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Superficial dissection shows the median nerve lies deep to and between the tendons of the palmaris longus muscle and the flexor carpi radialis muscle at the wrist order bimat 3 ml with visa treatment quadricep strain. Carpal tunnel syndrome can be caused by a variety of structural and anatomic abnormalities and is associated with a number of pathologic conditions order 3ml bimat overnight delivery symptoms ms women. While the clinical presentation of carpal tunnel syndrome is consistent buy bimat 3ml online medicine universities, this entrapment neuropathy has many causes and is associated with many pathologic conditions (Table 48 generic 3 ml bimat treatment authorization request. Carpal tunnel syndrome presents as pain and dysesthesias with associated numbness and weakness in the hand and wrist that radiate to the thumb, index finger, middle finger, and radial half of the ring finger. These symptoms may also radiate proximal to the level of nerve entrapment into the distal forearm. Decreased sensation in the distribution of the median 446 nerve of the thumb, index finger, middle finger, and radial half of the ring finger is often present as weakness of thumb opposition. A positive Phalen test is highly suggestive of the diagnosis of carpal tunnel syndrome. Phalen test is performed by having the patient place the wrists in complete unforced flexion for at least 30 seconds (Fig. The test is considered positive if this maneuver elicits dysesthesia, pain, or numbness in the distribution of the median nerve. Wasting of the thenar eminence may be seen in more advanced cases of carpal tunnel (Fig. Patients suffering from carpal tunnel syndrome will exhibit a positive Tinel sign over the superficial median nerve. The Phalen test for carpal tunnel syndrome is performed by having the patient place the wrists in complete unforced flexion for at least 30 seconds. The test is considered positive if this maneuver elicits dysesthesia, pain, or numbness in the distribution of the median nerve. The numbness and dysesthesias of entrapment or compromise of the palmar cutaneous branch of the median nerve are limited to the proximal palm and thenar eminence and motor findings are conspicuously absent (Fig. The overlap of symptoms of carpal tunnel syndrome and entrapment and/or compromise of the palmar 447 cutaneous branch of the median nerve can lead to many clinical misadventures and the use of ultrasonography and electromyography can help solidify the clinical diagnosis. The clinician should entertain a high index of suspicion for iatrogenic damage to the palmar cutaneous branch of the median nerve following carpal tunnel surgery if the patient complains of persistent numbness in the proximal palmar triangle and over the thenar eminence. To perform this assessment, the patient is placed in the sitting position with the elbow flexed to about 100 degrees and the forearm resting comfortably palm up on a padded bedside table with the fingers slightly flexed which will relax the flexor tendons. With the patient in the above position, the distal crease of the wrist is identified (Fig. A high-frequency linear ultrasound transducer is placed in a transverse position over the distal crease of the wrist and an ultrasound survey scan is taken (Fig. The median nerve will appear as a bundle of hyperechoic nerve fibers surrounded by a slightly more hyperechoic neural sheath lying beneath the flexor retinaculum and above the superficial flexor tendons (Fig. The median nerve can be distinguished from the flexor tendons by simply having the patient flex and extend their fingers and observing the movement for the tendons. The flexor tendons will also exhibit the property of anisotropy with the tipping of the ultrasound transducer back and forth over the tendons. Color Doppler may aid in the identification of the ulnar artery so it can be avoided when performing in plane needle placement (Fig. After the ulnar artery is identified, the ultrasound transducer is slowly moved medially until the median nerve is again easily identifiable in the transverse ultrasound image. B: Proper transverse position for the linear high- frequency ultrasound transducer to perform ultrasound guided injection for carpal tunnel syndrome. Transverse ultrasound image demonstrating the median nerve lying above the superficial flexor tendons. The ulnar artery is identified on transverse ultrasound scan so it can be avoided during needle placement when injecting the median nerve at the wrist. After the median nerve has been identified, a quantitative assessment as to the shape, size, echogenicity, echotexture, and overall appearance of the nerve is carried out in both the transverse and longitudinal planes. On ultrasound, the nerve fibers of the normal median nerve are clearly identified and symmetrically placed between the hypoechoic endoneurium. The epineurium should appear as a hyperechoic margin surrounding the nerve fibers. The shape of the median nerve in the transverse plane should be ovoid, without asymmetry. Enlargement and loss of ovoid symmetry is a characteristic ultrasound finding in carpal tunnel syndrome (Fig. When the median nerve is entrapped at the carpal tunnel, there is often a loss of the normal intraneural fascicular architecture secondary to intraneural edema (Fig. These findings will become more evident as the entrapment of the median nerve persists (Fig. The median nerve is then evaluated for swelling and flattening at a point just proximal to it passing under the flexor retinaculum and entering the carpal tunnel. Often an inverted notch sign is identified, which signals an abrupt change in the diameter of the median nerve secondary to compression and strengthens the sonographic diagnosis of carpal tunnel syndrome (Figs. The flexor retinaculum is then evaluated for thickening and for extrinsic compression from external masses including ganglion cysts (Figs. The contents of the carpal tunnel are then evaluated by abnormal nerve configurations, e. Color Doppler of the median nerve will help identify vascular abnormalities within the carpal tunnel as well as the hypervascular changes often seen in median nerve entrapment at the carpal tunnel (Fig. Normal transverse ultrasound image of the median nerve at the distal wrist crease. Short axis color- optimized image of the carpal tunnel demonstrates the normal sonographic appearance of the median nerve: hypoechoic with an echogenic margin of fibrofatty tissue. Ultrasound appearance of the median nerve in patient with moderately severe carpal tunnel syndrome. Note the loss of the normal intraneural fascicular architecture secondary to intraneural edema. Ultrasounds made longitudinal (A) and transverse (B) to the median nerve at the wrist show hypoechoic swelling and flattening of the median nerve (arrowheads) just proximal to the carpal tunnel and flattening more distally (arrow). Transverse ultrasound image demonstrates nerve enlargement, hypoechoic medial nerve swelling and edema, loss of normal internal nerve architecture, and diffuse echogenic spots within the nerve, reflecting fibrotic changes. Perineural echogenic thickening is characteristic of long-standing carpal tunnel syndrome disease. Longitudinal (A) and transverse (B) ultrasound images of the median nerve in a patient with carpal tunnel syndrome. A: Note loss of echogenicity (echogenicity is more normal proximally; blue arrow), diffuse swelling distally, and loss of the normal fascicular echotexture. B: Measurements of nerve clearly demonstrate compression as the nerve passes beneath the flexor retinaculum. Longitudinal ultrasound image of the wrist demonstrating a notch sign, signaling an abrupt change in the nerve diameter. Longitudinal ultrasound image of patient with acute wrist trauma demonstrating effusion and a notch sign.

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Tey reported drug accumulation in the fetus (mean umbili- non-linear generic 3ml bimat overnight delivery medications 4 less, with less than proportional increases in serum levels cal cord–maternal serum concentration ratio 1 bimat 3 ml fast delivery symptoms during pregnancy. In the newborn period there seemed to with gastric juices purchase bimat 3ml without a prescription treatment anal fissure, the tablets swell to a size that prevents passage be a lower capacity to eliminate gabapentin than in adults generic bimat 3ml without prescription medicine you can overdose on. 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. The conduct and qual- A double-blind placebo-controlled trial of 129 patients aged 12 ity of this trial, however, have been questioned [57]. Responder rate and median decrease in seizure frequency are calculated from the total number of evaluable patients after exclusions. Although an intention-to-treat fnal 12 weeks of treatment, a period far shorter than desirable in and evaluable-patient analysis both showed that gabapentin caused assessing efcacy in newly diagnosed patients. The number of pa- greater reduction in the frequency of generalized tonic–clonic sei- tients with primarily generalized tonic–clonic seizures in this study zures than placebo, the result did not reach signifcance. Results in the subgroup of children eralized tonic–clonic seizures randomized to gabapentin met exit included in this study were not reported separately. Monotherapy in epilepsy A randomized, double-blind, parallel-group trial in 593 elder- ly American veterans compared three monotherapy treatments: Conversion to monotherapy in patients with refractory gabapentin (target dose: 1500 mg/day), lamotrigine (target dose: focal seizures 150 mg/day) and immediate-release carbamazepine (target dose: In a randomized double-blind study, 275 patients with complex 600 mg/day) [65]. Continuation of the assigned treatment at 12 partial or secondarily generalized seizures were randomized to re- months was higher for both gabapentin and lamotrigine than for ceive 600, 1200 or 2400 mg/day gabapentin [61] and then under- carbamazepine (49%, 55. If seizure ence was mainly because of a higher rate of withdrawals resulting deterioration occurred during the withdrawal phase, patients were from adverse events in patients randomized to carbamazepine required to exit the study. This randomized higher among patients who were not withdrawn from carbamaze- open-label trial included predominantly (82%) newly diagnosed pine (27%) than among those who were (16%). The outcome variable was median time to at the usual dose used by the clinician [66]. For the other primary exit (due to defned seizure-related end-points or adverse events) in outcome measure, time to 12-month remission, gabapentin was sig- the course of an 8-day period, which was found to be signifcantly nifcantly inferior to carbamazepine (hazard ratio 0. Newly diagnosed absence seizures Studies in patients with predominantly newly diagnosed A total of 33 children aged 4–12 years with newly diagnosed ab- focal seizures sence epilepsy were included in two identical, double-blind, A randomized trial compared outcome in 218 patients treated with placebo-controlled trials, in which gabapentin was tested at dos- gabapentin monotherapy for newly diagnosed focal seizures (300, es of 9. A 2-week double-blind treatment 900, 1800 mg/day) and 74 patients treated with 600 mg/day carba- phase was followed by a 6-week open-label phase. The allocation to carbamazepine or gabapentin was not signifcantly decrease or increase seizure frequency (derived not blinded but the dose of gabapentin was double blind. In addition, patients could be withdrawn for lack of efcacy, adverse Gabapentin in non-epilepsy indications events or non-compliance. Completion rate was 37% in the carba- Gabapentin has efcacy in a number of non-epilepsy indications. Although the completion ly for postherpetic neuralgia [68] and diabetic neuropathy [69]. It rates for 900 and 1800 mg/day gabapentin were similar to that of car- has also been useful in trigeminal neuralgia [70]. The Cochrane bamazepine, more patients exited from the gabapentin arms because group analysed 37 studies of the use of gabapentin in 12 chronic of seizures (40% and 43%, respectively) than from the carbamazepine pain conditions, including a total of 5633 patients, 84% of whom arm (30%), while more patients withdrew because of adverse events had neuropathic pain [71]. Gabap- gabapentin versus lamotrigine monotherapy was completed in 309 entin has also been shown to be of some beneft in acute postoper- patients with newly diagnosed focal and/or generalized tonic–clon- ative pain [72] In addition, there are reports that gabapentin may ic seizures [64]. Gabapentin was maintained at 1200–3600 mg/day, be useful in essential tremor [73], visual and musical hallucinosis and lamotrigine at 100–300 mg/day. Overall, 72% of the gabapentin in patients with sensory impairments [74,75], hiccups [76], chronic group and 67% of the lamotrigine group completed the 30-week cough [77], restless legs syndrome [78], some forms of insomnia study, and 76% of patients in both groups were seizure-free for the [79], menopausal hot fushes [80], nystagmus [81] and uraemic 484 Chapter 36 pruritus [82]. The α2-δ-1 protein, to which gabapentin is a therapy for focal seizures, showed good tolerability up to doses of ligand, has recently been shown to increase in the nucleus accum- 3600 mg/day, but beyond that dose there were too few patients to bens afer cocaine administration and there is evidence that use of draw meaningful conclusions [91]. Gabapentin has also cognition, compared with average performance of the subjects in been demonstrated to be efective in the treatment of alcohol de- the drug-free state [94]. While a Cochrane review in 2004 found evidence in healthy volunteers, gabapentin produced signifcantly less cogni- that gabapentin was efective in the prophylaxis of migraine [86], tive impairment than carbamazepine on 8 of 31 variables measured this conclusion was reversed in an updated Cochrane review in [95] and similarly caused less impairment in cognitive performance 2013 that included data brought into the public domain only by lit- than topiramate [40,41].

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Once muscle reduction has been achieved proven bimat 3ml medications blood thinners, subsequent treatments are less frequent [25] generic 3ml bimat free shipping medications zocor. Complications due to the spread of the toxin into perioral muscles are unusual [26] buy discount bimat 3ml medications 126. Aging features include skin laxity buy 3ml bimat fast delivery medicine cabinets recessed, lipodystrophy in the submental and jowl areas, submandibular gland ptosis, Fig. Always start with low with skin resection and platysmaplasty is appropriate doses (Dysport 2 U per site) to avoid excessive weakness or with advanced signs. A slightly laterally placed injection reduces the opportunity for the toxin to affect the depressor labii muscles. Three injections are made in the masseter over the angle this muscle produces a sad or sullen look of the mandible 124 P. Prendergast into muscular bands, softens the vertical “turkey neck” reduced submental volume postoperatively reveals appearance (Fig. Although the bands may be visible at rest, asking the patient to forcefully grimace will make 10. Occasionally, intradermal injections of more provide some improvement to superfcial lines where diluted botulinum toxin can be made along horizontal fbers of platysma insert into the dermis [30]. Small “necklace” lines to soften the dermal insertions of plat- intradermal blebs are raised with 2 U aliquots of ysma along these horizontal creases. For best results, in the neck is also appropriate following lipoplasty when chemodenervation of the décolleté is combined with a b Fig. Excessive sweating, or hyperhidrosis, may be focal or general- ized and primary or secondary [32]. Topical agents such as aluminum salts and aldehyde agents are often ineffective and may cause irritation [33]. Intradermal injections of botulinum toxin represent a novel man- agement option for focal primary hyperhidrosis [34]. To delineate the area of maximal sweating, the starch-iodine test can be performed. To perform the test, the skin is dried and an iodine solution is applied and left to dry. Areas of excessive sweating turn a blue/ black color as iodine reacts with starch. In practice, the entire surface of the axilla, palms, or soles of the feet are treated and the test is not essential. Injections that are below the der- mis in the subcutaneous plane spread too deeply and have little effect on the eccrine sweat glands that are located predominantly in the deep dermis. To inject superfcially, the needle is angled at 30° to the skin and small blebs are raised at 1 cm intervals throughout the treatment area (Fig. Using Dysport, a 500 U vial is reconstituted pulsed light, laser resurfacing, chemical peels, and with 5 mL physiologic saline to enhance the spread of rejuvenation mesotherapy with hyaluronic acid and the solution in the dermis. The pal- mar surfaces of the hands and fngers are extremely sensitive and patients may not tolerate the procedure unless proper regional anesthesia is performed. However, the author rou- spaced intradermal injections tinely performs bilateral wrist blocks to achieve 10 Botulinum Toxins 127 a Fig. W ith proper technique, intrader- Following nerve blocks, 250–400 U Dysport can be mal injections are well tolerated. The patient should be accompanied for the pro- and fngers is similar to that for axillary hyperhidrosis. If the tip is too superfcial, or if injections are placed perpendicularly, the solution will leak from the puncture 10. Deep injections should also be avoided to minimize potential denervation of the intrinsic muscles Injection-related complications following botuli- of the hand. Regular needle changes during the proce- num toxin injections for facial rejuvenation include dure facilitate puncture of the dermis. To placed at 1 cm intervals over the palms and fngers, avoid these problems, visible vessels should be including the sides of the fngers and fngertips avoided and the needle should be placed either in (Fig. The patient should be warned that transient the belly of the muscle or more superfcially, avoid- weakness of the hands might occur but usually resolves ing the periosteum. Typically, a Brow ptosis occurs with excessive denervation of total of 500 U Dysport provides excellent reduction in frontalis, especially in patients with pre-existing der- palmar hyperhidrosis with results lasting 6–8 months. Even denervation of the glabellar muscles can lead to medial brow ptosis if there is 10. Conservative denervation of procerus and corrugators A similar technique to palmar injections is used to without treating the brow elevators is the best way to treat the relatively larger plantar surfaces of the feet. Eyelid ptosis is Pain on injection makes this a challenging treatment rare when botulinum toxin is carefully placed using unless plantar nerve blocks are accurate and thorough. For “etched- treating the medial frontalis and completely avoiding in” lines around the eyes or mouth, laser skin resurfacing the lateral frontalis over the lateral brow in a patient combined with botulinum toxin yields excellent results. In these patients, the lateral frontalis aesthetic medical procedure provided there are no con- should be treated with 1–2 injections, with reducing traindications. An additional injec- techniques, chemical peels, soft tissue augmentation, tion in fbers of orbicularis oculi at the brow alleviates and photorejuvenation [43]. Botulinum toxins also com- the downward pull on the brow here and helps reduce pliment such cosmetic surgical procedures as brow lift, the likelihood of lateral brow ptosis, even when fronta- blepharoplasty, face lift, and platysmaplasty [44]. This can result in paralysis of zygo- References maticus major or minor with drooping of the upper lip (Fig. The American Society for Aesthetic Plastic Surgery (2009) Cosmetic surgery national databank statistics. The most inferior injections botulinum, botulinum toxin, and the idea of the therapeutic should remain high, close to the lateral canthus and use of the toxin. Z Hyg medial to this for lower lid lines should only be placed Infektionskr 26:1–56 in pretarsal orbicularis oculi close to the eyelash in the 4. Invest Ophthalmol around the mouth include lip weakness, diffculty 12(12):924–927 speaking or eating, and smile asymmetry. J Dermatol Surg Oncol 18(1):17–21 Although chemodenervation with botulinum toxin is the 10. Botulinum toxin is almost always the Comparisons among botulinum toxins: an evidence-based frst-line choice for treating hyperdynamic lines, but it review. Plast Reconstr Surg 121(6):413e–422e does not address deeper folds, facial volume loss, and 12. Karsai S, Raulin C (2010) Botox and Dysport: is there a actinic textural and pigmentary changes. J Am Acad Dermatol 62(2):346–347 in the glabella or outside the vermilion border of the lip, 13.

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Sub- sequently buy bimat 3 ml lowest price medications you can crush, owing to the emphasis given to the progressive course of (a) some of these mechanisms bimat 3ml medicine you can take while pregnant, the term epileptogenesis has ofen been employed to defne the process whereby an initial event leads to the constitution of a persistent epileptic condition discount bimat 3 ml on line symptoms 0f high blood pressure. In this chapter the term epileptogenesis will be used in Prince’s original context purchase bimat 3ml on line medications kidney failure, irrespective of whether the mechanisms that we are referring to are the result of a progressive process or not. As in the case of many other pathological conditions, experimen- 100 ms tal models have made a major contribution to our understanding of (b) epileptogenesis. The term ‘experimental models of epilepsy’ should be restricted to animals presenting spontaneous or experimental- ly induced epileptic seizures, whereas in vitro or computer mod- els are more properly called models of epileptogenic mechanisms. This is not just a question of semantics, because the relevance of experimental results to the advances made in our understanding of epilepsy depends on how suitably the experiment has been de- 10 s signed for this purpose. Operationally, it is enough to say that an experimental preparation should be referred to as a model (of ep- Figure 3. Lower trace: feld recording of the discharge a number of diferent agents that afect excitatory or inhibitory synchronously involving a large neuronal population. Similar efects can also be obtained by means of epilep- bled, their stoichiometric characteristics and the relative position togenic agents acting on the intrinsic mechanisms responsible for of each subunit within the hetero-oligomeric complex. When investigating the elementary determinants of neuronal This chapter deals with the epileptogenic mechanisms that pu- excitability (e. The expression pattern of putative epileptogenic dysfunctions Membrane ion channels therefore needs to be carefully investigated, not only at the level of The excitability of nerve cells depends on the movement of ions brain topography, but also at cellular and subcellular levels. The kinetics of transmembrane ion currents has been ex- Voltage-gated channels tensively investigated by means of various types of voltage-clamp Tese form a category of ion channels that undergo recordings, whereas the efects of ion currents on cell membrane voltage-dependent conformational changes leading to transitions potential can be detected by means of current clamp recordings. Ion channels are hetero-oligomeric membrane proteins, typical- Each domain contains six transmembrane segments, the fourth ly consisting of 2–6 subunits including transmembrane segments one being the voltage sensor, and the loop between the ffh and sixth that are assembled in a variable number of domains. Owing to the efect of ion pumps in resting I (gK+) conditions, membrane potential is kept around A −70 mV. The lines below the tracings depict the time I (gK+) C course of ion currents with diferent kinetics. In the uppermost part is a schematic representation of the protein structure of α, β1 and β2 subunits. Note the tetrameric structure of α-subunit with four transmembrane domains each composed by six transmembrane segments, the fourth is the voltage sensor whereas the loop between the ffh and six segments forms the ion selective pore. This structure sat- channels, and thus with a pathologically increased membrane excita- isfactorily correlates with the functional properties demonstrated by bility [16,21]. However, the efects of other mutations indicate a com- electrophysiological recordings, which allow characterization of the plete loss of function. Experiments aimed at clarifying this apparent- activation and inactivation kinetics of the main transient component ly paradoxical defect suggested that the prominent presence of the of current (I ) and of the persistent Na+ component (I ), which mutated channel subunit on inhibitory interneurons [22,23] reduces NaT NaP is due to to a fraction of Na+ channels that fail to inactivate. Moreover, it has been found that molecular interactions epilepsies and indicated that de novo channel mutations may cause with modulatory proteins or drugs can partially rescue the function of neurological disease in the absence of a positive family history [20]. This evidence further shows that more research is need- channel subunits showed a large spectrum of functional efects. Mechanisms of Epileptogenesis 41 K+ channels high-voltage activated Ca2+ currents are I (a slow current with an L Unlike Na2+ and Ca2+ channels, which are large monomeric proteins activation level positive to –30 mV), I , I and I (fast currents, N P/Q R that include four homologous repeats, K+ channels are made by the activation positive to –20 mV), and it has been found that they are assembly of four proteins each of which contain six transmembrane diferently expressed in brain cells and other excitable tissue. In ad- domains and is therefore similar to one Na+ or Ca2+ repeat, thus the dition, a low-threshold I current that is inactive at resting mem- T resulting structure is similar to that of Na+ and Ca2+ channels, but brane potential and reactivated by membrane hyperpolarization the number of possible subtypes is much higher because of the large (activation level positive to −70 mV) has been found to be particu- number of possible combinations. Although it is assumed that there larly pronounced in some regions of the central nervous system, are subtle functional diferences between the diferent subtypes, the such as the inferior olivary nucleus and the thalamic nuclei (for currents fowing through the K+ channels are grouped in a relatively review see [34]). Other than the ‘delayed As Ca2+ is a divalent cation, its cross-membrane movements rectifer’, frst described by Hodgkin et al. This is probably due to the fect that has to be taken into account when evaluating membrane combined infuence of I , I , I and I. However, because it excitability as a function of Ca2+ concentration; and (iii) a number K A K(Ca) K(Na) is active at about the resting potential, I is particularly efective of the Ca2+-dependent K+ currents contributing to cell excitability M in distancing the threshold of the membrane potential for the gen- may be impaired when Ca2+ concentration is artifcially lowered, eration of the high-frequency action potentials characterizing the thus leading to indirect and somehow unpredictable consequenc- neurons belonging to epileptic neuron aggregates. Epileptiform es that may obscure the direct efect of Ca2+ movement across the discharges can be easily obtained in in vitro preparations by per- membrane. Experiments carried out in our laboratory [38,39,40,41] indicate [29] have demonstrated the pathogenetic role of a genetically deter- that overexpression of the low-threshold Ca2+ current in reticular mined I defect. The characterized malfunctioning of other voltage sensitive channels can be critical to 42 Chapter 3 generate pathological oscillations and paroxysmal events. From the functional point of view, two main recep- generalized seizures [44] or with Dravet syndrome [45], further tor types have been identifed. Ligand-gated channels are classifed according to a scheme tor interaction only when the membrane potential is depolarized based on the ligand (neurotransmitter or neuromodulator), with enough to remove the Mg2+ block. Furthermore, the hyperexcitable Membrane ion channels as targets for dentate gyrus removed from patients with temporal lobe epilepsy antibodies in acquired autoimmune retains bicuculline-sensitive synaptic inhibition [53]. Neuronal function can be rotransmission matures sooner than glutamate neurotransmission signifcantly modifed by alterations in the levels of receptors, ion and has a plastic efect. Some mutations in Na+ channel combinations of eight α-subunits and three β-subunits. This defect can lepsy brought about by a genetically determined channel alteration. As the α4-subunit is motif critical to calmoduline binding, can be conversely rescued widely distributed in the mammalian brain, it is puzzling how the by β1-subunit coexpression but not by other β-subunits, calmod- mutation can cause a focal hyperexcitability syndrome. 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. In fact, beside inherited channelopathies, nectivity enables them to synchronize the activity of synaptically evidence obtained in models of acquired epilepsies also point to- connected neuronal populations. 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.

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