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B. Miguel. University of Charleston.

To detect antinuclear antibodies purchase 75 mg clopidogrel overnight delivery, the patient’s serum is incubated with Hep-2 cells and the pattern of nuclear staining is determined by fuorescence microscopy purchase clopidogrel 75 mg visa. If there led pattern of staining is seen in several connective tissue are no other platelet or coagulation defects buy clopidogrel without prescription, they do not diseases. In involved, but the skin manifests erythematous plaques and this method, fuorescence of the kinetoplast, which contains telangiectasis with plugging of the follicles. The “revised criteria” for rheumatoid arthritis are as follows: Alopecia areata (Figure 17. It is a structure degree of the IgG or IgA classes, with reactive specifcity that develops in synovial membranes during the chronic for the Fc region of IgG. This antiimmunoglobulin antibody, proliferative and destructive phase of rheumatoid arthritis. They stimulate macrophages to release interleukin-1, fbro- blast-activating factor, prostaglandins, substance P, and platelet-derived growth factor. This entire process can fll the joint space, leading to demin- eralization and cystic resorption. Immunological Diseases and Immunopathology 577 Rheumatoid Arthritis allotypic markers of the human IgG subclasses. Although rheumatoid factor titers may not be clearly corre- lated with disease activity, they may help perpetuate chronic Pleural effusion infammatory synovitis. When IgM rheumatoid factors and IgG target molecules react to form immune complexes, com- Pericardial effusion plement is activated leading to infammation and immune injury. IgG rheumatoid factors may self-associate to form Splenomegaly IgG–IgG immune complexes that help perpetuate chronic Kidney amyloidosis synovitis and vasculitis. Cartilage Inflammatory infiltrate Necrosis Tissue Fibrous destruction tissue Bone Palisading at the pannus margin epithelioid cells Figure 17. Perinuclear antibodies are antibodies against perinuclear granules in buccal mucosal cells in man. Their presence portends a poor prognosis in the rheumatoid fac- tor negative group. Perinuclear antibodies may also be found in selected other rheumatic diseases and are often present in subjects infected with Epstein–Barr virus. They are also demonstrable in approximately one-fourth of primary biliary Figure 17. These antibodies facilitate crystallization of genes that govern pathogenic autoimmunity. There is a strong male predominance with tuberculosis, leads to the production of aseptic synovitis, onset in early adult life. Sterile infamma- is elevated, but subjects are negative for rheumatoid factor tion occurs in the joints and lesions of the skin. Immunological Diseases and Immunopathology 579 or swallowing diffculties, 50% of the patients show parotid gland enlargement. A lip biopsy to exam- ine minor salivary glands is needed to diagnose Sjögren’s syndrome. Infammation of the salivary and lacrimal glands was previously called Mikulicz’s disease. Mikulicz’s syn- drome refers to enlargement of the salivary and lacrimal glands due to any cause. Enlarged lymph nodes that reveal a pleomorphic cellular infltrate with many mitoses are typical of Sjögren’s syndrome and have been referred to as “pseudo- lymphoma. Antibody to blurry vision, dry mouth (xerostomia) and dry throat leading ductal epithelium. Autoantibodies are produced against antigens of of the patients form rheumatoid factor. Numerous antibodies are pro- duced, including autoantibodies against salivary duct cells, There is acute injury of glands, yet tissue damage resolves spontaneously 4 to 5 weeks after immunization. These antibodies from 580 Atlas of Immunology, Third Edition the mother may mediate congenital heart block. Fewer than 1% of normal subjects have low levels individuals experience Raynaud’s phenomenon. The skin may exhibit a tight, smooth, and waxy appear- syndrome react with the 52-kDa protein alone, whereas 20% ance in the sclerotic phase with no wrinkles or folds apparent. Most Ulcers may develop on the fngertips in many patients, with a patients with neonatal lupus erythematosus and complete mask-like appearance of the face with thin lips. Fetal cardiac tissue of the lungs may be involved, leading to dyspnea on exertion. Approximately one-third of the individuals Sjögren’s syndrome as well as other connective tissue (rheu- with diffuse involvement of the trunk reveal antibodies spe- matic) diseases. It represents a genetically transmitted Progressive systemic sclerosis (scleroderma) (Figure 17. The effects of the Tsk1 mutation is a connective tissue or collagen–vascular disease in which include an excessive accumulation of collagen in the dermis the skin and submucosal connective tissue become thickened and various internal organs, thereby mimicking major aspects and scarred. The principal visceral changes It is slowly progressive and chronic and may involve internal in Tsk1/+ occur in the lungs and heart. Although the etiol- tended and histologically resemble human emphysema with ogy is unknown, patients demonstrate antinuclear antibodies, little fbrosis. Alveolar spaces are markedly dilated with thin rheumatoid factor, and polyclonal hypergammaglobulinemia. There is There is no demonstrable immunoglobulin at the dermal– myocardial hypertrophy with increased collagen deposition. The epidermis is thin, dermal appendages atrophy, Tight skin-2 mouse (Tsk2) is a mouse strain with features resembling those of both human systemic sclerosis and the original tight skin mutation of the mouse, Tsk1. Anti-topoisomerase I (Scl 70) antibodies are associated with diffuse cutaneous systemic sclerosis and are specifc to this disease. Scl-70 antibody is an antibody found in as many as 70% of diffuse-type scleroderma (progressive systemic sclerosis) patients, who experience extensive and rapid skin involve- ment as well as early visceral manifestations. All types of amyloid link to Congo red and manifest an nary hypertension are complications. All forms of amyloid share the P component in com- phenomenon, esophageal dysmotility, sclerodactyly, and mon. Amyloid has a β-pleated sheet structure; it is insoluble and fngers with only lateral visceral manifestations. These patients have free light-chain production in promise the function of vital organs. Diseases with which it association with the development of Bence-Jones proteins in Figure 17. The light-chain quality and degradation mecha- β-pleated sheet nisms are critical in determining whether or not Bence-Jones proteins will be deposited as amyloid. These secondary amyloidosis deposits consist multiple myeloma or another plasma cell neoplasm. Amyloidosis may homogenous, and eosinophilic material deposited in various also be heredofamilial or associated with aging. It is composed chiefy of protein and shows Sago spleen describes the replacement of lymphoid follicles a green birefringence when stained with Congo red and by amyloid deposits that are circular and transparent in amy- observed by polarizing light microscopy.

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The tendon is also evaluated for the presence of crystal tendinopathy from gout or pseudogout (Figs order clopidogrel on line. Dynamic ultrasound imaging while flexing and extending the elbow will help identify subluxation of the triceps tendon responsible for snapping tendon syndrome (Fig generic clopidogrel 75mg overnight delivery. If snapping is present clopidogrel 75 mg on line, careful evaluation of accessory ossicles with the tendon substance should be carried out. If there is a history of trauma, the ultrasound transducer is moved proximally and the muscle is evaluated for presence of hematoma, partial tear, or rupture (Figs. Proper ultrasound transducer placement for ultrasound evaluation of the triceps tendon and muscle. Longitudinal ultrasound view of the triceps muscle and tendinous insertion into the olecranon process. Long-axis ultrasounds comparing triceps tendinopathy (A) with the asymptomatic contralateral distal 335 triceps tendon (B) in an 18-year-old high school wrestler with chronic right elbow triceps pain. Thickening (interposing arrows) and mild heterogeneity of the distal triceps tendon were revealed. Longitudinal ultrasound image demonstrates discontinuity of the distal triceps tendon. Arrowheads indicate normal fibrillar appearance of intact superficial triceps tendon, arrow indicates hematoma, and asterisks indicate olecranon. The patient’s forearm is stabilized and the patient is then asked to extend his or her arm against resistance to contract the triceps muscle and place tension on the distal musculotendinous unit. The size of the tophi ranges from millimetric hyperechoic spots to large aggregates, with or without hypoechoic halo. Representative examples of intratendinous tophaceous deposits (arrowheads) without (tt, triceps tendon) posterior acoustic shadowing (u, ulna). Example of intratendinous calcium pyrophosphate deposits (arrowheads) within the triceps tendon (u, ulna). Ultrasound images over the medial epicondyle in short-axis show (A) normal position of ulnar nerve (arrow) in elbow extension and (B) dislocation of ulnar nerve and subluxation of the medial head (curved arrow) of the triceps brachii (T) relative to the medial epicondyle of the humerus (E) in elbow flexion. Focal discontinuity of the fibers in the long head of the triceps, with torn remnants seen “floating” (arrow) in the hypoechoic hematoma. Extended field-of-view sonogram shows development of myositis ossificans following triceps brachii injury. Arrowheads denote sheet-like calcification within triceps with posterior acoustic enhancement. Careful evaluation of the triceps tendon should be carried out in all patients suffering from olecranon bursitis given the high correlation between these two pathologic processes. Complete rupture of the musculotendinous unit of the triceps will require urgent surgical repair. Longitudinal ultrasound image demonstrating a large septated, hypoechoic mass (rheumatoid nodule) adjacent to the triceps tendon. As the ulnar nerve exits the axilla, it passes inferiorly adjacent to the brachial artery. At the middle of the upper arm, the ulnar nerve turns medially to pass between the olecranon process and medial epicondyle of the humerus where it passes beneath a tendonous arch made up of an aponeurotic band connecting the a humeral and ulnar heads of the flexor carpi ulnaris muscle (Figs. It is at this point that the ulnar nerve is subject to compression and entrapment in a manner analogous to carpal tunnel syndrome (Fig. Continuing its downward path, the ulnar nerve passes between the heads of the flexor carpi ulnaris moving radially along with the ulnar artery. At a point approximately 1 in proximal to the crease of the wrist, the ulnar nerve divides into the dorsal and palmar branches. The dorsal branch provides sensation to the ulnar aspect of the dorsum of the hand and the dorsal aspect of the little finger and the ulnar half of the ring finger (Fig. The palmar branch provides sensory innervation to the ulnar aspect of the palm of the hand and the palmar aspect of the little finger and the ulnar half of the ring finger. At the middle of the upper arm, the ulnar nerve turns medially to pass between the olecranon process and medial epicondyle of the humerus where it passes beneath a tendonous arch made up of an aponeurotic band connecting the a humeral and ulnar heads of the flexor carpi ulnaris muscle forming the cubital tunnel. Cubital tunnel syndrome is an entrapment neuropathy involving the ulnar nerve as it passes beneath the cubital tunnel retinaculum. Patients suffering from cubital tunnel syndrome will experience pain and dysesthesias radiating from the elbow to the lateral forearm and into the wrist, ring, and little finger. The onset of cubital tunnel syndrome can be insidious and is usually the result of misuse of overuse of the elbow joint although direct trauma to the nerve as it passes through the cubital tunnel may also result in a similar clinical scenario. If this entrapment neuropathy is not treated, pain and functional disability may become more severe and, ultimately, permanent numbness and flexion contractures of the ring and little finger may result (Fig. A: Long-axis sonogram of compressed ulnar nerve at cubital tunnel demonstrates ulnar nerve that is hypoechoic and enlarged proximally (right in image) because of edema and abruptly compressed at the level of the fibrous band between the heads of flexor carpi ulnaris distally (cursors). B: Short-axis sonogram of compressed ulnar nerve at cubital tunnel in same patient demonstrates the degree of flattening of the ulnar nerve (arrows), where it is compressed by the flexor carpi ulnaris (arrowheads). Entrapment of the ulnar nerve resulting in wasting of the small muscles of the hand, particularly the first dorsal interosseous. A Tinel sign will be present at the point where the ulnar nerve passes through the cubital tunnel and the nerve will be tender to palpation (Fig. Weakness of the adductor pollicis muscles can be demonstrated by performing the Froment and Jeanne test (Fig. Weakness of the interosseous muscles can be demonstrated by performing the crossed finger, finger flexion, little finger adduction, and Egawa tests (Fig. Weakness of the hypthenar muscles can be demonstrated by performing the Wartenberg, Masse, and Pitres–Testut tests. It should be remembered that the ulnar nerve is the largest unprotected nerve in the body and that it is subject to trauma or entrapment at many points along its course and that more than one ulnar nerve lesion may coexist. The little finger adduction test evaluates the strength in the interosseous muscles of the hand, which are innervated by the ulnar nerve. It is performed by asking the patient to touch his or her little finger to their index finger. Cubital tunnel syndrome often is misdiagnosed as golfer’s elbow and can be distinguished from golfer’s elbow by determining the site of maximal tenderness to palpation. Patient’s suffering from cubital tunnel syndrome will experience maximal tenderness to palpation over the ulnar nerve 1 in below the medial epicondyle, whereas patients suffering from golfer’s elbow will experience maximal tenderness to palpation is directly over the medial epicondyle. Cubital tunnel syndrome also should be differentiated from cervical radiculopathy involving the C7 or C8 roots and golfer’s elbow. Furthermore, it should be remembered that cervical radiculopathy and ulnar nerve entrapment may coexist as the so-called “double crush” syndrome. The double crush syndrome is seen most commonly with median nerve entrapment at the wrist or with carpal tunnel syndrome, but has been reported with the ulnar nerve. Electromyography and nerve conduction velocity testing are useful in helping in the differentiation of cubital tunnel syndrome from cervical radiculopathy and gofer’s elbow. Plain radiographs, ultrasound imaging, and magnetic resonance imaging are indicated in all patients who present with cubital tunnel syndrome in order to rule out occult bony pathology involving the cubital tunnel and to identify occult fractures, masses or tumors that may be responsible for compromise of the ulnar nerve (Fig.

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The total weight of the four glands is about 200 mg buy 75mg clopidogrel overnight delivery, the anterior aspect of the neck embedded posteriorly at four each gland weighing approximately 50 mg purchase 75 mg clopidogrel with visa. The chief cells are the predominant cells in the parathy- Regulation of Secretion roid gland that are present throughout life buy 75 mg clopidogrel amex. They appear in the glands during puberty and then the number ear between 3–6 mg% of the ionized plasma calcium increases with the advancement of age. Plasma phosphate: Usually phosphate does not affect acids is removed from amino terminal in endoplasmic parathormone secretion. Chapter 62: Parathyroid Gland, Calcitonin and Vitamin D 559 Increased reabsorption of calcium 2. About 1–2% of filtered load is bone fluid into the osteocyte and then from osteo- excreted in urine. Areas of osteoclastic hyperactiv- facilitates the hydroxylation of 25-hydroxycholecalciferol ity and bone resorption are present along with excessive to 1,25-dihydroxycholecalciferol, the active form of and disorganized trabecular bone formation. These include calcium, phosphate, hypophosphatemia, demineralization of bone, hyper- hydroxyproline and hydroxylysine. The chronic effect of parathyroid excess results in cially that of hydroxyproline is an index of osteo- the bone disease called osteitis fibrosa. In this disease, the bone marrow is fibrosed and bone In hypoparathyroidism, hypocalcemia and increased resorption exceeds the bone formation. Secondary Hyperparathyroidism Hypocalcemic Tetany Secondary hyperparathyroidism occurs in chronic renal Hyposecretion of parathyroid is rather common following disease and rickets. In these diseases, the chronic hypocalcemia causes removed by mistake along with thyroid tissue. The symptoms of tetany following thyroid surgery cer cells that cause local osteolysis which results in develop in 24 to 48 hours postoperatively. Chapter 62: Parathyroid Gland, Calcitonin and Vitamin D 561 Calcitonin Source and Structure Calcitonin is secreted from parafollicular cells (C cells) of the thyroid gland. The parafollicular cells develop from ultimobranchial bodies, a pair of glands that develop from 5th branchial pouch. Synthesis, Secretion and Metabolism Synthesis and Secretion the treatment of hypocalcemic tetany includes imme- the major stimulus for calcitonin secretion is the rise in diate administration of ionized calcium and parathor- plasma calcium level. Gastrin is a strong stimulus This is called parathyroid hormone related protein for calcitonin release (Clinical Box 62. It also acts as a growth factor for the development of the hormone is degraded in the liver. Thus, it inhibits the Hypercalcemia of Malignancy: Hypercalcemia is common in malignancy. During and after pregnancy, calcitonin protects bone loss in pregnant and lactating mother. This and in the diseases in which osteoclastic activity needs is due to inhibition of bone resorption, facilitation of to be reduced, for example in Paget’s disease. Calcitonin phosphate entry into the bone, and also mild increase is sometimes used as a central analgesic as it blocks the in urinary phosphate excretion. Thus, the hypophosphatemic effect of calcitonin is Paget’s Disease independent of hypocalcemic effect. In this disease, increased osteoclastic activity of unknown Effects on Kidney etiology results in localized regions of bone resorption followed by a compensatory osteoblastic activity causing It decreases calcium reabsorption from kidney. X-ray pictures show areas of increased density and Calcitonin Escape resorptive cavities. However, this antiresorptive matic, bone deformities resulting in compressive neu- action of calcitonin begins to wane within hours. It is probably due to rapid down regulation of calcium are more useful in preventing bone resorption. Therefore, calcitonin is effective in decreas- ing plasma calcium only for a short duration. This limits the use of calcitonin in long-term manage- Vitamin D increases plasma calcium level by increasing ment of hypercalcemia. Calcitonin is secreted more in young individuals, Vitamin D is acquired from two sources in human being. Chapter 62: Parathyroid Gland, Calcitonin and Vitamin D 563 From Skin oil and milk. When the skin is exposed to sunlight (ultraviolet radia- hydroxylations in the liver and kidney. In the liver, it is hydroxylated at position 25 by micro- is converted to previtamin-D3. For this conversion to somal and mitochondrial enzyme, to form 25-hydroxy- occur, minimum 20 mJ radiation energy per sq-cm of cholecalciferol which undergoes further hydroxylation skin is required. Previtamin-D3 is then automatically converted to vita- cholecalciferol (Flowchart 62. However, continuous exposure to sun light prevents cells of proximal and straight tubules. Physiological Actions Vitamin D increases plasma calcium level by acting on intestine, kidney and bone (Flowchart 62. On small intestine: Vitamin D mainly acts on the intes- tine to facilitate calcium absorption against the concen- tration gradient. It also facilitates the absorption of phosphate and • a‑Klotho facilitates membrane localization of proteins that are magnesium across the intestinal epithelium. It increases number of calcium pumps in the epithelial Vitamin D Deficiency cells of proximal and distal tubules. Deficiency of vitamin D causes rickets in children and On bone: It acts on osteoblasts that have receptors for osteomalacia in adults. Anticonvulsant drugs like phenobarbital various paracrine signals that originate from the oste- 7. Activated osteoclasts produce a number of a-hydroxylase, an autosomal recessive disorder). It promotes development of osteoclasts from their the disease is characterized by inadequate mineralization precursor cells. Thus, the direct effect of vitamin D on bone is to mobi- osteoid accumulates in the bone. The concentration of lize calcium, which is contrary to its overall effect of calcium and phosphate is significantly low. Thus, vitamin D increases plasma level of cal- In Children cium and phosphate (Flowchart 62. This overshadows the direct action of vita- results in bowing of the long bones of lower limbs and min to mobilize these minerals from bone. The epiphyseal growth centers are affected Other actions: Receptors for vitamin D are also found by defective mineralization of bone. It stimulates transport of calcium into skeletal and As longitudinal growth of long bone is already completed cardiac muscle. However, due of vitamin D results in muscle weakness and cardiac to increased unmineralized osteoid content, bone pain, dysfunction. Anti-aging protein exerts effects partly via 1,25-dihy- Vitamin D excess usually occurs due to excess intake of droxycholecalciferol (Application Box 62.

Recognize the limitations of therapy Patient registers and data collection A vital function of the epilepsy Counsel and provide information on the above points to centre will be to collect data on outcome and quality order 75 mg clopidogrel with amex. This would be patients facilitated by a register of patients served in the population clopidogrel 75mg without a prescription, and we recommend that this be started wherever possible order discount clopidogrel. In such cases, the approach to management is divisible into Information provision and links with local support groups The epi- two clearly distinct phases: assessment and treatment (Table 11. Faced with a new presentation of chronic epilepsy, the physician should gather and document information with which to form the Research and teaching The epilepsy clinic is well suited to clinical basis of future recommendations for treatment. The following fac- research and teaching both for medically trained personnel and tors should be assessed – this list of factors is not exhaustive but is professions allied to medicine. The centre would be a natural setting the minimum required before considering therapy. Services for children require ad- It may be surprising to know that 20% or more of patients referred to ditional features, and are not considered here. In addition, it was neurology clinics with chronic epilepsy do not in fact have epilepsy concluded that epilepsy surgical facilities should be provided in a at all [27]. Many diferent conditions may be confused with epilep- small number of selected regional centres, and the particular facili- sy, but the most common are psychogenic seizures, refex syncope ties that are required are outside the scope of this chapter. As emphasized there, an eye-witness account of the attacks should be obtained and will usually be diag- Treatment approach for chronic active nostic. A detailed description of therapy sibility that the attacks are non-epileptic, although this is not an in specifc epilepsy syndromes can be found elsewhere in this book. A video recording of an attack is extremely helpful Also, the special considerations in treatment of specifc patient in deciding its nature, and many patients are now able to have their groups such as children, the elderly, those with learning disabilities, attacks recorded on a mobile phone. Such recordings ofen obviate in pregnancy and in those with comorbidities are discussed in the the need for video-telemetry and it is surprising how ofen a short relevant chapters. Here, the approach to therapy in a typical outpatient case of non-syndromic adult chronic epilepsy is outlined, as these cas- Establishing the aetiology of the seizures es make up the bulk of those attending specialist epilepsy clinics The cause of the epilepsy must be established [28]. Of course, individuals have diferent requirements and conditions require therapy in their own right, and the prognosis therapy should be tailored to individual need. Nevertheless, broad and response to therapy of the epilepsy are strongly infuenced by 144 Chapter 11 its cause. The plan should be devised to trial suitable antiepi- patient with chronic epilepsy without a known cause, and not infre- leptic drugs in turn, in a reasonable dose, singly or as two-drug (or quently will reveal a previously undetected cause [29,30]. The sequence of drugs to be apy of epilepsy is ofen uninfuenced by the cause but establishing tried should be clearly documented and discussed with the patient. The procedure should be explained in advance to maintain apeutic approach should be. Ideally, each antiepileptic drug should be tried in a reasonable dose added to a baseline drug regimen (usu- Classifying seizure type and syndrome ally one or two other antiepileptic drugs) which does not change. As is noted repeatedly throughout this book, epilepsy is a high- The duration of the trial will depend largely on seizure frequency, ly heterogeneous condition, and varies considerably in form and and the higher the frequency the shorter the trial. It is important to classify formally the seizure type and, cussed further in Chapter 9. The choice of drug for each seizure type is dis- reduction), which drugs to trial and in what sequence, which drugs cussed in detail in Chapter 27. Documenting previous treatment history The response to an antiepileptic drug is ofen relatively consistent Choice of drug to trial over time. A knowledge of the previous treatment history therefore is The choice of drugs is discussed in detail in Chapter 27 , and other vital to the formulation of a rational treatment plan. It is important to ascertain what previous drugs have been tried, at The drug should usually be one that has not been used before, or what dose (if possible), for how long, in what combinations and with not previously used in optimal doses, or which has been used and what result. The initial dose and maximum Reviewing compliance incremental increases in dose in routine practice are shown in Poor compliance can also be a reason for poor seizure control, and Chapter 9. A Drug choice is an individual decision for a patient to make and drug should not be presumed to be inefective if it was taken errat- will depend on on factors related to patient variables, epilepsy var- ically. People difer in their will- ingness to risk adverse efects or to try new therapy, and patients’ Identifying and treating other factors and comorbidities preferences should be overriding factor in dictating choice. The role The comorbidities of epilepsy can infuence markedly the response of the physician is to provide sufcient information for the patient to therapy. Choice of drug to retain as the baseline regime It is usual to aim for therapy with either one or two suitable antie- Treatment pileptic drugs. If drugs are being withdrawn, it is wise to maintain Treatment of chronic epilepsy (as all epilepsy) should be based on one drug as an ‘anchor’ to cover the withdrawal period. The advan- balancing the benefts of therapy against the potential risks – and tages and place of monotherapy versus polytherapy are discussed where to strike this balance is a personal decision for each patient. The role of the physician in this regard is to provide estimates of the potential benefts and risks and to discuss these with the patient [31]. The sudden reduction in dose of an Personal patient-related factors antiepileptic drug can result in a severe worsening of seizures or Age and gender in status epilepticus – even if the withdrawn drug was apparently Comorbidity (physical and mental) not contributing much to seizure control. Experience from telemetry units suggests that most with- Emotional circumstances drawal seizures have physiological features similar to the patient’s Attitude to risks of seizures and of medication habitual attacks. This caution applies particularly to barbiturate Factors related to the epilepsy drugs (phenobarbital, primidone), benzodiazepine drugs (cloba- Syndrome and seizure type zam, clonazepam, diazepam) and to carbamazepine. The only advantages to fast withdrawal Factors related to the drug are better compliance and the faster establishment of a new drug Mechanism of action regimen. If the withdrawal Strength and nature of side-effects period is likely to be difcult, the dangers can be reduced by cov- Formulation ering the withdrawal period with a benzodiazepine drug (usually Drug interactions and pharmacokinetic properties 10 mg/day clobazam), given during the phase of active withdrawal. Cost A benzodiazepine can also be given if there is clustering of seizures following withdrawal. It is not It is sometimes difcult to know whether seizures during with- comprehensive, and the importance of factors will vary from individual to drawal are a result of the withdrawal or simply the background individual. Whenever possible, a long-term view should be taken and over-reaction in the short-term reaction to seizures should be likely to be involved in drug–drug interactions are carbamazepine, avoided. Drug addition Epilepsy surgery New drugs added to a regimen should also be introduced slowly, at Resective or functional surgery for epilepsy should be considered least in the routine clinical situation. This results in better tolerabili- in any patient with epilepsy not responding to drug therapy and if ty, and is particularly important when adding benzodiazepines, car- the potential benefts are considered to outweigh the potential risks bamazepine, lamotrigine, levetiracetam, primidone or topiramate. This assessment is complex and presurgical evalua- Too fast an introduction of these drugs will almost invariably result tion should be carried out in an experienced epilepsy surgery unit. It is usual to aim initially for a low maintenance dose The elements of assessment are given in Section 4 of this book, but in severe epilepsy higher doses are ofen required. It is a multidisciplinary process, involving neurologist, neurosurgeon, Concomitant medication psychologist, psychiatrist, neurophysiologist and radiologist. On- Changing the dose of one antiepileptic (either an increment or ward referral to a specialized unit should be made for all patients in a decrement) can in many instances infuence the levels of other whom surgery is considered an option. Limits on therapy Terapy will fail to control seizures in the long-term in about 10–20% Serum level monitoring of all patients developing epilepsy, and a higher proportion of those For drugs whose efectiveness and/or side-efects are closely linked to serum level – notably phenytoin, carbamazepine and phenobar- Table 11. Monitoring serum level is particularly important in the case • Nature of epilepsy of phenytoin, which has a non-linear relationship between dose and • First aid management of seizures serum level. Tese issues are considered in more depth in Chapter • Avoidance of precipitating factors, including alcohol and sleep 10.

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