PowerPoint Presentation

-epilepsy. Epilepsy PH3601 – Prof. Gavin Woodhall.

LEARNING OBJECTIVES. After the lecture you should be able to: Describe what a seizure is and how it relates to brain function Describe the kinds of epilepsy in basic terms Discuss treatment of the epilepsies and how pregnancy affects treatment (and vice versa).

How many brain cells do we have?. How many synapses do we have?.

BRAIN SIZE AND NEURON COUNT Cerebral cortex mass and neuron COIJnt for various mammals. 5 cm Capybara non-primate 48.2 g 0.3 billion neurons Rhesus Macaque primate 69.8 g 1.71 billion neurons Western Gorilla primate 377 g 9.1 billion neurons Human primate 1232 g 16.3 billion neurons African Bush Elephant non-primate 2848 g 5.59 billion neurons 1.

What do brain cells do?. neuron Autonomous spiking 120 mv _40 mV 20 mv GP LC 1 ms.

INHIBITION. excitation. Why don’t neurons all fire at once?.

20 mv. inhibition. Spiking activity is STOPPED by GABA inhibition.

“….epilepsy is the name for occasional, sudden, excessive, rapid and local discharges of grey matter.” J. Hughlings-Jackson (1873) On the anatomical, physiological and pathological investigation of epilepsies. West Riding Lunatic Asylum Medical reports. Vol 3: 315-339.

0.5 - 1% of population suffers from epilepsy i.e. 450,000 people in the UK.

1. 2. 3. 4. 5. 6. 1. 2. 3. 4. 5. 6. 1. 2. 3. 4. 5.

Fp2 - F4. F4 - C4. C4 - P4. P4 - O2. Fp1 - F3. C2 - P3.

generalized whole cortex bilateral. tonic-clonic motor seizures.

An aside – reflex epilepsy. Affects about 7% of epilepsy sufferers Seizures are triggered by: TV, sunlight through leaves, strobe light, sunlight on water 0.001% of sufferers have musicogenic seizures Other triggers: eating, tooth brushing, certain smells, playing chess, writing, reading, or doing sums/puzzles.

LETTERS TO THE EDITOR of reflex epilepsy? Reflex epilepsies Can be defined as sies in which all or a significant part of the seizures can regularly provoked by a given factor, most Often a Sensory stimulus. Sometimes it may be unexpected, such as, reading or decision—making.i We report a Very unusual epilepsy in Which seizures when the patient lied. A 51 year Old patient had recently experienced three attacB with loss of consciousness and generalised convulsions. Afterwards he Was a min— utes. attacks started with sensations the had regularly felt several each day, in clusters of one or two weeks for five years. ney consisted of epigastric con- Striction, a sensation Of hot flush rising from his stomach to his head, and then auditory and visual illusions, for instance Of hearing in echo or metamorphopsia, With intense anxiety. More than a third of the attack while the patient was lying, for business reasons. ne other without any obvious trigering factor. An EEG Showed a anterior and temporal slowing but no epileptc:genic activity. Cerebral showed a menin- gioma, 30 mm in diameter, located on the right cavernous sinus wall and the anterior clinoid process, near the turcica (fie It compressed the medial part of the right temporal with a mass effect. No further attack has been reported since the tion of carbamazepine therapy and then meninøoma ablation. attacks fit With the diapto- sis of partial vegetative seizures and the Of fulfils the criteria Of reflex epilepsy. Lying has not previously tren described as a trig-cring factor Of seizures but, according to certain authors, in some very rare cases seizures have been regularly provoked by emotion. a Emotions are said Figure TI tuighted MRI after gadolinium the and effect o" lobe. to linked to limbic excitability Was probably enhanced by its compression by the meningioma. When the patient Was lying he probably felt a particu— lar emotion and this limbic stimulation may have epileptic discharges in thc amygdala. As in tale, in which lies made PinocchWs wow, our lies obvious for his interlocutors. As he was an "eurocrat", using lies to evoke the truth in EEC negotiations, it is thanks to carbamazepine that he has been able to Work again. Y CHEVALIER M couARD 67091 cede% Beaumanoir A, Gastaut 1 gosss. 2 Gutwt H, CA. 1966,-7-.85-138. Of Acute senting as a Guillain-Barré syndrome Peripheral nerve complications of acute leukaemia arc uncommon. neuropaåy in these cases is frequently related to haem- orrhage, into a nerve infarcticm or leukaemic infiltration. Symmetrical periph— eral neuropathy in acute leukaemia is much less common and other pathogenic åctors could be involved." We a Very unusual case of acute non-lymphoblastic presented initially Barré syndrome. 69 year old man developed symmet— ric paresthesiae and painful dysesthesiae Of acute onset in the distal lower limbs. In the É'llOwing days thcsc increased in severity and he developed generalised pro- gessive weakness, with greater involvement in the legs than in Four after appearance of the symptoms he Went to a hospital because he Was unable to walk. Routine blood tests revealed severe abnormali6cs the patient was immediately admltted to the unit of a central hospital. On admission he WES alert, Orientated and pale, and febrile. BICKpd pressure was 130/60, pulse rate 72/minute and respiratory rate 19/minute. Purpura, lymphadenopathy and hepatosplenomegaly were absent. nere Was generalised flaccid motor Of grade TIL'V (MRC) in the upper limbs and Of Fade LV (MRC) in limbs. Deep tendon reflexes Were Very much in arrns and wcrc abscnt in the legs. Pinprick sensation was symmetri- cally impaired in the lower limbs in a ing distribution and was preserved in the arms. Joint and Vibration Sense Were impaired in thc and preserved in the arms. Signs of meningeal irritation, cor- ticospinal tracts, cranial nerves and auto— nomic involvement were absent. Higher mental function normal. haæ.c-globin was 6-7 reticulo— cytes. couru was With 6% polymorphonuclear neutmphils, 5% and 84% blast cells. platelet Count Was 81 marrow aspirate men showed increased cellularity due to and I 936—938 infiltration (67%) by blasts, Peroxidase + and 5% of promyelcwytes. ne haematolog- Was classified as acute non- lymph oblasti c leukemia, (FAB M2) Chemotherapy was immediately started and daunoru- bicin 40 intravenously for three days and cytosine arabinoside mp'rr* in con- tinuous for Seven days. A remis- Sion Of the haematological measures WAS obtained with one cycle, after a 22 day Of aplasia Complicated with infection and gastrointestinal haemorrhage _ Consolidation of thc haematological remis- Sion Was out 38 days thc induc- tion, "'cording to a similar protocol. As therapy, cycles of cytosine arabinoside associated alternatively With VP16, 6-thioguanine and daunorubicin have been perfomed cach month to date , Considering the severity of the haemato- logical on admission the emergency chemotherapy, lumbar puncture was delayed until nine weeks after the onset Of the Symptoms. CSF WAS Clear and colourless, with normal pressure, cell Count (one lymphocytcjmm') and glu— cose concentration. A pure transudate was found with a protein content of 132 midl (normal mg/dl) and an albumin tient (CSF/serum albumin x 10') of 38•2 (normal <9)_ Oligoclonal bands of gamma globulins in Serum and CSF protein elec— trophoresis were not observed. nere was no evidence Of intrathecal immunoglobulin synthesis. Electrophystoloøcal studies were first performed eight wccb after the onset Of symptoms. Motor nerve conduction Of median nerve was 38' 4 (normal ms-') With a distal motor latency Of (normal, up to 4-2). Distal sensory action potential Was absent. Motor conduction velocity Of Was 25 (nor- mal Ins-I) with a distal motor latency of 8 •7 (normal, up to Six). Electromyovaphy of the pollis brevis, tibialis anterior and extensor digitorium brevis muscles revealed a pattern Of discrete activity With an increase of mean duration of individual motor unit potentiab_ Fibrillation potentials and gubitive waves were observed in these muscles. A sural nerve biopsy showed a mild perivascular mononuclear cell in endoneurium, and marked demyelin- ation in several foci Of nerve was observed. In addition, there was some axonal cell infil- or areas Of necrosis Were not pre- sent. A progressive improvement of the picture Was weeks after the onset of symptoms. Thirteen weeks later, he was able to walk Without assistance. TWO months later, deep tendon reflexes were present slightly decreased in the legs. Ten months thc onset of the symptoms, the neurological examination Was normal and the patient now leads a normal social life and only complains of slight sporadic paresthesie in his feet. •ms patient had a neurolopcal illness that the criteria for the dianosis Of Guillain-Barre syndrome (GBS)-': he oped progresswe areflexia and symmetrical Of four limbs, and had charac- teristic CSF and electrophysiological fea- natural cotuse Of his neurological illness, with the phases of prwession (four weeks), plateau (Six weeks) and remission (40 wecb) was also typical Of Cancer patients With GBS differ Sißlifi- candy patients by a more.

So – why do seizures happen?.

Regular Sample Networks Small-world Random p=l Increasin randomness.

Neuronal networks. Connections ALL excitatory. Some connections inhibitory.

Small world Neuronal networks with excitation AND inhibition produce oscillations.

Asleep Deep sleep 1 sec 1. BrainAmp 2x32 ch EEG amphfier USB EEG/PC 'nterface BrainVision Recorder ActiCap active Voicekey MIC Buttonbox Auditory stimulus Isual stimulus Presentation.

Tonic phase. clonic phase. post-ictal phase. Left temporal lobe seizure onset.

Figure 11-28-01. PC2. PC1. Cobb et al. (1995) Nature 378: 75.

So – why do seizures happen?. Imbalance between excitation and inhibition? Damage to network and maladaptive response?.

Learning objectives. You need to have an idea of how to: Discuss the main antiepileptic drugs and the epilepsy types in which they are used Describe and discuss some of the adverse effects of AEDs Discuss how we treat epilepsy in pregnancy.

So – How do we treat epilepsy?. Restore balance between excitation and inhibition? anticonvulsants (stop a seizure) Prevent damage to network and maladaptive response? antiepileptics (stop epilepsy).

Epilepsy treatment in history. ballen. schilf. brot.

45-day Warranty on wives and slaves. « back.... » Institutions....

5000 BC Sacred origins. 500 BC 200 BC. Hippocrates suggests an excess of phlegm in the brain.

Heracles. Saul. Socrates. Ceasar. Paul. Jean D’Arc.

Most AEDs have a synaptic action. Inhlbltory synapse Valproate Vlgabatrln GABA<-+SSA Glial cell Topiramate Gabapentin Carbamazepine Oxcarbazepine Phenytoin Lamotrlglne Felbamate Topiramate Excitatory synapse Glutamate Levetiracetam GABA SSA 00 Topiramate Postsynaptic neuron V2A GLU mGluR Lamotrigine Oxcarbazepine Gabapentin Pregabalin Topiramate Felbamate.

anticonvulsant. Drugs that reduce glutamate release.

vigabatrin (++) sodium valproate (+) GABA transaminase inhibitor blocks GABA breakdown increases GABA levels increases GABA release.

Diagnosis of epilepsy. After a second seizure: Diagnosis by a specialist (neurology) is required EEG is used to confirm (but may not help!) may need to be repeated may need to be long-term (ambulatory) EEG may need to be during sleep (most seizures) may require sleep deprivation of melatonin administration Seizures may be provoked (light) Neuroimaging (MRI, MEG) required if diagnosis of idiopathic generalized epilepsy is made (why?).

Treatment with antiepileptic drugs (AED). Main points: Treatment starts after the second seizure (but after first if there is clear evidence of EEG abnormality, structural abnormality or neurological deficit Monotherapy is the goal (why?) When switching from one AED to another, careful tapering (both drugs) is needed (why?) Adjunct therapy considered when Pt does not achieve seizure freedom Status epilepticus is an acute emergency.

Choosing Antiepileptic Drugs. Considerations: Seizure type Epilepsy syndrome (West Syndrome, Dravet ) Pharmacokinetic profile wrt patient Interactions/other medical conditions Efficacy Expected adverse effects Cost.

Choosing Antiepileptic Drugs. Focal seizures: Carbamazepine (CBZ) or lamotrigine (LTG) 1 st line for children, young people and adults levetiracetam, oxcarbazepine or sodium valproate if CBZ or LTG ineffective/not tolerated If these 5 drugs do not work then consider: eslicarbazepine acetate, lacosamide , phenobarbital, phenytoin, pregabalin, tiagabine, vigabatrin and zonisamide . Issue 1: the risk–benefit ratio when using vigabatrin because of the risk of an irreversible effect on visual fields (severe, symptomatic, persistent field constriction) Issue 2: Valproate - valproate treatment must not be used in girls and women including in young girls below the age of puberty, unless alternative treatments are not suitable and unless the conditions of the pregnancy prevention programme are met..

Choosing Antiepileptic Drugs. Generalized tonic- clonic seizures (GCTS): Valproate is offered first to children and young people newly diagnosed with GCTS LTG is offered second (may exacerbate myoclonic seizures) CBZ and oxcarbazepine may be offered but risk augmenting absence and myoclonic seizures.

Choosing Antiepileptic Drugs. Absence seizures: Valproate or ethosuximide is offered first to children and young people LTG is offered second If these two drugs do not work adjunct with two of these three drugs: ETX, VAL, LTG If adjunct therapy ineffective try clobazam, levetiracetam, topiramate, zonisamide Do not use: CBZ, gabapentin oxcarbazepine, phenytoin, pregabalin, tiagabine or vigabatrin (why?).

Choosing Antiepileptic Drugs. Myoclonic seizures: Valproate is offered first to children and young people Levetiracetam or topiramate offered second If adjunct therapy ineffective try clobazam, levetiracetam, topiramate, zonisamide Do not use: CBZ, gabapentin oxcarbazepine, phenytoin, pregabalin, tiagabine or vigabatrin (why?).

Choosing Antiepileptic Drugs. Dravet syndrome and Lennox- Gastaut syndrome: Devastating seizure syndromes with 10-100 seizures per day, treatment resistant, associated with sodium channel mutations ( Dravet ) or in case of LGS, anoxia abnormal development of the brain cortex (cortical dysplasia), congenital infections, stroke, trauma, reduced oxygen supply that occurs before birth (perinatal hypoxia), infections of the central nervous system such as encephalitis or meningitis and a rare, genetic disorder called tuberous sclerosis Very difficult to treat, requires specialist CBD, fenfluramine have proved effective also valproate Felbamate may be used as drug of last resort in specialist centres (why?).

Choosing Antiepileptic Drugs. Cannabidiol (CBD) In the news a lot 38-41% reduction in seizures even in Dravet /LGS Similar effectiveness to previous AED May be effective in preventing refractory status epilepticus.

Adverse Effects of AED. Acute dose-related—reversible Idiosyncratic— uncommon potentially serious or life threatening Chronic—reversibility and seriousness vary.

Acute, Dose-Related Adverse Effects of AEDs. Neurologic/Psychiatric – most common Sedation, fatigue Unsteadiness, lack of coordination, dizziness Tremor Paraesthesia Diplopia, blurred vision Mental/motor slowing or impairment Mood or behavioural changes Changes in libido or sexual function.

Acute, Dose-Related Adverse Effects of AEDs. Gastrointestinal (nausea, heartburn) Mild to moderate laboratory changes Hyponatremia (may be asymptomatic) Increases in ALT or AST Leukopenia Thrombocytopenia Weight gain/appetite changes.

Idiosyncratic adverse effects of AEDs. Rash, Exfoliation Signs of potential Stevens-Johnson syndrome Hepatic Damage Early symptoms: abdominal pain, vomiting, jaundice Laboratory monitoring probably not helpful in early detection Patient education Fever and mucus membrane involvement.

Idiosyncratic adverse effects of AEDs. Hematologic Damage (marrow aplasia, agranulocytosis - CBZ) Early symptoms: abnormal bleeding, acute onset of fever, symptoms of anemia Laboratory monitoring probably not helpful in early detection Patient education.

Long-Term Adverse Effects of AEDs. Neurologic:.

Answer: nifedipine; cyclosporin; oral contraceptives with high oestrogen content.

gingival hyperplasia.

Status epilepticus. Life-threatening and highly dangerous seizure(s) lasting longer than 5 mins (or 3 in an hour) In convulsive SE main goal is to stop the seizure 1 st line treatment is Buccal midazolam in children (perhaps rectal diazepam or IV lorazepam) 2 nd line treatment IV phenobarbital or phenytoin Refractory SE is super high-risk, treated in ICU, may use thiopental, midazolam, propofol.

Pregnancy and Epilepsy. All AED carry teratogenic risks Most pregnancies in mothers with epilepsy produce normal children Fetal anomalies (up to 10% of pregnancies) are multifactorial Drug effects Consequences of the mother ’ s underlying diseases Consequence of maternal seizures during pregnancy Polytherapy increases risk of teratogenic effects.