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By Z. Cole. Claflin College.

Hypothetical mechanisms for the cellular and neurophysio- mas: neuroanatomical analysis of brain lesions in 100 patients female cialis 20mg line breast cancer walk in chicago. Brain 2011; 134: logic basis of secondary epileptogenesis: proposed role of synaptic reorganization cheap female cialis 10mg on line menopause or pregnant. Int Rev Neurobiol pothalamic hamartomas correlates with anatomic features but not with expression 2001; 45: 435–446. In: Tuxhorn I, Holthausen two patients with gelastic seizures and hypothalamic hamartomata. The clinical spectrum of epilepsy in children of the corpus callosum, and hamartoma. Gamma knife surgery for epilepsy related to toring has limited utility in patients with hypothalamic hamartoma and epilepsy. Hypothalamic hamartoma and treatment of gelastic epilepsy due to hypothalamic hamartomas. Electroencephalogr Clin lamic hamartomas: new lessons from an experiment of nature. Psychiatric aspects of patients with hypotha- with hypothalamic hamartoma and catastrophic epilepsy. Intrinsic epileptogenesis of hypothalamic tients with hypothalamic hamartoma and refractory epilepsy. Precocious puberty due to a hypothalamic ic hamartomas: infrequent epilepsy and normal cognition in patients presenting hamartoma. Surgical treatment of intractable seizures Acad Child Adolesc Psychiatry 2001; 40: 696–703. Gamma knife surgery for epilepsy related Cambridge University Press, 2011: 449–458. Orbitozygomatic resection for hypotha- lamic hamartomas, with control of seizures, in children with gelastic epilepsy. Epilepsy related to hypothalamic hamarto- doscopic surgery and stereotactic radiosurgery: a case report. Minim Invasive mas: surgical management with special reference to gamma knife surgery. Outcome and predictors of in- hamartomas causing medically refractory gelastic epilepsy. Childs Nerv Syst2006; terstitial radiosurgery in the treatment of gelastic epilepsy. Lef vagal nerve stimulation in six patients otactic radiosurgery in patients with epilepsy due to hypothalamic hamartoma. Subsidence of seizure induced by stereotactic associated with hypothalamic hamartomas. Electrical stimulation of the anterior nucleus of thalamic hamartomas in patients with medically intractable epilepsy and preco- thalamus for treatment of refractory epilepsy. The use of radiosurgery to treat intractable cordings of the mammillary body in epilepsy patients. Gamma knife surgery for epilepsy related to lamic tract for the treatment of resistant seizures associated with hypothalamic hypothalamic hamartoma. Deep brain stimulation for the treatment of surgery for hypothalamic hamartomas accompanied by medically intractable drug-refractory epilepsy in a patient with a hypothalamic hamartoma: case report. Gamma knife radiosurgery for re- report of two cases surviving surgical removal of the tumour. Stereotactic radiofrequency ablation for ses- crosurgery: a novel strategy to approach complex ventricular lesions. A certain proportion of patients who undergo eval- produced an epileptic focus with aluminium gel lesions in the lef uation for possible surgical resection are found to have an epilepto- precentral motor cortex, which resulted in the development of focal genic zone originating in, or overlapping with, eloquent cortex. Using a small wire, he disconnected the horizontal patients traditionally have been denied surgery because resection of fbres at 5-mm intervals throughout the epileptogenic zone. This pro- primary speech, motor, sensory or visual cortex would result in unac- cedure, the frst subpial transection for epilepsy, stopped the seizures, ceptable defcits. The purpose of this technique is confrm that what he had transected was motor cortex, 1 year lat- to disrupt the intracortical horizontal fbre system while preserving er Morrell surgically removed the transected area, resulting in the the columnar organization of the cortex (i. With this experimental evidence, Morrell and put and output systems and vascular supply) [1]. The transection of colleagues moved forward into the treatment of intractable human horizontal fbres is aimed at preventing the propagation of epileptic neocortical epilepsy arising in or overlapping eloquent cortex. The pres- ervation of the columnar organization of the cortex prevents or min- Planning for multiple subpial transection imizes the disruption of the functional state of the transected cortex. Multiple subpial transection is indicated in any patient in whom the ep- The development of this technique was derived from three sets of ileptic zone arises from or overlaps with eloquent cortex. The procedure experiments, each unrelated to the others or to the feld of epilepsy is performed afer a detailed presurgical evaluation, which includes surgery. The frst set of experiments by Asanuma and Hunsperger closed-circuit video electroencephalographic recording of habitual sei- [3], Hubel and Wiesel [4] and Mountcastle [5] demonstrated that zures using scalp and intracranial electrodes, mainly subdural grids. In the vertically oriented micro- and macrocolumns (with their ver- addition, detailed functional mapping to identify eloquent cortex by tically oriented input, output and vascular supply) are the organi- electrical cortical stimulation and evoked potentials is performed. The functional role ropsychological testing and functional neuroimaging studies all assist of the intracortical horizontal fbre system is yet to be frmly estab- in defning the baseline function and risks of the procedure. However, this system is composed of fbres responsible for encephalography studies have also been very useful in the evaluation of recurrent inhibition and excitation underlying neuronal plasticity. It allows more accurate identifcation gical disruption of the horizontal fbre system in the visual cortex of the source of the dipole, especially its depth within a sulcus [12,13]. In the third set of experiments, Tarp with resection of non-eloquent cortex, depending on the extent to related the importance of the horizontal fbre system as a ‘critical which the epileptogenic zone involves eloquent cortex. Epileptic activity in the form of typically patients with dominant temporal mesial or neocortical ep- spikes or sharp waves requires a synchronous neuronal activation ilepsy, dominant frontal lobe epilepsy, or primary sensory, motor or of a contiguous cortical surface of at least 12 to 25 mm2[7,8]. In patients undergoing resection/transec- found that epileptic foci would synchronize their activity if the dis- tion, resection of non-eloquent cortex is performed to within 1. We recognize that this pa- between the foci would desynchronize the epileptic activity. However, the microgyral patterns of in- Afer the frst transection is completed, bleeding from the pial dividual gyri may be considerably variable. Tese cortical variations opening is controlled with small pieces of Gelfoam and a cotton- must be taken into account in a procedure where transections are oid. The 4-mm tip is then placed up against the cortex next to the being made perpendicular to the long axis of a gyrus. Tus, careful transection so as to select the next transection site 5 mm from the inspection of each gyrus prior to the procedure is important. This is repeated until the identifed epileptogenic zone is tran- matter is, on average, 5 mm thick over the crown of a gyrus; howev- sected. Over a few minutes, the lines take on a striped appearance er, the depth of each sulcus is variable. Minimal bleeding Tese points are critical in subpial transection procedures be- is encountered if the transections are done properly.

Bioavailability increases by about 40% when the drug is taken with food Time to peak levels 4–6 h Elimination Primarily by hydrolysis of the carboxamide group The Treatment of Epilepsy buy female cialis online now womens health kettlebell workout. Increases with increasing dosage order 10mg female cialis with amex women's health problems and solutions, because actual bioavailability decreases as dose is increased Elimination half-life 8–12 h (shorter in patients co-medicated with enzyme-inducers) Plasma clearance On average about 90 mL/h/kg in adults at a dosage of 45 mg/kg. Increases with increasing dosage, and is higher in children than in adults Protein binding 30% Active metabolites None Comment A potentially valuable drug. In February 2004, Eisai Company Ltd acquired the rights to develop rufnamide for epilepsy from Novartis. Of two monotherapy trials in adults with focal seizures, one was positive and the other did not meet the primary end-point. In a trial in Lennox–Gastaut syndrome, a relatively large efect size was 200 demonstrated. In addition, there has been a negative trial in pa- tients with primary generalized tonic–clonic seizures and another negative trial in the add-on setting in children with focal seizures. A pi- lot trial in patients with diabetic neuropathic pain was negative but 0 suggestive of a small efect size. Rufnamide has a chemical formula of C10H8F2N4O, which corresponds to a molecular weight Pharmacology of 238. The drug does not show any hygroscopicity; no water was absorbed Activity in experimental models of seizures and epilepsy by the drug when placed in an environment of up to 100% relative The activity profle of rufnamide in experimental models has been humidity. Pharmacokinetics Repeated dosing for 5 days at a single dose of 6 mg/kg orally did not induce tolerance to the anticonvulsant efects of rufnamide. Absorption and bioavailability The anticonvulsant efect in the maximal electroshock test was Rufnamide is relatively slowly absorbed from the gastrointesti- maintained for 4 h in mice and 8 h in rats [8,9,10]. However, it was hardly efective in the gly- dissolution into gastrointestinal contents [13]. It has also shown efectiveness in reducing seizure plasma rufnamide concentration and dose during treatment with a frequency in rhesus monkeys with chronic alumina foci in the dose of 3600 mg twice daily was approximately half that recorded at motor cortex. Hippocampal and cortical aferdischarges induced a dose of 400 mg twice daily [13]. It is also partially efective in the strychnine test, although availability during multiple dosing has not been clearly established, it appears that, among the various seizure models tested, strych- it is recommended that rufnamide always be taken at meal times. In contrast to rufnamide, phenytoin did not provide protection Distribution against various types of chemically induced seizures [12]. The plasma protein binding of rufnamide is low, at about 26–34% In most animal models, the therapeutic index of rufnamide was [13]. As expected, larger Vd/F values Although the precise mechanisms of action of rufnamide are in- have been measured in subjects receiving higher dosages, as a result completely known, based on in vitro studies the principal mecha- of the dose-dependent decrease in bioavailability [13]. Rufnamide nism of rufnamide’s antiepileptic activity appears to involve mod- is evenly distributed between erythrocytes and plasma. An additional potential and rabbits afer administration of radioactive rufnamide (Eisai, mechanism is represented by inhibition of responses at the gluta- data on fle). The concentrations in the embryo and the amniotic mate receptor subtype mguR5, which is observed at high concen- fuid were about half of those in the maternal blood afer 24 hours. In rats and rabbits, radioactivity was turnover at 100 µmol/L concentrations) [9]. For example, it was calculated that, at a rufnamide latter diference, which persisted afer adjusting for body size, was dosage of 45 mg/kg in the absence of interacting co-medications, not considered clinically signifcant [20]. Concentrations of radioactive ruf- T e elderly namide and its metabolites were measured in blood, plasma, urine Chang et al. Absorption at this low dose was demonstrated to be at in seven elderly healthy subjects (age range 66–77 years) com- least 85%. The main radioactive compound in plasma was rufna- pared with seven younger gender-matched healthy subjects (age mide. Rufnamide was extensive- tiple-dose (400 mg given twice daily for nine doses) open-label ly metabolized, with only 4% recovered unchanged in urine (2%) parallel-group study. A the elderly and the young volunteers under both single-dose and few minor metabolites were detected in the urine that appeared to multiple-dose conditions. This might suggest that dialysis can be used to treat patients with toxic levels of the drug. Children Only limited data exist on the efect of young age on rufnamide Impaired liver function pharmacokinetics. In studies conducted to date, dosage and The efect of hepatic impairment on rufnamide pharmacokinetics co-medications varied among age groups, and it has been difcult has not been evaluated. Rufnamide was administered orally in equal- Effect of other drugs on rufnamide pharmacokinetics ly divided twice daily doses of 10 mg/kg/day (week 1) and 30 mg/ Using population pharmacokinetic modelling [13,26,27,28], kg/day (week 2), and at the end of each week blood samples were enzyme-inducers, such as carbamazepine, phenytoin and phenobar- taken for pharmacokinetic profling. The data showed a less than bital, have been shown to reduce serum rufnamide concentrations. Although no and primidone (assessed together in the model) by 25–46%; and vi- signifcant diferences in pharmacokinetic parameters as a function gabatrin by 14–30% [13]. Valproic acid increased the serum concen- of age were noted, the small size of the age subgroups makes the tration of rufnamide by 12–70% on average, the highest increases data difcult to interpret. This analysis showed a decrease in seizure counts with increasing serum rufnamide con- Effect of rufnamide on the pharmacokinetics of centrations, at least within the concentration ranges encountered other drugs in clinical trials. The plasma rufnamide concentration estimated In an in vitro study [18], rufnamide was incubated at concentra- to be associated with a mean 25% reduction in seizure frequency tions up to 300 µmol/L, with various substrates, in human liver was 13 µg/mL, which is within the range expected to be achieved microsomal fractions to evaluate any potential inhibitory efect on with the recommended dose range. This suggests that data to determine the value of serum level monitoring in optimiz- rufnamide is unlikely to inhibit the biotransfomation of drugs that ing therapy with this drug. Effcacy However, the efect of rufnamide on the serum levels of carbamaz- To date, a total of 10 double-blind efcacy studies have been con- epine, lamotrigine, phenobarbital, phenytoin, topiramate and val- ducted. Of those studies, one was terminated early due to poor en- analysis of measurements made during clinical trials. Of the remaining nine, six were reported to demonstrate at a concentration of 15 µg/mL, was estimated to cause a small de- rufnamide efcacy as compared to the control group, and three crease in clearance of phenobarbital and phenytoin. Rufnamide was also estimated to cause a small increase in the A multicentre, double-blind, low-dose active-control, randomized, clearance of lamotrigine and carbamazepine, which would result in parallel-group monotherapy study (Study 0016) compared 300 mg/ a decrease of 7–13% in the concentration of these drugs [26]. Patients were allowed to exit the study maintained on the pill for at least two cycles prior to initiation of by meeting criteria based on seizure frequency or severity, or com- the study, and rufnamide 800 mg twice daily was taken on days pleting 112 days of treatment. Tese fndings suggest that exit criterion showed a trend favouring the high dose (56 days) over rufnamide stimulates the metabolism of contraceptive steroids by the low dose (32 days), but again the diference was not statistically a moderate degree. Another double-blind, randomized, placebo-controlled, In another study, rufnamide, given at the low dose of 800 mg/ parallel-group study (Study 0038) was conducted in patients with day for 11 days to 18 healthy subjects, caused a 36% decrease in focal seizures who completed inpatient evaluation for epilepsy 622 Chapter 47 Table 47. Each patient had to have 2–10 focal seizures during the 48-h 3-month double-blind phase. Afer completing this phase, patients were rand- linear trend of dose response in seizure frequency per 28 days in omized to receive rufnamide (n = 52) or placebo (n = 52) for the the treatment group (P = 0. Rufnamide dose was 2400 mg/ with ≥50% decrease in seizure frequency compared with baseline) day on day 1 and 3200 mg/day on days 2–10, given on a three times (P = 0. The patients continued on treatment until they com- cy between placebo and each rufnamide arm revealed a signifcant pleted 10 days or met one of the exit criteria. The mean dose of ru- reduction in patients treated with rufnamide 400 mg/day (11% de- fnamide was 2970.

Rett syndrome discount 20mg female cialis visa breast cancer 9 lymph nodes, Angelman syndrome) buy generic female cialis online menopause rosacea, lepsy, whereas a mild head injury has a low odds ratio, and can be chromosomal disorders (e. Provoking factors are ofen ig- head injury may have greater signifcance than the population odds nored in a classifcation of cause. With these caveats in mind, a listing of causes (or more accurate- by the causal mechanism of a seizure). For instance, trauma and ly causal factors) has been attempted, and a classifcation of aetiolo- tumour might cause seizures by membrane efects or by the dep- gies is shown in Table 1. This ignores seizure type and syndrome osition of haematin – and in this sense the membrane dysfunction altogether, and the mapping across of aetiology/syndrome/seizure or haematin deposition is the immediate (proximate) ‘cause’ not type is inexact. A book also cataloguing all the causes of epilepsy (or the trauma/tumour (which is the remote cause). He postulated that classifcation by proximate cause would allow a ‘botanical’ rather than a ‘gardening’ Classifcation by semiology and anatomical site approach. Unfortunately, in many instances, knowledge is not suf- One other major insight of Jackson (and his colleagues Sir David fciently advanced to attempt this. As most future advances in the Ferrier and Sir Victor Horsley) in the 1860s was the recognition that feld of causation of epilepsy are likely to be in the feld of molecular the clinical form of an epileptic seizure gives a clue to the position of science, it may be that a classifcation based on molecular mecha- the epileptic focus in the brain. This would lead to a radi- functions were localized within the cerebral cortex; (ii) a seizure cally diferent approach to classifcation, and is the sort of paradigm discharge in these areas will produce symptoms of ‘overactivity’ of shif that epilepsy classifcation is sorely in need of. This logic remains ular changes occurring afer the onset of epilepsy, which may in the basis for all clinical localization for epilepsy surgery to this day. In such cases, the internal pro- precisely now named semiology) as a basis for categorizing an in- cess can be considered at least in part as the ‘cause’ of the chronic dividual epilepsy, and again this focus has remained to this day. The molecular nature of these processes at present is not Jackson wrote in 1868, ‘One of the most important questions we can clearly understood. Tese two types of begins, for the inference is, that the frst motor symptom is the sign seizures are physiologically and clinically diferent. Tere is also of the beginning of the central discharge’ and ‘The mode of onset ofen a latent period which can extend for months or even years is the most important matter in the anatomical investigation of any between the acute insult (e. The semiological classifcation embedded within this scheme Epileptic seizure has a number of drawbacks. It introduced new terms (seizure de- Aura scriptors) which some fnd unnecessary and obscure, such as dia- Somatosensory aura leptic, automotor, hypomotor and hypermotor. This classifcation Visual aura was devised by a unit focusing on epilepsy surgery, and hence the Auditory aura prominence given to structural aspects of epilepsy and aspects most Gustatory aura pertinent to surgery. Tere is no doubt that it works best for focal Olfactory aura lesional epilepsies but less well for the common or garden varieties. Autonomic aura Its major role is in presurgical assessment, where the meticulous Abdominal aura unpackaging of seizure semiology provides useful information in Psychic aura some cases [41]. However, its use even for surgical assess- Typical dialeptic seizure ment is limited by the fact that partial seizures, as Gastaut himself Motor seizure realized, are ofen not localized to one area of cortex but are formed Simple motor seizure by neuronal networks which can be extensive. This is a fact ofen Tonic seizure swept under the carpet by enthusiasts of seizure localization, hunt- Myoclonic seizure ing for an illusory ‘focus’ using semiological clues. No amount of Epileptic spasm semiological analysis in this signifcant number of patients will be Clonic seizure able to overcome this essentially insurmountable obstacle. Tonic–clonic seizure Versive seizure Complex motor seizure Defnition Hypermotor seizure Acute symptomatic seizures Gelastic seizure Another rather simpler classifcation system has been used, espe- Automotor seizure’ cially in epidemiological work, which divides epilepsies and sei- Special seizure zures into acute symptomatic, remote symptomatic and idiopathic Atonic seizure categories. This schema seems frst widely applied in the 1970s in Astatic seizure the landmark epidemiological work from Rochester. It then fell Hypomotor seizure from fashion, and interestingly neither acute symptomatic nor Akinetic sieuzre remote symptomatic are terms included in the 2001 glossary. The Negative myoclonic seizures main reason for categorizing epilepsy in this way was to ensure that Aphasic seizure ‘acute symptomatic seizures’ were not included within the term ‘ep- ilepsy’, as these seizures difer in context and prognosis from those Paroxysmal events (of non-epileptic origin) in ‘genuine’ epilepsy. Tere are two problems with the usage proposed by the Commis- In this classifcation, the ictal symptoms were divided into senso- sion. First, the term covers two quite diferent clinical situations: ry, consciousness and motor categories. Tere is an emphasis on the (i) The ‘early seizures’ in acute brain insults; and (ii) the seizures aura (demonstrating the Jacksonian principle that the frst symp- provoked by reversible environmental metabolic disturbances or tom of a seizure gives away its cerebral location) and also on the toxins. The two clinical categories could not be more diferent and temporal sequence of events in a seizure. In the frst there is severe destruction description using this scheme is olfactory aura → automotor seizure of brain tissue and many patients progress to develop chronic ep- → lef versive seizure → generalized tonic–clonic seizure. In the second category there is no In 2005, the authors went further and proposed a fve-tier clas- underlying brain pathology and there are no known physiological sifcation system. Two tiers (semiology and frequency) defne diferences from patients with existing epilepsy who experience the symptoms {the epileptic seizure] and three tiers (aetiology, seizures provoked by the same cause or indeed from individuals associated neurological defcits and location of the epilepsy) defne who do not have seizures when exposed to the same precipitant. This is an important consideration, as, Once the metabolic or toxic exposure is reversed, the prognosis is for instance, the legal requirements for driving are not necessarily excellent and none of these patients progress to have chronic epi- the same as the clinical requirements in terms of treatment. Provoked epilepsy and refex epilepsy The second problem is the arbitrary nature of the criteria for It has been known for centuries that seizures can be ‘provoked’ by inclusion. In the nineteenth century, all seizures were ‘acute symptomatic’ within 1 week of trauma and stroke, but longer considered to have both predisposing and also exciting compo- (not specifed) for a subdural haematoma or infections. Parasitic nents, and the production of seizures was considered invariably infections are included but congenital toxoplasmosis excluded. Seizures caused by environmental triggers such as visual phasizes the point that epilepsy has a multifactorial causation, and stimulation are not included but seizures induced by hypoglycae- really the diferentiation of ‘underlying cause’ from a ‘seizure pre- mia are included. Furthermore, the term has even been extended to cipitant’ is simply one of degree. In a recent survey, it was found include seizures that lead to the diagnosis of progressive conditions that 97% of patients with epilepsy believe that there is at least one such as tumours (primary and secondary) which are in fact ‘remote’ precipitant for some of their seizures, and 28% believe that there is symptomatic seizures’. In the metabolic conditions, arbitrary cut-of a precipitant for all of their seizures [44]. The line between the two is For these reasons, in the author’s opinion, the classifcation of ep- not easy to defne, and to do so is to apply largely arbitrary criteria. If ring or artifcial stimulation of a certain receptor or group of recep- the term ‘acute symptomatic’ is to be retained, it should be restrict- tors, and a similar formulation was given by the 2001 glossary. In ed to the physiologically distinct ‘early seizures’ afer acute brain a recent textbook, the working defnition of refex epilepsy was ‘an injury. Acute seizures caused by metabolic disturbance or toxins epilepsy in which seizures are reliably provoked by a specifc identi- should be simply referred to as ‘provoked seizures’ [43]. Whatever term is used, it is important to point out that the ear- Currently, the refex epilepsies are commonly subdivided into ly seizures afer acute brain injury are quite diferent from the late two categories. In early seizures, the epilepsy may be caused 1 Simple refex epilepsies – where the seizures are precipitated by by contusions, haemorrhage, metabolic change, endocrine change, simple sensory stimuli (e. Tese are mechanisms that have nothing in tive epilepsy is by far the most common type and has been ex- common with the late seizures of post-traumatic epilepsy. Epilepsy in remission 2 Complex refex epilepsy – where the stimuli are more integrative Another important distinction for clinical practice is the diference and complicated.

It is almost antiseizure action discount 20 mg female cialis with visa women's health clinic tucson, carbamazepine and oxcarbazepine difer in sec- insoluble in water but slightly soluble in some organic compounds ondary mechanisms of action purchase female cialis now pregnancy ticker, metabolic pathways and propensi- [4]. Instead of a hydroxyl group at the 10 position of the central ty for drug interactions, and are therefore not interchangeable in ring, oxcarbazepine contains a ketone moiety, resulting in a major therapeutic use [1]. The L-enantiomer of the principal metabolite of diference in its metabolic pathway compared with carbamaze- oxcarbazepine, eslicarbazepine, also has antiseizure properties, but pine. Instead, ox- in 1977, and it was introduced commercially in Denmark, Mexi- carbazepine is rapidly reduced on the frst pass through the liver, co and Argentina in 1990 [3]. In most (10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxam- countries it is approved for use as monotherapy or add-on treat- ide) (Figure 40. Monohydroxycarbazepine is found in serum as a mixture for adults and children aged 4 and above [4]. Oxcarbazepine 535 is found in serum at concentrations several-fold higher than those Pharmacokinetic properties of the parent drug and is therefore primarily responsible for the pharmacological efect. Monohydroxycarbazepine has greater wa- Absorption ter solubility, but a parenteral preparation of monohydroxycarbaze- Immediate-release oxcarbazepine is rapidly and completely ab- pine has not been developed, partly because of the large volume of sorbed (>95%) [4]. However, the extended-release formulation solvent needed to deliver a therapeutic dose. While a lower peak serum exhibit similar activity in standard animal seizure models. In the concentration may reduce the incidence of peak-time side-efects, maximal electroshock test, which predicts efficacy against focal the necessity for an increased dose may reduce this advantage. Carbamazepine, oxcarbazepine and monohydroxycarbaze- transformation to monohydroxycarbazepine renders this peak con- pine lacked efficacy in seizure models predictive of efficacy against centration very low. Monohydroxycarbazepine reaches peak con- absence seizures (strychnine, pentylenetetrazole and picrotoxin) centrations in 4–6 h [7] afer immediate release tablets, and slightly [4,8]. The prod- Oxcarbazepine and monohydroxycarbazepine modulate volt- uct information for the reference brand of the immediate-release age-sensitive cationic channels [8]. The mechanism of blockade of formulation states that absorption of these tablets is unafected by sodium channels has been considered to be similar to that of pheny- food once steady-state is reached [4]. The extended-release tablets toin and carbamazepine, although monohydroxycarbazepine has a display an earlier peak concentration in the fed state and, for that greater affinity for the fast inactivated state of the channel. However, reason, it is recommended that they be taken at least 1 h before or the two enantiomeric forms of monohydroxycarbazepine may af- 2 h afer a meal [5]. Occasional patients report spontaneously that fect these channels in diferent ways [9]. The R-enantiomer, (R)-li- dosing of immediate-release tablets with breakfast produces more carbazepine, appears to have a greater afnity for the voltage-gated peak-time mid-morning side-efects than if they are taken fasting. This mechanism is commonly attributed to phenytoin The volume of distribution of oxcarbazepine is 0. As a lipophilic sub- but may exert a major antiepileptic action by modifying properties stance, monohydroxycarbazepine is widely distributed in the body of the slow inactivation state of these sodium channels [2], a mech- and easily passes the blood–brain barrier. The channels enter the slow inactivat- monohydroxycarbazepine exhibit low protein binding (33–38% ed state only afer prolonged depolarizations and this mechanism for monohydroxycarbazepine and 60–67% for oxcarbazepine), in- is thought to both raise action potential thresholds and limit their dependent of the dose [4,15]. It is not clear from these data protein-binding interactions with highly protein-bound drugs such which enantiomeric form of monohydroxycarbazepine is most re- as phenytoin and valproic acid. The following relationship between monohydroxycarbazepine channel currents, unlike carbamazepine, which has a greater efect concentration and dose of oxcarbazepine has been described, over on L-type channels [8]. N- and P/Q-type channels are activated by the range of 300–2700 mg/day [16]: high voltage changes and are important for linkage of membrane potentials to intracellular mechanisms of neurotransmitter release monohydroxycarbazepine concentration (mg/L = 0. The elimination Tere are reports that monohydroxycarbazepine elevates hip- half-life of monohydroxycarbazepine is 9. Neve- The metabolic pathways of carbamazepine and oxcarbazepine theless, the major efect appears to be on voltage-gated sodium difer significantly (Figure 40. Oxcarbazepine is rapidly and 536 Chapter 40 extensively reduced by cytosolic aldoketoreductase enzymes in pharmacokinetics of oxcarbazepine has not been evaluated in se- the liver to the active metabolite monohydroxycarbazepine (96%). Monohydroxycarbazepine exists in two isomeric tion, but patients with creatinine clearances of <30 mL/min/1. At steady-state about 81% of the monohydroxycarbazepine exhibited significant increases in elimination half-life and plasma concentration is in the form of the L-enantiomer (eslicarbazepine) concentrations of monohydroxycarbazepine [16]. Before steady state is reached, the proportions of the two enantiomers are more similar, suggesting that the R-enantiomer is Drug interactions cleared more rapidly [9]. The addition of oxcarbazepine can produce a small in- unchanged monohydroxycarbazepine (28%). A tive accounts for 3% of the dose excreted in the urine, with <13% of variable increase in phenytoin concentration can occur, mainly at the drug excreted as minor conjugates of oxcarbazepine and mono- higher phenytoin serum levels because at high serum levels pheny- hydroxycarbazepine [18]. Serum monohydrox- An open-label study of oxcarbazepine as monotherapy or adjunc- ycarbazepine concentrations can decrease by 29–40% (Table 40. In 109 children, aged 3–17 years, oxcar- when oxcarbazepine is added to a stable regimen of oral contra- bazepine was found to have a low propensity to inhibit or induce ceptives, as a result of induction of the metabolism of both ethi- oxidative enzymes. Young chil- epine, oxcarbazepine does not interact significantly with warfarin, dren can be given higher milligram per kilogram doses than older cimetidine, propoxyphene or erythromycin [30]. This may be explained by age-related decreases in creatinine minophen (paracetamol) and amiodarone [22]. Because of their difering efects on the drug metabolizing en- Mild to moderate hepatic dysfunction did not alter the pharma- zyme systems, substituting carbamazepine with oxcarbazepine cokinetics of oxcarbazepine or monohydroxycarbazepine, but the may result in de-induction and a consequent increase in the serum Table 40. Oxcarbazepine is not indicated for absence, myo- clonic and other types of generalized seizures other than tonic– clonic seizures, and indeed may exacerbate them [49]. Serum level monitoring Measurement of monohydroxycarbazepine, not oxcarbazepine it- Double-blind trials in comparison with carbamazepine self, may be useful. The usual method is high-performance liquid Tree randomized double-blind controlled trials compared ox- chromatography. If a carbamazepine level is ordered in error, it will carbazepine with carbamazepine (Table 40. In a group of 214 patients treated with a clinically opti- enrolled 40 patients whose phenytoin therapy had been unsatis- mized dose, the mean serum level of monohydroxycarbazepine was factory, and randomized them to either carbamazepine or oxcar- 15. A reference (optimal) range of monohydroxycarbazepine con- with either focal or primary generalized seizures, but equivalent ef- centrations of 3–35 mg/L has been suggested, although this is not fcacy for the two drugs was noted. Routine monitoring of levels is not pine for 12 weeks each in random order, in addition to the titra- recommended, although it may be helpful to assess compliance or tion period. Oxcarbazepine significantly reduced tonic–clonic and to gauge dosage in the presence of enzyme-inducing concomitant tonic seizures in comparison with carbamazepine, but there was no drugs. As monohydroxycarbazepine levels have been reported to diferential efect on complex partial seizures. Tese trials conception, during pregnancy and in the immediate post partum were far too small to prove non-inferiority of either drug, but the period. In a larger double-blind controlled monotherapy trial enroll- ing 235 patients with newly diagnosed epilepsy [35], patients with Effcacy previously untreated primary generalized tonic–clonic seizures The efficacy of oxcarbazepine has been established in many rand- or focal seizures with or without secondary generalization were omized controlled clinical trials.

The E-line is another comet tail–shaped artifact that differs from Z- and B-line in that it never arises from the bright-line pleural sunset line purchase female cialis 20 mg visa womens health clinic, but arises at a point superficial to the pleural line from subcutaneous emphysema or multiple shotgun pellets in the subcutaneous tissue (Figs buy female cialis 20 mg overnight delivery breast cancer prevention. Compared with B-lines, they are ill defined, they quickly vanish, after less than 4 cm, and they do not erase the A-line. These comet tails, which spread up to the edge of the screen without fading, do not arise from the pleural line (the rib shadow, which is part of the bat sign, is not visible). The patient has subcutaneous emphysema with extensive collections of gas between anatomic structures—a condition generating E-lines. B: Ill- defined comet-tail artifacts (arrowheads) arise from the pleural line but do not erase the physiologic A-lines (arrows) and quickly vanish without reaching the edge of the screen. Patients suffering from pneumonia will often exhibit the “ragged line” sign which is caused by the reflection of ultrasound waves at the margin of lung consolidation (Figs. Patients suffering from pulmonary embolism will present clinically with shortness of breath, pleuritic chest pain, hemoptysis, and ultrasound scan of the lung demonstrates pleura-based lesions that are most often wedge shaped, although rounded pleura-based defects can be seen in smaller pulmonary infarcts (Figs. Large pleural effusions are easily identified by ultrasound as anechoic areas with well-defined borders. Often the clinician can identify the sharp sign, which has the appearance of the sharp sign used in music or a hashtag or pound sign. The four lines that make of the sharp sign are the upper and lower acoustic shadows of the ribs, the pleural line, and the deep border of the fluid itself (Fig. M-mode ultrasound will help confirm the presence of pleural effusion by demonstration of the “sinusoidal sign” (Fig. The sine wave appearance is caused by the compression of the fluid between the layers of pleura as respiration causes the intrapleural distance to change. Ultrasound can be used not only to identify the presence and location of pleural effusions, but also to quantify their size and impact on the underlying lung (Fig. Ultrasound measurement of the size of effusion pre- and postthoracentesis may also be clinically useful, especially in the setting of recurrent pleural effusions (Fig. The ultrasonic echotexture of the effusion may give the clinician the nature of the effusion, with more echogenic textures suggestive of significant exudate and/or empyema (Fig. Hypoechoic subpleural lesion, with blurred irregular margins and pleura breakdown. Real-time lung ultrasound for the diagnosis of alveolar consolidation and interstitial syndrome in the emergency department. A: Laterobasal transthoracic scan showing massive consolidation of the lower lobe because of pneumonia (C). The echotexture is similar to liver (L) showed on the right side of the diaphragm (white arrow). Real-time lung ultrasound for the diagnosis of alveolar consolidation and interstitial syndrome in the emergency department. A: Ultrasound image depicts an area with irregular and serrated margins consistent with the ragged line sign and an inhomogeneous echotexture, caused by an air bronchogram. B: Corresponding computed tomography reveals lobar pneumonia in the left lower lobe. Representative sonograms of parenchymal and pleural alterations that are associated with pleural effusion. C: A small, wedge-shaped hypoechoic parenchymal lesion with widening of the adjacent pleural space representing a localized pleural effusion. Disruption of the pleural line (white arrow) with a wedge-shaped, pleural-based hypoechoic image with sharp margins and some B-lines in the surrounding area (asterisks). This image is typical of a small lung consolidation due to a peripheral infarction. The sonogram depicts two triangular, wedge-shaped hypoechoic, pleural-based parenchymal lesions within the area of thoracic pain. Note one basic static sign, the sharp sign, as the effusion (E) is outlined by four regular borders: pleural line, shadow of ribs, visceral pleura. Note that the lung at this area is not consolidated, as air artifacts are visible. B: the sinusoidal sign is a dynamic sign seen on M-mode ultrasound that is associated with pleural effusion. B: Transverse ultrasound image at lung base showing a moderate effusion (E) surrounding consolidated lung (L). Usefulness of ultrasonography in predicting pleural effusions >500 mL in patients receiving mechanical ventilation. Ultrasonographic measurement of interpleural distance in patients with relevant pleural effusions. The probe is applied on the dorsolateral chest wall and the interpleural distance delimited by the effusion that layers in the dependent region of the pleural space are measured between the posterior surface of the retracted lung and the posterior chest wall (arrow). Corresponding two- dimensional ultrasound images obtained at the level of the left apex (B) and at the level of the left thoracic base (C) show the maximal interpleural distance measured at end-expiration (arrows). In this patient in the strict supine position, the interpleural distance was greater at the apical pleural space than at the thoracic base. Quantitative assessment of pleural effusion in critically ill patients by means of ultrasonography. The sonogram demonstrates an echo-rich effusion with multiple echogenic structures within the effusion. It should be remembered that while the presence of lung sliding (especially when combined with the findings of B-lines and waves on a sandy beach) essentially rules out pneumothorax, the converse is not true and further investigation is always indicated. It should also be remembered that the patient who has previously undergone complete pneumonectomy will by definition have no sliding lung sign, waves on a sandy beach, or lung point, but does not have a pneumothorax. Intensive use of general ultrasound in the intensive care unit, a prospective study of 150 consecutive patients. A bedside ultrasound sign ruling out pneumothorax in the critically ill: lung sliding. The cartilage of the first rib articulates directly with the manubrium of the sternum and is a synarthrodial joint that allows a limited gliding movement. The cartilage of the second through sixth ribs articulates with the body of the sternum via true arthrodial joints. The eighth, ninth, and tenth ribs attach to the costal cartilage of the rib directly above. The cartilages of the 11th and 12th ribs are called floating ribs because they end in the abdominal musculature (Fig. Weakness of the costosternal, costochondral, and occasionally the costovertebral joints may contribute to the development of slipping rib syndrome by allowing hypermobility of the ribs. Most often involving the tenth rib, and sometimes the eighth and ninth ribs, slipping rib syndrome is almost always the result of trauma to the anterior costal cartilages. Patients suffering from slipping rib syndrome complain of sharp, knife-like 657 pain with any movement of the lower anterior cartilages.

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