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By K. Nemrok. University of Notre Dame. 2019.

Determination of the anticon- by further reductions as felbamate dose is increased proven eulexin 250mg. Determination of the anti- especially if the goal is to attain monotherapy with felbamate buy generic eulexin 250mg line. Some convulsant felbamate and its three metabolites in brain and heart tissue of rats generic eulexin 250mg amex. J patients have tolerated doses as high as 7200 mg/day as monother- Chromatogtr 1993; 614: 285–292 buy eulexin us. Efects of anticonvulsant drugs on ing patients is to start at approximately 20 mg/kg and increase to 4-aminopyridine-induced seizures in mice. Efects of felbamate and other anticon- vulsant drugs in two models of status epilepticus in the rat. Interaction of felbamate with several other antiepileptic drugs against seizures induced by maximal electroshock in mice. Interaction of felbamate and diazepam permit patients to have an adequate exposure to this drug. Pharmacol tient with refractory epilepsy with particularly intense seizures or a Biochem Behav 1991; 40: 109–113. Mechanism of action of the anticonvulsant day with weekly incremental increases to 45 mg/kg/day. A review of its pharmacodynamic and phar- concentrations afer felbamate initiation [Abstract]. Felbamate in vitro metabo- guidelines for therapeutic drug monitoring: A position paper by the subcommis- lism by rat liver microsomes. Felbamate pharmacokinetics in the rat, trolled trial in patients with partial onset seizures. Isolation and identifcation of childhood epileptic encephalopathy (Lennox–Gastaut syndrome). N Engl J Med 3-carbamoyloxy–2-phenylpropionic acid as a major human urinary metabolite of 328: 29–33. Identifcation of modifed atropal- patients undergoing presurgical evaluation of partial seizures. Epilepsy Res 1995; dehyde mercapturic acids in rat and human urine afer felbamate administration. Felbamate in the treatment of Lennox–Gastaut syndrome: results of felbamate: a retrospective analysis using nonlinear mixed-efects modeling. Single-dose pharmacokinetics of felbamate in the treatment of patients with intractable epilepsy. Trombocytopenia in association with ad- Res Commun Chem Pathol Pharmacol 1985; 48: 467–470. A preliminary report on alteration of car- anemia among patients treated with felbamate. Efects of felbamate on the pharmacokinet- by massive crystalluria and acute renal failure. Dosage is generally adjusted on the basis of clinical response Reference range 2–20 mg/L Common/important adverse Drowsiness, dizziness, ataxia, headache, tremor, diplopia, nausea, effects vomiting, rhinitis, non-pitting leg oedema, weight gain Main advantages Good tolerability, including in the elderly, and lack of drug interactions Main disadvantages Modest efcacy, particularly in severe cases, and spectrum of efcacy restricted to focal epilepsies Mechanism of action Modulates neurotransmitter release by binding to the α2-δ subunit of voltage-gated calcium channels. Additional actions are possible Oral bioavailability <65% (decreases with increasing dose) Time to peak levels 2–3 h Elimination Renal excretion in unchanged form Volume of distribution 0. However, subsequent studies have shown that gabapen- entin can afect excitatory neurotransmission. Similarly, blockade of voltage-gated though originally available to clinicians as Neurontin® (Pfzer), it is sodium channels is thought not to contribute to the pharmacologi- now of patent and a large number of generic versions are available. The protein to which gabapentin appears to bind specifcally in the brain was discovered in 1996 by column fractionation of pig brain membranes which had been treated with [3H]gabapentin. Chemistry Fractions that retained radiolabelled gabapentin-binding activity Gabapentin is a highly water-soluble bitter-tasting white crystal- were isolated and sequenced, demonstrating that gabapentin bound line substance with a molecular weight of 171. Subsequently, new neutral compound that carries both positive and negative charges 3 α2-δ subunit isoforms were isolated but it appears that [ H]gabap- on diferent atoms [4]. This permits absorption from the gut via entin binds only α2-δ-1 and -2 subunits [17]. Although not all researchers have Pharmacology found this, perhaps relating to strain diferences in the mice used for the research [3,12], it seems that the predominant action of gab- Activity in experimental models apentin is as a selective inhibitor of calcium channels that contain Tere have been many studies of the efect of gabapentin in animal the α2-δ-1 subunit and that its efect is dependent on the presence, seizure models, with some correspondence to results from subse- structure and biochemical state of the α2-δ-1 protein [8,18,19]. Prevention of hind limb addition, there are several studies indicating that gabapentin, and extensor response in rats in the maximum electroshock model has the closely related compound pregabalin, subtly reduce the release been a standard method to identify compounds with the potential of a wide variety of neurotransmitters including noradrenaline, to treat generalized tonic–clonic and focal seizures. Gabapentin was found to be inefective at preventing fash-induced myoclonic sei- Pharmacokinetics zures in the photosensitive baboon (Papio papio). Evidence on the use of gabapentin in non-epilepsy indications Absorption has been available from animal studies for over a decade (reviewed Gabapentin is absorbed from the small intestine through an active in [6]). Gabapentin also has anxiolytic-like efects and can prevent transport system, the L-amino acid transporter, which becomes sat- the nociceptive responses from hyperalgesia [7]. Absorption and bioavailability of gabapentin vary between patients, such that Mechanisms of action diferent doses may be required for therapeutic efect [21]. This, gabapentin concentrations are higher than in non-elderly adults of course, must be weighed against the inconvenience of such fre- taking the same dose, presumably due to an ageing-related decrease quent dosing. As the half-life of gabapentin is fairly short (little more than 5 h Little is known of the pharmacokinetics of gabapentin in preg- [24]), it takes only 1–2 days before steady state is achieved with re- nancy. Because of dose-dependent bioavailability, the gabapentin at delivery, and during the neonatal period and lacta- relationship between serum gabapentin concentration and dose is tion. Tey reported drug accumulation in the fetus (mean umbili- non-linear, with less than proportional increases in serum levels cal cord–maternal serum concentration ratio 1. In the newborn period there seemed to with gastric juices, the tablets swell to a size that prevents passage be a lower capacity to eliminate gabapentin than in adults. The The elimination half-life of gabapentin is prolonged with renal other preparation, gabapentin enacarbil, is a prodrug hydrolysed failure, and the clearance of the drug has been found to be propor- in the intestine and liver to yield gabapentin [26]. A reduced dose should there- is not saturable, resulting in greater bioavailability. It is available fore be used in the presence of renal failure and the interval between in an extended-release formulation that has received approval for doses may be lengthened. If haemodialysis is used, a supplemental the treatment of restless legs syndrome and post-herpetic neu- dose is required afer each dialysis [39]. Both formulations result in more sustained plasma levels renal impairment are included in the product information sheet, of gabapentin allowing a reduced frequency of dosing, but these and failure to adjust the dose may result in neurotoxicity [40]. Drug interactions Distribution Tere are no interactions between gabapentin and hepatical- Gabapentin has minimal or no binding to plasma proteins [22] and ly cleared medications because gabapentin is not metabolized in it has a volume of distribution of approximately 0. Antacids containing aluminium or magnesium hydroxide can reduce gabapentin absorption by about 20% [4,42], so it is recom- Elimination mended that administration of antacids and gabapentin should be Although in the dog there is considerable formation of separated by at least 2 h. N-methyl-gabapentin, no biotransformation of gabapentin has been observed in humans [22]. In humans, gabapentin is excreted unchanged in the urine, and has an elimination half-life of 5–9 h in patients with normal renal function [30]. Tere is no signifcant Serum level monitoring efect of gender, but a signifcant linear decrease in clearance has Gabapentin should be titrated according to clinical efect. Case reports suggest the development of tremor and mild changes in Pharmacokinetics in special groups cognition with much higher serum levels (up to 85 mg/L) but lack Clearance is fastest in young children, and those from 1 month to of serious toxicity even in overdose [45,46]. In 48 healthy children aged be- tween 1 month and 12 years, peak plasma concentrations occurred Effcacy 2–3 h afer administration [34]. An Italian group [36] studied gab- The efcacy of gabapentin has been subject to a number of reviews apentin plasma concentrations in a group of 41 patients with re- [47,48,49]. It should be highlighted that the dosage used in many fractory epilepsy and confrmed that children may require larger early trials was relatively low (up to 1800 mg/day), and efcacy may doses of gabapentin than adults to achieve comparable serum drug be improved by higher dosage up to, and in some cases exceeding, concentrations. Gab- viding class I evidence of the efcacy of gabapentin as adjunc- apentin was titrated to a dose of 23–35 mg/kg/day. Each study had a treatment phase of approxi- seizures of 35% (versus a 12% reduction on placebo), and a reduc- mately 3 months’ duration. Overall, these trials indicated that with tion in frequency of secondary generalized seizures of 28% (versus daily doses of 1200–1800 mg, 16–33% of patients showed a more a 13% increase on placebo). The discontinuation rate because of adverse events among aged between 1 and 36 months [59]. Seizures were diagnosed either patients treated with gabapentin ranged between 3% and 11. A 40 mg/kg/day dose of gabapentin (intended to be equiv- these trials plus a similar paediatric study [54] and found a risk ratio alent to 30 mg/kg/day in older children and 1200 mg/day in adults) for 50% reduction in seizure frequency of 1. An increase was noted in the cumulative percentage of responders and Generalized seizures of seizure-free patients as dosage increased.

Cysticercosis Description: Cysticercosis is the most common parasitic infection of the central nervous system buy 250mg eulexin mastercard. Endemic in Mexico buy generic eulexin canada, Central and South America purchase eulexin 250 mg with visa, Eastern Europe order eulexin mastercard, Africa, and parts of Asia. A scolex (the attachment organ of a tapeworm) may be seen in the center of the cyst on T1-weighted images. Surgical intervention may be required to remove intraventricular cysts, ventricular shunting, or both. Prognosis: Morbidity usually results from dying larvae that bring about an intense inflammatory response. There is mild hyperintense signal consistent with edema around the posterior cysts. Depending on the direction of the force created by the mass effect, five types of herniations may be seen. The cerebellar tonsils and cerebellum are forced down through the foramen magnum resulting in compression on the brainstem. Vermian: Superior cerebellar mass effect resulting in an upward herniation of the vermis and cerebellar tissue. Transalar: Central anterior mass effect results in a herniation of the frontal lobe over the greater wing of the sphenoid bone and backward movement of the Sylvian fissure, middle cerebral artery, and temporal lobe. A better prognosis may be seen in patients who have experienced a short time of unconsciousness. Etiology: Results from a rapid deceleration such as in a high-speed motor vehicle accident. Epidemiology: This injury can occur in anyone who experiences a high- speed rapid deceleration. Damage to the axons occurs at the time of the accident, and swelling occurs as a secondary factor. Epidural Hematoma Description: An epidural hematoma is a mass of blood frequently formed as a result of a trauma to the head. Though mostly arterial in origin, it is located between the skull and the dura mater in the temporoparietal region. Epidural hematomas are strongly associated with a linear skull fracture, which can cause a tear of the middle meningeal artery. Less common in occurrence are venous epidural hematomas which typically occur in the posterior fossa or adjacent to the occipital lobes of the cerebrum. Etiology: Usually caused as a result of blunt trauma to the head with a tearing of the middle meningeal artery and blood then hemorrhaging into the epidural space. Epidemiology: Individuals who have experienced blunt trauma to the head are at risk. Imaging Characteristics: Appears to be biconvex in shape and displacing the brain away from the skull. Acute stage hemorrhage will appear isointense on T1-weighted images and hypointense on T2-weighted images. Prognosis: As a result of irreversible brain damage, mortality rates remain high even when diagnosed and treated early. With early diagnosis and treatment prognosis is good; however, with large epidural hematomas, the outcome may result in neurologic deficit. Etiology: Subarachnoid hemorrhages occur most often as a result of a ruptured saccular (Berry) aneurysm. The maximal incidence rate for a subarachnoid hemorrhage is in the fourth and fifth decade of life. Other complications may include loss of consciousness and focal neurologic deficits. Conventional angiography is the gold standard for the diagnosis of cerebral aneurysms. Treatment: Treat the underlying aneurysm by placing a small metal clip or ligation around the neck of the aneurysm. Prognosis: Varies depending on the severity of the initial hemorrhage and possibility of rebleeding and vasospasm. Carotid arteriogram demonstrates a large lobulated aneurysm of the internal carotid artery near its bifurcation. A subdural hematoma usually develops as a result of the head hitting an immovable object. High-speed acceleration- or deceleration-related head injuries could result in the tearing of the veins between the cerebral cortex and the dural veins. Epidemiology: Individuals who have experienced blunt trauma to the head are at risk. These time intervals vary from (1) 24 to 48 hours after injury is defined as acute; (2) between 48 hours and 2 weeks as subacute; and (3) 7 to 10 days as chronic. Signs and Symptoms: Patients may present with headaches, a change in 128 mental status, motor and sensory deficits, increased intercranial pressure, and possible deterioration of the neurologic status. Subdural hematomas typically are crescentic shaped, conforming to the contour of the cranium’s inner table. Subacute stage appears hyperintense on T1-weighted images and hypointense on T2-weighted images. Treatment: A subdural hematoma may be drained through a burr hole or require a craniotomy to drain the accumulated blood. Prognosis: the mortality rates for acute and chronic subdural hematomas are greater than 50% and less than 10%, respectively. They are characterized by a downward elongation of the brainstem (medulla oblongata), cerebellum (cerebellar tonsils), and the fourth ventricle into the cervical portion of the spinal cord. In an Arnold-Chiari Type I, the cerebellar tonsils alone are displaced 5 to 6 mm or more below the foramen magnum. There is no hydrocephalus involved and the fourth ventricle remains in its normal location. This type is associated with myelomeningocele and agenesis of the corpus callosum. Encephaloceles result from a herniation of the brain or meninges, or both, through a skull defect. Etiology: Though there are several theories of the cause of this malformation, the one that is generally accepted is that the posterior fossa is too small, causing a herniation of the brain stem and cerebellar tonsils through the foramen magnum into the upper cervical spinal canal. Signs and Symptoms: Hydrocephalus and developmental defects may be seen early on in infants. Young adults may be asymptomatic until neurologic deficits such as craniocervical junction abnormalities (e. Prognosis: Depends on the type, age of the patient when diagnosed, and extent of other related developmental defects. T1-weighted sagittal image demonstrates downward herniation of the cerebellar tonsils (arrow) through the foramen magnum into the upper cervical spinal canal with compression of the medulla oblongata. Syringomyelia/Hydromyelia Description: Syringomyelia refers to any fluid-filled cavity within the spinal cord. A cavity in the cord may be due to central canal dilatation (hydromyelia) or a cavity eccentric to the central canal (syrinx). Etiology: Approximately 50% of syringomyelias are congenital (Chiari malformation). Acquired cases are the result of intramedullary tumors, trauma, infarction, and hemorrhage. Epidemiology: Approximately 90% of syringomyelias occur in association with an Arnold-Chirai Type I malformation, but also may include, myelomeningocele, basilar skull impression (platybasia), atresia of the foramen of Magendie, or Dandy-Walker cysts. The patient 134 may experience sensory loss (loss of pain and temperature), muscle atrophy (lower neck, shoulders, arms, and hands), and thoracic scoliosis. Axial T2W of the cervical spine shows hyperintense fluid in the spinal cord (arrow) consistent with a syrinx. Tethered Cord Description: A tethered cord is a condition in which the conus medullaris is prevented from ascending to its usual position at the level of L1-L2. It is tethered at an abnormally low position by a tight, short, thickened filum terminale, fibrous bands, intradural lipoma, or some other intradural abnormality. Signs and Symptoms: Patient presents with muscle weakness, abnormal lower limb reflexes, bowel and bladder dysfunction, back pain, and scoliosis. The conus medullaris may be tethered by spina bifida occulta and/or intradural lipoma (posteriorly displaced by fat), glial cells, and collagen.

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Some of these mutations appear to Chagnac-Amitai and Connors [78] have shown that one-third of act through decreasing binding of calmoduline which impairs the the layer V pyramidal neurons of the rat neocortex are endowed exit of Kv7 order 250 mg eulexin otc. In fact discount eulexin 250mg free shipping, beside inherited channelopathies buy eulexin once a day, nectivity enables them to synchronize the activity of synaptically evidence obtained in models of acquired epilepsies also point to- connected neuronal populations buy cheap eulexin 250 mg line. Dreier and Heinemann [82] have developed a technique for spontaneous seizure recurrence and benzodiazepine pharmacore- preparing in vitro slices including the full circuit, and demonstrat- sistance [77]. The knowledge of protein trafcking defects and ed that it is necessary and sufcient to sustain persistent epileptic adaptive mechanisms taking place during epileptogenic processes activities (Figure 3. The physiology of this multisynaptic system might open new strategies in the therapeutic interventions. In addition to the Na+ and K+ conductance responsible for action potentials, both the granule cells making up the principal popula- Network and system involvement in tion of the fascia dentata and the pyramidal cells of Ammon’s horn also possess a broad repertoire of Ca2+ and K+ conductance (includ- epileptogenesis ing Ca2+-dependent K+ conductance) that contribute towards mod- Although an alteration in neuronal excitability is a primary prereq- ulating their fring properties. In this section the role of local circuits regional networks conductance is essentially responsible for the pronounced aferhy- and system are considered. Such networks can be discretely local- 3 ized or more widely distributed within one hemisphere [83]. The main limbic structure and its interconnections are schematically depicted in Figure 3. Above all, these have demonstrated a fundamental rela- tionship between the discharging properties of hippocampal cells Figure 3. In the lowermost part of the fgure, the reciprocal connections of the above structures creating the persistently increase the efectiveness of synaptic transmission to hippocampal–entorhinal circuitry are represented by a wiring diagram. Reproduced with permission Tanks to these properties, the limbic (and particularly hippocam- from Springer Science and Business Media. The role of such an epilep- entorhinal circuit is plasticity (discussed in the next section). The arrows in parts (a) and (b) indicate eferent and aferent connections, sep sep am respectively. Sensory information reaches the amygdala through the lat- system prone to seizure generation is matter for hypothesis-driven eral nucleus and is then distributed in parallel to the various other investigations, putative mechanisms include genetic and develop- nuclei by means of a system of highly organized intra-amygdaloid mental factors and their interaction, but also environmental factors circuits. Amygdala discharges are ofen associated with oral feeding that electively afect the excitable properties of the relevant system. One condition that exemplifes well the concept of SystE is ab- sence epilepsy and its relationship with thalamo-cortical system. A key role is played by the reticular thalamic (Rt) nu- partial alterations in consciousness [91]. Rat neurons have a low-threshold Ca2+ current (I ) which T tine nuclei, the ventral part of the periaqueductal grey matter and is particularly efective in generating sequences of 7–9 Hz Ca2/ the deep strata of the superior colliculus. The posterior or retrosple- K+-dependent bursts afer hyperpolarizing complexes [38,100]. Recent evidence indicates that account for the clinical manifestations of limbic seizures and that a non-inactivating Na+ current component may act synergisti- for the spread of the generating discharges inside and outside the cally with the T-type Ca2+ current [101]. Both the thalamic Other networks The organization of the fbre connections within the brain is so rich that the number of circuits that one can identify is virtually unlim- Cortex ited. Moreover, mice lacking α(1G) T-type Ca2+ channels hippocampus of patients with epilepsy [116]. Tese fndings have show a lack of the burst fring of thalamocortical relay neurons and been confrmed by others [117]. In human mesial temporal lobe epilepsy hypothesis, however, this debate is relatively unimportant. Similar considerations can be made for juvenile myoclonic epilep- Experiments in various animal models have shown that sprouted sies, benign childhood epilepsy with centrotemporal spikes and West mossy fbres make synaptic contacts in ectopic locations, and thus syndrome, which are discussed in Avanzini et al. Recurrent axon collaterals also make synaptic contacts with zures) seems to be the result of a process that develops progres- inhibitory interneurons, leading to an enhanced inhibition [124] sively from an initial event. The biological mechanisms responsible that, rather than preventing the generation of epileptic discharges, for this progressive course of the epileptogenic process have been contributes to it by promoting synchrony [125]. The obvious difculty is with the diferentiation of enhanced excitability in postsynaptic neurons, nor the contribution cause and efect (i. Tese molecular changes result in the enhancement of Na+ current, which can con- tribute to epileptogenesis [106]. Moreover, complex changes in neurotransmitter and neuromodulator systems have been reported (for review see [112]), which can participate in epi- leptogenic mechanisms. Particular attention has been devoted to the neuromodulatory action of neuropeptides, namely neuropeptide Y, which is overexpressed in the hippocampus of various seizure mod- els. Neuropeptide Y inhibits glutamatergic transmission and has been proposed to act as an endogenous anticonvulsant [113] and could therefore be a privileged target for gene therapy [114]. According to the current interpretation, the inner An impressive number of data demonstrate that in several instanc- molecular layer, deprived of the mossy fbres because of the degeneration es epileptogenesis is associated with circuitry reorganization. The of hilar mossy cells, is reoccupied by newly formed axon collaterals of frst evidence was provided by the demonstration that the kindling granule cells. Comparisons of human and lation between high seizure frequency and bad outcome does not animal studies have shown that an initial episode of persisting epi- necessarily demonstrate a cause–efect relationship, rather high leptic activity can set in motion a cascade of events leading to sprout- seizure frequency and bad outcome can both refect an inherently ing and neosynaptogenesis, which may account for the tendency of aggressive epileptogenic process. Once established, the aberrant hippocampal available drugs and, even more, of new strategies aimed at prevent- circuitry creates a condition of hyperexcitability that leads to chron- ing the development of epilepsy and its worsening afer onset. Here we summarize some data that might open the way to future However, a number of other observations do not support this lin- progress. First of all, experimental interventions that pre- vent sprouting do not impair the acquisition of epileptic properties [128]. Tird, the role of the putatively seizure-dependent cell epilepticus induced in rats by electrical stimulation or kainic acid. Protein kinase inhibitors are therefore potential candidates for epi- Finally, the relevance of seizure-stimulated modulations of adult lepsy [137]. Metabotropic glutamate receptors G-protein-coupled receptors Whichever is its pathogenic role, sprouting remains an important which at presynaptic level control synaptic release and postsynapti- morphological correlate of epileptogenesis and a better knowledge cally modulate membrane properties by the second messenger have of its neurobiological mechanisms can advance our understanding been proposed as targets for antiepileptic strategies [138]. Should it be possible to re- tor allosteric modulation by neurosteroids has been proposed [139]. Infammation Another modern approach is aimed at identifying genes that may The role of infammation in ictogenesis is supported by results ob- afect the development of an epileptogenic process set in motion by tained in experimental animals and humans [140,141]. The role of infammatory mediators in oniensi Scientiarum et Artium Institutoatque Academia 1791: 363–418. Versuche über die gereizte Muskel-under-Nervenfaser, oder brain dysfunction resulting in chronic epilepsy is being intensively Galvanismus, nebst Vermuthungen über den chemischen Process des Lebens in der investigated as it could provide the basis of new strategies aimed Tier-und Pfanzenwelt. London Medical infammatory mediator signalling could have an impact on epilep- Gazette 1849; 8: 661–671; 724–729; 766–772; 815–822; 837–846. Cortical cellular phenomena in experimental involvement of which in the development of epilepsy itself has not epilepsy: interictal manifestations. Eur J Pharmacol found up- or down-regulated the tuberous sclerosis complex, corti- 1998; 342: 1–13. Efects of phenytoin on the persistent Na+ current of mam- matic brain injury [144]. Inhibition of transient and persistent Na+ current fractions by the new anticonvulsant quency in with tuberous sclerosis treated with rapamycin for sub- topiramate. Lan- action has been hypothetically ascribed to their regulation of ion cet Neurol 2010; 9: 413–424. Annu Many diferent types of experimental manipulations afecting neu- Rev Pharmacol Toxicol 2014; 54: 317–338. Generalized epilepsy with febrile seizures plus: a genetic led to a greater understanding of how these elementary alterations disorder with heterogeneous clinical phenotypes. The data relating to seizure-related brain plasticity fcking defective epileptogenic Nav1. J Neurosci 2007; 27: are particularly interesting because they shed further light on the 11037–11046. Ionic current underlying activity in the giant epilepsies to progress towards a condition of medical intractability. A potassium channel mutation in ne- ‘Antiepileptogenic’ strategies aimed at preventing the development onatal human epilepsy. Potassium channels: a review of broadening therapeutic pos- markers has been seen as a priority by the scientifc community. Basic developmental rules and their implications for epilepsy in the um channels by synthetic compounds. Localization of a gene for autosomal dominant nocturnal frontal lobe epilepsy to 36.

These investi- of autoimmunity cheap 250mg eulexin fast delivery, which has signifcance not only for selected gators aimed at solving the mechanism and other aspects of disease mechanisms but also for many features of normal immunological enhancement eulexin 250mg with visa. Karl and Ingegerd self-antigens failed to elicit an immune response in the autol- Hellström demonstrated immune complexes that acted as ogous host order eulexin 250mg line. On discovering that goats immunized with their blocking factors in the serum of certain cancer patients order discount eulexin on-line. They own erythrocytes failed to produce autoantibodies, Ehrlich subsequently discovered unblocking factors capable of elimi- formulated a concept of “horror autotoxicus” to explain the nating complexes that interfere with the immune system of the animal body’s failure to mount an immune response against tumor-bearing host. Nevertheless, he recognized also that autoimmunity treatment occurred following the demonstration that tumor- might occur as an aberration and lead to disease. He found that immunity could constitute a part of the etiopathogenesis of ligation and atrophy of methylcholanthrene-induced sarcoma selected disease states. An investigator of rare genius and in mice of the C3H-He pure line were followed by immunity. At frst Subsequently, Donath and Landsteiner showed that autoanti- there was great hope that the detection of this antigen in the bodies were responsible for paroxysmal cold hemaglobinuria blood sera of patients might aid in the diagnosis of cancer. Wassermann and colleagues reported a diagnostic Unfortunately, patients with other types of cancer as well as serologic test for syphilis based on autoantibodies. Meanwhile, certain nonneoplastic diseases may experience derepression many claims were made that one type of disease process or of α gene encoding its formation. For many years immunologists accepted Ehrlich’s have undergone surgical excision of colonic cancer, to signal dictum that the animal body would not form harmful immu- any recurrence or metastasis of the malignancy. Burkitt lymphoma, a B-cell malig- Once early investigators began to use antigens from diverse nancy, which shows strong evidence of association with the sources, Metchnikoff and other pathfnders in immunology History of Immunology 39 reported the development of cytotoxic antibodies in animals 3. Associated with this response, the animal develops immunized with spermatozoa and tissue cells, thereby initiat- pathological changes that are basically similar to ing the concept of autoallergy in which an animal mounts an those of the human; autoimmune response against its own self-antigens. The experimental disease can be transferred to non- coveries about eye diseases in which autoallergy was found to immunized animals by serum or by lymphoid cells. Sympathetic ophthalmia was also these criteria to establish a particular disease process as hav- found to occur as a result of autoallergic sensitization follow- ing an autoimmune etiology or pathogenesis. Witebsky’s ing trauma to one eye, leading to immunologic sensitization of postulates refect the thinking of that period concerning the host against the uninjured companion eye. In comparison with Although the use of adjuvant substances to potentiate the Koch’s postulates, where a single microorganism was proven immune response to antigens dates from the time of Pasteur, to be the etiologic agent of an infectious disease, Witebsky’s Freund and co-workers established (1942) the effciency of postulates were designed to follow the same pattern. The water-in-oil emulsion without Many investigators suspected that viruses were especially added mycobacteria, known as incomplete adjuvant, stimu- signifcant etiologic agents of autoimmune diseases. Indeed, lated sensitivity of the immediate (immunoglobulin-medi- viruses do represent one of several factors important in ated) variety, which was dependent upon antibody titers in the etiology and pathogenesis of autoimmunity. It was also the serum, in contrast to sensitivity of the delayed or tuber- widely held that disease resulted from qualitative abnor- culin-type, which was mediated by sensitized lymphoid malities resulting in autoimmune disease. It was soon found that the incorporation of various nor- several investigators have attempted to present a unifying mal tissues into Freund’s adjuvant, or similar adjuvant-like concept of autoimmunity since the demonstration that auto- materials, could lead to the production of an autoimmune immune reactions may be physiologic as well as pathologic. In 1951, Voisin and colleagues Contemporary immunologic research has demonstrated produced aspermatogenesis experimentally by the injection clearly that self-reactivity is entirely normal. It immune function and immune regulation are dependent upon was postulated that the use of an adjuvant material such as appropriate self–self interactions. It is now recognized that Freund’s adjuvant might cause stimulation of so-called for- quantitative rather than qualitative abnormalities, including bidden clones, according to the clonal selection concept of the relative quantities of autoantibody or immune complexes acquired immunity, and that these forbidden clones might formed or the degree of stem cell proliferation, may lead augment an immune response against self-antigens leading to disease. Witebsky developed certain crite- mune diseases have a multifactorial etiology, where genetics, ria later known as Witebsky’s postulates that were patterned environmental and hormonal factors, and defective immune after Koch’s postulates in bacteriology. Ernest Witebsky (1901–1969), German–American immu- nologist and bacteriologist who made signifcant contribu- In contrast to the horror autotoxicus concept of Ehrlich tions to transfusion medicine and to concepts of autoimmune and Morgenroth and Burnet’s forbidden clone explanation, diseases. He was a direct descendent of the Ehrlich school of Boyden, Grabar and Kay, and Makinodan emphasized the immunology, having worked at Heidelberg with Hans Sachs, physiologic regulatory functions of autoimmunity. Sinai attempt to explain how physiologic autoimmunity might be Hospital in New York in 1934 and became professor at the both physiologic and pathologic, and in an attempt to account University of Buffalo in 1936, where he remained until his for the various etiologic factors, Beutner and colleagues death. A major portion of his work on autoimmunity was the presented a “unifed concept of autoimmunity. Rose of experimental autoim- this concept on the effects produced in vivo by autoantibod- mune thyroiditis. Smith and Steinberg described a new classifcation for autoimmune dis- According to these criteria, an autoimmune response should eases, in the light of current information. Immunization of an experimental animal with anti- gen from the appropriate tissue causes the animal to Medawar (1944–1946) provided the frst convincing proof make an immune response (i. The fuorescent antibody technique was a major breakthrough for identifcation of antigens in tissues and subsequently for demonstrating antibody synthesis by individual cells. While attempting to immunize chickens in which the bursa of Fabricius had been removed, Glick and colleagues noted that antibody production did not take place. Left This was the frst evidence of bursa dependence of anti- to right: Professor Ian Mackay; Sir Macfarlane Burnet; Sir Gustav body formation. He and his associates in Minneapolis and Miller in England went on to show the role of the thymus in the an immunological basis. During the same period, Owen immune response, and various investigators began to search described dizygotic cattle twins in which blood cells of one for bursa equivalents in man and other animals. In 1959, Gowans proved that lym- Burnet and Fenner at the Walter and Eliza Hall Institute phocytes actually recirculate. In 1966 and 1967, Claman and colleagues, Davies and to the template theory of antibody production. The second colleagues, and Mitchison and associates showed that T and edition of their classic monograph entitled the Production B lymphocytes cooperate with one another in the produc- of Antibodies, published in 1949, contains an exposé of their tion of an immune response. Modifying their views through vari- switch from forming one class of immunoglobulin to another ous explanations that included a self-marker hypothesis to by B cells, were demonstrated to be dependent upon a signal explain antibody production, Burnet noted with interest that from T cells activating B cells to change from immunoglobu- Jerne had proposed a selective theory of antibody formation lin IgM to IgG or IgA production. Whereas Jerne discussed various antibody popula- gen in which no T-cell signal was given continued to produce tions, Burnet and Talmage independently emphasized rep- IgM antibody. Such antigens were referred to as thymus- licating cells in a cell selection theory in 1957, leading to independent antigens, and others requiring T cell participa- formulation of a new hypothesis which Burnet termed the tion as thymus-dependent antigens. The template theory of antibody production, which had been Research focused next upon subpopulations of T lympho- popular with the chemists for so many years, could no longer cytes. Mitchison and colleagues described a subset of T explain these new biological revelations that included immu- lymphocytes demonstrating helper activity (i. In 1971, Gershon and this hypothesis was the observation that mature antibody- Kondo described suppressor T cells that prevent develop- synthesizing cells contained no antigen. The concept of suppressor T cells has been brought into question because of the inability to characterize Antigen would have no effect on most lymphoid cells but them by molecular biological analysis. However, the concept would selectively stimulate those cells already synthesizing of immunosuppression, possibly through the action of cyto- the corresponding antibody at a low rate. Subsequent studies concerned interactions among the vari- Burnet introduced the “forbidden clone” concept to explain ous cell types of the immune system including interaction autoimmunity. Thus, elucidation of the T- and normal self-antibody were forbidden and eliminated during B-cell populations and subsets and their role in immuno- embryonic life. Since that time various modifcations of the regulation was requisite for improved understanding of auto- clonal selection hypothesis have been offered. Especially critical to autoimmunity sance of cellular immunology developed following Burnet’s research was the discovery of the regulatory role of T cells in description of the clonal selection theory of acquired the immune response. History of Immunology 41 Benacerraf and colleagues, Benacerraf and McDevitt, and McDevitt and Chinitz demonstrated the signifcant role played by gene products of the major histocompatibility complex in the specifcity and regulation of T cell-dependent immune responses. For a review of genetic control of autoimmunity, the reader is referred to Rose and associates and Vaughan. In his network theory of immunity, Jerne suggested that the formation of antibodies against idiotypic specifcities on antibody molecules followed by the formation of anti- anti-idiotypic antibodies constituted a signifcant additional immunoregulatory process for proper functioning of the immune system. The spleen cells con- antibody against guinea pig erythrocytes to produce experi- ferred the antibody-producing capacity while the tumor cells mental hemolytic syndromes, with associated spherocyto- provided the capability for endless reproduction. Monoclonal sis, increased fragility of cells, and reticulocytosis, closely antibodies are the valuable homogeneous products of hybri- resembling comparable human disorders. Coombs later credited Moreschi with devel- opment of a similar test after the turn of the century, even Au t o i m m u n e He m o l y t i c An e m i A though this was unknown to Coombs and colleagues when the association of autoantibodies with blood diseases dates they developed the antiglobulin technique. The test was devel- formed studies suggestive of a role for autohemagglutinins oped in the 1940s to demonstrate autoantibodies on the sur- in acquired hemolytic icterus, and Chauffard and Vincent face of red blood cells that failed to cause agglutination of the pointed to the action of hemolysins in the production of cells.

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As it descends into the scrotum during development purchase cheap eulexin on line, the testis carries with it the same blood supply that it received whence it was positioned on the posterior abdominal wall (i 250mg eulexin free shipping. On the right side proven 250mg eulexin, the testis drains by way of the pampiniform plexus into the inferior vena cava purchase eulexin 250 mg free shipping, but the left testis drains into the left renal vein. The testis, thus, drains lymph to the para-aortic set of lymph nodes, since the testicular artery arises from the aorta. The clinical consequence of this is that a testicular carcinoma metastasises to the para-aortic group of lymph nodes and never results in inguinal lymphadenopathy, unless the scrotum is also involved. Thus, a renal calculus may refer pain down to the testis, as is seen in classical renal colic. Skin Subcutaneous tissue (containing dartos muscle) Colles’ fascia External spermatic fascia (external oblique) Cremaster muscle and fascia (internal oblique/transverses abdominis) Internal spermatic fascia (transversalis) Parietal layer of tunica vaginalis Visceral layer of tunica vaginalis Tunica albuginea of testis Ureters What type of muscle do the ureters consist of? The ureters are segmental muscular tubes, 25 cm long, composed of smooth (involuntary) muscle throughout their entire length. The ureters are lined by transitional epithelium (urothelium) throughout their length. Transitional epithelium is almost exclusively confined to the urinary tract of mammals where it is highly specialised to accommodate stretch and to withstand the toxicity of the urine. How may the ureters be identified at surgery so as to prevent inadvertent ligation? The ureter is characteristically a whitish, non-pulsatile cord, which shows peristaltic activity when gently pinched with forceps (i. The upper third is supplied by the renal arteries, the middle third from branches given off from the descending abdominal aorta and the lower third is supplied by the superior and inferior vesical arteries. Consequently, the middle third of the ureter is most vulnerable to post-operative ischaemia and stricture formation if blood supply to it is endangered by stripping the ureter clean of its surrounding tissue at surgery. Along the course of the ureter are three narrowings that often form the site of obstruction in ureteric calculus disease: Pelvi-ureteric junction Where the ureter crosses the pelvic brim in the region of the bifurcation of the common iliac artery Vesico-ureteric junction the vesico-ureteric junction is the point of narrowest calibre. In both sexes, the ureters run obliquely through the bladder wall for 1–2 cm before reaching their orifices at the upper lateral angles of the trigone. This forms a flap valve preventing reflux of urine retrogradely back up the ureters. As with all joints, stability is brought about by the way the various bones articulate with one another (through their incongruous surfaces) and through the various ligaments, tendons and muscles that surround the joint. Stability is achieved largely as a result of the adaptation of the acetabulum and femoral head to one another, with a snug fit of the femoral head into the acetabulum, deepened by the labrum and further reinforced by three ligaments on the outside of the capsule (the iliofemoral, ischiofemoral and pubofemoral ligaments). Since the hip is such a stable joint, it requires considerable force to become dislocated. When it does occur, it usually dislocates in the setting of a road traffic accident, where typically the hip joint dislocates posteriorly. 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). Consequently, the sciatic nerve is at risk in a posterior surgical approach to the hip, or in a posterior dislocation. 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.

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Isolated subacromial bursitis in a patient with inflammatory arthropathy seen on a sagittal fat- suppressed T2-weighted image (arrow) discount eulexin express. A: Long axis view of a 72-year-old man with acute onset of pain after reaching to pick up his grandchild order eulexin now. A free suture (S) is evident extending into a distended subdeltoid bursa (arrows) containing low-level echoes order eulexin 250mg with mastercard. A 20-gauge 251 spinal needle (N) is present within the distended bursa where 15 mL of hemorrhagic material was aspirated from the bursa purchase eulexin on line amex. A: Coronal section of T2-weighted magnetic resonance image showing the subacromial fluid collected (white arrows) and the large loculated subdeltoid fluid collected (asterisk). B: Contrasted coronal section showed peripheral enhancement (arrowheads) adjacent to the subdeltoid abscess (asterisk). Synchronous subacromial and subdeltoid bursal abscess and pyomyositis of rotator cuff muscles caused by Viridans Streptococcus. If there is significant inflammation, rubor and color may be present and the entire area may feel boggy or edematous to palpation. Passive elevation and rotation of the shoulder may exacerbate the pain of subdeltoid bursitis and the patient will often exhibit a positive drop arm test when the affected upper extremity is passively elevated with the elbow flexed and supported by the examiner and then suddenly released. The sudden release of the elevated extremity will cause the patient to cry out in pain. Active resisted abduction and lateral rotation of the affected extremity will also reproduce the patient’s pain and a sudden release in resistance to active abduction will also markedly exacerbate the pain. If calcification has occurred, the examiner may appreciate crepitus with active range of motion of the affected shoulder. Alternatively, the patient can be placed in the modified Crass position by positioning the hand of the affected extremity over the posterior hip as if reaching into his or her hip pants pocket to retrieve a comb. The physician stands behind or at the side of the patient and palpates the tip of the acromion. The high-frequency ultrasound transducer is placed over the lateral tip of the acromion in the coronal plane and is angled slightly toward the scapula (Fig. A survey scan is taken and the supraspinatus tendon is identified as it exits from beneath the acromion and curves over the head of the humerus to attach to the greater tuberosity (Fig. The tendon should be carefully examined for calcifications or tendinopathy that may be contributing to the patient’s shoulder pain (Figs. The subdeltoid bursa is then identified as a fluid-containing structure lying between the deltoid muscle and acromion on top and the supraspinatus tendon below (Fig. Although the normal or mildly inflamed subdeltoid bursa most often appears on ultrasonic imaging as a hypoechoic curvilinear layer of fluid sandwiched between a hyperechoic layer of bursal wall and peribursal fat, inflammation and distention of the bursal sac may make the bursal contents appear anechoic or even hyperechoic (Figs. Color Doppler may help further delineate the extent of inflammation of the subdeltoid bursa and surrounding structures (Fig. If inflammation secondary to collagen vascular disease or infection of the subdeltoid bursa are being considered, a search for rice bodies, which are free floating rice-shaped cartilaginous structures of synovial origin is undertaken (Figs. In this setting, aspiration of the subdeltoid bursa for culture and sensitivity can be carried out under ultrasound guidance (Fig. Proper coronal ultrasound transducer position for ultrasound evaluation of the subdeltoid bursa with the patient in the neutral sitting position. Coronal ultrasound image demonstrating the relationship of the subdeltoid bursa to the deltoid muscle. Ultrasound image of subdeltoid bursitis associated with a partial tear of the supraspinatus musculotendinous unit. Longitudinal ultrasound image demonstrating tearing of the bursal surface fibers of the supraspinatus tendon. Transverse ultrasound image of the long head of the biceps tendon demonstrating moderate subdeltoid bursitis of the left shoulder. Transverse (A) and longitudinal (B) ultrasound images of the left shoulder show an arc-shaped bright interface with acoustic shadowing and effusion in the subacromial-subdeltoid bursa. C: Longitudinal scan during compression with the transducer shows that the mass moved away from its original site. Synovial osteochondromatosis in the subacromial bursa mimicking calcific tendinitis: sonographic diagnosis. Dynamic longitudinal ultrasound image of the right shoulder demonstrating subdeltoid bursal impingement at the coracoid process. Color Doppler demonstrating increased vascularity only within the rotator interval (A), only in the subdeltoid bursa (B), or both (C). Transverse ultrasound of long head of biceps tendon demonstrating subdeltoid bursitis. Note the rice bodies within the massively enlarged bursa and fluid around biceps tendon. Transverse ultrasound image demonstrating subdeltoid bursitis in a patient with connective tissue disease. Staphylococcus aureus septic subacromial-subdeltoid bursitis in a 52-year-old with endocarditis. Sagittal gray scale (A) and color Doppler (B) ultrasound images along the greater tuberosity of the humerus (arrowhead) show hypoechoic fluid in the subacromial-subdeltoid bursa (arrow), with surrounding vascular flow in B indicating inflammation. C: Coronal T2 fat-saturation magnetic resonance image oriented in the same plane as the ultrasound images shows a large amount of hyperintense fluid in the subacromial-subdeltoid bursa (arrow) over the greater tuberosity (arrowhead). D: Sagittal ultrasound image along the greater tuberosity of the humerus demonstrates needle aspiration of the fluid with the needle tip in the bursa. A high index of suspicion for infection of the subdeltoid bursa is indicated in any patient with shoulder pain and fever. Rarely, tumors or other muscle abnormalities involving the deltoid muscle and subdeltoid bursa can occur. Magnetic resonance scanning may provide complementary information when used in conjunction with ultrasound evaluation of the subdeltoid bursa. Compromise of the subcoracoid space by tendinitis, boney deformity following fracture of the coracoid, or osteophytes can irritate the subcoracoid bursa and cause bursitis. It is also susceptible to irritation during extreme arm movement, when the biceps tendon is pressed against the humeral head (Fig. This process can be accelerated if previous trauma to the shoulder joint has compromised its stability and abnormal movement of the head of the humerus in the glenoid fossa occurs. Anatomic coronal section demonstrating the relationship of the coracoid process, the biceps tendon, 260 and the humeral head. The bursa serves to cushion and facilitate sliding of the musculotendinous unit of the subscapularis muscle. The bursa is subject to inflammation from a variety of causes with acute shoulder trauma and repetitive microtrauma being the most common. If the inflammation of the bursa is not treated and the condition becomes chronic, calcification of the bursa with further functional disability may occur. The patient suffering from subcoracoid bursitis most frequently presents with the complaint of severe pain especially with forward movement, internal rotation, and abduction of the shoulder. Activities requiring abduction of the affected upper extremity are particularly painful and the patient may complain bitterly of a knife-like catching sensation when using the shoulder upon first awakening. The pain of subcoracoid bursitis is localized to the area of the coracoid and is often referred to the medial shoulder. Physical examination of the patient suffering from subcoracoid bursitis will reveal point tenderness at the acromion process as well as in the subacromial region. If there is significant inflammation, rubor and color may be present and the entire area may feel boggy or edematous to palpation. Passive elevation and active internal rotation of the shoulder may exacerbate the pain of subcoracoid bursitis and the patient will often exhibit a positive adduction release test when the affected upper extremity is adducted against the examiner’s resistance and the resistance is suddenly and unexpectedly released (Fig. The coracoid impingement test may also be positive and is performed by flexing the shoulder 90 degrees, internally rotating the shoulder, and then horizontally adducting the arm. If calcification of the bursa and surrounding tendons has occurred, the examiner may appreciate crepitus with active range of motion of the affected shoulder. Rarely, the subcoracoid bursa may become infected and failure to diagnosis and treat the acute infection can lead to dire consequences (Fig. Septic subdeltoid and subacromial bursitis consistent with tuberculosis infection.

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For drugs that can be given once or Antiepileptic drug treatment is indicated whenever expected twice daily but do not have a long half-life purchase online eulexin, a twice-daily schedule benefts outweigh the risks discount 250 mg eulexin fast delivery. The risk–beneft equation eulexin 250mg overnight delivery, in turn 250mg eulexin mastercard, is may be preferable because it minimizes the adverse consequences determined by many factors, including the type of epilepsy, the fre- of missing one dose. In general, once-daily dosing does not entail quency and severity of the seizures, the age and the occupation of better compliance than twice-daily dosing, but it may have psycho- the individual, associated pathological conditions, the character- logical advantages, particularly in individuals who are seizure-free istics of the drug(s) being considered and the presumed infuence and perceive each act of pill-taking as the only unpleasant reminder of treatment on the individual’s well-being and aspirations. In many situations, the decision on whether to start treatment or Prevention of epileptogenesis to withhold it will involve no uncertainty, but grey areas exist where Experiments in animal models suggest that some antiepileptic the optimal therapeutic strategy is uncertain [34]. In any case, the drugs not only exert a symptomatic efect by raising seizure thresh- individual should always be involved in the therapeutic decision, old, but might also antagonize epileptogenic processes (i. The suggestion has been made that recurrent clinical establishing the indications for treatment. The actual decision de- seizures may also lead to irreversible neuroanatomical changes that pends on individual factors. A number of diferent scenarios are may render the disease more difcult to control, but evidence for discussed briefy in this chapter, and other aspects are covered in this is controversial [27]. However, available stud- The most common situation where there may be uncertainty about ies suggest that currently available antiepileptic drugs exert merely whether chronic treatment is justifed is when a person presents a symptomatic efect and do not afect the natural course of the with a single unprovoked tonic–clonic seizure whose nature is con- disease [28,29]. Admittedly, special conditions may exist in which sidered to be probably epileptic [35]. Because many such individu- early efective treatment may improve the ultimate prognosis, als will not have a recurrence when lef untreated [36], and because General Principles of Medical Management 113 treatment afer a frst seizure does not improve long-term progno- Other situations sis [34,37], indiscriminate prescription of antiepileptic drugs afer Occasionally, treatment may be justifed without a clear diagnosis of a frst tonic–clonic seizure, while efective in reducing the risk of epilepsy. When even intensive monitoring fails to provide diferen- relapse [34,38], will unnecessarily expose many patients to adverse tiation between epileptic seizures and pseudoseizures, in rare cases efects. Terefore, drug therapy is generally deferred until a second a therapeutic trial may be indicated. Treatment afer a frst seizure, however, may be suggests a non-epileptic nature of the attacks, but it should not be considered when specifc prognostic factors indicate a high risk of regarded as a conclusive proof for this. Interpretation of response to treatment is also situations where a diagnosis of epilepsy can be made afer a single complicated by the fact that epileptic seizures and pseudoseizures seizure [40], treatment decisions should not be automatically linked may coexist. Specifcally, treatment is It has been argued that under certain circumstances prophylac- not necessarily indicated in all individuals fulflling the criteria for tic treatment may be justifed even in the absence of any previous a diagnosis of epilepsy, while conversely there may be individuals in seizure. For example, it has been suggested that in infants with tu- whom treatment can be justifed in the absence of such diagnosis. Antiepileptic drugs are at times prescribed person (or parents) should be involved in the decision process. While phenytoin has been found to reduce the risk of early treatment was investigated recently in a subcohort of 331 patients in post-traumatic seizures (i. Afer 2 years of follow-up, individuals rand- ter head trauma) [44], neither phenytoin nor other drugs have been omized to deferred treatment were no more likely to report impair- found to be of value in the long-term management of individuals ments in general health, cognitive function, psychological well-be- with head trauma or brain surgery. In fact, the vast majority of these ing or social function than individuals assigned to immediate individuals will not develop seizures in the long term and, more treatment. One area where a diference was identifed was driving, importantly, no antiepileptic drug has been found to be efective in where those randomized to deferred treatment were disadvantaged. Exceptions may be individuals with optimization very minor seizures or rare seizures, particularly when these are Rational therapy requires not only choosing the most appropriate mild, brief or occur only during sleep, and do not interfere with drug, but also identifying the optimal dosage [45]. Indeed, one of daily activities, occupation, psychological state and social integra- the most signifcant advances in the modern treatment of epilepsy tion. Pharmacological treatment is also generally not indicated in has been the recognition that dose requirements vary greatly across some self-limiting childhood epilepsies which have a self-remitting individuals, because of pharmacokinetic and pharmacodynamic course, when the side-efects of antiepileptic drugs are expected to diferences. Optimizing drug choice and dosage are complex pro- adversely afect quality of life to a greater extent than the seizures cesses, and diferent aspects need to be addressed. The best example is represented by children with self-limited focal epilepsy with centrotemporal spikes Choice of the most appropriate drug (rolandic epilepsy), in whom treatment is usually indicated only in As a general rule, treatment should be started with a single drug the few cases in whom seizures are frequent, severe and occur dur- (Table 9. Critical Individuals with seizures precipitated by specifc triggers medication-related features include spectrum of efcacy against dif- When seizures are precipitated by specifc triggers, avoidance of the ferent seizure types, expected magnitude of therapeutic response, latter may be sufcient. Some forms of photosensitive epilepsy, for indications and contraindications, characteristics of available for- example, can be managed by prescribing appropriate lenses, or by mulations, dose escalation and dosing regimen requirements, ad- instructing the patient on how to avoid exposure to the ofending verse efects profle, interaction potential, impact on comorbid light frequencies. Continuous pharmacological prophylaxis is also conditions, cost and reimbursability. Patient-related factors to be not indicated in most children with febrile seizures who are older considered include seizure type and syndromic diagnosis, age, than 1 year (the treatment of febrile seizures is considered further gender, comorbidities, comedications, risk factors for potential in Chapter 14) [42]. Phenobarbital may also be started at a ‘thera- used) peutic’ dosage, but because of its long half-life the time-course of Easy management (effcacy and safety of individual drugs can be pharmacological action is infuenced by the slow accumulation of evaluated separately) the drug in plasma, a process that may require several weeks. Children, elderly individuals and individuals with certain comorbidities or comedications may require doses and titration rates diferent from those given in Table 9. The rate of dose escalation is also partly dependent on the treatment setting: a pa- as personal attitudes in relation to possible recurrence or seizures tient with frequent seizures, for example, may require more rapid or appearance of specifc adverse drug efects. Initial target maintenance dosage The initial target maintenance dosage can be defned as the dosage Dose escalation at which the patient is stabilized at the end of the initial dose esca- When an immediate therapeutic efect is required, as in the man- lation phase [45]. In general, this corresponds to the lowest daily agement of status epilepticus or frequently recurring seizures, treat- dosage that is expected to produce seizure control in that individual. In most situations, how- This approach is justifed by the desire to minimize the probability ever, this aggressive approach is neither necessary nor desirable, of exposing individuals to long-term treatment with dosages higher and treatment should be initiated with a small dose and increased than necessary. Gradual dose escalation has In recent years, evidence has accumulated that most individuals several advantages. In a slowly afer initiation of treatment [46], and immediate use of a large single-centre study that explored the efectiveness of the frst full maintenance dosage may cause major tolerability problems. In a recent randomized trial that com- topiramate, tiagabine, zonisamide and perampanel. Primidone pared carbamazepine and levetiracetam in adults with newly di- may cause a particularly marked transient intolerance reaction in agnosed focal epilepsy, about 90% of seizure-free individuals were individuals not previously exposed to barbiturates, and it should controlled at doses of 400 mg/day for carbamazepine and 1000 mg/ be started at a dose (62. An indication of possible initial target maintenance dosages • Despite common belief, allergic and idiosyncratic reactions are is provided in Table 9. In practice, the target dosage should be ofen dependent on starting dose and rate of dose escalation [47]. Many genetic (syn: idiopathic) general- ated at too-high doses are especially frequent with carbamaze- ized epilepsies respond well to treatment, and it may be justifed in pine, phenytoin and lamotrigine. Because valproic acid increases these individuals to aim at initial maintenance dosages and plasma the plasma levels of lamotrigine, the risk of lamotrigine-induced drug levels in the low range. For example, the dosage of valproic allergic reactions is greatly increased in individuals comedicat- acid required to control primary generalized tonic–clonic seizures ed with valproic acid, and in these individuals it is essential that has been found to be about 30% lower than that required to control lamotrigine dosage is escalated at a very slow rate. A high seizure frequency before starting ther- • Some individuals can be optimally controlled at doses below the apy, symptomatic epilepsy, focal seizures, multiple seizure types, initial target maintenance dosage. When seizure frequency is suf- associated neurological handicaps and an unfavourable response to fciently high to permit a meaningful assessment of therapeutic previous antiepileptic drug therapy all infuence the prognosis neg- response over a short period, slow dose escalation may allow atively [51,52], and individuals with these features are expected to identifcation of the lowest dose regimen at which individuals require comparatively higher doses and plasma drug levels. Conversely, some individuals are unusually sensitive to factors afecting choice of the initial maintenance dosage include adverse efects, and slow dose escalation will prevent them from the presence of physiological or pathological conditions leading being exposed to dosages higher than those tolerated. Elderly individuals, in par- tration rates are seldom established in regulatory clinical trials and ticular, generally require dosages in the low range, because they therefore they are mostly identifed through postmarketing experi- exhibit an increased sensitivity to the efects of antiepileptic drugs ence. Usual initial target Usual maintenance maintenance Frequency of Drug dosage (mg/day) dosage (mg/day) administration Suggested titration rate Carbamazepine 400–600a 400–1600 2–3 times/day (twice Start with 100 or 200 mg/day and increase to target daily with controlled- dosage over 1–4 weeks release formulations) Clobazam 10–20 10–40 Once or twice daily Start with 10 mg/day. If indicated, increase to 20 mg/ day after 1–2 weeks Eslicarbazepine 800 800–1200 Once daily Start with 400 mg/day and increase to target dosage acetate after 1 or 2 weeks Ethosuximide 500–750 500–1500 2–3 times/day Start with 250 mg/day and increase to target dosage over 1–3 weeks Felbamate 1800–2400 1800–3600 3 or 4 times/day Start with 600–1200 mg/day and increase to target dosage over 10–21 days Gabapentin 900–1800 900–3600 2 or 3 times/day Start with 300–900 mg/day and increase to target dosage over 5–10 days Lacosamide 200–300 200–400 Twice daily Start with 100 mg/day and increase to target dosage by increments of 100 mg/day every week Lamotrigine 50–150 50–200 Twice daily (once Monotherapy: start with 25 mg/day for 2 weeks, then (monotherapy); (monotherapy or daily possible with increase to 50 mg/day for 2 weeks. Further increases 50–100 (patients on patients on valproic monotherapy by 50 mg/day every 2 weeks valproic acid); acid); 200–500 and valproic acid Valproic acid comedication: start with 25 mg on 200–300 (patients (patients on comedication) alternate days for 2 weeks, then 25 mg/day for 2 weeks. Further increases by 50–100 mg/day every 2 weeks Levetiracetam 1000–2000 1000–3000 Twice daily Start with 500 or 1000 mg/day and increase, if indicated, after 2 weeks Oxcarbazepine 600–900 600–3000 2 or 3 times/day Start with 300 mg/day and increase to target dosage over 1–3 weeks Perampanel 4–8 4–12 Once daily Start with 2 mg and increase to target dosage at 2-week intervals (weekly intervals may be used for patients taking comedications that shorten the half-life of perampanel) Phenobarbital 50–100 50–200 Once daily Start with 30–50 mg at bedtime and increase, if indicated, after 10–15 days Phenytoin 200–300 200–400 Once or twice/day Start with 100 mg/day and increase to target dosage over 3–7 days Pregabalin 150–300 150–600 2 or 3 times/day Start with 75 mg/day for 3 days, then increase to 150 mg/day. If indicated, increase to 300 mg/day after 2 weeks Primidone 500–750 500–1500 2 or 3 times/day Start with 62. In patients on enzyme-inducing comedication a faster titration may be used Retigabine 600 600–1200 3 times/day Start with 50–150 mg/day and increase to target dosage at about weekly intervals Rufnamide 1200 1200–3200 Twice daily Start with 400 mg/day and increase by 400 mg/day increments every 2–4 days (Continued) 116 Chapter 9 Table 9. This information refects the author’s assessment of available evidence and may differ from information reported in data sheets in individual countries. Some patients will require dosages, titration rates and dosing regimens different from those given in this table. The individual’s attitude and circumstances should also be con- with valproic acid, which prolongs the half-life of lamotrigine (see sidered. Some neurologists have agabine, more than two daily administrations may be required to also in the past favoured the use of relatively high initial mainte- minimize excessive fuctuations in plasma concentration. This is nance dosages out of a fear that a delay in achieving complete sei- especially important for individuals in whom half-lives are at the zure control might increase the probability of the epilepsy becom- shorter end of the spectrum, such as children and enzyme-induced ing intractable. With these drugs, intermittent adverse efects are for most of the epilepsy syndromes, there is no evidence that this not uncommon at the time of peak drug concentration, whereas is the case.

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