behaviour, glassy stare, aimless walking, hallucinations (visual, auditory), aggressive behaviour. c) Secondary generalized seizures: Partial onset evolving to generalized tonic-clonic seizures.

10. 2. GENERALIZED SEIZURES: a) Absence seizures: It is also known as ‘petit mal’ seizure. It happens exclusively in childhood and early adolescence. It is associated with alterations of consciousness, staring with occasional eye-blinking, enuresis. These attacks last only for few seconds and often go unrecognized. b) Myoclonic seizures: It is also known as ‘bilateral massive epileptic myoclonus’. It is associated with involuntary, rhythmic jerking of facial, limb/trunk muscles. c) Clonic seizures: It is associated with sustained muscle contractions, altering with relaxation. d) Tonic seizures: It is associated with sustained muscle contractions (stiffening).

11. CONTD… e) Generalized tonic-clonic seizures: It is also known as ‘grand mal’ seizure. It leads to sudden loss of conscious, the individual becomes rigid and falls to the ground. It is associated with interrupted respirations, extended legs, rapid bilateral muscle jerking, heavy salivation, tongue biting, headache, confusion. It lasts for one minute. In some cases, grand mal seizure occurs repeatedly with no recovery of consciousness between attacks, leading to state known as ‘status epilepticus’. f) Atonic seizures: It is also known as ‘drop attack’. It occurs mainly in children. It is associated with sudden loss of postural tone and the individual falls to the ground.

12. RISK FACTORS: Sleep deprivation. Missed doses of anti-epileptic drugs (AEDs) in treated patients. Alcohol withdrawals, recreational drug misuse. Physical and mental exhaustion. Flickering lights (includes TV, computer screens; comes under generalized epilepsy syndrome). Intercurrent infections. Metabolic disturbances. Uncommon reasons like loud noises, very hot baths etc.

13. DIAGNOSIS: Neurological examination/neuropsychological tests: Doctor tests for behavior, motor abilities, mental function and other symptoms. Medical history. Genetic testing. Electroencephalogram (EEG): Tracks electrical signals from the brain. CT scan, MRI scan: Used to detect abnormalities in brain (tumors, bleeding, cysts).

14. CONTD… fMRI: Used to measure the changes in blood flow. PET (Positron Emission Tomography): Used to visualize active areas of brain and detect abnormalities. SPECT (Single Photon Emission Computerized Tomography): Used when MRI and ECG did not pinpoint the location in brain where the seizures are originating. SISCOM (Subtraction Ictal SPECT Categorized to MRI): A form of SPECT test which may provide even more detailed results.

15. TREATMENT: Goals of treatment: To control and reduce seizure frequency. To focus on minimum possible dosage of AEDs To minimize ADRs associated with therapy. To ensure patient medication compliance. To ensure that the person lives a normal life as far as possible. To reduce morbidity and mortality, to improve quality of life.

16. NON-PHARMACOLOGICAL TREATMENT: 1) Ketogenic diet: Ketogenic diet containing high content of fats, followed by proteins, carbohydrates were found to reduce seizures in some children. Side effects: Constipation, slow growth because of nutritional deficiencies, build up of uric acid in blood, kidney stones. 2) Surgeries: Medications can control seizures in most people with epilepsy, but they don’t work for everyone. About 30% of people taking the drugs can’t tolerate the side effects. In such cases, brain surgery may be an option.

17. CONTD... i ) Lobe resection: The lobe within which seizures focus is located is cutoff. Extemporal resection involves brain tissue from areas outside of the temporal lobe. ii) Lesionectomy: This surgery removes brain lesions, areas of injury or defect like a tumor or malformed blood vessel that cause seizures. Seizures usually stop once the lesion is removed.

18. CONTD… iii) Corpus callostomy or split-brain surgery: Corpus callosum is a band of nerve fibers connecting the two halves (called hemispheres) of the brain. In this operation, corpus callosum is cut off and the communication between hemispheres is prevented, no spread of seizures from one side to other side. It works best for people with extreme forms of uncontrollable epilepsy who have intense seizures that can lead to violent falls and serious injury. iv) Functional hemispherectomy: Entire hemisphere or half of the brain is removed. It is mostly used for children younger than 13 who have one hemisphere that doesn’t work like it should.

19. Contd… v) Multiple subpial transection (MST): This procedure can help to control seizures that began in areas of the brain that can’t be safely removed. The surgeon makes a series of shallow cuts in the brain tissue. These cuts interrupt the flow of seizure impulse but don’t disturb normal brain activity. vi) Vagus nerve stimulation (VNS): A device implanted under skin sends an electronic jolt to the vagus nerve, which controls activity between brain and major internal organs. It lowers seizure activity in some people with partial seizures.

20. Contd … vii) Responsive neurostimulation device (RNS): Doctor’s implant a small neurostimulator in skull, just under your scalp. They link it to one or two wires that they place either in the part of brain where seizures start or on brain surface. This device detects abnormal electrical activity in the area and sends an electric current. It can stop the process that leads to a seizure.

21. Pharmacological treatment: Classification of anti-epileptic drugs: Barbiturates: Phenobarbitone Hydantoins: Phenytoin, Fosphenytoin Succinimide: Ethosuximide Benzodiazepines: Clonazepam, Diazepam, Lorazepam, Clobazam Deoxybarbiturate: Primidone Iminostilbenes: Carbamazepine, oxcarbazepine Aliphatic carboxylic acid: Valproic acid (valproate sodium), Divalproex Phenyl triazine: Lamotrigine Cyclic GABA analogues: Gabapentin, Pregabalin Newer drugs: Topiramate, Zonisamide, Levetiracetam, Vigabatrin, Tiagabine, lacosamide

22. Contd … 1. Barbiturates (phenobarbitone): MOA: Phenobarbitone acts on GABA(A) receptors and enhances the action of inhibitory neurotransmitters (e.g. GABA) and suppresses the excitatory neurotransmitters (Ach), opens Cl - ion channels and decreases the seizures. ADRs: hyperactivity, behavioural changes, metabolic bone disorders, ataxia, unsteadiness, blood, dyscrasias, sedation, headache, respiratory depression (when given i.v.) Dose: Phenobarbitone- 60mg OD (child 3-6mg/kg/day), 100-200mg i.m./i.v. Uses: It is used in the treatment of febrile convulsions, neonatal seizures, status epilepticus (SE), generalized tonic-clonic seizures.

23. Contd … 2. Hydantoins (phenytoin): MOA: Phenytoin acts by blocking the voltage-dependent sodium channels in post synaptic neuron and reduces the influx of sodium ions across cell membrane and also reduces high-frequency neuronal discharge/inhibits the action potential of neurons. ADRs: Gingival hyperplasia, hirsutism, megaloblastic anaemia, diabetes mellitus, visual blurring, ataxia, behavioural changes, foetal hydantoin syndrome (drug when used in pregnancy causes cleft lips, microcephaly in neonates). Dose: 100-200mg BD (child 5-8mg/kg/day) oral, 25mg/min slow i.v. injection (max 1.0g). Uses: It is mainly used in the treatment of generalised tonic-clonic seizures, status epilepticus, partial seizures etc.

24. Contd … 3. Succimides (ethosuximide): MOA: Ethosuximide acts by blocking the voltage-sensitive T type Ca +2 channels in thalamic neurons (the T type Ca +2 current is thought to provide a pacemaker current in thalamic neurons responsible for generating the rhythmic cortical discharge of an absence attacks) and reduces the low-threshold (T-type) current. ADRs: GI disturbances, dizziness/drowsiness, unsteadiness, hiccoughs etc. Dose: 500mg/day (20-30mg/kg/day) Uses: It is commonly used in the treatment of absence seizures.

25. Contd … 4. Benzodiazepines (clonazepam, diazepam, lorazepam, clobazam): MOA: Benzodiazepines work by increasing the efficiency of a natural brain chemical, GABA, to decrease the excitability of neurons. Binding of benzodiazepines to GABA A receptor complex promotes binding of GABA, which in turn increases of chloride ions across the neuronal cell membrane, resulting in inhibition of neuronal firing. ADRs: Blood disorders, respiratory depression, hypotension, jaundice etc. Dose: clonazepam-1.5mg/day, diazepam- 4-40mg PO or 5-10mg IV, lorazepam- 10mg/day or 0.044mg/kg/day IV, clobazam- 10-20mg/day (max 60mg/day). Uses: They are used in the treatment of panic disorder, seizure disorder, status epilepticus, pre-operative medication, insomnia associated with anxiety etc.

26. Contd … 5. Deoxybarbiturate (primidone): MOA: Primidone after entering into the body metabolized by the liver to phenobarbitone (active anticonvulsant) and shows anti-epileptic activity. ADRs: Slow or slurred speech, loss of control of bodily movements, vertigo, blurred vision, skin rashes, loss of appetite etc. Dose: Primidone- 250-500mg BD (child 10-20mg/kg/day) Uses: It is generally used in combination with other anticonvulsants to treat generalised tonic-clonic seizures (GTCS), partial epilepsy.

27. Contd … 6. Iminostilbenes (carbamazepine, oxcarbazepine): MOA: Carbamazepine is a tricyclic compound. It has good anti-seizure activity; its mechanism of action and anti-epileptic action are similar to phenytoin. ADRs: Drowsiness, vertigo, nausea & vomiting, ataxia, hepatitis, pancreatitis, arrhythmia, hyponatremia, rashes, CHF etc. Dose: Carbamazepine- 200-400mg/day (children 15-30mg/kg/day); oxcarbazepine- 300-600mg BD. Uses: They are mainly used in the treatment of trigeminal neuralgia, generalized tonic-clonic seizures, bipolar disorder, simple & complex, partial seizures etc.

28. Contd … 7. Aliphatic carboxylic acids (valproic acid, divalproex): MOA: Valproic acid enhances the level of GABA (reduces the metabolism of GABA), blocks the sodium channels which decreases low threshold Ca +2 in thalamus and reduces seizure activity. ADRs: Stevens-Johnson syndrome (SJS), pancreatitis, thrombocytopenia, increased bleeding time, encephalopathy, dementia etc. Dose: Valproic acid- 200-800mg; divalproex- 250-500mg Uses: Valproic acid is mainly used as a single drug therapy for treating patients with a combination of generalized tonic-clonic, absence or myoclonic seizures.

29. Contd … 8. Phenyl triazines (lamotrigine): MOA: Lamotrigine inactivates/inhibits voltage-sensitive Na + channels and inhibits the release of glutamate and aspartate (excitatory neurotransmitters) and therefore reduces the seizure activity. ADRs: Ataxia (inability to coordinate voluntary muscle movements), diplopia, unsteadiness, skin rash (Steven-Johnson syndrome) etc. Dose: Lamotrigine- 25mg/day for initial 14 days; then 50mg/day for next 14 days; then increase dose to 50-100mg/day for next 7-14 days. Uses: Lamotrigine is commonly used in the treatment of bipolar disorders and generalized tonic-clonic seizures.

30. Contd … 9. Cyclic GABA analogues (gabapentin, pregabalin): They are structurally similar to GABA, but has no effect on binding, uptake/ degradation of GABA. MOA: These drugs act by modulating voltage sensitive calcium channels and decreases the entry into presynaptic neurons, decreases glutamate release which in turn decreases neuronal excitability. ADRs: Steven-Johnson syndrome (SJS), acute renal failure, hepatitis, primary AV block, CHF etc. Dose: Gabapentin- initial dose 300mg OD (max 300-600mg); Pregabalin-75-150mg BD (max 600mg/day).

31. Drugs of choice for specific-seizure disorders: Seizure type First line drugs Alternative drugs Partial seizures Carbamazepine, phenytoin, lamotrigine, valproic acid, oxcarbazepine Gabapentin, topiramate, levetiracetam, Zonisamide, tiagabine, primidone, phenobarbital, felbamate Absence seizures Valproic acid, ethosuximide Lamotrigine, levetiracetam Myoclonic seizures Valproic acid, clonazepam Lamotrigine, levetiracetam, topiramate, Zonisamide Tonic-clonic seizures Phenytoin, Valproic acid Lamotrigine, topiramate, oxcarbazepine, levetiracetam

32. Treatment algorithm for epilepsy

33. References/bibliography: Text book of pathology by Harsh Mohan Clinical Pharmacy and Therapeutics – Roger and Walker, Churchill Livingstone publication Pharmacotherapy: A Pathophysiologic approach – Joseph T. Dipiro www.slideshare.net