1. Problem 1: A strange fever By Aneesa Naadira KhanA person with a new idea is a crank until theidea succeeds. Call me crazy

2. Objective 1Briefly describe the histology of the cerebral cortex 3. The cerebral cortex Has a thickness varying 1 to 4mm Is composed of glial cells and neurons Has six layers: I Molecular layer II External granular layer III External pyramidal layer IV Internal granular layer V Internal pyramidal layer VI Multiform (polymorphic layer) 4. Layer 1 consists mainly of apical dendrites from pyramidalcells from lower layers plus axons synapsing on thosedendrites. It contains almost no neuron cell bodies. Layer 2 contains many small densely-packed pyramidalneurons giving it a granular appearance. Layer 3 contains medium-sized pyramidal neurons whichsend outputs to other cortical areas. Layer 4 contains many spiny stellate (excitatory)interneuronsLayer 5 contains the largest pyramidal neurons, whichsend outputs to the brain stem and spinal cord(the pyramidal tract) Layer 6 consists of pyramidal neurons and neurons withspindle-shaped cell bodies. 5. 6 layers of the cerebral cortex: Molecular (plexiform) layer apical dendrites of pyramidal cells large no. of synapses happen here OUTER granular layer stellate cells OUTER pyramidal cell layer pyramidal cells smaller INNER granular layer closely packed stellate cells horizontal fibres (of Baillarger) INNER pyramidal cell later (ganglionic layer) large pyramidal cells particularly in motor area inner fibres of Baillarger Multiform cell layer fusiform cells many nerve fibres entering white matter 6. Stellate (Granule) Cells These come in a wide assortment of shapes. They are typically small (< 10 micrometres) multipolar neurons. Their short axons do not leave the cortex. Stellate cells are the principal interneurons of the neocortex. 7. Pyramidal Cells These cells are shaped as they are named. Pyramidal cells range in size from 10 micrometres in diameter to 70-100micrometres of the giant pyramidal cells (Betz cells) of the motor cortex. A long apical dendrite leaves the top of each pyramidal cell and ascendsvertically to the cortical surface. A series of basal dendrites emerges from nearer the base of the cell andspreads out horizontally. The apical dendrites of pyramidal cells are studded with dendritic spines. These are numerous small projections that are the preferentialsite of synaptic contact. It has been suggested that dendritic spines may be the sites of synapses that areselectively modified as a result of learning. Most or all pyramidal ells have long axons that leave the cortex to reacheither other cortical areas or to various subcortical sites. Therefore, pyramidal cells are the principal output neurons. 8. Fusiform Cells These are found in the deepest cortical layer. They are spindle-shaped with a tuft ofdendrites emerging from each end ofthe spindle. They are, however, otherwise like pyramidalcells with an axon that leaves the cortex. 9. Objective 2Describe typical brain waves seen on the eeg and howit is conducted 10. What is EEG? An electroencephalogram (EEG) is a painless procedure that uses small, flat metal discs (electrodes) attached to your scalp to detect electrical activity in your brain. Your brain cells communicate via electrical impulses and are active all the time, even when youre asleep. This activity shows up as wavy lines on an EEG recording.From : myoclinic.com 11. During the procedure A standard noninvasive EEG takes about 1 hour. The patient will bepositioned on a padded bed or table, or in a comfortable chair. Tomeasure the electrical activity in various parts of the brain, a nurse orEEG technician will attach 16 to 20 electrodes to the scalp. The braingenerates electrical impulses that these electrodes will pick up. Toimprove the conduction of these impulses to the electrodes, a gel will beapplied to them. Then a temporary glue will be used to attach them tothe skin. No pain will be involved. The electrodes only gather the impulses given off by the brain and donot transmit any stimulus to the brain. The technician may tell thepatient to breathe slowly or quickly and may use visual stimuli such asflashing lights to see what happens in the brain when the patient seesthese things. The brains electrical activity is recorded continuouslythroughout the exam on special EEG paper. 12. Normal brain waves Alpha waves occur at a frequency of 8 to 12 cycles per second in aregular rhythm. They are present only when you are awake but haveyour eyes closed. Usually they disappear when you open your eyes orstart mentally concentrating. Beta waves occur at a frequency of 13 to 30 cycles per second. Theyare usually associated with anxiety, depression, or the use of sedatives. Theta waves occur at a frequency of 4 to 7 cycles per second. They aremost common in children and young adults. Delta waves occur at a frequency of 0.5 to 3.5 cycles per second. Theygenerally occur only in young children during sleep. 13. Beta waves (15-30 oscillations (or waves) per second (Hz)). This is the brain rhythm in the normal wakeful stateassociated with thinking, conscious problem solving and active attention directed towards the outer world. You aremost likely in the "beta state" while you are reading this. Alpha waves (9-14 Hz). When you are truly relaxed, your brain activity slows from the rapid patterns of beta intothe more gentle waves of alpha. Fresh creative energy begins to flow, fears vanish and you experience a liberatingsense of peace and well-being. The "alpha state" is where meditation starts and you begin to access the wealth ofcreativity that lies just below our conscious awareness. It is the gateway that leads into deeper states ofconsciousness. Theta waves (4-8 Hz). Going deeper into relaxation and meditation, you enter the "theta state" where brain activityslows almost to the point of sleep. Theta brings forward heightened receptivity, flashes of dreamlike imagery,inspiration, and,sometimes, your long-forgotten memories. It can also give you a sensation of "floating". Theta is one of the more elusive and extraordinary realms we can explore. It is also known as the twilight statewhich we normally only experience fleetingly as we rise up out of the depths of delta upon waking, or drifting off tosleep. In theta, we are in a waking dream, and we are receptive to information beyond our normal consciousawareness. Some people believe that theta meditation awakens intuition and other extrasensory perception skills. Delta waves (1-3 Hz). This slowest of brainwave activity is found during deep, dreamless sleep. It is alsosometimes found in very experienced meditators. 14. Objective 3Explain the mechanism of action of anticonvulsants 15. Predominant MOA of anticonvulsantdrugs 16. Phenytoin Alters Na , K , and Ca conductance, membranepotentials and the concentrations of amino acids andthe neurotransmitters norepinephrine, acetocholineand y-aminobutyric acid (GABA) Blocks sustained high-frequency repetitive firing ofaction potentials. It is a use-dependent effect on Na conductancearising from preferential binding to and prolongation ofthe inactivated state of the Na channel 17. Na channel blockersSome antiepileptic drugsstabilize inactiveconfiguration of sodium(Na+) channel,preventing high-frequency neuronalfiring. During an action potential, these channels exist in the active state and allow influx of sodium ions. Once the activationor stimulus is terminated, a percentage of these sodium channels become inactive for a period known as the refractoryperiod. With constant stimulus or rapid firing, many of these channels exist in the inactive state, rendering the axonincapable of propagating the action potential. AEDs that target the sodium channels prevent the return of these channels to the active state by stabilizing them in theinactive state. In doing so, they prevent repetitive firing of the axons 18. Na channel blockers Sodium channel blockade is the most common and best-characterized mechanism of currently available antiepileptic drugs (AEDs). AEDs that target sodium channels prevent the return of the channels to the active state by stabilizing the inactive form. In doing so, repetitive firing of the axons is prevented. Presynaptic and postsynaptic blockade of sodium channels of the axons causes stabilization of the neuronal membranes, blocks and prevents posttetanic potentiation, limits the development of maximal seizure activity, and reduces the spread of seizures. 19. Calcium channel blockers Low-voltage calcium (Ca2+) currents (T- type) are responsible for rhythmic thalamocortical spike and wave patterns of generalized absence seizures. Some antiepileptic drugs lock these channels, inhibiting underlying slow depolarizations necessary to generate spike-wave bursts.Calcium channels exist in 3 known forms in the human brain: L, N, and T. Thesechannels are small and are inactivated quickly. The influx of calcium currents in theresting state produces a partial depolarization of the membrane, facilitating thedevelopment of an action potential after rapid depolarization of the cell.Calcium channels function as the " pacemakers " of normal rhythmic brain activity.This is particularly true of the thalamus. T-calcium channels have been known toplay a role in the 3 per second spike-and-wave discharges of absence seizures.AEDs that inhibit these T-calcium channels are particularly useful for controllingabsence seizures 20. enhancersGABA is produced bydecarboxylation of glutamatemediated by the enzymeglutamic acid decarboxylase(GAD). Some AEDs may actas modulators of thisenzyme, enhancing theproduction of GABA anddown-regulating glutamate(see the image below).Some AEDs function as anagonist to chlorideconductance, either byblocking the reuptake ofGABA (eg, tiagabine [TGB])or by inhibiting itsmetabolism as mediated byGABA transaminase (eg,vigabatrin [VGB]), resultingin increased accumulation ofGABA at the postsynapticreceptors.Gamma-aminobutyric acid (GABA)-A receptor mediates chloride (Cl-) influx,leading to hyperpolarization of cell and inhibition. Antiepileptic drugs mayact to enhance Cl- influx or decrease GABA metabolism. 21. GABA Receptor Agonists The benzodiazepines most commonly used for treatment of epilepsy arelorazepam, diazepam, clonazepam, and clobazam. The first 2 drugsare used mainly for emergency treatment of seizures because of theirquick onset of action, availability in intravenous (IV) forms, and stronganticonvulsant effects. Their use for long-term treatment is limitedbecause of the development of tolerance. The 2 barbiturates mostly commonly used in the treatment of epilepsyare phenobarbital (PHB) and primidone. They bind to a barbiturate-binding site of the benzodiazepine receptor to affect the duration ofchloride channel opening. They have been used widely throughout theworld. They are very potent anticonvulsants, but they have significantadverse effects that limit their use. With the development of new drugs,the barbiturates now are used as second-line drugs for the treatmentof chronic seizures. 22. Glutamate blockers Glutamate receptors bind glutamate, an excitatory amino acidneurotransmitter. Upon binding glutamate, the receptors facilitatethe flow of both sodium and calcium ions into the cell, whilepotassium ions flow out of the cell, resulting in excitation. The glutamate receptor has 5 potential binding sites, as follows: The alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid(AMPA) site The kainate site The N -methyl-D-aspartate (NMDA) site The glycine site The metabotropic site, which has 7 subunits (GluR 1-7) 23. GABA Transaminase Inhibitors Gamma-aminobutyric acid (GABA) is metabolized by transamination in the extracellular compartment by GABA-transaminase (GABA-T). Inhibition of this enzymatic process leads to an increase in the extracellular concentration of GABA. Vigabatrin (VGB) inhibits the enzyme GABA-T. 24. Objective 4Discuss the pathophysiology of febrile convulsions andepilepsy 25. Febrile seizures occur in young children at a time in their development when the seizure threshold is low. This is atime when young children are susceptible to frequent childhood infections such as upper respiratory infection, otitismedia, viral syndrome, and they respond with comparably higher temperatures. Animal studies suggest a possiblerole of endogenous pyrogens, such as interleukin 1beta, that, by increasing neuronal excitability, may link fever andseizure activity.[3]Preliminary studies in children appear to support the hypothesis that the cytokine network isactivated and may have a role in the pathogenesis of febrile seizures, but the precise clinical and pathologicalsignificance of these observations is not yet clear.[4, 5] Febrile seizures are divided into 2 types: simple febrile seizures (which are generalized, last < 15 min and do notrecur within 24 h) and complex febrile seizures (which are prolonged, recur more than once in 24 h, or arefocal).[6]Complex febrile seizures may indicate a more serious disease process, such asmeningitis, abscess,or encephalitis. Viral illnesses are the predominant cause of febrile seizures. Recent literature documented the presence of humanherpes simplex virus 6 (HHSV-6) as the etiologic agent in roseola in about 20% of a group of patients presentingwith their first febrile seizures. Shigella gastroenteritis also has been associated with febrile seizures. One studysuggests a relationship between recurrent febrile seizures and influenza A. [7, 8] Febrile seizures tend to occur in families. In a child with febrile seizure, the risk of febrile seizure is 10% for thesibling and almost 50% for the sibling if a parent has febrile seizures as well. Although clear evidence exists for agenetic basis of febrile seizures, the mode of inheritance is unclear. [9] While polygenic inheritance is likely, a small number of families are identified with an autosomal dominant pattern ofinheritance of febrile seizures, leading to the description of a "febrile seizure susceptibility trait" with an autosomaldominant pattern of inheritance with reduced penetrance. Although the exact molecular mechanisms of febrileseizures are yet to be understood, underlying mutations have been found in genes encoding the sodium channeland the gamma amino-butyric acid A receptor. 26. Objective 5Describe the role and synthesis of GABA in the brain 27. GABA-A GABA-A receptors are coupled to chloridechannels activation of GABA receptors will permit chlorideto diffuse into the cell, hyperpolarize themembrane and decrease the excitability of thecell. 28. GABA-B The GABA-B receptor is coupled to potassiumchannels, forming a current that has a relativelylong duration of action compared with the chloridecurrent evoked by activation of the GABA-Areceptor. inhibit membrane excitability by openingK+ channels and inhibiting Ca++ channels. 29. Role of GABA GABA is made in brain cells from glutamate, and functions as an inhibitory neurotransmitter meaning that it blocks nerve impulses. Glutamate acts as an excitatory neurotransmitter and when bound to adjacent cells encourages them to fire and send a nerve impulse. GABA does the opposite and tells the adjoining cells not to fire, not to send an impulse. 30. Synthesis of GABA