By Y. Cobryn. University of Natural Medicine.

The recommended mean dose in chil- with Dravet syndrome afer 2 months of treatment proven 20 mg atorlip-20. Treatment is usually started with a lower dose purchase 20mg atorlip-20 amex, and is gradually re-evaluated in a randomized order atorlip-20 20 mg with mastercard, placebo-controlled setting with en- increased to the recommended dose over 3 days cheap 20mg atorlip-20 with visa. The primary end-point was an increase in seizures tinal adverse efects, it seems to be, overall, relatively well tolerated. A decrease in seizure frequency com- References pared with baseline, which was the secondary end-point, was great- 1. Arzneimittelforschung1984;34: efects are usually reversible and they respond to reduction of the 199–204. Efcacy of stiripentol in the intravenous pen- ed adverse events are drowsiness, ataxia, tremor, hypotonia, dys- tylenetetrazol infusion seizure model in the rat. The discontinuation rate due to adverse events seems to be pharmacokinetics of (+)- and (–)-enantiomers of stiripentol. Reassessment of stiripentol pharmacokinetics tol group compared with 35% in the placebo group. The clinical pharmacokinetics of the newer antiepileptic drugs: focus on topiramate, zonisamide and tiagabine. Concentrations of stiripentol in children and Current place in therapy adults with epilepsy: the infuence of dose, age, and comedication. Ter Drug Tere is no clear evidence of efcacy of stiripentol in refractory focal Monit 2012; 34: 390–397. Infuence of stiripentol on cytochrome P450-mediat- ed metabolic pathways in humans:in vitro and in vivo comparison and calculation indicate that stiripentol is efcacious in Dravet syndrome, a severe of in vivo inhibition constants. Stiripentol in atypical absence seizures during stiripentol therapy: infuence of cytochrome P450 inhibition by stiripentol. Berlin: Springer-Verlag, 1999: pine plasma concentration and metabolism in epileptic children. In vitro andin vivoinhibitory efect of stiripen- in infancy: a randomised placebo-controlled syndrome-dedicated trial. Severe myoclonic epilepsy in infancy: a sys- nytoin, carbamazepine, and stiripentol on formation of 4-ene-valproate, a hepato- tematic review and a meta-analysis of individual patient data. Stiripentol in childhood partial epilepsy: ran- convulsant drug, in complex partial seizures uncontrolled by carbamazepine. Clinical antiepileptic efcacy of myoclonic epilepsy of infancy (Dravet’s syndrome)]. Children show higher clearance values Protein binding 96% Active metabolites None Comment A valuable drug for the adjunctive treatment of refractory focal seizures The Treatment of Epilepsy. First, unlike direct agonists, which produce a improved ability to cross the blood–brain barrier compared with continuous or non-physiological pattern of receptor stimulation, nipecotic acid. This is the only known mecha- Activity in animal models of seizures and epilepsy nism of tiagabine action. Tiagabine prolongs the duration, but not the magnitude, and pentylenetetrazole in mice and by pentylenetetrazole in rats of the peak inhibitory postsynaptic current, consistent with tem- [1]. Tiagabine does not induce the zures, and completely blocks the expression of focal seizures [2]. The drug is rapidly and nearly completely absorbed afer oral lethargic mouse model [7,8]. At even higher doses, a similar pattern could be pro- elimination half-life, the smoother absorption produced by con- duced in normal rats as well. Neuronal cell death Protein binding is high at 96%, but tiagabine does not displace was also reduced by tiagabine in the hippocampus of gerbils sub- highly protein-bound drugs, such as phenytoin and valproic acid, jected to cerebral ischaemia [11] and in the rat cerebral ischaemia from their binding sites. The volume of distribution is approximately model of delayed pyramidal cell death [12]. Less than 1% is Serum level monitoring excreted unchanged in the urine, and no active metabolites have Tiagabine should be titrated according to clinical efect. Pharmacokinetics in relation to age Moreover, due to the high plasma protein binding of tiagabine, The apparent oral clearance of tiagabine afer multiple dosing in total serum concentrations may not provide a reliable estimate of eight elderly subjects was found to be about 30% lower than in the amount of unbound, pharmacologically active drug. Elderly patients taking enzyme-inducing therapeutic drug monitoring for tiagabine is also complicated by co-medication also had tiagabine clearance values that were twice the fact that serum tiagabine concentrations are in the nanomolar as high as those of age-matched subjects not taking enzyme-induc- range, and technically difcult to measure reliably. Based on these ers, indicating that responsiveness to enzyme induction is not im- considerations, it is not surprising that clinical efects such as ad- paired in old age [24]. In one study, the Despite these limitations, a tentative reference serum con- apparent oral clearance of tiagabine normalized to body weight was centration range of 0. In practice, however, there are no clear in- in historical adult control subjects [25]. This implies that children dications for monitoring serum tiagabine levels, except for a check require higher doses than adults to achieve similar serum drug for compliance. The diference in apparent oral clearance between children and adults was much less when clearance values were nor- malized for body surface area than for body weight. Children re- Effcacy ceiving enzyme-inducing co-medication also had higher tiagabine clearance values than children on non-inducing co-medication. Pharmacokinetics in disease states The pharmacokinetics of tiagabine is unafected in patients with Cross-over placebo-controlled adjunctive therapy trials renal impairment or in subjects with renal failure requiring haemo- The initial phase 2 studies of tiagabine in focal epilepsy were two dialysis [27]. Patients with mild or moderate liver function impair- small placebo-controlled, adjunctive therapy, cross-over enrich- ment have been shown to have higher and more prolonged plasma ment trials. In the frst of these trials, 94 patients with complex concentrations of both total and unbound tiagabine than normal focal seizures, with or without secondary generalization, were subjects [28]. Patients with hepatic impairment also had more neu- started on a tiagabine dose of 8 mg/day, which was gradually in- rological adverse efects. Tiagabine should therefore be given with creased over a period of up to 8 weeks until seizures were suf- caution to patients with epilepsy who have a mild to moderate im- ciently reduced or unacceptable adverse efects occurred [33]. Patients then entered reduced initial and maintenance doses of tiagabine and/or longer a 4-week fxed-dose, open-label period on the dose attained afer dosing intervals compared with patients with normal hepatic func- titration. Patients with mild to moderate impairment of hepatic func- phase if their seizure frequency had been reduced by at least 25% tion should also be monitored closely because of the potential for during the fxed-dose period. Tiagabine should not be under double-blind conditions to switch to placebo or to continue used in patients with severely impaired liver function. Afer a 3-week washout period, each patient was switched to the alternative treatment, so those who had received tiagabine Drug interactions in the frst period were switched to placebo and those who re- Tere is no evidence that tiagabine causes either induction or inhi- ceived placebo were switched to tiagabine. Available evidence indicates that tiaga- of tiagabine in the double-blind phase was 32 mg/day. From the 42 bine does not modify the serum concentrations of concomitantly patients who contributed data for both periods of the cross-over administered drugs [22,29]. In vitro, valproic median seizure rate during the tiagabine treatment period was sig- acid may displace tiagabine from plasma protein binding sites, but nifcantly lower than during the placebo period for complex partial it is unclear whether serum unbound tiagabine concentrations are seizures (P = 0. Responder rate (percentage of patients with >50% seizure reduction) for all focal seizures (%) Reference Number of patients Daily dose of tiagabine (mg/day) Tiagabine Placebo Richens et al. The second phase 2 trial used the same design but allowed a max- groups occurred in the proportion of patients experiencing >50% imal dose of 64 mg/day [34]. The intent-to-treat group comprised rate reduction for complex partial, simple partial and all focal sei- 36 patients who received a mean total daily dose of 46 mg in the zure rates (Table 49. Tiagabine was signifcantly better than The three times daily dosing study was a northern Europe- placebo in reducing all focal seizures (P = 0. A total of 46% of patients with complex partial double-blind treatment phase and a 4-week termination period. Tiagabine was signifcantly more efective than placebo in parallel-group, double-blind, add-on studies in which tiagabine was patients with simple partial seizures with respect to the proportion compared with placebo in patients with refractory focal seizures. The patients then remained on a fxed dose for 12 weeks monly with tiagabine than with placebo in the three placebo-controlled of double-blind treatment. Median decreases in 4-week complex parallel group add-on trials in focal epilepsy [35,36,37]. Overall, 20% and 29% (n = 275), n (%) (n = 494), n (%) of patients in the 32-mg and 56-mg groups had a 50% or greater Dizziness 41 (15) 131 (27)** reduction in the frequency of complex partial seizures, compared Asthenia 39 (14) 99 (20)* with 4% in the placebo group (P = 0. During the frst month of treatment, doses were in- concentration/attention creased weekly to 32 mg/day. The treatment groups were placebo, Depression 2 (<1) 17 (3)* 16 mg tiagabine twice daily and 8 mg tiagabine four times daily The median changes in 4-week complex partial seizure rates were –1. Reproduced by permission of John Libbey the 8 mg four times daily group, versus –0. Tiagabine 637 Other randomized adjunctive therapy trials following regulatory approval [45]. Two hundred and ninety-two A multicentre, open-label, randomized, parallel-group study com- patients (39 children) were enrolled to be treated long term with pared the efcacy and tolerability of three times daily and twice dai- tiagabine.

Storage: Blood is the storage site of electrolytes buy atorlip-20 20 mg online, nutri­ cal or primitive blood cells (atypical mononuclear cells purchase atorlip-20 amex, ents order 20mg atorlip-20 fast delivery, chemicals buy atorlip-20 line, hormones, etc. Nutritive functions: Blood delivers all nutrients, such as glucose, lipids, proteins, vitamins, minerals, etc. Oncotic pressure: the albumin present in blood exerts coat for the detection of the abnormal cells in blood. Also, buffy coat osmotic pressure, known as oncotic pressure that con­ preparationis very useful for the detection of bacteria, fungi or parasites trols capillary filtration and prevents edema formation within neutrophils, monocytes or circulating macrophages. Respiratory functions: Blood transports oxygen from the total blood volume can be roughly calculated as lungs to tissues, and carbon dioxide from tissues to 70–80 ml/kg of body weight. Thus, by transporting gases blood serves an ume of blood is about 5 to 6 liters and in females about important function of respiration. Transport medium: Blood acts as the transport of blood present is significantly less than adults, the vol­ medium for various hormones, chemical substances, ume expressed per kg of body weight is more (80–90 ml/ nutrients, vitamins, etc. Temperature regulation: Blood plays an important Blood volume is determined by determining the plasma role in temperature regulation as it conducts heat volume and cell volume separately. The normal ratio of from the interior of body to the surface through blood plasma volume to cell volume is 55:45. Measurement of Cell Volume Cell volume is measured by measuring the volume of red cells. Note, 92% of plasma is water and they constitute minor fraction of the total cell volume. Usually, loss of water from blood as occurs in dehydra­ 59 tion increases specific gravity. The commonly used chromium isotope is Cr, which is attached to red cells through incubation of cells in the 1. It is mainly due to the number of cells and macromole­ cules like proteins present in the blood. Plasma volume is also meas­ Plasma is the fluid component of blood which constitutes ured by injection of serum albumin labeled with radioac­ about 55% of the total blood volume. However, to preserve clotting factors plasma should be Effective blood volume = the total blood volume – the frozen within 6 hours after collection. This means the volume which is present actually in the circulation that helps in perfusion of tissue. However, it is Composition of Plasma difficult to estimate the sequestered volume of blood in the visceral organs. The Specific Gravity and Viscosity of Blood major solute (solid) content is the plasma proteins, which Specific gravity: Specific gravity or density of whole blood constitutes about 7% of the plasma and other solutes is approximately 1. Globulins include different transport proteins like During blood coagulation, a soluble plasma protein called transferrin, ceruloplasmin, hemopexin, etc. They form different lipoproteins in combination with ting factors is called serum. Antibodies (immunoglobulins) are γ­globulins that are ing serum from blood by allowing the blood to clot formed by plasma cells. The serum is separated from blood by allowing the blood to Fibrinogen coagulate (serum = blood – fibrinogen and other clotting factors). Osmotic pressure: Plasma proteins are osmotically Types of Plasma Proteins active molecules, and the osmotic pressure of plasma Plasma proteins are of three types: albumin (4–5. Oncotic pressure retains fluid in the Albumin vascular compartment and, therefore, prevents loss This is the major constituent of plasma proteins. Being smallest in diameter among the plasma proteins, and kidney diseases, edema manifests due to escape in kidney diseases with glomerular injury it appears of water into the interstitial tissue space. Viscosity: Plasma protein contributes to about 50% Hypoalbuminemia also occurs in in liver diseases due of the viscosity of blood (red cells account for rest of to decreased formation of albumin. The viscosity depends on the molecu- tions, decreased colloidal osmotic pressure (oncotic lar shape of the plasma protein. This is why fibrino­ pressure) of plasma results in edema formation (see gen molecules that are elongated and fibrillar in shape below). Immunity: Antibodies are plasma proteins (gamma This is formed in the liver, cells of reticuloendothelial sys­ globulins). Globulins are divided into three categories: α (α1, α2), cellular pathogens and from the effect of toxic sub­ β (β , β1 2) and γ. Also, other clotting factors like pro­ facilitates rouleaux formation, which in turn increases thrombin are plasma proteins. Buffering: Plasma proteins form an important buffe­ ring system of the body called protein buffers. Protein store: Plasma proteins serve as mobile protein Plasma proteins can be separated by methods like salt reserve of the body, which can be utilized for tissue separation, paper electrophoresis, Cohn’s fractionation, growth, especially in situations of protein depletion. Blood is defined as liquid connective tissue that fills the heart and blood vessels. The normal blood volume in adults is 5 to 6 liters, which accounts for about 8% of the body weight. The plasma consists of about 55% of the total blood volume which is made up of water and solid particles. When blood is collected in an anticoagulated tube and allowed to settle by centrifugation, three layers are distinctly visible. The upper plasma layer is separated from lower red cell mass by a thin buffy coat. Many biochemical tests are performed by separating serum from blood by allowing the blood to clot. Determination of blood volume, types of plasma proteins, and functions of plasma proteins may be asked as Short Notes/Questions in exams. In Viva, examiners invariably ask the definition of blood, composition of blood, functions of blood, composition of plasma and function of each constituent, importance of buffy coat, how are plasma and serum separated, fresh frozen plasma, types of plasma proteins, functions of plasma proteins. When a student fails to answer the composition of blood and plasma, and functions of plasma proteins, it becomes difficult for examiner to give the pass mark. Outline the steps of different series (erythropoiesis, leucopoiesis and thrombopoiesis) of hemopoiesis. Hemopoiesis (or hematopoiesis) describes the for­ Types of Bone Marrow mation of blood cells, which is an active process that There are three types of bone marrow: red marrow, yellow must maintain normal number of blood cells in peripheral marrow and white marrow. During Red Marrow fetal life, hemopoiesis mainly occurs in the spleen and liver, and subsequently in red bone marrow present in the the red marrow is the active marrow and is red in colour. From childhood, red marrow consists of many blood vessels that contain sinusoidal capil­ is progressively replaced by fat tissues (yellow marrow). Therefore, normal hemopoiesis in adults is restricted to Marrow stroma: the marrow stroma consists prin­ vertebrae, sternum, ribs, clavicles, pelvic bones, skull and cipally of a network of sinuses that originate at the ends of humerus and femurs. All blood cells are derived from trilaminar sinus wall contains three components: the pluripotent stem cells, referred to as hemopoietic 1. Red cells develop from mopoietic activity ceases in tibia and femur by third decade of life, ‘erythroid nests’. Yellow marrow can revert Red Marrow Yellow Marrow back to hemopoietically active red marrow when pro­ 1. Activity Red in color, and contain Yellow in colour, longed demand persists as occurs in chronic hemolytic active hemopoietic tissue and Inactive anemia. Cellularity Highly cellular; contains all Very less cellular; con- listed in Table 10. Sites In adults, it is restricted to In all other bones White Marrow vertebrae, sternum, ribs, except ends of long In very old individuals, a gelatinous transformation of fat clavicles, pelvic bones, skull bones, and axial and ends of humerus and skeletons to a mucoid material occurs in bone marrow. Bone Marrow Examination the bone forming cells are present between the sinusoidal capillaries. The adventitial reticular cells are Bone marrow examination is indicated in complex hema­ fibroblasts capable of transforming into adipocytes (fat tological disorders and malignant hematological condi­ cells). Endothelium and reticular cells are the sources of tions that require detailed analysis of cellularity and activ­ cytokines that profoundly influence hemopoiesis. The bone marrow examination is done of precursor cells (blast cells, progenitor cells, megakary­ for the following types of assessments: ocytes) are present in the bone marrow trabeculae. Cellularity of the marrow (normocellualr, hypercellular cells are produced from the erythroid ‘nests’. State of erythropoiesis, myelopoiesis and megakary­ row is replaced by fatty tissue and slowly becomes inac­ opoiesis tive. Number of lymphocytes (normal, increased or abnormal) cease to produce cells, and active marrow is limited to the 5. Other cells : Metastatic tumor cells, parasites (malaria, membranous bones like skull bones, vertebrae, ribs, ster­ Leishmania Donovani, etc.

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Location: generalized (including bilateral synchronous patterns) discount atorlip-20 20 mg, (a) Generalized lateralized order atorlip-20 20 mg without prescription, bilateral independent 20 mg atorlip-20 visa, multifocal i buy atorlip-20 from india. Atypical absence status pattern duration and index, onset (sudden or gradual) and iii. Adolescence and adulthood (13–60 years) Boundary syndromes (currently indeterminate conditions) 5. This is perhaps because at one level it is and 1989 are amongst the organization’s greatest achievements. A the work of gardeners not botanists, and thus has been usually a number of general observations concerning classifcation and ter- matter of opinion (assertion) and not of fact. The fare-up of pas- minology in epilepsy become apparent when an historical approach sions in 1969/1970, in 1989 and now in 2010–2014 are evidence is taken, and I end this chapter with a brief consideration of these. Everyone can have an opinion, and it seems that everyone What is abundantly clear from the historical perspective is that does, ofen from a limited viewpoint (the current author is guilty the state of knowledge in the feld of epilepsy is such that our cur- of this), and it is sad to see the intrusion of politics and personal rent and past classifcations schemes have been by necessity utilitar- opinions and vanities into a feld that should be dry and academic. Although much efort has been expended, ture, must win the approval of the community at large and cannot and with boring regularity unsubstantiated claims to the contrary be forced through on to unwilling recipients. To try to do so sim- have been made, we are as far as ever from being able to devise a ply causes confict, as has been evident on several occasions. First, there is a danger that, through a desire to be too However, this only works if the results of the consultation are heed- all-inclusive, the schemes become too complex and unwieldy, there- ed, as Gastaut found to his cost in 1969/1970. Given that they are gardening in tion schemes have also depended on an acceptance of the authority character and thus derive their worth entirely from their utility in of their authors, and the widespread respect that Jackson, Gastaut common practice, complexity is an enemy. The failure of uptake and Dreifuss commanded was instrumental in the success of their of the 1989 Classifcation of the Epilepsies and Epileptic Syndromes schema. Let us hope a botanical scheme, fully sci- ity (indeed, on the contrary, it is of excellent quality) but due to entifcally justifed, based on such aspects as pathophysiology, neu- its complexity. Similarly, Gastaut’s summary classifcation of 1964 rochemical systems, or physiological or anatomical networks, and (Table 1. As knowledge advances, the feld becomes more complex, but the difcult trick for classifcationists is to maintain a balance between the Scylla of superfciality and the Charybdis of Acknowledgement intricacy. Of course, these ‘axes’, known then as ‘criteria’ or ‘parameters’, were used in all the previ- ous schemes, but were not there separated so conclusively as is the References current trend. On the anatomical, physiological and pathological investigation of are difcult to beat in this regard. London: Hodder and spuriously justifed as being needed by advances in science, should Stoughton, 1930: 162–172. International League Against Epilepsy – the second peri- Neurol 2011; 52: 541–547. Modern technology calls for a modern Against Epilepsy 1909–2009: A Centenary History. Oxford: Wiley Blackwell, 2009: approach to classifcation of epileptic seizures and the epilepsies. Commission on Classifcation and Terminology of the International League Adults and Children. Classifcation of the epilepsies: proposal for an international classifca- cause in epilepsy. Commission on Classifcation and Terminology of the International League the epileptogenic zone. Seizure precipitants (triggering factors) in patients with epi- Science, 2009: 3–20. Terminology and organization of seizures and epilepsies: radical Treatment Advances in Neurology, Vol 34. Although the diagnosis of an epileptic disorder can important single component of the assessment. Ascertain precise- be straightforward, it is ofen not so, and this is especially the case if ly the circumstances of the event, any warning that occurred, the the event is unwitnessed, or if the history is incomplete. Tere are a duration of the attack, exactly what occurred during the event, the wide variety of neurological and non-neurological conditions that nature and speed of recovery and as well as whether there were any are mistaken for epilepsy, and the most frequent and challenging focal or lateralizing signs afer the event. Tere is no substitute for a distinction is between epileptic events and syncope or presyncope. What was the patient engaged in the day and evening ies have shown that syncope is commonly misdiagnosed as epilepsy, prior to the event? Was there sleep deprivation or were there other largely through ignorance of the complex prodrome that may occur, medical problems? Ob- and the sometimes dramatic nature of a clinical event that shares taining an eyewitness account is crucial and the telephone is now an many features with epileptic convulsions [1]. Whereas the patient may re- are confused with epilepsy include cerebral ischaemia or paroxys- call a simple fall or brief loss of consciousness, an eyewitness may mal symptoms of demyelinating disease, raised intracranial pressure, provide a detailed account of generalized convulsion with postictal Tourette syndrome and other movement disorders. Patients present- confusion, tongue biting and so on, for which the patient is ofen ing with behavioural symptoms most ofen have a primary psychiat- amnesic. Clinical examination can provide useful information, particularly if The surprising abundance of misdiagnosed epilepsy has been con- undertaken in the hours afer the event, but is most ofen non-con- frmed in a number of studies, and is cause for much concern [2,3]. Supportive investigations including electroencephalo- Epilepsy remains primarily a clinical diagnosis. Loss of driving privileges is ofen the the adult patient with epilepsy and, conversely, on interictal traces most immediate and traumatic component for patients whose liveli- around 20% of people have minor and irrelevant abnormalities that hood depends on a valid driving licence. From all perspectives, the are frequently misinterpreted as confrming a diagnosis of epilepsy. Tere are obvious causes, such as sudden pain, venesection, emotion, standing for long periods or watching unpleasant movies. However, mechanical causes, such as cough, General approach to the diagnosis of urination or defecation, may also provoke syncope; the diferenc- episodic disturbances es between syncope and epilepsy are detailed later in the chapter. As an enormous variety of conditions can cause episodes of tran- Episodes of loss of consciousness occurring with postural change siently disturbed consciousness or function, the major component are more likely to be syncopal. Determining the nature of events such as change in head position, rolling in bed, looking up at a high The Treatment of Epilepsy. Relationship to eating raises the possibility of a hypoglycaemic may be minor tone changes or fickering of the eyelids but marked basis. Classic complex partial seizures Events that occur from sleep, even if only some of the time, are are easy to diagnose if they comprise a warning followed by loss almost always epileptiform. Sleep disorders enter the diferential di- of contact, oral and manual automatisms and postictal confusion, agnosis. Generalized tonic–clonic seizures may or may not zures are sometimes linked to particular phases of the menstrual be preceded by a warning; the event usually lasts less than a min- cycle, and while once thought to indicate a functional element, this ute or two, lateral tongue biting and incontinence are common, the is very common in women with epilepsy. The total absence of circumstances, particularly in the cognitively impaired, might be confusion afer a generalized convulsive event should immediately behavioural in origin rather than due to seizure activity; however, raise the suspicion that the event was not epileptic. Tose who describe focal neurological the events usually draws the attention of those around the patient. Partial sei- are likely to be experiencing seizures; however, some symptoms can zures of temporal lobe origin are usually associated with altered be fairly non-specifc, such as light-headedness and dizziness. True consciousness, at least to some degree, although this is ofen not vertigo is rarely a feature of epileptic attacks but it is not always perceived by the patient. Tere are accounts of patients experienc- easy to distinguish vertigo from brief seizures. A visual aura can be ing generalized tonic–clonic convulsions and being able to recall epileptiform but more ofen is migrainous. When this occurs, it is usu- shimmering scotomatous defcit evolving over some minutes with ally because the motor activity is actually caused by partial seizures or without a headache following, and possibly associated with oth- of frontal or parietal origin, when consciousness can sometimes be er neurological symptoms, is described then migraine becomes a preserved despite the bilateral symmetry of the motor activity [6]. Similarly, seizures of extratemporal origin, particularly those The duration of attacks is probably the best single guide when originating in the frontal lobes, sometimes have bizarre features that considering the nature of the episodes. Migrainous neurological monitoring with scalp electrodes can be unremarkable during these symptoms are usually 15–20 minutes in duration; the subsequent events, obscuring the issue diagnostically. Helpful clues are the ste- headache can last for hours but may occasionally be absent, and if reotypic nature of attacks, which ofen cluster, and the fact that they so there is a much greater likelihood that they will be misdiagnosed ofen arise from sleep. With epileptic events, there is ofen some warning and a structural cerebral pathology, the diagnosis is usually clear. The convulsive scribes driving or walking some distance, and then fnding them- phase of generalized tonic–clonic seizures typically lasts 40–90 s selves at their destination (or just missing it), and not able to recall but is occasionally longer. Although sta- vehicle, it is highly unlikely such activity occurred during a seizure. It can be difcult to provide Afer an event, rapid recovery, perhaps with sweatiness or nau- satisfactory reassurance that this is a benign phenomenon experi- sea and vomiting, is more typical of syncope than of epilepsy.

Relapse rates in vigabatrin-treated infants in the three active-con- trol randomized trials summarized here ranged between 8% and Efcacy versus aetiology: infantile spasms 20% buy discount atorlip-20 line. Complete cessation of (11 of 11) of vigabatrin-treated patients compared with 45% (5 of spasms occurred in 68% of patients (131 of 192) atorlip-20 20mg visa, 19% had a reduc- 11) of hydrocortisone-treated patients purchase 20mg atorlip-20 with visa. Relapses occurred in 21% (28 of Response was observed within 1 week in the majority of patients discount atorlip-20 online visa. At the mentioned in all studies) varied between 50% and 100% in crypto- fnal evaluation (follow-up at least 3. A signifcant diference in seizure outcome low, ranging from single cases to a maximum of 14%. Efcacy in and intellectual development was found between infants treated terms of complete cessation of spasms did not difer between newly with vigabatrin within the frst weeks afer seizure onset, and in- diagnosed infants (43%, 45%) [43,44] and infants who were initially fants with a treatment delay of 3 weeks or more. Sometimes was present in 61% of children in the early treatment group and in response was observed afer one or two doses [50]. The for qualifying responders was proposed in diferent controlled and degree of intellectual disability correlated with seizure outcome. In group 1 of spasms and hypsarrhythmia at doses ranging from 25 to 135 mg/ (‘standard therapy’, 31 of 45) vigabatrin was started early afer the kg/day in 12 of 20 infants. At 24 months of age, mental disa- average dose (59 mg/kg/day) at the time of relapse and responded bility was signifcantly more frequent and severe in the ‘standard’ to an increase in dose to a mean of 83 mg/kg/day. A maximum treatment duration of 6 months was pro- pared with the ‘standard’ therapy group. Vigabatrin controlled the spasms in fve of these pa- frequency compared with those treated with placebo: relative risk tients (26%) [60]. Efcacy versus aetiology: infantile spasms with other In addition to placebo-controlled trials, there have been many aetiologies uncontrolled studies. Several open-label studies children with focal cortical dysplasia who presented with early focal have assessed long-term efcacy. Focal seizures remained medically re- to maintain their initial positive response [74,75]. Patients were required a favourable response in infantile spasms associated with Aicardi to exit the study if a >50% increase in seizure frequency occurred. An open-label prospective study that included 175 mostly in- Focal seizures fants, but also neonates, children and adolescents with focal sei- zures assessed the response to vigabatrin given as add-on to car- Adjunctive therapy studies in adults bamazepine, phenytoin or benzodiazepines. Tirty per cent of the The efcacy of vigabatrin as adjunctive therapy in adults with patients became seizure-free, and a >50% reduction in seizure fre- refractory focal epilepsy was initially demonstrated in several quency was achieved in 70%. The highest percentage of respond- double-blind, placebo-controlled, cross-over studies. In contrast, over study from Australia [68], demonstrated a clear response at in another cohort of 121 patients aged 1 month to 29. Most patients in the placebo group were responders, whereas responder of the children (46 of 80) had focal epilepsies. While low-up, 33% of the children on lamotrigine showed a sustained 6 g/day provided no improvement in efcacy over 3 g/day, adverse improvement in seizure frequency, compared with 19% of those efects increased substantially at the higher dose. However, no signifcant diferences in efcacy among doses between 1 and 6 g/day [71]. Patients treated with vigabatrin treatment groups were found for children with focal seizures. Vigabatrin 673 Another study followed-up 56 children with difcult-to-treat ep- in Lennox–Gastaut syndrome have not produced promising results ilepsies who had received vigabatrin (n = 56) or lamotrigine [81]. Possible precipita- with 11 having unclassifed epilepsy), whereas the proportion of tion or exacerbation of myoclonic seizures, absence seizures and lamotrigine-treated patients with focal epilepsy was lower (23 of non-convulsive status epilepticus has also been reported by other 39). No loss of initially observed ef- Overall, available data suggest that vigabatrin might have a very cacy was apparent in the lamotrigine group, whereas 10 of the 18 limited role as add-on treatment in some generalized epilepsy syn- initial responders on vigabatrin appeared to lose their response, dromes, but not in patients with myoclonic seizures as the main usually within the frst 9 months. In a long-term follow-up study of 196 children with various refractory epilepsies, non-progressive myoclonic epilepsy Monotherapy studies in adults and children and Lennox–Gastaut syndrome showed the highest increase in sei- A double-blind, double-dummy substitution trial compared add- zure frequency (38% and 29%, respectively) [97]. The two groups juvenile absence epilepsy, juvenile myoclonic epilepsy and epilep- showed similar percentages of responders (53% versus 51%) and sy with grand mal on awakening [98]. Seizure aggravation has also similar proportions of patients maintained on alternative mono- been described in children with Angelman syndrome [99]. Vigabatrin monotherapy in adults with newly diagnosed focal epilepsy was investigated initially in an open-label randomized Adverse effects study in 100 patients, using carbamazepine as a comparator [83]. Apart from visual feld constriction, vigabatrin can induce a num- In this study, there was a clear trend for seizure freedom rates to be ber of other adverse efects, most of which relate to the central nerv- greater on carbamazepine. In adults and older children, the most common ble-blind, parallel-group study also compared vigabatrin with car- adverse efects are fatigue, drowsiness, dizziness and weight gain. Nystagmus, agitation, amnesia, abnormal vision, ataxia, confusion, Fify-three per cent of 229 patients on 2 g/day vigabatrin and 57% psychosis, depression and diarrhoea have also been reported [100]. However, signifcantly more patients on vigabatrin with- dation, insomnia, hyperactivity, agitation, weight gain and hyper- drew due to lack of efcacy than with carbamazepine, and time to tonia or hypotonia [35,42,91,92]. Most of these adverse efects are frst seizure afer the frst 6 weeks from randomization also showed dose-related and reversible when the dose is reduced. Formal testing of mood disturbances in 73 adults with refrac- genic and symptomatic cases. In two of the studies, allocation to tory epilepsy treated with vigabatrin revealed that mood problems treatment was randomized [85,86]. In all three trials, the efcacy of were the main reason for discontinuation of the drug [104]. A re- vigabatrin and carbamazepine did not reveal signifcant diferences, view of double-blind, placebo-controlled trials of adjunctive vigab- and there was a suggestion for a better tolerability profle of vigaba- atrin therapy in a total of 717 patients with refractory focal epilepsy trin during the 2-year follow-up [86]. Tese studies have limitations confrmed that vigabatrin, when compared with placebo, was as- because of their small sample size and lack of blinding, but they sociated with a signifcantly higher incidence of depression (12. Depression was usually mild, and psychosis was re- Generalized epilepsies ported to respond to reduction or discontinuation of vigabatrin or An early multicentre study assessed outcomes of add-on therapy to treatment with antipsychotic drugs. Efcacy was better in children with focal seizures than in those pected, amino acid chromatography should be performed before with generalized seizure types. In addition, vigabatrin can gabatrin more efcacious against focal seizures [89,90], although interfere with urinary amino acid analysis due to inhibition of ca- this has not been an invariable fnding [91]. Visual feld constriction Anecdotal case reports described favourable efects of vigaba- Severe symptomatic visual feld defects associated with vigabatrin trin in neonatal seizures due to Ohtahara syndrome [93]. A further 674 Chapter 52 120 105 90 0 70 135 45 60 50 30 150 40 30 165 15 20 10 180 90 80 70 60 50 40 30 20 10 10 20 30 40 50 60 70 80 90 0 30 10 20 195 345 30 40 210 50 330 60 225 70 315 240 255 270 285 300 Figure 52. Usually, the constric- Reported prevalence data for vigabatrin-associated visual feld tion of the visual feld is concentric, afects both eyes and is gen- constriction in children are variable, presumably due to diferences erally more marked nasally than temporally (Figure 52. In the in perimetric techniques and difculties in ensuring the child’s co- central visual feld (within 30 degree of eccentricity), frequently an operation. Several studies using Goldmann perimetry or the Hum- annular nasal defect can be observed [110]. The visual defects are phrey feld analyser in patients aged 5–21 years found prevalence irreversible. The prevalence of vigabatrin-induced visual feld constriction [52] performed Goldmann perimetry tests in 91 visually asympto- varies depending on age, gender, extent of exposure to vigabatrin matic Finnish children aged 5. Because of slow development of the visual constriction in repeated test sessions in 17 children (18. A total of 734 patients exposed to vigabatrin (44%) had cluding 49 aged 8–12 years) treated with vigabatrin for >6 months, visual feld loss compared with 30 (7%) vigabatrin-naïve patients. Perimetric testing was performed every 6 months for up to for patients with greater mean cumulative dosage and older age. In group I, visual feld constriction at the last visit with a small study which reported serial monitoring of 14 adults exposed a conclusive examination was diagnosed in 31. Visual feld degree of variability in visual feld size between successive test ses- constriction was signifcantly associated with duration of vigabatrin sions. Tere was a trend for visual feld constriction to be less in three and severe in four cases). Overall, these data indicate that frequent in the younger age groups, but the statistical power of the the risk of peripheral visual feld constriction afer vigabatrin ex- comparisons was limited by the small size of the subgroups. In con- posure during early life is low when duration of treatment is short clusion, approximately one-third of patients aged ≥8 years exposed and cumulative dose is low. However, the risk increases rapidly with to vigabatrin exhibited visual feld defects which were not encoun- treatment duration over 2 years.

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Patients suffering from slipping rib syndrome will also exhibit a positive ultrasound slipping rib test on transverse ultrasound imaging of the affected rib cheap atorlip-20 20 mg without a prescription. The ultrasound slipping rib test is performed by imaging the rib and associated anterior costal cartilage suspected of slipping with the patient’s abdominal wall completely relaxed and then having the patient perform a vigorous Valsalva maneuver trusted atorlip-20 20 mg. The test is positive if the affected rib moves cranially and overlaps the rib above it (Fig buy atorlip-20 20 mg with visa. If the anterior costal cartilage and adjacent ribs are intact order 20 mg atorlip-20 otc, under ultrasound imaging, with vigorous Valsalva maneuver, the adjacent ribs will be seen to move in concert downward (Fig. The hooking maneuver test for slipping rib syndrome is performed by having the patient lie in the supine position with the abdominal muscles relaxed while the clinician hooks his or her fingers under the lower rib cage and pulls gently outward. Pain and a clicking or snapping sensation of the affected ribs and cartilage indicate a positive test. B: When rectus muscle (rm) contraction is initiated, the eighth rib moves cranially and overlaps the seventh rib (curved arrow). D: At maximal contraction, the two ribs are at the same depth, below the rectus muscle. E: As the contraction decreases, the eighth rib jumps away from the seventh rib (arrow). Slipping rib syndrome: a place for sonography in the diagnosis of a frequently overlooked cause of abdominal or low thoracic pain. High-resolution longitudinal ultrasound images of the lower right thoracic wall in a healthy volunteer, with transverse sections of the seventh (asterisks) and eighth (hashtag) ribs. B: When rectus muscle (rm) contraction is initiated, the seventh and eighth ribs move down jointly (arrows). C: As the muscle contraction increased, the ribs continue to be pushed down together (arrows). D: At maximal contraction, the two ribs are at the same depth, below the rectus muscle. Slipping rib syndrome: a place for sonography in the diagnosis of a frequently overlooked cause of abdominal or low thoracic pain. Based on the patient’s clinical presentation, additional testing may be indicated, including complete blood cell count, prostate-specific antigen, sedimentation rate, and antinuclear antibody testing. Computed tomographic, magnetic resonance, or ultrasound imaging of the affected ribs and cartilage is indicated to help confirm the diagnosis of slipping rib syndrome and to help identify occult mass and/or lower intrathoracic or upper intra-abdominal tumor (Figs. Computed tomographic image demonstrating infarction of the hepatic flexure of the colon secondary to avulsion of the mesenteric artery following blunt upper abdominal trauma. The anterior costal cartilage and associated ribs at the level to be blocked are then identified by palpation. A linear high-frequency ultrasound transducer is then placed in the transverse plane with the superior aspect of the ultrasound transducer rotated approximately 15 degrees laterally over the affected costal cartilage and rib and an 659 ultrasound survey scan is obtained (Figs. The rib will be identified as a slightly hyperechoic ovoid structure with a hypoechoic center. The affected costal cartilages and associated ribs are then identified by the ultrasound slipping rib test (Figs. Longitudinal placement of the ultrasound transducer over the anterior costal cartilage and associated ribs with the superior aspect of the transducer rotated laterally approximately 15 degrees. Longitudinal ultrasound image demonstrating the adjacent ribs and the rectus muscles. Reassurance is required, although it should be remembered that this musculoskeletal pain syndrome and intra-abdominal pathology can coexist. One of the challenges in the treatment of the patient suffering from slipping rib syndrome is the fact that repeated abnormal movement of the affected rib segments promotes ongoing laxity of supporting ligaments and cartilage of the ribs delaying healing of the problem. Slipping rib syndrome: a place for sonography in the diagnosis of a frequently overlooked cause of abdominal or low thoracic pain. The muscle fibers of the diaphragm converge on a strong central aponeurotic tendon. The superior surface of the dome of the diaphragm serves as the floor of the thoracic cavity, with the inferior potion of the dome serving as the roof of the abdominal cavity. The musculofibrous fibers of the central portion of the diaphragm attaches anteriorly to the xiphoid process, with the ventral aspect of the diaphragm attaching laterally to the costal cartilages of the seventh through twelfth ribs as well as the transverse processes of the first lumbar vertebra and the vertebral bodies of the first through third lumbar vertebra (Fig. Peripherally the diaphragm attaches to the lower confines thoracic outlet by a musculotendinous structure called the diaphragmatic crura (Fig. The crura attach anteriorly and laterally to the thoracic wall, with the posterior portion of the diaphragm attaching into the posterior abdominal wall, which means that the diaphragm is set obliquely relative to the coronal plane with the anterior portion of the diaphragm attaching superiorly when compared with the posterior portion (Fig. The top of the dome-shaped portion of the diaphragm lies in a roughly horizontal plane relative to the thoracic and abdominal viscera when in a relaxed state. As the dome-shaped portion curves down to attach to the thoracic and abdominal walls, the diaphragm assumes a more vertical position relative to the thoracic and abdominal viscera as it attaches to the thoracic and abdominal wall. This vertical area is called the zone of apposition as the vertical portion of the diaphragm is apposed to the abdominal contents (Fig. The diaphragm is a fibromuscular, elliptically shaped cylinder that is capped by a dome that separates the thoracic and abdominal cavities and functions as the main muscle of respiration. Note how the musculotendinous fibers attach to the xiphoid and the costal cartilage of the anterior chest wall. The diaphragm attaches peripherally to the lower confines thoracic outlet by a musculotendinous structure called the diaphragmatic crura. The crura attach anteriorly and laterally to the thoracic wall, with the posterior portion of the diaphragm attaching into the posterior abdominal wall, which means that the diaphragm is set obliquely relative to the coronal plane with the anterior portion of the diaphragm attaching superiorly when compared with the posterior portion. The diaphragm is primarily innervated by the phrenic nerve which is comprised of fibers from the third, fourth, and fifth cervical nerves. The phrenic nerve provides motor innervation and also carries afferent sensory information from the central portion of the diaphragm, with fibers from the fifth through eleventh intercostal and the subcostal nerves providing sensory innervation to the more peripheral portions of the diaphragm. A,B: A number of apertures allow the passage of the aorta, esophagus, and vena cava from the thoracic to the abdominal cavity as well as lymphatics. This increase in intrathoracic volume creates an interthoracic pressure that is lower than that of the upper airways causing air to flow into the lungs. When the diaphragm relaxes, the elastic recoil of the chest wall and lung causes air to flow from the lungs. With contraction of the internal intercostal and abdominal muscles, forced expiration will occur. In addition to its function as the main respiratory muscle, the diaphragm is also involved in a variety of nonrespiratory functions including hiccups, vomiting, urination, defecation, as well as helping 664 prevent stomach acid reflux by compressing the esophagus as it passes through the esophageal diaphragmatic aperture. Causes of diaphragmatic dysfunction are many and include central, spinal, and peripheral neurologic disease, muscular disease, structural abnormalities of the chest wall and spine such as flail chest and sever scoliosis, pulmonary diseases that cause hyperinflation of the lungs, thoracic and abdominal masses, abnormal fluid accumulations, metabolic diseases, glucocorticoids, and idiopathic causes (Fig. Diaphragm dysfunction can be caused by neurologic disease from the cerebral cortex to the peripheral nerve as well as by structural abnormalities of the chest wall, spine, and abdomen. Dysfunction of the diaphragm can range from mild weakness of muscle contraction to complete paralysis and can affect one or both hemidiaphragms. In the otherwise healthy patient who is suffering from mild to moderate unilateral diaphragmatic dysfunction, the patient will be asymptomatic at rest, with some noticeable dyspnea with exertion. With unilateral diaphragmatic paralysis, the otherwise healthy patient will usually notice some dyspnea at rest, especially when the patient assumes the supine position. With mild to moderate bilateral diaphragmatic dysfunction, even healthy patients will be symptomatic at rest, with bending, submersing in water above the waist, bending and exertion exacerbating the feeling of breathlessness. In this setting, most patients must sleep in a recumbent position and most experience easy fatigability, abnormal sleep patterns that may include periods of hypoventilation, and frequent respiratory infections. Comorbidities including significant obesity, pulmonary, and/or cardiac disease will worsen the patient’s dyspnea. A history of the acute onset of neck and shoulder pain without antecedent trauma suggesting Parsonage–Turner syndrome, recent injury of the cervical spine, recent neck or cervical spine surgery, recent manipulation of the cervical spine, should point the clinician toward a diagnosis of diaphragmatic dysfunction as should a history of neuromuscular disease. The first step in assessing the patient suspected of diaphragmatic dysfunction, regardless of cause is the immediate assessment of the adequacy of ventilation with pulse oximetry determination at rest and on exertion. If there is significant hypoxemia, arterial blood gasses to evaluate carbon dioxide levels and acid–base status should be 665 obtained on an emergent basis. Physical examination should evaluate if tachypnea is present and determine the patient is using accessory respiratory muscles to breath by gentle palpation of the sternocleidomastoid muscles to identify rhythmic muscle contraction and relaxation during inspiration and expiration. Careful examination of the chest wall and abdomen for hyperinflation associated with chronic obstructive pulmonary disease, abnormal mass and/or structural abnormality that may be causing impairment of diaphragmatic excursion is carried out as well as careful observation for the abdominal paradox which is pathognomonic for diaphragmatic dysfunction (Fig. This paradoxical breathing pattern is observed in patients who must use of the accessory muscles of respiration including the internal intercostal muscles to maintain adequate respiration.

Nitroso-urea-cisplatin-based chemo- quences of the co-administration of lamotrigine and a combined oral contracep- therapy associated with valproate: increase of haematologic toxicity purchase atorlip-20 20 mg fast delivery. For all these reasons order atorlip-20 discount, it is imperative that The World Health Organization estimates that epilepsy causes diagnosis of epilepsy is accurate and that the individual is provided 6 buy 20mg atorlip-20 mastercard. In fact purchase generic atorlip-20 online, the epilepsy services and in- Clinical history vestigation modalities are ofen inversely proportional to the bur- Epilepsy is primarily diagnosed based on a detailed description of den of epilepsy. Despite the wide availability of simple and efective the clinical features of the episode in question by the patient, eye- methods in evaluating and managing the epilepsies, it is reported witness or both [12]. Patients may use rather vague terms to represent [3] and, even if they do, their situation is made more difcult by a otherwise specifc descriptions and this warrants the information high burden of stigma [4,5]. The latter is woefully under- sudden catastrophic nature of epileptic events can render eyewit- funded and highly stigmatized. The diagnosis epilepsy syndrome-specifc diagnosis which must also be taken into of epilepsy in a particular individual is viewed with trepidation, account during the clinical history. Even with these limitations, the and has signifcant social and medical implications which include epilepsy care provider must take a detailed and credible history loss of job, signifcant worry about transmission to children, loss of without overlooking specifc details. The patient’s history should independence and a traditional or socially generated anxiety about include birth history, developmental history including trauma with the underlying cause [9,10]. With such beliefs, microorganisms, malnutri- person’s interests, personality and life history. All these will usually tion and defciency states are ofen not regarded as disease-causing be relatively easy to acquire, unless there are cognitive comorbidi- agents. Traditional medical practices and treatment are Preliminary data from an epilepsy project currently running in thus widely accepted, and faith and psychic healers thrive. The project is based on the primary care approach and perceptions of causes and treatments for diseases such as epilepsy uses the existing healthcare structure. Even though these data are yet to be care system, the cost of this service is not covered and it is there- replicated, they hold the promise of providing a basic approach to fore out of the reach of many patients. It has low sensitivity in the frst instance with a epilepsy: serum calcium, magnesium, and renal and liver function 50% case identifcation rate for epilepsy but the sensitivity increases tests. Tese are ofen of little diagnostic value in otherwise healthy on prolonged or repeated recordings. However, to antiepileptic therapy can result in unwarranted further labora- lack of political will and health investment, poverty or both, and the tory evaluations and the improper discontinuation of antiepileptic absence of adequate manpower limit the use of simple procedures therapy. This serves as a flter When this is done, pertinent conditions that are later inadvertently to reduce wholesale use of neuroimaging. Blood about 65–85% of patients with a subsequent diagnosis of epilepsy monitoring of antiepileptic drugs is expensive and an unrealistic [22,23,24]. In the major- standard investigation, a wholesale policy of unselected neuroimag- ity of patients, however, knowledge of common adverse reactions ing for epilepsy is unrealistic in many situations. However, this can be very dif- Available data exist for over 25 diferent medications used in the fcult in cultures where diseases like epilepsy are believed to be the treatment of epilepsy with more than half having been developed result of witchcraf and social wrongs. Tese drugs are usually available as pro- grammed drugs to the psychiatry services but have frequent sup- ply chain breaks. Concern about the This results in situations where a patient may be exposed to perhaps disease is far more than just the medical burden of the disease. In Ghana, the standard anticonvulsants are available on ious countries and having a broad template for application in the a national health insurance drug list. Newer anticonvulsants are not available wholesale, and thus es as the way forward to providing an efective epilepsy service. Without reasonable estimates of the dis- ken teeth and tongue laceration result from the inadvertent inser- ease burden, many programmes will not stand the test of time. Large community-based studies can be restricted Tese practices are fuelled by age-old beliefs, for example that epi- because of fnancial constraint but simple hospital-based studies lepsy can be cured by burning in an open fre [5]. In Ghana, epilep- provide useful insights into the prevalence of epilepsy in many sy is the most common presentation for more than 70 degree burns communities. The fnding from such studies could help in the re- to the burns and reconstructive surgery centre. This will pave way for formal studies that can provide accurate estimates Non-pharmacological care of epilepsy and lead to major policy formulation and the sourcing of external Non-pharmacological care is complementary to drug therapy in the funding. Education of This identifes the epilepsy type, seizure types, the standard inves- the patient with epilepsy, their family and community has a major tigations carried out based on afordability to the patient, and the role in care of epilepsy beside medical and clinical management. This database is at an The patient and family should be educated on what to do should early stage but provides a springboard from which future research seizures occur. The risk of injury during seizures and open fres, and major policy change can be realized in the care for patients with with certain jobs like rice feld workers who spend their day in epilepsy in that country. The massive public education drives have made these once mys- tical conditions widely accepted, leading to improved health care References 1. The ‘Newly Defned’ Burden of Mental Prob- to funding for such community and public driven campaigns, but lems. Epilepsy in developing countries: a review of epidemio- logical, sociocultural, and treatment aspects. Based on this experience, a massive public education drive cial landscape of a disease. Scaling up community-based services and improving quality of care in the state psychiatric hospitals: the way forward for observer. An overview of Ghana’s mental health system: agnosis, as this improves management both medically and socially. The attitudes of clergy in Benin A glance at unpublished data from the epilepsy clinic and an City, Nigeria towards persons with mental illness. Afr J Psychiatry 2013; 16: 196– ongoing epilepsy study in Ghana demonstrates that the percep- 200. As epilepsy surgery is not widely infuence on epileptogenesis and epilepsy comorbidities. Neurobiol Dis 2014; 72: practiced, the requirement for specialized investigations may not be 233–241. Electroencephalography: General Principles and Electrodiagnosis in cal history in these settings supersedes all types of investigations. Epilepsia2006;47: and the level of empathy by the clinician may have to be higher than 1225–1231. Patterns of diagnosis and therapeutic care of epilepsy at a tertiary referral center in Nigeria. Do patients who require emergency surgical procedures and in patients sphenoidal electrodes aid in surgical decision making in drug resistant temporal in whom the clinical history and geographical location support a lobe epilepsy? The selection of antiepileptic drugs for the treatment of epilepsy in ry investigations in infants and children presenting with fever and seizures at the children and adults. Only a handful of drugs could be prescribed, and making a choice among them was not a major prob- Medication-related characteristics lem. Today, with about 25 diferent antiseizure medications on the Spectrum of effcacy against specifc seizure types and syndromes market, drug selection is a much more complex process. In fact, the Expected magnitude of therapeutic response in the specifc seizure existence of a broad pharmacological armamentarium is a mixed type or syndrome blessing. On one hand, as each drug difers from the others, a wide Approved indications and contraindications choice of medications means that physicians have unprecedented Adverse effect profle, including teratogenicity opportunities to tailor treatment choices to the characteristics of Potential for interacting with other medications the patient [1]. On the other hand, familiarizing with the indica- Potential positive or negative impact on any comorbidities tions, contraindications, specifc properties and dosing schedules of Dose escalation requirements, and ease of use in adjusting dosage 25 diferent drugs is no easy task, and there are concerns that sub- Frequency of administration optimal knowledge could result in incorrect prescribing and related Availability of convenient formulations, including parenteral harmful consequences. Keeping up to date with rapidly expanding formulations knowledge is a challenge for every practitioner, and easy availabil- Cost and reimbursability ity of information in the electronic age does not necessarily imply ready access to high-quality, unbiased documentation. Other (mechanisms of action, monitoring requirements, quality In the era of evidence-based medicine, drug selection should be and amount of available information) best guided by careful assessment of the comparative benefts to Patient-related characteristics risks ratios of available treatments, based on results of well-designed, Seizure type and epilepsy syndrome randomized double-blind trials. Addition- Psychological and social setting, including personal concerns ally, therapeutic outcomes in many epilepsy syndromes have never about risk of seizure recurrence and specifc side-effects been evaluated in controlled trials [4]. Because of this, drug choice cannot be based solely on results of therapeutic trials, and a broader range of information must be taken into account. In fact, none of the patient, and ensures the highest probability of achieving seizure the available medications can be recommended as the treatment of freedom without causing undue adverse efects [6,7,8]. The overall objective is to select properties of individual drugs are discussed in the subsequent the treatment that provides the best match for the characteristics of chapters.

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Starting from the specifc inhibition reac- sus monkey were able to agglutinate the red blood cells of tion perfected by Landsteiner and colleagues (1902) to study many humans buy discount atorlip-20 20mg on line, who were termed Rh positive order 20mg atorlip-20, whereas those haptens buy atorlip-20 20mg visa, Moreschi reported in 1907 a new method to identify not possessing it were termed Rh negative buy generic atorlip-20 online. This factor was serological antibodies, which drew praise from Landsteiner shown to be important in hemolytic disease of the newborn. Coombs, Mourant, and Race, in the 1940s, devel- Landsteiner investigated poliomyelitis between 1908 and oped the antihuman globulin (Coombs) test based on the 1922. He discovered that a rhesus monkey became paralyzed same principle as Moreschi’s earlier report. After fnding no bacteria in the monkey’s nervous system, Landsteiner concluded that a virus must be the caus- ative agent. Landsteiner discovered that an extract of ox hearts could replace the antigen derived from livers of babies with con- genital syphilis, for use in the Wassermann test for syphilis. With his excellent background in chemistry, medicine, and pathology, Landsteiner continued his serology and immunol- ogy work at the Rockefeller Institute. He discovered that immuno- chemical specifcity was altered by the ortho, meta, or para position on aromatic rings of stereoisomers. Landsteiner further showed that partial antigens, termed haptens, were unable to elicit antibody formation, but could react with those formed in response to a complete antigen comprising a hapten bound to a carrier molecule. His extensive investigations on immunochemical specifcity were frst summarized in his book entitled Die Specifzitat der Serologischen Reactionen published in 1933. The English translation was published in 1936, and a revised edition appeared following his death in 1945 entitled the Specifcity of Serological Reactions. He found that haptens could com- bine with pre-existing antibodies to produce allergic desen- sitization. Damian transplanting the leg of modern immunology, including the construction of synthetic a Moor onto the stump of a young man who had lost his leg. A number of famous artists, including Fra Philip Levine (1900–1987), Russian–American immuno- Angelico and Fra Lippi, illustrated some aspects of this pop- hematologist. His work contributed much to transfusion possibility of transplantation, and was successful in replac- medicine and transplantation immunobiology. In time of war, in the days of hand-to-hand combat, the loss of a limb was the lot of many soldiers. He thought he was successful in transplanting a human for successfully joining blood vessels by end-to-end anasto- tooth into the comb of a cock, a specimen still on view at the mosis with triangulation sutures, thereby permitting the rapid Hunterian Museum. Early understanding of the principles of skin grafting by Alexis Carrel was born in 1873 in Sainte-Foy near Lyon, the Indian physician Sushruta can be found in a Sanskrit France. Grafts of skin from the and departed for America in 1904 to work in the Physiology forehead, neck, and cheek were used to restore mutilations of Department at the University of Chicago. Apparently the physicians the Rockefeller Institute for Medical Research in New York of the Alexandrian school understood how to repair such City as an associate member, achieving full membership in defects with skin faps also, which is documented in the De 1912. During the 13th and 14th centuries there was a resurgence of surgery practiced in the ancient medi- cal school of Salerno, and in the 15th century mention was made of two skilled practitioners of plastic surgery, Branca de Branca and his son Antonio, who practiced in Catania in Sicily. The next great step in transplantation was the work of Gaspare Tagliacozzi (Figure 1. He drew analogies from the agricultural practices of grafting in explaining his technique. He understood that xenografts were impossible and allografts were highly unlikely to unite, if only because of the awkwardness of keeping the two parts in close con- tact so that the graft could take. In spite of the excellence of Tagliacozzi’s book, the technique of skin grafting did not progress further until the 19th century when interest revived. A number of surgeons tried making free grafts in animals and also attempts were made in humans, although, without the refnements of aseptic technique and anesthesia and since the principles of immunology were not yet known, not much progress was made. Their aim following the liberation, Carrel was accused of collaborating was to grow cells from warm-blooded animals, although this with the enemy, but died before he could be arrested. Irwin of the University of Wisconsin in that employed a simple surgical technique, freshly sterilized Madison coined the term immunogenetics in 1933 to describe glassware, and instruments. They transformed the simple an uncertain association between immunology and genetics, technology of tissue culture into an elaborate laboratory ritual. He required technicians, including Charles Lindbergh of subsequent aviation fame, to dress somewhat theatrically in the studies of Jensen and Loeb, working independently with black, full-length gowns ftted with hoods. Little (1914) sug- other investigators to shy away from research involving tis- gested that dominant genes govern susceptibility to tumor sue culture because of its apparent complexity, the cost of allografts. Critics termed this Carrel’s more inbred strains of mice which became a valuable tool “mumbo jumbo” that stalled medical progress for years. Several investigators sought antibod- ies to tumor-specifc antigens in animals making an immune He developed the technique of end-to-end anastomosis of response against transplanted tumors, but without success. This technical advance permitted him It was Haldane in 1933 who pointed out that a tumor retains to transplant organs successfully 6 years later. For such a hypothesis to a skillful technique of approximating the ends of blood vessels have credibility, it would be necessary to demonstrate blood to be anastomosed through triangulation sutures. Peter Gorer In 1905, together with his colleague, Charles Guthrie, Carrel (Figure 1. He demonstrated that blood vessels could be maintained in the cold for “prolonged periods” before use for transplanta- tion. Carrel and Burrows used Harrison’s technique to grow sarcoma cells successfully in culture in 1910. Together with Tuffer, Carrel performed a number of successful experimen- tal valvotomies. In World War I, he and Dakin developed a treatment for wounds that was used extensively. A positive accomplishment in his tissue culture research was the Carrel fask which reduced bacterial contamination that had been a principal cause of failure of tissue cultures before the discovery of antibiotics in the 1940s. He also claimed to have developed an immortal cell line of chick embryo heart cultures that was begun in 1912 and supposedly maintained by him and a colleague, A. How this was accomplished remains an enigma, as cells are now known to have a fnite longevity. In 1938, Carrel retired from the Rockefeller Institute and returned to France, where he set up an Institute for the Study of Human Problems in Paris. This fnding led him to the belief that tumor regression in these animals had an immunological basis. The blood sera from animals rejecting the tumor allotransplant contained hemagglutinins specifc for red blood cells derived from A strain mice. Thus, Gorer’s research showed that genes governing susceptibil- ity to tumor allotransplants were the same as those encoding alloantigens. His demonstration that alloantibodies were pro- duced by mice rejecting tumor transplants proved that this process had an immunological basis. Gorer’s tissue trans- plantation concept proposed that both normal and tumor tis- sues contain genetically determined isoantigens, and that the figure 1. Medawar, Billingham, and Brent went on to conduct graft- Peter Alfred Gorer (1907–1961) was a British patholo- ing experiments in which tissues and cells from one strain of gist who was professor at Guy’s Hospital Medical School, mouse were successfully transplanted in recipients of a dif- London, where he made major discoveries in transplantation ferent strain that had been administered cells bearing donor genetics. Most of his work was in transplantation nological tolerance, which was published in Nature in 1953, genetics. After sev- eral days, however, host lymphoid cells may infltrate the skin graft and undergo blastogenesis. Twelve days later the allograft may appear necrotic, representing frst-set rejection. A second graft of the same donor specifcity is rejected at an accelerated rate, i. This is termed sec- ond-set rejection, which represents host sensitivity to trans- plantation antigens of the graft. Ray David Owen (1915– ) is an American geneticist who described erythrocyte mosaicism in dizygotic cattle twins. This discovery of reciprocal erythrocyte tolerance contributed to the concept of immunological tolerance. This observation that cattle twins that shared a common fetal circulation were chimeras and could not reject transplants of each other’s tis- sues later in life provided the groundwork for Burnet’s ideas about tolerance and Medawar’s work in transplantation. He became director of the Medical Research Council, 1962 and of the Clinical Research Center at Northwick Park, 1971. Together with Billingham and Brent, he made seminal discoveries in trans- plantation and immunobiology and described immunologi- cal tolerance and its importance for tissue transplantation. He shared the 1960 Nobel Prize in Medicine or Physiology with Sir Frank Macfarlane Burnet.

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