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The possibility of tuberculosis must never be for- however viagra with fluoxetine 100/60mg overnight delivery, be the initial sign of the disease buy generic viagra with fluoxetine 100/60 mg, which should gotten in the etiology of anal nodular and ulcerated lesions generic viagra with fluoxetine 100/60 mg amex, always be suspected with the appearance of a fistula in a regardless of the presence or absence of pulmonary tubercu- susceptible individual from the situations mentioned above purchase 100/60mg viagra with fluoxetine with mastercard. The patient’s continence is another important A good digital examination is usually sufficient for the facet that needs to be included, as well as any history of diagnosis and the treatment planning of anal fistula. The external opening may be a pinhole or appear as an irreg- Investigations ular ulcer of varying size (Fig. The granulations As tuberculosis of anal region is a rare entity and there is no are pale and flabby. A gaping external fistulous orifice with characteristic clinical picture, it is very difficult to diagnose it detached margins and highly vascular in nature is suggestive preoperatively. The discharge is frequently continuous and is thin and be missed for months or even years. These form the majority of the tuberculous fistulae ing the diagnosis of perianal tuberculosis can result in chronic and are labeled as the superficial or low variety. The deep or morbidity and often mortality, especially among immuno- high tuberculous fistula forms a tract with little induration compromised patients. The physician must take a thorough and often leads to a palpable submucous thickening high up history, look for acid-fast bacilli in the discharge from the (Fig. Most authors report a higher frequency of com- lesion, carefully examine excised tissue, and culture for plex tuberculous fistula forms (62–100 %) which sometimes M. The tract of the fistula and its relationship to the the tuberculin skin test is one of the few investigations sphincter muscle can be investigated by probing and/or dye- dating from the nineteenth century that is still widely used as ing intraoperatively with the patient under anesthesia. It was devel- It is not necessary that all reported cases of anorectal oped by Koch in 1890, but it was Charles Mantoux, who tuberculosis are patients with old tuberculotic lesions or with described the intradermal technique currently in use in 1912. Histological has been exposed to the bacteria is expected to mount an examination is mandatory if the patient has had or still has immune response in the skin containing the bacterial pro- tuberculosis elsewhere in the body. The test has a ter muscle is normal, scarred, or disrupted, as well as the poor positive predictive value for current active disease. With the use of high-frequency the formation of vesicles, bullae, or necrosis at the test site linear or curved array probes on the perineum in both trans- indicates high degree of tuberculin sensitivity and thus pres- verse and longitudinal planes, fistulous and sinus tracts, ence of infection with tubercle bacilli [27 ]. A high sensitivity of 96 % is has been infected recently and not enough time has elapsed reported for the detection of tracts, with a negative predic- for the body to react to the skin test. The typical histological lesion is the late fluid or hyperechoic moving reflections created by air epithelioid and giant cell tubercle around a zone of caseous bubbles and pus. Highly complex trans-sphincteric tracts, necrosis, but the pathognomonic presence of caseation is which may extend to involve the deep tissues of the buttocks, not constant and presents diagnostic problems, especially in the perineum, the scrotum in men, and the labia and vagina the case of Crohn’s disease with anoperineal localization. Perianal fluid collections and abscesses present as inflammation is characteristic of Mycobacterium infection, oval hypo to anechoic masses, most often with a direct asso- it can also be found in other disease entities such as sarcoid- ciation with a fistulous tract [34]. The poor sensitivity and specificity of commercial and defects may confuse sonographic interpretation and assays preclude their use as the sole means of diagnosis. There is a high possibility of false positive and false deep abscesses and characterize complex fistulae. The overall sensitivity of these tests for well suited for this examination, with almost no motion arti- extrapulmonary tuberculosis is as low as 16 % [39]. The cryptoglandular anal fistu- serologic tests make them poor tools for the diagnosis of lae are nonspecific in origin and are usually simple, whereas tuberculosis. The T2W sequences give the more interesting information, Sometimes, a cluster of epidemiologic, clinical, histologi- but the sequences with fat-suppression and gadolinium cal, radiologic, and evolutive arguments can contribute to chelate injection are also very useful. The virus has altered the balance openings between human beings and Koch’s bacillus, as well as hav- ing a noticeable impact on the epidemiology, natural history, and clinical evolution of tuberculosis. Antituberculosis drug resistance and an increased risk of transmission have also emerged as problems due to noncom- pliance with the tuberculosis treatment [46]. There is a high prevalence of anal lesions because of acquired immunodeficiency syndrome that is the histological features of Crohn’s disease is a granuloma estimated as being between 16 and 34 %. T lymphocytes), natural killer cells, and macrophages that Other possible granulomatous diseases of the anus can leads to reactivation of latent seats of mycobacteria, which mimic anal fistula, such as amoebiasis, actinomycosis are generally localized in pulmonary adenopathies or in the (Fig. Individuals become vulnerable when they assume that they are not at risk and therefore neglect self-care; in addition, limited access to health care increases Medical Treatment patient vulnerability. These measures are performed and is immediately followed by appropriate anti- performed under separate programs, which do not coordinate tubercular treatment are most gratifying [55]. This supple- efforts and which adopt control policies at different levels of mentation shortens postoperative period required for the health care. It is seen that combining with medical therapy, the wound usually heals within As in most of the cases, the diagnosis of tubercular infection 4–6 weeks as like any other anal fistula wound. However, a shorter course of 4 or 6 months of chemotherapy is sufficient for the treatment of Surgical Treatment anal tuberculosis. Isoniazid, rifampicin, and A diagnosis of anal fistula is usually an indication for surgery pyrazinamide, with or without ethambutol, are normally in order to prevent a recurring septic process. After this 6–12-week operative technique is governed by the fistula tract and its course, isoniazid and rifampin should be continued for an relation to the anal sphincter. However, resistance is reportedly technique in use is fistulotomy, that is, division of the tissue developing, particularly to rifampicin, isoniazid, and strepto- between the fistula tract and the anal canal. Rates of impaired continence vary Nevertheless, patient compliance and follow-up are between 0 and 45 %. For low fistulas, a healing rate of almost important factors that affect and can complicate the success 100 % can be achieved [51]. The material used is either outcomes, mortality, and morbidity and improve nutritional a strong braided non-resorbable suture or a plastic (vessel- and immunological parameters. Three different techniques which nutrients vitamins A, B-complex, C, E, and selenium may are in use include the cutting seton, the fibrosing seton, and reduce the recurrence of tuberculosis during standard the draining or loose seton [52]. Other techniques of fistula treatment include the flaps, use However, the standard 6- or 9-month course of chemo- of biomaterials, fulguration of the tract, stapling, etc. Newer drugs like Rifapentine, 20 Tuberculosis Fistulas 167 Rifabutin, Linezolid, Capreomycin, Ethionamide, and unrecognized, they ought to be recognized, because they Diarylquinoline R207910 are under evaluation for patients require specific treatment. There is no functional sign or preferred site that allows a tuberculous fistula to be Vaccination distinguished from a cryptoglandular fistula. It is routinely administered to managed surgical treatment may give a hint of possibility of infants in many countries worldwide and provides signifi- tubercular affliction of the fistula. Moreover, many new approaches and strategies are under the clinical features, which include symptoms and signs evaluation for further improvement of these and other vac- of anal pain or discharge, multiple or recurrent fistula- cines [69]. Anal fistula is cious anal lesions is mandatory for a correct diagnosis of the most frequent symptom of anorectal tuberculosis. Tuberculosis of the gastrointestinal tract and perito- tuberculosis and tuberculosis in special situations. Overcoming the global crisis: “yes, we can”, but also tive assessment of anal fistula: a comparative study. The role of three-dimensional endolumi- origin: report of two cases and review of the literature. Gastroenterol nal ultrasound imaging in the evaluation of anorectal diseases: Clin Biol. Evaluation of perianal sepsis: comparison of anal tuberculosis: a prospective study. Clin Colon Rectal assay in diagnosis of intestinal tuberculosis and differentiation from Surg. Rapid and efficient and perianal tuberculosis: a report of three cases in 10 years. Surgical management of anal fistulae: a A new recombinant bacille Calmette-Guerin vaccine safely induces systematic review. World Health Organization: Treatment of tuberculosis: guidelines thinking outside the box. Nelson and Herand Abcarian We live in an era when at least in the academic and scientific various degrees of fecal incontinence differ greatly from coun- circles, evidence-based medicine has definitely replaced its emi- try to country as well [5]. They also recommend document- twentieth anniversary this year is replete with such data. Finally, they conclude century, there is very little in the Cochrane data base to rely on.

Characteristically purchase viagra with fluoxetine 100/60mg line, the disorder is photocoagulation for peripheral neovascularization asso­ bilateral discount 100/60 mg viagra with fluoxetine overnight delivery, although asymmetry is common safe 100mg viagra with fluoxetine. Patients may be ciated with capillary non perfusion is not well defined but diagnosed early in childhood with findings identical to may be considered cheap viagra with fluoxetine 100/60mg without a prescription. It is usually possible with other vitreoretinopathies and the fact that phenotypic to elicit a family history or to find subtle peripheral retinal expression may not occur in some cases until the third vascular changes in family members, allowing the identifi­ decade of life, all family members should be closely cation of the dominant inheritance. Children may present observed and should not be considered disease-free even with decreased visual acuity and sometimes, if vision loss is with a benign-appearing fundus. In stage 1, patients are largely asymptomatic and prematurity or supplemental oxygen exposure. White-with- Oliver, in 1971, described a large family and defined the pressure and white-without-prcssurc can be seen in the clinical staging still generally in use. Miyakubo and progressive; however, several later studies have dem on­ coworkers described a temporal wedge-shaped avascular strated that the majority of cases may remain stable. Termination of retinal capillaries, forming (See Chapter 35 for a complete discussion of this dis­ a scalloped border with associated angiographic leakage, order. There is a characteristic finding of a temporal these were related to more advanced fundus changes and fibrovascular mass fed by large arteriovenous shunt ves­ worse visual acuity. Traction on the characteristic history of gestational prematurity, low birth- retinal microvasculature can stimulate perifovcal leakage weight, and/or supplemental oxygen exposure. Ocular toxocariasis, retinoblastoma, and retinal trization of the temporal fibrovascular proliferative mass. Peripheral neovascu­ As the mass contracts, it exerts traction on the retina, caus­ larization can also be seen in sickle cell retinopathy, incon­ ing an expanding retinal detachment. These, however, only limited; however, it often progresses with the development occasionally provide a diagnostic dilemma. Massive intraretinal and subretinal exudation, vascular lesions, but is usually symmetrical and bilateral mimicking Coats disease, may occur. Furthermore, there is disease, anterior segment changcs, including neovascular­ often associated microphthalmia, corneal opacification, ization of the iris and angle with resultant neovascular progressive mental retardation, and deafness. Three inheritance forms no abnormalities of arachidonic acid-induced platelet (autosomal dominant, autosomal recessive, and X-linked) aggregation were noted. No specimens pathway, which regulates cellular adhesion, proliferation, reflectingearly or mild disease have been studied. Boldrey has also reported two cases enucleated for some asymptomatic individuals detected only because neovascular glaucoma. Criswick Prophylactic cryopexy or laser photocoagulation of avascular and Schepens stressed the importance of the abnormal retina can probably be delayed until evidence of neovascu­ vitreoretinal interaction. The pathogenesis for the vascular occlusion prevent the progression of disease to stage 3. In one large series reported by demonstrated reduced platelet aggregation with collagen Miyakubo, retinal detachments secondary to traction were 523 present in 17% of eyes, and rhegmatogenous detachments circumferential coarse peripheral pigmentary degeneration were present in 26%. Abnormalities in the vit­ with scleral buckling that is often performed in conjunc reous, retina, and choroid are present. The age of patients described in the literature as rubeosis iridis and neovascular glaucoma, an attempt ranges from 7 to 88 years. An autosomal dominant pattern should be made to induce regression of proliferative of inheritance has been easily identified in published tissue with scatter laser photocoagulation or cryopexy. Occasionally, Surgical realignment of eyes with strabismus should also mild complaints of decreased night vision may be elicited, be considered. In contrast to some of the other hereditary vitreoretinopa- thies, patients generally maintain relatively good vision. An “optically empty" vitreous is not 1982, is characterized by the presence in the fundus of seen. Perhaps pathognomonic for this condition is the cir­ cumferential pigmentary degeneration extending from the ora serrata to the equatorial region, where there is a more or less discrete posterior border, separating normal- appearing retina from the more peripheral hyperpigmenta­ tion. Breakdown of the blood retina bar­ rier is demonstrable in some cases with fluorescein angiog­ raphy and vitreous fluorophotometry. Pre-sen ile cataracts, which are a common finding, may be secondary to the retinal vascular incompetence. Anterior segment abnormalities other than presenile cataract, such as micro­ cornea, shallow anterior chamber, and anglc-closure glau­ coma, have been reported. Traboulsi and coworkcrs reported an 88-year-old patient who developed a unilateral aphakic traumatic rheg­ matogenous retinal detachment at age 53, which was suc­ figure зб. Note sm all tuft of vitreoretinal opacification along Inferonasal retinal arteriole. Affected individuals complex may have been present prior to the development exhibit variable expressivity of the genetic mutation. Qu and cowork- fluorophotometry has demonstrated a breakdown of the ers have show that bestrophins are Ca-activated chloride blood-rctina barrier and retinal vascular incompetence. Cystoid macular edema is chloride channel function, whether playing a role in regula­ often evident in the later frames. Retinal neovascularization tion of cell membrane potential or cell volume at the plasma in the posterior pole has also been observed. A marked multifocal loss Because of the paucity of clinical experience, specific treat­ of photoreceptor cells was present at the equator and an ment recommendations arc difficult to make with confidence. Patients can be myopic or hypermetropic, decline in visual acuity, cataract extraction is likely to be of and develop complicated lenticular changes. Patients benefit, because most patients seem to maintain good have also been noted to have anterior chamber inflamma­ central vision. Dendritic, whitish retinal prednisone (40-60 mg daily) was tried in an attempt to vessels have been noted in the posterior pole (Fig. They arc helpful, when pres­ apparently effective, with improved visual acuity and a ent, as a diagnostic sign. Retinal capillary abnormalities, lessening of retinal thickening, prednisone was discon­ appearing as leakage on fluorescein angiography, have also tinued secondary to systemic side effects. It is peripheral retinoschisis, vascular occlusion has been unclear, therefore, whether steroid treatment is of benefit observed and may account for the dendritic appearance of in the condition, but it is certainly not unreasonable to the opaque blood vessels. These arc ture arc noted both by fluorescein angiography and vitreous usually without consequence; however, retinal detachments, fluorophotometry, overt retinal ischemia is not a conspicu­ which may be difficult to repair, may also result. Therefore, it is unclear whether there would be advancing age macular atrophy may ensue (Fig. It is an autosomal recessive disease with wide normal or subnormal S-conc function. Typically, patients Visual fields may be abnormal, reflecting the absolute complain of progressive night blindness early in the course scotomas related to the peripheral retinoschisis. Fluorescein angiography reveals areas of retinal capil­ Males and females are equally affected. Central visual lary leakage and non-perfusion, with cystoid leakage pres­ acuity may be affcctcd by the central retinoschisis or by the ent in the late frames. I Jistopathologic examination from a full-thickness eyeЛ thick preretinal membrane composed of glial tissue was wall biopsy of a 27-year-old woman with Goldmann-Favre also reported. Based on these findings, it was postulated Goldmann-Favre syndrome is differentiated from the that a primary degeneration of the photoreceptors may be latter on the basis of its autosomal recessive mode of involved. Thickening of the retinal vasculature’s basement inheritance, whereas juvenile retinoschisis is X-linkcd membranes and areas of vascular occlusion were noted. Histopathologic and ultrastructural findings in three eyes were reported by Condon and colleagues and sug­ ш gested a defect in Muller cells. Ultrastructural examina­ in both eyes and typical m acular lesion was present in the other eye. Vitreous hemorrhage can occur secondary to unsup­ They hypothesized that intraretinal filaments were pro­ ported retinal vessels bridging the schisis cavity and duced by defective Muller cclls, and that their extracellular cause a sudden decrease in visual acuity. We have accumulation may lead to cellular degeneration and subse­ observed intraretinal and subretinal hemorrhages in one quent schisis formation. Visual field abnormalities arc related to areas of peripheral involvement, resulting in an absolute scotoma in regions of retinoschisis. In addition, the characteristic combination tified as rctinoschisin, which has been localized to the pho­ of a maintained a-wave and depressed b-wave is absent in toreceptors and bipolar cells. Furthermore, that holds layers of the retina together as well as promoting nyctalopia is a more frequent and prominent complaint in normal electroconduction within the retina.

The hip joint lies deep to the pulsation of the femoral artery at the mid-inguinal point (half way between the anterior superior iliac spine and the symphysis pubis) viagra with fluoxetine 100mg otc. Consequently buy discount viagra with fluoxetine 100mg online, the sciatic nerve is at risk in a posterior surgical approach to the hip discount viagra with fluoxetine 100 mg mastercard, or in a posterior dislocation viagra with fluoxetine 100 mg fast delivery. The hip joint is innervated by the sciatic, femoral and obturator nerves (Hilton’s Law). In a child that presents with a painful knee, always examine the ipsilateral hip joint, in addition to examining the knee, to avoid missing a diseased hip. Most importantly, via retinacular vessels that run up from the trochanteric anastomosis and then along the neck of the femur to supply the major part of the head. The trochanteric anastomosis is formed by an anastomosis of the medial and lateral circumflex femoral arteries and the superior and inferior gluteal arteries. Via the nutrient, or diaphyseal, artery of the femur, originating from the second perforating artery of the profunda femoris artery. An intra-capsular fractured neck of the femur may disrupt the retinacular fibres and consequently disrupt the blood flow to the femoral head resulting in avascular necrosis. Garden 1 and 2 fractures are undisplaced fractures, whilst 3 and 4 are displaced fractures. The exception is the young patient with a 3 or 4 where the aim is to try and save the hip and therefore open reduction and internal fixation with cannulated screws is preferable in the first instance to avoid multiple hip revisions in the patient’s lifetime. The shoulder joint, like the hip joint, is a synovial joint of the ball and socket variety. Coracobrachialis Pectoralis minor Short head of biceps What important nerve lies in close proximity to the shoulder joint? It must never be forgotten that the axillary nerve lies in close proximity to the shoulder joint and the surgical neck of the humerus. Consequently, it is vulnerable to injury at the time of a shoulder dislocation, or whilst attempting to reduce the shoulder back into its normal position following a dislocation. It is therefore imperative (from both a clinical and medico-legal point of view) that the integrity of the axillary nerve is documented, both after seeing the patient who has a dislocated shoulder, but also following successful reduction. The knee joint is a synovial joint (the largest in the body), of the modified hinge variety. The cruciate ligaments are two very strong ligaments that cross each other within the joint cavity, but are excluded from the synovial cavity by a covering of synovial membrane (they are therefore described as being intra-capsular, but extra- synovial). Thus, the anterior cruciate ligament is attached to the anterior inter-condylar area of the tibia and runs upwards, backwards and laterally to attach itself to the medial surface of the lateral femoral condyle. Backward displacement of the tibia on the femur is prevented by the stronger posterior cruciate ligament which runs from the posterior part of the tibial inter- condylar area to the lateral aspect of the medial femoral condyle. The integrity of the latter is therefore important when walking down stairs or downhill. Tears of the anterior cruciate ligament are common in sports injuries; tears, however, of the posterior cruciate ligament are rare since it is much stronger than the anterior cruciate. Bursae are lubricating devices found wherever skin, muscle or tendon rubs against bone. An effusion of the knee may therefore extend some three to four finger breadths above the patella into the supra- patellar pouch. The pre-patellar and infra-patellar bursae do not communicate with the knee joint, but may become inflamed causing a painful bursitis. Inflammation of the pre-patellar bursa is known as housemaid’s knee, whereas that of the infra-patellar bursa is called clergyman’s knee. The menisci, or semilunar cartilages, are cresent-shaped laminae of fibrocartilage, the medial being larger and less curved than the lateral. Contributing to stability of the knee by their physical presence and by acting as providers of proprioceptive feedback 3. Probably assisting in lubrication the menisci are so effective that if they are removed, the force taken by the articular hyaline cartilage during peak loading increases by about five-fold. Meniscectomy (removal of the menisci), or damage to the menisci, therefore exposes the articular hyaline cartilage to much greater forces than normal and evidence of degenerative osteoarthritis is seen in 75% of patients 10 years after meniscectomy. The menisci are liable to injury from twisting strains applied to a flexed weight- bearing knee. The medial meniscus is much less mobile than the lateral meniscus (because of its strong attachment to the medial collateral ligament of the knee joint) and therefore cannot as easily accommodate abnormal stresses placed upon it. This, in part, explains why medial meniscal tears are more common than lateral meniscal tears. Upper lateral – Biceps femoris Upper medial – Semimembranosus and semitendinosus Lower lateral – Gastrocnemius (lateral head) and plantaris Lower medial – Gastrocnemius (medial head) Floor – Popliteus, capsule, femur Roof – Short saphenous and communicating veins, lateral sural cutaneous nerve, sural communicating nerve, end of posterior femoral cutaneous nerve and fascia lata Contents – Popliteal artery and vein (artery is deepest structure within the popliteal fossa and therefore the popliteal pulse is often difficult to palpate), tibial nerve, common fibular nerve, lymph nodes and fat Femoral triangle What are the boundaries of the femoral triangle? The boundaries of the femoral triangle are the inguinal ligament superiorly, the medial border of adductor longus medially and the medial border of sartorius laterally. The roof is fascia lata and the floor is made up of the following muscles: iliacus, psoas, pectineus and adductor longus. Within the femoral sheath lies the femoral artery, vein and a space most medially known as the femoral canal. The boundaries of the femoral canal are the femoral vein laterally, the lacunar ligament medially, the inguinal ligament anteriorly and the pectineal ligament posteriorly. Within the space of the femoral canal normally lies extra-peritoneal fat and a lymph node which is often given its eponymous name, Cloquet’s lymph node. Cloquet’s lymph node drains the lower limb, perineum and anterior abdominal wall inferior to the umbilicus. It may be enlarged (as inguinal lymphadenopathy) in cases of carcinoma and infection at these sites. The purpose of the femoral canal is to allow the laterally placed femoral vein to expand into it thereby encouraging venous return. However, a piece of bowel or omentum may extend down into the femoral space causing a femoral hernia. The femoral artery lies at the mid-inguinal point (half-way between the anterior superior iliac spine and symphysis pubis), not to be confused with the mid-point of the inguinal ligament (half-way between the anterior superior iliac spine and the pubic tubercle) which is the surface marking of the deep inguinal ring. This landmark can be used to assess the femoral pulse, but it also provides the clinician with a surface landmark for gaining access to the femoral artery for procedures such as coronary angioplasty and lower limb angiography and embolectomy. The adductor canal (also known as the subsartorial canal or Hunter’s canal) is an aponeurotic tunnel in the mid-third of the thigh extending from the apex of the femoral triangle proximally through to an opening in the adductor magnus distally (known as the adductor hiatus) to enter the popliteal fossa. Its boundaries are as follows: Roof – Sartorius and fascia Laterally – Vastus medialis Medially – Adductor longus (superiorly) and adductor magnus (inferiorly) Contents – Superficial femoral artery and femoral vein (latter deep to artery), saphenous nerve, nerve to vastus medialis (in upper part), small branch of posterior division of obturator nerve supplying knee joint, lymphatics Note that the saphenous nerve and the nerve to vastus medialis do not exit through the adductor hiatus. The femoral artery and vein become the popliteal artery and vein, respectively upon exiting the adductor hiatus. The adductor canal is anatomically narrow and is therefore a common site of turbulent blood flow leading to atherosclerosis. Two-thirds of the way along a line drawn from the anterior superior iliac spine to the adductor tubercle of the femur. Place your stethoscope at this point to auscultate for bruits in distal superficial femoral arterial disease in the claudicant patient since this is the commonest site of lower extremity peripheral vascular disease. In 10% of cases, the brachial plexus may be either pre-fixed (C4–C8) or post-fixed (C6–T2). The relation of the roots, trunks and divisions of the brachial plexus to the scalene muscles, first rib and clavicle are important. Compression within a fixed space (the thoracic outlet) may lead to symptoms resulting from compression of the brachial plexus and/or nearby vascular structures (subclavian artery and vein). Lateral cord – Musculocutaneous nerve Medial cord – Ulnar nerve Posterior cord – Radial nerve, axillary nerve Medial and lateral cords – Median nerve What is the innervation of the serratus anterior muscle? The serratus anterior muscle is innervated by the long thoracic nerve of Bell (C5, 6, 7). There are two recognised types of brachial plexus palsy; both usually occur as a result of trauma or obstetric injury. The first follows injury to the upper roots of the brachial plexus (typically C5–C7) and is known as the Erb–Duchenne palsy. The second follows injury to the lower roots of the brachial plexus (typically C8, T1) and is known as Klumpke’s palsy. The carpal tunnel is a fibro-osseous tunnel situated on the flexor aspect of the proximal part of the hand and lying between the flexor retinaculum and the carpal bones.

The median daily maintenance or 1200 mg/day oxcarbazepine for a period of up to 90 days or until dose was 900 mg for each drug viagra with fluoxetine 100 mg amex. Tese very short end-points raise a question as epine effective viagra with fluoxetine 100/60 mg, lamotrigine generic viagra with fluoxetine 100 mg, gabapentin and topiramate for treatment of to whether this cohort was truly representative of a population of patients with newly diagnosed and mostly focal epilepsy [50] generic 100/60mg viagra with fluoxetine overnight delivery. Patients exited the ences in efficacy between oxcarbazepine and the other drugs were trial afer completing 10 days of treatment, or afer meeting exit cri- found, although fewer patients took oxcarbazepine than the other teria indicating drug failure, such as four focal seizures within this drugs because it was added as a treatment arm later. Forty-seven per cent in the oxcarbazepine arm and 84% in 210 patients randomized to receive oxcarbazepine remained on the placebo arm met one of the exit criteria, a statistically signifcant Table 40. Percentage of drop- Number and type of Effcacy results (% outs for adverse Study patients Mean dose/day seizure-free) events Bill et al. This study also demonstrated 50% for placebo and 600, 1200 and 2400 mg/day oxcarbazepine, the feasibility of quick initiation of oxcarbazepine when necessary respectively. However, discontinuation rates for adverse events also for inpatients: 1500 mg on the first day, then 2400 mg on subse- increased with increasing dosage, with 66. Among the 75% of Two outpatient studies employed a more gradual conversion to patients who were taking carbamazepine as one of their baseline oxcarbazepine monotherapy for patients with refractory focal sei- drugs, the improvement in seizure frequency afer adding oxcar- zures [44,45]. As there are no controlled studies designed, it was believed that the minimum efective dose of drug of the efect of adding carbamazepine to oxcarbazepine, the con- might be 300 mg/day, as in the absence of enzyme-inducing drugs verse of this efect may or may not occur. In any case, the results this dose was felt to have comparable efcacy to 600 mg/day given of this study do not fully answer the question of whether the ad- to patients taking enzyme-inducers [44]. In retrospect, it is clear dition of oxcarbazepine to carbamazepine produces a qualitatively that 300 mg/day is not an efective dose, but positive results from diferent efect on seizure frequency or merely an additive one (i. The primary end-point, 41% of patients in the high-dose group met one of the exit criteria percentage change in seizure frequency from baseline, was 35% for compared with 93% of patients in the low-dose group. Forty-one per cent of patients kg/day oxcarbazepine added to one or two baseline drugs [48]. This was a multicentre, multination- (or a low-dose active control) were added to existing therapy for al, adjunctive-therapy trial in which 366 patients aged 18–65 with patients with inadequately controlled focal seizures are listed in refractory focal seizures were allocated to either placebo, 1200 or Table 40. Only the diference between A dose-ranging trial enrolled 694 patients aged 15–65 years in the placebo group and the 2400 mg/day group was statistically sig- a parallel comparison of placebo and three doses of oxcarbazepine nifcant (P = 0. A linear dose–response association was found, with median efcacy in this trial was ascribed by the authors to the very high percentage reductions in seizure frequency of 8%, 26%, 40% and placebo response rate, and a subanalysis of patients enrolled only at Table 40. Number and type of Mean percentage reduction in seizure frequency Percentage of drop-outs Study patients (versus baseline) for adverse events Barcs et al. Oxcarbazepine has been used as an adjunct in Uncontrolled studies acute bipolar depression and bipolar depression prophylaxis. A ran- Uncontrolled studies have very limited value in assessing efcacy, domized, prospective, double-blind trial of carbamazepine and ox- but may provide some insight into the performance of a drug in carbazepine as add-on therapy to lithium for residual (non-acute) clinical practice. Tese results refected median daily doses of for bipolar afective disorders in children and adolescents [66]. Pilot randomized, controlled, double-blind trials for with a 4-week taper of concomitant drugs, 52% were found to have treatment of migraine ([68] and alcohol withdrawal [69] demon- their seizures reduced by half or more and 18% were seizure-free strated no beneft compared with placebo. Among 147 newly diagnosed patients treated at single centre in Turkey and followed prospectively, 63% achieved at least a 12-month remission but 37% Adverse effects continued to have seizures despite maximum tolerated doses of oxcarbazepine [55]. Still better results were reported from a similar study in It- exacerbate myoclonic and absence seizures in patients with genetic aly, with a 72% 1-year seizure-free rate for a series of 202 new-onset (idiopathic) generalized epilepsy [70,71]. In a retrospective study of 290 children with epilepsy treated with A prospective, multicentre, open label trial of oxcarbazepine oral oxcarbazepine, 12 children with new-onset seizures developed ei- suspension monotherapy was carried out in children with newly ther worsening of pre-existing seizures, new seizure types and/or diagnosed focal seizures [57]. The Tree children with electroclinical patterns consistent with be- mean maintenance dose was 25 mg/kg/day. In another study, ox- nign epilepsy with centrotemporal spikes were reported to have carbazepine was reported to be efective in the treatment of eight seizure exacerbations during oxcarbazepine therapy [42]. The third pa- sults from several open-label patient series suggest that retention tient developed more frequent partial motor seizures, which were on oxcarbazepine therapy is relatively high. Ataxia, fatigue and diplopia or visual blurring The authors of a Cochrane review of oxcarbazepine for neuropathic were uncommon during monotherapy, although present much pain concluded that there was ‘moderate’ evidence for efectiveness more ofen than with placebo in adjunctive-therapy trials. This was based on verse efect profile is qualitatively similar to that of carbamazepine. Long-term use in diabetic neuropathy is reported to be accept- serum levels of monohydroxycarbazepine, with levels over 30 mg/L ably safe and tolerable [62]. Initial monotherapy trials Initial monotherapy trials Adjunctive trials Adjunctive trials Adverse effect Oxcarbazepine (n = 440) Placebo (n = 66) Oxcarbazepine (n = 705) Placebo (n = 302) Headache 37 12 26 21 Somnolence 22 6 26 12 Dizziness 20 4 30 11 Ataxia 2 0 17 5 Diplopia 0. In these direct comparative trials, discontinuation bazepine (20 of 210) or carbamazepine (38 of 378) developed an rates were significantly lower for oxcarbazepine in comparison with allergic rash [50]. Cross-reactivity with carbamazepine is also fre- carbamazepine (14% versus 26%) [38] and phenytoin [39,40], but quent, with 25. Discontinuation rates are, carbamazepine also developing a rash when they were converted to as expected, higher in adjunctive-therapy trials, mostly because of oxcarbazepine [75]. In an adjunctive The risk of serious dermatological reactions exceeds the back- study in children [47], there was a 10% drop-out rate in the ox- ground population risk by 3- to 10-fold [4]. Because persons car- carbazepine treatment group, versus 3% in the placebo group [47]. Drop-out for serious skin reactions with carbamazepine (see Chapter 32), the rates due to adverse efects may be lower with more gradual intro- same may be true for oxcarbazepine. If it is essential to use one of these cognitive efects appear to be relatively benign. Small studies have drugs in a person of at-risk ancestry, genotyping can be carried out. In an open-label 6-month trial enroll- haematologic reactions are less common than with carbamazepine, ing 112 children randomized to oxcarbazepine, carbamazepine or but dose-related mild leucopenia is less common. Hyponatraemia The only side-efect that is clearly more problematic with oxcarba- Gastrointestinal effects zepine than with carbamazepine is hyponatraemia. In a series of 73 adults, every 1 mg/day increase in dose increased ing adjunctive oxcarbazepine therapy: 22. The incidence of hyponatraemia to <4 years, gastrointestinal efects and somnolence were the two varies directly with age, with sodium levels <135 mEq/L occurring most common adverse efects of adjunctive oxcarbazepine, and at least once in 0. Patients prone to hyponatraemia for other reasons, such as those taking natriuretic diuretics, may be at Rash and serious idiosyncratic reactions higher risk. The fall in serum sodium usually occurs within the first In most studies, oxcarbazepine was found less likely to cause 3 months of therapy, but may happen later if the dosage is increased. In a single study, from all clinical trials suggest that there is a 3% incidence of rash both carbamazepine and oxcarbazepine reduced serum vitamin with oxcarbazepine compared with 7% with carbamazepine [4]. The authors suggest that these drugs may produce 542 Chapter 40 a secondary hypoparathyroidism and that patients may need sur- because of the open-label uncontrolled design, and possible bias veillance of bone density or need for replacement therapy. Oxcar- due to the fact that the study population was preselected because bazepine was reported to stimulate linear growth in children with of inadequate efcacy or poor tolerability on the medications taken ‘idiopathic’ epilepsy afer 6 and 18 months of therapy through before conversion to oxcarbazepine. Oxcarbaze- pine monotherapy caused alterations in lipid and thyroid profles Mode of use in children with epilepsy [83]. Clinical experience suggests, however, that for many out- Types and rates of adverse efects among children [40,47], and patients a slower titration schedule is better tolerated. Although hyponatraemia initiation at 300 mg/day, beginning with 150 mg at bedtime on the is more common in the elderly [79], discontinuation rates due to first day and then 150 mg twice daily thereafer [92]. Other author- adverse efects among elderly adults were similar to those among ities also suggest beginning with lower doses, such as 300 mg/day younger adults [86]. The most common adverse efects among 52 in two divided doses, or even 150 mg/day with increases of 150 mg/ patients aged 65 or older were vomiting (19%), dizziness (17%), day every 2 days [93]. The extended release When given to pregnant rats at intermediate to high doses, oxcar- preparation can be started as one 600-mg tablet at bedtime [5], al- bazepine was associated with an increased incidence of craniofacial, though some patients tolerate 300 mg better at frst. Outpatients needing rapid attainment well-controlled studies of oxcarbazepine in pregnant women, and of an efective dose can be started at 600 mg/day, and inpatients the drug should be used only if the benefits outweigh the risk to the can be started at 900–1200 mg/day. In a retrospective database review, six ponatraemia another drug may be preferable [94], congenital malformations occurred among 248 infants born to For children aged 4–16 years, the recommended starting dose women who had received oxcarbazepine monotherapy during is 8–10 mg/kg/day [4]. Weekly increases of about mark identifed 1532 infants who had received one of fve newer 5 mg/kg/day are appropriate. Among 393 in- fants exposed to oxcarbazepine, there were 11 major birth defects, Conversion from carbamazepine for a rate of 2. This number tial percentage of patients enrolled in controlled clinical trials either had risen to 211 according to the Fall 2014 newsletter of the North were converted from carbamazepine or had oxcarbazepine added American Registry. Making this change because of carbamazepine Quality of life for persons with epilepsy depends upon the occur- side-efects is less appealing as evidence has accumulated that the rence of side-efects as well as the degree of seizure control. A conversion otherapies: carbamazepine (n = 121), phenytoin (n = 65) or val- ratio of carbamazepine to oxcarbazepine of 1.

This process occurs first in the implants viagra with fluoxetine 100/60mg for sale, orbital osteotomies order 100 mg viagra with fluoxetine with visa, bone grafts order viagra with fluoxetine 100 mg visa, and/or orbital equatorial portions of the eye and proceeds proximally expanders cheap 100/60 mg viagra with fluoxetine fast delivery, may improve the appearance of patients with and distallv. Yamani and colleagues have found that Optic stalk the sclera of nanophthalmic eyes contains irregularly arranged collagen lamellae, an absence of elastic fibers, Inner Lum en of and abnormal glycogen-like deposits. It is likely that this abnormal fissure fluid dynamics in nanophthalmic eyes contributes to their Hyaloid artery increased risk of uveal effusions and choroidal detachment, and vein particularly after surgery. As the optic veiscle invaginates, it for autosomal dominant nanophthalmos to a 14. The inferior part of the invagmating cup or fetal fissure closes around blood vessels that form the retinal and hyaloid circulation. While we follow this distinction here, it is likely that “simple" and “complex" microphthalmia Failure of the optic fissure to close during the fifth week of represent points along a phenotypic continuum in which human gestation results in uveal coloboma. Depending upon which areas of the Л word of caution concerning the word “coloboma” is fissure remain open, uveal coloboma may affect the iris in order. Colobomas may be unilateral or bilateral and around the eye where some piece of tissue is missing. In the left eye the coloboma is extensive and involves the optic nerve head and a major part of the inferior fundus and macula. In the left eye there is a large chorioretinal coloboma involving the optic nerve head and infenor fundus. Ihis chapter will limit itself to those disorders that involve optic fissure closure when using the word “coloboma. Thus, neither all eyes with coloboma are Abnormalities in the ciliary body caused by coloboma microphthalmic, nor do all microphthalmic eyes have may result in an absence of zonules in the alfected area. Cataracts optic fissure interferes with the development of intraocular may develop at a younger age in patients with coloboma," pressure, ergo eye growth. Other iris abnormalities that have a similar configu­ ration but that are displaced in other directions arc likely not due to an abnormality in optic fissure closure and therefore should not be referred to as colobomas. A mild manifesta­ tion of iris coloboma may be iris transillumination limited to the inferior quadrant of the iris (Fig. This has of light sensitivity and may be bothered by the cosmetic resulted In loss of zonules and straightening of the lens equator in the appearance of the displaced pupil and/or iris heterochromia. Postoperative monocular diplopia has been reported and may be managed by pupilloplasty. In general, chorioretinal colobomas appear as areas of well-demarcated bare sclera in the inferior quadrant of the fundus with varying degrees of irregular, surrounding pigment abnormality. Gopal and associates have shown using opti­ cal coherence tomography that the transition from normal retina to the intercalary membrane covering the coloboma derives from the inner retinal layers and may be either gradual or abrupt. Right eye is small and punched forward imaging, they can grow to compress the developing eye by cyst. Although most cases of microphthalmia with cyst are sporadic, familial cases have been reported, with ence of progressive growth. Microphthalmos with cyst should be differentiated from congenital cystic eye that results from failure of invagination of the optic vesicle. Right eye is pushed up under upper Microphthalmia with Malformations of the Hands and Feet lid and cyst results In bulging of lower lid. Zlotogora and colleagues reported five families with autosomal reccssivc coloboma­ Microphthalmia and Intrauterine Insults tous microphthalmia and stated that the gene for this Maternal drug intake: thalidomide, alcohol, isotretinoin, others condition has a high frequency among Iranian Jews. There were eight reviewed the chromosomal abnormalities associated with pedigrees where the mode of inheritance could be determined: microphthalmia/coloboma until 1987 and provided an five were autosomal dominant and three were presumably extensive bibliography on the subject. From their data, Maumenee and mosomal defects are more common than others and are Mitchell calculated an empirical risk of 9% for a subsequent associated with consistent phenotypes. The risk increased to 46% if one syndrome), llq-, I3q-, 18q-, ring 18, trisomy 18, and parent was atfccted. Ihis section will focus on anophthalmia, microphthalmia, Autosomal dominant microphthalmia/coloboma may and optic fissure closure dcfects from a genetic and develop­ be isolated or may be associated with congenital cataracts"2 mental standpoint. M Hence, it is mutations in patients with uveal coloboma have also been important to perform ocular examination of all family reported. Because of incomplete penetrance, Examination of parents for a subclinical fundus coloboma Fujiki and coworkers estimated that, in families with domi­ can help establish an autosomal dominant mode of inheri­ nant microphthalmia/coloboma, unaffected individuals tance. Otherwise the risk of recurrence in siblings may соworkers described 14 affected members of a four- be as high as 25% (for possible autosomal recessive genes) or generation Italian family with reduced total axial length of may be as low as that in the general population (in possible the eye (18. A good maternal gestational Five patients were examined and had varying degrees of history should be obtained to rule out environmental etiolo­ hyperopia, choroidal thickening, glaucoma, nystagmus, gies, and a pedigree should be drawn and other family mem­ visual loss, and corneal opacification. When inherited, isolated anophthalmos is usually auto­ An interstitial deletion of chromosome 14q22—23 has been somal recessive. Thus, patients with what were assumed to be purely developmental abnormalities may in fact also have a degenerative component to their disease. However, because some of these mutations are in patients with Lenz microphthalmia. They identified a single patient Although most cases are sporadic, autosomal dominant with a S7031. In mouse, semaphorin 3E, along with In 2004, using comparative genomic hybridization, its receptor, plexin-Dl, regulates endothelial cell position­ Vissers and colleagues uncovered a 2. ChxlO is normally expressed in uncommitted retinal pro­ genitor cells and in mature bipolar cells. In zebrafish, gd/6 is expressed in the developing of this family had microcornea and one had bilateral iris retina at 18 and 24 hours post-fertilization. Homozygous M af mice show cataract and gd/6 results in a range of ocular abnormalities, including microphthalmia, consistent with this human phenotype. The break­ expressed prenatally and appears to be important in the point in the X chromosome was at Xp22. In In 2008, Schorderet followed up on a consanguineous Swiss 2006, Wimplinger and coworkers identified one nonsense family originally reported by Franceschetti and Valerio. R217C) Affected family members had a complex ocular phenotype in the mitochondrial holocytochrome c-type synthase and external ear abnormalities. In addition, this group identified a m oth­ Linkage analysis and mutation screening demonstrated a er-daughter pair who had a submicroscopic 8. These findings raise the gene, which codes for a homeodomain-containing tran­ interesting notion that mitochondrial genes may play a scription factor. Tliis mutation leads to a truncated protein role in development (perhaps by regulating apoptosis) as lacking a complete homeodomain. In addition, they identified a second that is expressed during development in the ventral optic family that exhibited autosomal dominant pulverulent cup prior to fissure closure. It is unclear whether some of the lap with the previously described Matthew-Wood syndrome phenotype in reported patients may be due to involvement (anophthalmia with pulmonary hypoplasia). Telangiectasias and nodules of herniated tract malformations, renal abnormalities, mild facial dysmor- fat may be covered by thin strands of connective tissue. Nasolacrimal duct obstruc­ tion with recurrent dacryocystitis occurs in 75% of patients. Two patients in the series of Lin and coworkers had severe anterior segment malformations. The disease is frequent Syndactyly of the lingers and toes, especially the third and in the Haliwa triracial isolate group in North Carolina, fourth fingers, is common. Short stature, joint hypermobility, con­ Sweden the prevalence of the disease varies between 0. In both patients there was 100% inactivation diplegia is noted before the age of 3 years. The mental of the paternally inherited X chromosomes in peripheral retardation may be severe. These findings indicated a common bright glistening intraretinal dots in all 35 Swedish patients mutational mechanism for focal dermal hypoplasia, pos­ with the Sjogren-Larsson syndrome. Gilbert and associates described body, iris, and lens, as discussed extensively by Morton punched-out macular lesions in both eyes of one patient Goldberg in his Edward Jackson Lecture, in which he who also had glistening dots. Photophobia, present in Elongated ciliary processes converge to and arc pulled all patients, is likely a result of punctate keratitis, a likely towards the retrolental fibrovascular tissue (Fig. Neuroimaging does not assist the presence of blood vessels inside the crystalline lens, in making the diagnosis. Sometimes the anomaly is so mild as to appear like a small starfish on the back of the lens (Fig.

No other drug has been shown to be more efective than carbamaz- A more recent randomized double-blind fexible-dose trial epine for this indication in randomized controlled trials order 100/60mg viagra with fluoxetine amex. Carba- compared controlled-release carbamazepine with zonisamide in mazepine is therefore established as a standard treatment for focal patients with newly diagnosed focal seizures [55] 100/60 mg viagra with fluoxetine with amex. Withdrawal rates for adverse events were 11% for zonisamide and open-label randomized controlled studies that compared the and 12% for carbamazepine cheap viagra with fluoxetine 100 mg overnight delivery. Of the randomized pa- carbamazepine with lamotrigine in 185 newly diagnosed patients viagra with fluoxetine 100/60mg visa, tients, 88% were considered to have symptomatic or cryptogenic 65 years or older, with focal or generalized tonic–clonic seizures focal epilepsy. Similar percentages of patients completed the 40-week study was signifcantly better than gabapentin and had a non-signifcant period: 67% with carbamazepine and 73% with lamotrigine. How- proportion completing the study and being seizure-free in the last ever, lamotrigine was signifcantly better than carbamazepine with 20 weeks was also similar: 57% with carbamazepine and 52% on respect to time to treatment failure. Adverse events leading to withdrawal occurred in 14% explained by fewer withdrawals for adverse events with lamotrig- of patients in the lamotrigine group and 25% in the carbamazepine ine. Overall, the tolerability of carbamazepine was more favour- with some caution in open-label studies. Selection of an unnec- able in this trial using a sustained-release formulation than in the essarily high target dose and use of immediate-release rather than other two trials. In one of A double-blind randomized trial compared 600 mg/day car- these studies, 300 adults with newly diagnosed seizures (about half bamazepine with 1250 mg/day valproate or 100 or 200 mg/day with focal seizures) were randomized to either carbamazepine or topiramate in newly diagnosed epilepsy (patients with focal sei- valproate [58]. In the focal seizure group, 12-month remission rates zures in the majority of cases) [53]. In the paediatric subgroup of were similar (72% for valproate and 76% for carbamazepine). In patients with focal seizures, time to exit (primary outcome meas- another open-label study, Heller et al. Although results were not presented for focal seizures the frst of these trials, Verity et al. Carbamazepine and valproate showed simi- compared levetiracetam with ‘standard treatment’ according to the lar efcacy in controlling both primary generalized seizures and physician (i. Adverse lease valproic acid) as monotherapy in a total of 1688 patients with efects were mild and necessitated drug withdrawal in only a few newly diagnosed epilepsy [60]. In the second study, 167 children aged 3–16 years, with not signifcantly diferent between levetiracetam and carbamaz- tonic–clonic or focal seizures, were randomly allocated to treat- epine (hazard ratio 0. Estimated 12-month seizure domized children), phenytoin (n = 54), carbamazepine or val- freedom rates from randomization were 50. Among the drugs for which rand- The efcacy of carbamazepine in elderly patients with newly di- omization was allowed until completion of the study, phenytoin agnosed epilepsy was assessed in three double-blind randomized was more likely to result in withdrawal (9%) than carbamazepine comparative trials [61,62,63]. Withdrawals because of adverse Primary generalized tonic–clonic seizures events were more common with carbamazepine (42%) than with In addition to focal seizures, carbamazepine is approved by many lamotrigine (18%), but there was no diference between the two regulatory agencies for the treatment of primary generalized ton- drugs in time to frst seizure. Nevertheless, documentation in terms of dou- of poor tolerability, a greater percentage of lamotrigine-treated pa- ble-blind randomized trials in this indication is sparse. In fact, there 600 mg/day), lamotrigine (150 mg/day) or gabapentin (1500 mg/ are no double-blind randomized monotherapy studies specifcally day) [62]. The primary outcome measure was retention in the trial targeting patients with primary generalized tonic–clonic seizures. Tere were no statistically signifcant diferences in The best available evidence is derived from trials in which such seizure-free rates at 12 months among those remaining in the study patients constitute a subset of the included population, and results (64% with carbamazepine, 51% with lamotrigine and 47% with are difcult to interpret not only because of the small sample sizes, gabapentin). However, early termination for adverse events was but also because of the possibility that in some patients secondary more common with carbamazepine (31%) than with lamotrigine generalized seizures without an evident focal onset may have been (12%). Another study compared fexible-dosage sustained-release erroneously classifed as primary generalized. Carbamazepine 439 Similar proportions of patients in each group were seizure-free in Other epilepsy syndromes the subset of adults with generalized tonic–clonic seizures included In some patients with symptomatic myoclonic–astatic epilepsy or in the double-blind randomized trial comparing carbamazepine Lennox–Gastaut syndrome, carbamazepine can improve at least with oxcarbazepine [54]. Although specifc combina- the last 6 months of treatment in the trial comparing carbamaze- tions have rarely been evaluated, when using combination therapy, pine, valproate and two diferent dosages of topiramate [53]. In addition, there may be pharmacodynamic with focal and generalized tonic–clonic seizures have compared interactions. In the study by mon when carbamazepine is combined with oxcarbazepine [71], Callaghan et al. In another trial comparing Effcacy in non-epilepsy conditions carbamazepine and valproate in mixed seizure types, there was no In many countries, the efcacy of carbamazepine in trigeminal diference between the two treatments in 12-month remission rates neuralgia was demonstrated even before the drug was licensed for in the subset of 138 patients with primary generalized tonic–clonic epilepsy [73]. Randomized controlled trials have also shown efcacy reported separately for focal and for generalized tonic–clonic sei- in other neuropathic painful disorders, such as diabethic neurop- zures, seizure control did not difer signifcantly among the groups athy [74]. The efcacy of carbamazepine in the maintenance treat- randomized to carbamazepine, phenytoin and valproate [59]. Another meta-analysis found no signifcant diferenc- es between carbamazepine and phenytoin for outcomes examined Adverse effects for generalized tonic–clonic seizures [68]. In clinical trials, approximately 10–25% of patients randomized to Although the available evidence suggests that carbamazepine is carbamazepine discontinued treatment because of adverse efects efective in the treatment of primary generalized tonic–clonic sei- [48,50,51,57,75]. The frequency is even higher in some studies in zures, it should be borne in mind that other data suggest that carba- the elderly [52,62]. Titration rate and target dosage also afect the risk of some idiosyncratic efects [78]. Epilepsy syndromes The prevalence of adverse efects declines with duration of treat- ment. This has been attributed in part to autoinduc- sidered for this indication, based on its proven efcacy in patients tion of carbamazepine metabolism resulting in a gradual decline with focal seizures in general [47]. However, development of tolerance at pharmacodynamic level seems to be a Genetic (idiopathic) generalized epilepsies more important determinant of the time-dependent reduction in Although carbamazepine can be efective in the treatment of gener- adverse efects. Data or juvenile myoclonic epilepsy, because of the risk of precipitating on diferences in tolerability between carbamazepine and valproate or aggravating absences and myoclonic seizures. Carbamazepine has been the comparator may even precipitate non-convulsive status epilepticus in these pa- in a large number of randomized controlled trials of newer genera- tients [69]. This was interpreted as lack of a practice efect on test Adverse event performance in the carbamazepine group. Levetiracetam produced fewer adverse neuropsychological efects than carbamazepine in a Headache 3. This diference, how- ever, could be partly related to study designs and suboptimal use of carbamazepine. However, it has Cutaneous hypersensitivity reactions (including been suggested [76] that the use of suboptimal drug formulations, cutaneous reactions associated with systemic symptoms) dosages and titration rates may have contributed to the apparent Skin rashes occur typically in 5–15% of patients started on carba- poorer tolerability of carbamazepine compared with lamotrigine mazepine, but in up to 19% of cases in the elderly [61]. Rash rates [52,57,61,62], gabapentin [57,62,74], oxcarbazepine [54] and vigab- appear to be lower in children, being estimated at approximately 5% atrin [50,79]. The vast majority of these reactions a slow titration and with an adequately low target dosage in three are benign. Tey tend to occur within the frst 8 weeks of treatment double-blind randomized trials, overall tolerability was essentially and disappear on drug withdrawal. Between 30% The most common adverse events reported by patients on car- and 60% of patients who experienced a rash on carbamazepine will bamazepine in the two largest randomized monotherapy trials have a recurrence if switched to any of these drugs [78,86]. Tese, proportion of all cutaneous reactions observed in patients treated and other diferences between the two trials, may have contributed with this drug. Stevens–Johnson syndrome and toxic epider- ataxia, diplopia and blurring of vision. Less common neurological mal necrolysis are characterized by bullous skin reactions combined adverse efects include dystonic movements, choreo-athetosis and with mucosal and sometimes also systemic involvement. In this comparison, patients on carbamazepine had syndrome and toxic epidermal necrolysis [88,89,90]. Among 4877 screened patients who were consid- posed persons in the general population, in which the incidence is ered for carbamazepine treatment, 7. The presence of the allele increased the the questionable preventive efectiveness of blood cell counts, regu- risk of carbamazepine hypersensitivity from 5. It drome and toxic epidermal necrolysis in populations where this usually appears early, in most cases within 3–4 months afer initia- allele is common (Chinese, Tai, Indian, Malay, Filipino, Indone- tion of treatment. Such screening has been shown to be as cost-efective tients on carbamazepine treatment [44]. An isolated increase in gamma-glutamyltrans- carbamazepine treatment, but the recommendation is of a lower ferase does not justify drug withdrawal. In most cases, modest ele- level because the association with serious reactions such as Stevens– vations in aminotransferases are clinically insignifcant. Johnson syndrome and toxic epidermal necrolysis is less clear and as the preventive efect of such testing has not been demonstrated Endocrinological effects prospectively [93].