The authors concluded that racetam concentrations was set at 12–46 µg/mL order sotalol 40mg amex, although it was levetiracetam does not afect phenytoin disposition purchase sotalol 40 mg without a prescription. A recent study used plasma concen- icantly altered in any of the placebo-controlled adjunctive trials tration monitoring to demonstrate reduced levetiracetam levels of levetiracetam or in a pooled analysis in adults and in children in patients receiving co-medication with carbamazepine generic sotalol 40mg otc, but the (Figure 39. Monitoring plasma In interaction studies with oral contraceptives, digoxin and war- levetiracetam concentrations can be especially useful before and farin, no evidence of any specifc interaction between levetiracetam during pregnancy, and during puerperium. Serum level monitoring Plasma or serum concentrations of levetiracetam have been de- Effcacy termined using gas chromatography with nitrogen phosphorus detection , high-performance liquid chromatography with Adjunctive therapy trials in adults with refractory ultraviolet detection  or liquid chromatography with mass focal seizures spectrometric detection . It is recommended that the blood be The efcacy of levetiracetam in reducing the frequency of focal centrifuged within a short timeframe afer sampling, so as to avoid seizures in patients with treatment-resistant epilepsy was demon- levetiracetam hydrolysis in vitro that would result in spuriously strated initially in three pivotal randomized, adjunctive-therapy, lower concentrations being measured . The char- Levetiracetam exhibits moderate intra- and inter-individual var- acteristics of these studies can be found in Table 39. However, 904 subjects were randomized to placebo or levetiracetam 1000, because of its relatively short half-life, coupled with the common 2000 or 3000 mg/day. Tus, if monitoring is portion of patients with ≥50% reduction in weekly seizure frequen- performed for the purpose of measuring compliance, it should be cy from baseline) and percentage reduction in seizure frequency. P values refer to each Percentage levetiracetam group seizure-free Treatment compared with for full study Study n Design Inclusion criteria Doses duration placebo duration Shorvon et al. Responder rates were higher with Seizure freedom rates were investigated in a pooled analysis. When all stable dose period, and withdrawals were counted as not seizure-free, patients were converted to 4000 mg/day in a non-blinded extension seizure freedom rates were 0. With respect to long-term Pharmacological modelling of seizure count data from the four efcacy, Zaccara et al. Afer 1 junctive-therapy adult (as well as paediatric) trials in a total of 1861 year of treatment, levetiracetam retention rates, a combined esti- patients found that, at every dose analysed (1000–4000 mg/day in mate of efcacy and safety, ranged from 60% to 75%. Afer an 8-week prospective baseline, patients an experienced reader who was blinded to treatment groups. Among subjects who gories (1 month to <1 year; 1 year to <2 years; 2 years to <4 years). A large monotherapy study was performed in adults (age ≥16 years) with newly diagnosed epilepsy . A total of 198 more focal or generalized tonic–clonic seizures in the previous year, children were randomized and provided evaluable data. A 50% reduction in focal seizure frequency per week was attained levetiracetam (500 mg twice daily; n = 288) or controlled-release in 44. Patients achieving the primary end-point the short-term phase, 183 entered a long-term phase. The non-inferiority limit was pre-specifed only for the 6-month seizure freedom end-point. The response rate during the 16-week treatment for the primary end-point was above the non-inferiority limit set period (reduction of ≥50% in the number of days/week with my- by the study protocol (–15%), levetiracetam could be considered oclonic seizures) was 58. Levetiracetam Another randomized, double-blind, placebo-controlled, and controlled-release carbamazepine produced equivalent seizure parallel-group study enrolled adults and children (4–65 years of freedom rates in newly diagnosed epilepsy at optimal dosing in a age) with uncontrolled generalized tonic–clonic seizures associ- setting mimicking clinical practice. Patients An earlier randomized, controlled trial of refractory patients were randomized to levetiracetam (target dose 3000 mg/day for with focal seizures evaluated levetiracetam as monotherapy in a adults; 60 mg/kg/day for children) or placebo as adjunctive ther- step-wise fashion, frst adding it as an adjunct, then withdrawing apy. A total of 286 patients entered an placebo, n = 84), the percentage who had a ≥50% reduction in the initial double-blind randomized 18-week phase during which they frequency of generalized tonic–clonic seizures per week (respond- received add-on levetiracetam (3000 mg/day; n = 181) or placebo ers) during the treatment period was 72. Patients exited the study if they had worsen- racetam is an efective adjunctive treatment for patients with pre- ing of seizures, as measured by pre-established criteria. By the end viously uncontrolled genetic (idiopathic) generalized epilepsy with of the study, 19. Among the pa- An open-label, adjunctive-therapy uncontrolled study reported tients who completed the study, nine were seizure-free throughout 50% or greater response in 28 of 35 patients with eyelid myoclonia the 12-week evaluation period on levetiracetam monotherapy. The with absences (Jeavon syndrome) including 6 being seizure-free importance of this study was the demonstration of the feasibility of during a 12-week evaluation phase . Evidence for a possible efcacy of levetiracetam in symptomatic A withdrawal to monotherapy study was performed using the generalized epilepsies is scanty. If patients meet certain predetermined exit crite- juvenile absence epilepsy ria that signify worsening of seizures, they are removed from the Several small series reports and an open-label prospective uncon- study. The number of exits is compared with a historical control, trolled monotherapy multicentre study in 21 patients aged 5–13 ‘virtual placebo’ determined by a meta-analysis of prior trials years suggest that levetiracetam can be efective in the management . Patients were randomized in a 3 : 1 ratio to 2000 (n = 171) or of absence epilepsy . Tere was a trend in favour of le- refractory generalized epilepsies vetiracetam, with 23% in the levetiracetam group, compared with A randomized placebo-controlled trial of levetiracetam in patients 4. Notably, 41 of the children with genetic (idiopathic) generalized epilepsy with myoclonic sei- enrolled did not become seizure-free on levetiracetam in the trial zures evaluated the efcacy and safety of a 3000 mg/day dose as or the open-label period that followed, but subsequently became adjunctive therapy in 120 subjects (12–65 years old) diagnosed with seizure-free on other treatments. A 2-year observational study of 51 Myoclonus can be caused by multiple cortical, subcortical and spi- children with acute repetitive seizures or status epilepticus  in- nal aetiologies, with levetiracetam having the largest amount of an- itially used doses of 10 mg/kg, but later in the study the dose was ecdotal evidence of efect in cortical myoclonus, but with reports increased to 30 mg/kg, run over 15 min. Levetiracetam open case series, levetiracetam was reported to have been bene- was discontinued for sustained aggression in one child, and for lack fcial in 8 of 13 patients with Unverricht–Lundborg progressive of efectiveness in three children. Tere are case reports or small series describing levetiracetam Studies in the palliative care setting ameliorating post-anoxic myoclonus , negative myoclonus , Levetiracetam was used in a palliative care setting where seizures myoclonus in corticobasal degeneration , Gaucher disease  occurred, with the majority of patients having primary or metastat- and spinocerebellar ataxia , among others. Results reported retrospectively Studies in patients with neonatal seizures for 20 patients indicated that seizures or status epilepticus were Tere has been increasing interest in using levetiracetam in neo- interrupted in 80% of cases . Phenobarbital is considered the standard treatment for ne- skin irritation at the infusion site, although this could have been onatal seizures, but cardiorespiratory depression and somnolence due to the needle or infusion of other agents. Doses started at 10 mg/kg, increased An unblinded, non-randomized pilot study of 46 adults and 20 to 30 mg/kg over 3 days and increased again up to 60 mg/kg. Acute children evaluated the safety and tolerability of levetiracetam afer intervention with 20 mg/kg phenobarbital was permitted. Patients who had an early post-traumatic or collected over 12 months, although levetiracetam was discontinued intracranial haemorrhage, early post-traumatic seizure, penetrating in most before 4 weeks, and only 7 continued to or past 3 months. Tey were given either loraz- vetiracetam for (mostly) short-term seizure prophylaxis following epam (0. In two randomized controlled trials and four (20 mg/kg infused in 15 min) in an open-label fashion . If sei- observational studies, there was no superiority of either agent with zures continued 10 min afer completion of the infusion, the other respect to early or late seizures, but the quality of the evidence was medication was administered. At 24 hours, seizure-freedom did not difer quality of life in adults with epilepsy signifcantly, with a slight trend favouring levetiracetam over loraz- Results from a double-blind, placebo-controlled efcacy study of epam (79. Despite this, levetiracetam is frequently used well-being, overall quality of life, energy/fatigue, seizure worry of-label and outside of protocols because of its relatively low rate and medication efects) [105,106]. Specifcally, a benefcial impact of cardiorespiratory depression and lack of drug–drug interactions, of levetiracetam over placebo was seen for seizure worry, cogni- which can be important in medically complex patients. However, a recent Improvements observed in levetiracetam starters (n = 66) were neurocritical care guideline supported the use of 20–60 mg/kg sustained long term (mean follow-up 4. In the study in patients with genetic (idio- er adverse efects included dizziness and nervousness. A summary pathic) generalized epilepsy with generalized tonic–clonic seizures of adverse events recorded in placebo-controlled trials is given in , treatment with levetiracetam resulted in greater improve- Table 39.
Epileptic spikes: magnetoencephalogra- of patients generic 40mg sotalol fast delivery, and had a signifcant impact on clinical management in phy versus simultaneous electrocorticography generic sotalol 40mg with amex. Entorhinal–hippocampal interactions in mesial tempo- ness buy sotalol 40mg without a prescription, high spatial and temporal resolution, superior accuracy due to ral lobe epilepsy. Magnetoencephalography: theory, instrumentation, and applications to noninvasive studies of the working human is also applicable to projects screening outpatients. Magnetoencephalography in neurosur- decreased but have not altogether ceased and when, due to asym- gery. Seizure 2011; 20: vagus nerve stimulation device and who would still be considered 414–418. Multiple source analysis of interictal spikes: goals, re- new relevant fndings on neuroimaging studies that were not appre- quirements, and clinical value. Low resolution electromagnetic activity; tomography: a new method for localizing electrical activity in the brain. Int J Psy- • localization of epileptic activity to guide invasive procedures and chophysiol 1994; 18: 49–65. An improved boundary • localization of epileptic activity to guide detailed planning of element method for realistic volume-conductor modeling. Spatial relationship of source localizations We wish to express our gratitude to Dr. Magnetic brain source imaging of focal tivity in a case of medial occipital epilepsy. Magnetic source imaging as a localization complementary dipole maps of temporal lobe spikes. Temporal dynamics of visual-evoked neuromagnetic troencephalogr Clin Neurophysiol 1991; 79: 1–10. Odourants activate the human superior in perilesional, contralateral mirror, and ipsilateral remote areas in patients with temporal sulcus. Epilepsy Res magnetoencephalography: outcome in 50 patients with lesions around the motor 1992; 11: 171–178. Annals of Neurology 2014; 75: culus mapping in humans by using a large-array biomagnetometer. Role of multichannel magnetoencephalogra- surgical evaluation of children with the Landau-Klefner syndrome. Presurgical evaluation in frontal lobe epi- partial seizures agrees with intracranial localizations. Correlation between magnetoencephalogra- phy-directed surgery in patients with neocortical epilepsy. Seizure 2014; clusters can be identifed by efective conncectivity in focal cortical dysplasia. Ictal and interictal activity in partial epi- ing in relation with surgical outcome of cortical dysplasia. J Korean Neurosurg lepsy recorded with multichannel magnetoelectroencephalography: correlation of 2012; 52: 466–471. Role of multichannel magnetoencephalog- gle photon emission computed tomography, and positron emission tomography raphy in the evaluation of ablative seizure surgery candidates. Epileptic spasms in older pediatric rected surgery in patients with neocortical epilepsy. Elger and Bernd Weber University of Bonn Medical Center, Bonn, Germany Introduction avoid unnecessary, costly and ofen repeated presurgical work-ups. If no lesion is present or the lesion is resected confrmed about the underlying pathology and signifcantly con- incompletely, then the outcome based on the seizure freedom rate tributes to the prognosis for surgery . Additionally, non-lesional epilepsy surgery may have a formed as early as possible in patients with refractory epilepsy. In a more difcult situation, the presurgical evalua- the quality of images  (Figure 60. Artefacts, incomplete scans, a lack of knowl- at two distinct goals: to optimize visual inspection of the images edge concerning the particular lesions causing focal epilepsy and on and to allow for automated analyses and postprocessing. While the relationship between the seizure semiology and the brain area automated analyses and postprocessing are usually independent causing it are responsible for the high failure rates. The referral This general imaging protocol has been shown to detect more of a patient to a specialist centre afer a trial of two failed anticon- than 99% of lesions in 2740 patients who underwent a presurgical vulsive medication attempts should be mandatory. The signal-to-noise ratio is increased signifcantly on the 3T image, leading to a less noisy image, especially in fne structures (c, d). In the following section, we present typical features of pathologies The T2-weighted images should be acquired with higher in-plane that are commonly associated with epilepsy. Tese are divided – in resolution (below 1 mm) to allow the visualization and interpre- accordance with the Guidelines for Epilepsy of the German Neuro- tation of subtle lesions. Because these sequences are not isotropic logical Society  – into easy (A), moderately difcult (B), very dif- in resolution, the exact orientation is more important. New tech- Patients with perinatal infarctions of the media presenting with a niques might change this  and radiosurgery may be an alterna- porencephaly can also be classifed as class A candidates . Class B: moderately diffcult cases Class D: palliative surgery candidates Depending on the location of the lesion, patients may be classifed Palliative surgery is undertaken when epilepsy surgery cannot as class B although the underlying pathology is the same as class A realistically lead to seizure freedom, but may result in relief from patients. Closer vicinity to eloquent areas requires a more compli- particularly disabling seizures. Typical examples are patients who cated presurgical evaluation, possibly including invasive recording undergo a callosotomy for relief from tonic or atonic drop attacks. In the Class E: non-surgical candidates future, improved imaging sequences might help to increase the sur- Reasons for patients to be classifed as class E include no chance of gical outcomes of these patients. Most patients with post-traumatic achieving seizure freedom or relief, or the likelihood of unaccept- defects also belong to this group, especially because of multifocal able neurological defcits due to the surgery. The same probably holds true for patients with a pri- usually belong to this category, as do for example, bilateral migra- mary epileptogenic lesion and an additional secondary brain injury, tion disorders such as perventricular nodular heterotopias, bilateral for example due to a trauma. Another reason precluding surgical therapy is the inclusion of Controversial cases are patients with Rasmussen encephalitis, eloquent cortical areas in the lesion, which hinders a surgical in- who seem to beneft from an early presurgical evaluation, with a tervention without severe neurological defcits, independent of the specifc investigation of language and motor functions in the afect- type of underlying lesion. One group of patients who recently came into focus with regard to epilepsy surgery are those patients with limbic encephalitis. Tey Class C: very diffcult surgical cases are characterized by a swelling of the amygdala . While the application of difusion parameters in the Patients with monofocal nodular heterotopia must also be detection of seizure foci is discussed, it is mostly used in clinical set- considered very difcult surgical candidates. As the extent of the tings in the planning of surgical approaches to spare important fbre 772 Chapter 60 (a) (b) Figure 60. However, Special care should be taken in interpreting the activation in cases in the case of Meyer`s loop, visual feld defects could be predicted with lesions close to classical language areas and atypical activity but prevention using these techniques as a guidance remains patterns (see Figure 60. In the presurgical workup of which can also be entered into neurosurgical navigation systems. Depending on when old, that is, boundaries of activity clusters should not be interpreted the cause of the epilepsy originated, plasticity can take place .
After fnding no bacteria in the monkey’s nervous system 40 mg sotalol for sale, Landsteiner concluded that a virus must be the caus- ative agent sotalol 40mg otc. Landsteiner discovered that an extract of ox hearts could replace the antigen derived from livers of babies with con- genital syphilis generic sotalol 40 mg on line, for use in the Wassermann test for syphilis. With his excellent background in chemistry, medicine, and pathology, Landsteiner continued his serology and immunol- ogy work at the Rockefeller Institute. He discovered that immuno- chemical specifcity was altered by the ortho, meta, or para position on aromatic rings of stereoisomers. Landsteiner further showed that partial antigens, termed haptens, were unable to elicit antibody formation, but could react with those formed in response to a complete antigen comprising a hapten bound to a carrier molecule. His extensive investigations on immunochemical specifcity were frst summarized in his book entitled Die Specifzitat der Serologischen Reactionen published in 1933. The English translation was published in 1936, and a revised edition appeared following his death in 1945 entitled the Specifcity of Serological Reactions. He found that haptens could com- bine with pre-existing antibodies to produce allergic desen- sitization. Damian transplanting the leg of modern immunology, including the construction of synthetic a Moor onto the stump of a young man who had lost his leg. A number of famous artists, including Fra Philip Levine (1900–1987), Russian–American immuno- Angelico and Fra Lippi, illustrated some aspects of this pop- hematologist. His work contributed much to transfusion possibility of transplantation, and was successful in replac- medicine and transplantation immunobiology. In time of war, in the days of hand-to-hand combat, the loss of a limb was the lot of many soldiers. He thought he was successful in transplanting a human for successfully joining blood vessels by end-to-end anasto- tooth into the comb of a cock, a specimen still on view at the mosis with triangulation sutures, thereby permitting the rapid Hunterian Museum. Early understanding of the principles of skin grafting by Alexis Carrel was born in 1873 in Sainte-Foy near Lyon, the Indian physician Sushruta can be found in a Sanskrit France. Grafts of skin from the and departed for America in 1904 to work in the Physiology forehead, neck, and cheek were used to restore mutilations of Department at the University of Chicago. Apparently the physicians the Rockefeller Institute for Medical Research in New York of the Alexandrian school understood how to repair such City as an associate member, achieving full membership in defects with skin faps also, which is documented in the De 1912. During the 13th and 14th centuries there was a resurgence of surgery practiced in the ancient medi- cal school of Salerno, and in the 15th century mention was made of two skilled practitioners of plastic surgery, Branca de Branca and his son Antonio, who practiced in Catania in Sicily. The next great step in transplantation was the work of Gaspare Tagliacozzi (Figure 1. He drew analogies from the agricultural practices of grafting in explaining his technique. He understood that xenografts were impossible and allografts were highly unlikely to unite, if only because of the awkwardness of keeping the two parts in close con- tact so that the graft could take. In spite of the excellence of Tagliacozzi’s book, the technique of skin grafting did not progress further until the 19th century when interest revived. A number of surgeons tried making free grafts in animals and also attempts were made in humans, although, without the refnements of aseptic technique and anesthesia and since the principles of immunology were not yet known, not much progress was made. Their aim following the liberation, Carrel was accused of collaborating was to grow cells from warm-blooded animals, although this with the enemy, but died before he could be arrested. Irwin of the University of Wisconsin in that employed a simple surgical technique, freshly sterilized Madison coined the term immunogenetics in 1933 to describe glassware, and instruments. They transformed the simple an uncertain association between immunology and genetics, technology of tissue culture into an elaborate laboratory ritual. He required technicians, including Charles Lindbergh of subsequent aviation fame, to dress somewhat theatrically in the studies of Jensen and Loeb, working independently with black, full-length gowns ftted with hoods. Little (1914) sug- other investigators to shy away from research involving tis- gested that dominant genes govern susceptibility to tumor sue culture because of its apparent complexity, the cost of allografts. Critics termed this Carrel’s more inbred strains of mice which became a valuable tool “mumbo jumbo” that stalled medical progress for years. Several investigators sought antibod- ies to tumor-specifc antigens in animals making an immune He developed the technique of end-to-end anastomosis of response against transplanted tumors, but without success. This technical advance permitted him It was Haldane in 1933 who pointed out that a tumor retains to transplant organs successfully 6 years later. For such a hypothesis to a skillful technique of approximating the ends of blood vessels have credibility, it would be necessary to demonstrate blood to be anastomosed through triangulation sutures. Peter Gorer In 1905, together with his colleague, Charles Guthrie, Carrel (Figure 1. He demonstrated that blood vessels could be maintained in the cold for “prolonged periods” before use for transplanta- tion. Carrel and Burrows used Harrison’s technique to grow sarcoma cells successfully in culture in 1910. Together with Tuffer, Carrel performed a number of successful experimen- tal valvotomies. In World War I, he and Dakin developed a treatment for wounds that was used extensively. A positive accomplishment in his tissue culture research was the Carrel fask which reduced bacterial contamination that had been a principal cause of failure of tissue cultures before the discovery of antibiotics in the 1940s. He also claimed to have developed an immortal cell line of chick embryo heart cultures that was begun in 1912 and supposedly maintained by him and a colleague, A. How this was accomplished remains an enigma, as cells are now known to have a fnite longevity. In 1938, Carrel retired from the Rockefeller Institute and returned to France, where he set up an Institute for the Study of Human Problems in Paris. This fnding led him to the belief that tumor regression in these animals had an immunological basis. The blood sera from animals rejecting the tumor allotransplant contained hemagglutinins specifc for red blood cells derived from A strain mice. Thus, Gorer’s research showed that genes governing susceptibil- ity to tumor allotransplants were the same as those encoding alloantigens. His demonstration that alloantibodies were pro- duced by mice rejecting tumor transplants proved that this process had an immunological basis. Gorer’s tissue trans- plantation concept proposed that both normal and tumor tis- sues contain genetically determined isoantigens, and that the figure 1. Medawar, Billingham, and Brent went on to conduct graft- Peter Alfred Gorer (1907–1961) was a British patholo- ing experiments in which tissues and cells from one strain of gist who was professor at Guy’s Hospital Medical School, mouse were successfully transplanted in recipients of a dif- London, where he made major discoveries in transplantation ferent strain that had been administered cells bearing donor genetics. Most of his work was in transplantation nological tolerance, which was published in Nature in 1953, genetics. After sev- eral days, however, host lymphoid cells may infltrate the skin graft and undergo blastogenesis. Twelve days later the allograft may appear necrotic, representing frst-set rejection. A second graft of the same donor specifcity is rejected at an accelerated rate, i.
It is a of disorders in which pain is related to the intensity of the therapeutic agent administered orally that blocks the action infammatory process buy 40 mg sotalol. An anti-cancer drug used to treat low-grade leu- these drugs are able to inhibit the enzyme cyclooxygenase that kemias and lymphomas buy discount sotalol 40 mg line, it has been used in transplantation is the principal means by which they diminish pain discount 40mg sotalol visa, infam- to facilitate graft acceptance when used in combination mation, and fever. Cyclooxygenase catalyzes arachidonic acid with low doses of other immunosuppressive drugs. It is used for therapy of leukemia, Hodgkin Phenylbutazone (4-butyl-1,2-diphenyl-3,5-pyrazolidene- disease, lymphoproliferative disorders, and malignancies. Quinidine (β-quinine; 6′-methoxycinchonan-9-ol) is a stereoisomer of quinine recognized for its cardiac antiar- Vincristine is a chemotherapeutic alkaloid that lyses prolif- rhythmic effects. It blocks the secretion of proinfammatory anti-neoplastic substances including cyclophosphamide, cytokines and increases the secretion of antiinfammatory [H]-doxorubicin, [O]-vincristine, and prednisolone. Therapeutic Immunology 797 Intolerance refers to adverse reactivity following the admin- or treatment of interest is evaluated in human volunteers to istration of normal doses of a drug. L-phenlyalanine mustard is a nitrogen mustard that is employed for therapy of multiple myeloma patients. They may also include in which a sequence of controlled tests of a drug, vaccine, effcacy testing. Defense reactions in plants that are associated leads to lesions with death of host cells. It cross-links human Regulatory peptides in plants are generated as a compo- T lymphocyte surface molecules such as the T cell receptor, nent of local acquired resistance in plants. It permits lymphocytes to be activated in products that initiate further plant responses. Nonimmunologic phagocytosis refers to the ingestion of inert particles such as latex particles or of other particles that have been modifed by chemical treatment or coated with protein. Damaged cells may become coated with immunoglobulin or other proteins that facilitate their recognition. Phagocytosis of microorganisms involves sev- eral steps: attachment, internalization, and digestion. After attachment, the particle is engulfed within a membrane fragment and a phagocytic vacuole is formed. The vacuole fuses with the primary lysosome to form the phagolyso- some, in which the lysosomal enzymes are discharged and the enclosed material is digested. Remnants of indigestible material can be recognized subsequently as residual bodies. Chemotactic factors are released by the avr-R system is a plant immune response mechanism actively multiplying microbes. These chemotactic factors are in which the disease resistance (R) plant genes and microbial powerful attractants for phagocytic cells that have specifc avirulent (avr) interact. Certain pyogenic bac- off a pathogen and degrade it, the plant R product and the avr teria may be destroyed soon after phagocytosis as a result product of the invading pathogen must match. They might prove adequate cell-mediated immunity induced by interferon-γ less immunogenic than murine antibodies. The extrinsic vari- ety encompasses opsonin defciencies secondary to antibody Anti-microbial peptides are small peptides that injure or complement factor defciencies, suppression of phagocytic bacteria or fungi by rendering their cell walls permeable. Intrinsic phagocytic attack produce these peptides and some can be identifed dysfunction is related to defciencies in enzymatic killing in neutrophil granules. Examples of the intrinsic dis- cecropins, and drosomycin represent microbial peptides orders include chronic granulomatous disease, myeloper- in lower and primitive animals. Antimicrobial peptides in oxidase defciency, and glucose-6-phosphate dehydrogenase plants include defensins, thionins, and phytoalexins. Consequences of phagocytic dysfunction include increased susceptibility to bacterial infections but not to viral Phagocytosis is the uptake of particulate material, such as or protozoal infections. Particle ligands unite with numer- ders may be associated with severe fungal infections. Severe ous receptors on the surface of the phagocyte in a “zipper- bacterial infections associated with phagocytic dysfunction ing” effect and cause polymerization of actin, invagination range from mild skin infections to fatal systemic infections. Intricate genetic mechanisms control their surface mediates and reactive nitrogen intermediate species inside proteins. Restriction endonucleases are and disposition of foreign agents and particles or damaged believed to be responsible for the indentifcation and break- cells. Bacteriophages that develop resistance to this enzy- cells such as fbroblasts may show phagocytic properties; matic action infect bacterial cells successfully. Invertebrates do form certain members of the immunoglobulin superfamily such as adhe- sion molecules and receptors for tyrosine kinases. Within the immunoglobulin superfamily, only humulin, a protein isolated from lepidopterans, is induced following bacterial challenge. Humulin has four immunoglobulin-like domains whose primary structure will more closely resemble cell adhesion molecules than immunoglobulins. Invertebrates have cas- synthesized and released extracellularly by bacteria have cades of endogenous serine proteinases that are important a specifc effect on the bacteria. Once in the regulation of nonspecifc responses to tissue injury these agents are inside the bacterial cell they must remain and infection. Yet the strain producing the bacteriocin is usually able to resist its effect through specifc immunity Lower invertebrates are coelenterates, including corals peptides or proteins. Antibiotic synthesizing strains protect themselves from their own products by forming immunity proteins. Colicins and bac- to rejection of parabiosed fngers of different colonies within teriophages together with many other substances facilitate 7 to 9 d. Species-specifc glycoproteins of sponge cells are bacterial strain competitiveness. Immunity mechanisms used for identifcation of self and inhibition of hybrid colony are very specifc and depend on protein–protein, protein– formation. Second confer immunity to prokaryotic organisms against specifc grafts undergo accelerated rejection. A vestige of adaptive immunity Amebocytes are mobile phagocytic cells that mediate is revealed by limited evidence of immunological memory of defense by phagocytosis in addition to digestive and excre- a prior rejection episode. Worms: Four types of cells are present in the earthworm coelom, all of which are phagocytic. Some cells participate Invertebrate immunity: Invertebrates have various mech- in allograft rejection, whereas others synthesize antibacterial anisms to recognize and respond to nonself substances substances. They possess both cellular and humoral components that medi- Hemolymph is the invertebrate circulatory system liq- ate an immune-like response. Invertebrate internal defense uid that conveys nutritious molecules and waste products responses include phagocytosis, encapsulation, and nodule throughout the body of the organism.
Seizure freedom Conversion to monotherapy studies in refractory was attained during the monotherapy phase in 41% of lamotrigine epilepsies patients and 30% of carbamazepine patients buy generic sotalol 40mg on-line. Neither of these difer- A double-blind cheap sotalol 40 mg visa, short-term active–control study in adolescents and ences was signifcant purchase sotalol with amex. Among the 158 patients in the valproic acid adults with refractory seizures further confrmed the efcacy of arm (105 assigned to lamotrigine and 53 to valproic acid), mono- lamotrigine in focal epilepsy . A total of 156 patients on mon- therapy was completed in 49% of lamotrigine patients and 40% of otherapy with carbamazepine or phenytoin were assigned to receive valproic acid patients. While maintaining the concomitant freedom during the monotherapy phase with 32% versus 11% in drug at a steady dose level during baseline, the lamotrigine group favour of lamotrigine. Lamo- Monotherapy studies in newly diagnosed, trigine dosage was adjusted in the valproic acid group as valproic predominantly focal, epilepsy acid was withdrawn. In the remaining groups, serum lamotrigine As monotherapy, lamotrigine was reported to be no less efective concentrations rose as the concomitant drug was withdrawn. One study limited pathic’ tonic–clonic seizures (61%) than in those with focal seizures to focal epilepsy  allowed inclusion of 233 patients between 2 (43%). Tree studies [80,108,111] recruited elderly pa- statistical signifcance was reached for the focal seizures group only. Lamotrigine and carbamazepine were similar in efca- Although the valproic acid group experienced better seizure control cy, when evaluated in a diverse range of patient populations. How- during the add-on phase than the other groups, more patients in the ever, they difered in tolerability, because withdrawal secondary to valproic acid group tended to deteriorate during the phase of con- treatment-emergent adverse events was more likely with carbamaz- version to lamotrigine monotherapy. Tese results were interpreted epine, possibly most signifcantly in children and particularly in the as evidence of synergism between lamotrigine and valproic acid. In the studies for which only one seizure was A multicentre study from Poland recruited two equal groups of required for entry [25,108], seizure freedom attained tended to be 63 patients with uncontrolled focal or generalized seizures on mon- higher for both agents, without statistically signifcant diferences. The four study In a randomized comparative trial, lamotrigine and phenytoin phases consisted of a 4-week lamotrigine dose escalation, an 8-week were similarly efective  in terms of time to the frst seizure and lamotrigine add-on therapy, an 8-week carbamazepine–valproic time to discontinuation. The 181 recruited patients ranged from 14 acid withdrawal if clinically appropriate, and an 8-week lamotrigine to 75 years of age, and patients with primary generalized tonic– monotherapy. Adverse events led to discontinuation tion and add-on therapy, and 85 (68%) completed the lamotrigine of 13 patients (15%) in the lamotrigine group and 18 (19%) in the monotherapy phase. The other included patients data from a similar large international open-label conversion to with primary generalized tonic–clonic seizures or focal seizures Lamotrigine 505 Table 38. Proportion of patients seizure free Proportion Number of during fnal of patients patients Study 24 weeks of completing Reference on entry Dosage (mg/day) duration treatment (%) study (%) Versus carbamazepine Brodie et al. Marked seizure freedom difference in the trial versus valproic acid (not statistically signifcant) was attributed to worse outcome in 10 lamotrigine patients with juvenile myoclonic epilepsy. Although associated with similar seizure outcomes, but lamotrigine showed seizure freedom was attained in 47% of patients with both drugs, tolerability advantages in the elderly. In the other study, which required only one seizure (focal or newly diagnosed patients. A study with 225 patients consisted of generalized) for entry, neither seizure freedom nor withdrawal rates 506 Chapter 38 were statistically diferent between groups . However, among 72% of patients during the 12-week maintenance phase, while 43% patients with juvenile myoclonic epilepsy, there was a clear signal of 59 patients assigned to placebo had a greater than 50% seizure re- for seizure freedom to be achieved more commonly with valproic duction, a statistically signifcant diference. Another randomized, acid (3 out of 4 patients) than with lamotrigine (3 out of 10). The pri- mary outcomes were time to treatment failure and time to 12-month Monotherapy studies in newly diagnosed generalized remission. The secondary outcomes were time from randomization epilepsies to a frst seizure, time to 2-year remission, the incidence of clinically The efcacy of lamotrigine monotherapy in patients with newly important adverse events and adverse efects emerging afer rand- diagnosed childhood absence epilepsy was demonstrated in three omization. Carbamazepine had a non-signifcant advantage over blind dose escalation phase . In the subsequent double-blind, lamotrigine, topiramate and oxcarbazepine for time to 12-month placebo-controlled phase restricted to patients who had respond- remission. A per-protocol analysis supported non-inferiority of ed to open-label treatment, signifcantly more patients remained lamotrigine compared with carbamazepine. The results for arm B of seizure-free among those randomized to continue lamotrigine the study are reported in the section ‘Monotherapy studies in newly (62%, n = 15) than in those switched to placebo (21%, n = 14). In the second trial, 38 children (3–13 years of age) were randomly assigned to lamotrigine or valproic acid according to an open-label Adjunctive therapy studies in generalized epilepsies design . At 3 months, 63% of children taking valproic acid and In a multicentre double-blind cross-over study, a total of 26 pa- 37% of those taking lamotrigine were controlled. Afer 12 months, tients with various generalized epilepsies, including absence, were 68% of children taking valproic acid and 53% taking lamotrigine randomized to lamotrigine (at a maintenance dose of either 75 or remained seizure-free. Twenty-two patients completed signifcant, possibly because of the limited sample size. A greater than 50% seizure reduction A truly pivotal randomized double-blind trial of lamotrigine in occurred in 50% of patients with tonic–clonic seizures and in 33% comparison with valproic acid and ethosuximide in the treatment of those with absence seizures. In the continuation phase, fve pa- of childhood absence epilepsy was conducted more recently by tients (25%) remained seizure-free. All drugs were titrated according to clinical re- In a single-centre study employing an innovative design , sponse with maximal target doses of 60 mg/kg/day or 2000 mg/day 17 of 30 patients (57%) experienced a greater than 50% seizure for ethosuximide, 60 mg/kg/day or 3000 mg/day for valproic acid reduction when lamotrigine was added on in an initial open-label and 12 mg/kg/day or 600 mg/day for lamotrigine, and the children phase. Fifeen of the responders were then assigned, according to remained in the trial unless treatment had failed. At the 16-week as- a double-blind cross-over design, to lamotrigine or placebo afer a sessment, the primary comparison based on freedom-from-failure washout period, with the two double-blind phases consisting of 12- rates showed that lamotrigine (29% freedom-from-failure rate) was week periods separated by a 3-week cross-over. With the exception signifcantly inferior to both ethosuximide and valproic acid (53% of a single patient, the seizure count was lower during the lamo- and 58%, respectively), mainly due to inferior efcacy. Twenty of the 30 patients recruited at initiation had follow-up at 12 months, freedom-from-failure rates remained low- Lennox–Gastaut syndrome, and 11 of these patients (65%) were in er with lamotrigine (21%) than for ethosuximide and valproic acid the responder group. Almost two-thirds of the 125 The efcacy of lamotrigine in the management of Lennox– children with treatment failure as a result of lack of seizure control Gastaut syndrome was demonstrated in a double-blind, add-on were in the lamotrigine cohort. A higher rate of attentional dys- study  in which a total of 169 patients were randomized to function, already present at 16–20 weeks in the valproic acid group 16 weeks’ treatment with lamotrigine (n = 79) or placebo (n = 90). Based on these fndings, ethosuximide was consid- well as proportion of patients with greater than 50% seizure reduc- ered to represent the treatment of choice for childhood absence tion was signifcantly higher in the lamotrigine group than the pla- epilepsy, being superior to lamotrigine in efcacy and superior to cebo group. In this arm of the study, valproic acid was quency of primary generalized tonic–clonic seizures occurred in better than lamotrigine for time to 12-month remission, where- Lamotrigine 507 as topiramate was inferior to both valproic acid and lamotrigine Risk of seizure aggravation mainly in terms of tolerability. Lamotrigine can aggravate myoclonus [141,142,143,144,145] and even precipitate myoclonic status epilepticus , although im- Other studies proved control has also been reported in some cases . In a A large number of experiential clinical studies have documented recent prospective open-label trial from Cuba, 72 patients with the place of lamotrigine in epilepsy treatment [25,46,80,123,124,12 juvenile myoclonic epilepsy were randomized to valproate or lamo- 5,126,127,128,129,130]. In an open study, for example, 21 patients trigine, the primary end-points being time from randomization to (16–65 years old) with epileptic seizures of frontal lobe origin were treatment failure and time from randomization to seizures remis- maintained on a combination of lamotrigine and valproic acid . Lamotrigine was efective on both end-points and no At the end of 1 year, 17 patients continued on this combination and signifcant diference was seen between the two groups. Treatment outcome of some epilepsy syn- Dravet syndrome in whom lamotrigine use led to decreased seizure dromes was quantitatively evaluated with electroencephalogram duration and frequency. Myoclonus can represent a new symptom when lamotrigine verse events were recorded and compared with the patient’s treat- is initiated in a patient with genetically determined forms of epilepsy ment history as own control. Tere is a single case report of recurrent Successful applications of lamotrigine in refractory epilepsy have absence status epilepticus associated with lamotrigine therapy .
The Elo mutation is a frameshift that causes loss of the ciation of optic and renal defects is likely to have its roots С-terminal portion of the protein discount sotalol 40mg amex, and it may be significant in the highly conserved nature of not only genes order sotalol mastercard, but their that the mutation substitutes novel buy sotalol 40 mg with amex, functionally irrelevant functional partnerships. One theory is that expression of re-utilized in these two very different developmental this abnormal protein disrupts the normally orderly pack processes. Evolution has apparently chosen not to rein ing of highly concentrated crystallins within the cell, alter vent the wheel for a different tissue. Absence of the initial lens nucleus results in the disorganization of later lens fibers. Mutations in structural genes generally affect cataract,ismaps to the y-crystallin locus. In compar degenerations caused by mutations in photoreceptor ison with the Elo mutation of the mouse, the defect is very architectural components such as peripherin, and in the mild and nonprogressive, as later development of the lens phototransduction machinery. However, the Coppock cataract again developmental defects can also be caused by mutations in involves the уE gene, which in the human genome normally structural genes selectively expressed by an embryonic appears as a pseudogcne. The proposed mechanism for expressed in the fibers that form the central lens nucleus. This may be due to other differences between properties are responsible for the transparency and refractive mouse and human lens development, or to differences qualities of the lens. It should be noted that the anterior lens epithelium remains normal in appearance, and that the In the case of inherited birth defects, it is important to defect is confined to differentiating fiber cells, where the keep in mind that the primary site of the defect is the yE-crystallin gene is expressed. Molecular genetics of hum an kidney disease with mutations in the РЛХ2 gene is a prime visual pigments. M utations at the interactions in establishing separate identities for equivalent cells. Nature regulation of photoreceptor induction in the developing D ro s o p h ila 1996; 384: 515-516. Early evolutionary origin of m orphogenetic protcin-7 during developm ent of the m am m alian m ajor hom eodom ain sequence classes. Positional cloning and charac during distinct regulatory phases in the developing D ro s o p h ila eye. Cyclopia and defective axial of pax-6 are highly conserved between zebrafish and mice. Regional differences in eye-form ing capacity of the early Science 1991;265:785-89. The new dysm orphology: application of insights from than m eets the optic vesicle. Pax-2 controls multiple expressed throughout the corneal and conjunctival cpithclia. Development 1996; 122:3381 — the РЛХ6 gene in patients w ith autosom al dom inant keratitis. Prenatal developm ent o f the eye m urine hom eobox gene, C h i 10: evidence for roles in determ ination and its adnexa. Regulation of neuronal the gene m ap of inherited eye disorders: prim ary hereditary diseases diversity in the xenopus retina by delta signaling. J Embryol Activation o f the gE-crystallin pscudogenc in the hum an hereditary Exp M orph 1986;97:95-110. It could be used to describe a beautiful teratogenic exposure, but to increase awareness of possible creature as well as an ugly monster, and certainly there are new drugs or agents that may be a factor contributing to the many examples in ancient mythology that picture animal etiology of congenital anomalies. Frankenstein, Dracula, Superman, teratogens in the past such as rubella, thalidomide, and elves, and creatures from other planets arc the teras of today. The Bible (Judges 13:7) history when evaluating a child with a congenital anomaly. This has proven to be very Another reason for improved knowledge of teratogens incorrect. A well-known example is the Cyclops, with is high because of having had a child with a congenital only one eye in the middle of the face. They read about the potential environmental met with this “teras,” who wanted to kill him and his men. To exposures to a variety of proven and unprovcn teratogens save them, Ulysses put the monster out of action by running and look for an explanation of their child’s problems. In the Middle Ages grotesque it becomes necessary for the physician to know how to creatures like gargoyles protected the churches against evil obtain information about the potential teratogenicity of a powers. A teratogen, by definition, is It is difficult to determine the number of infants with con an environmental agent that has a permanent morphologic genital anomalies that arc caused by teratogens. If children 23 arc evaluated at 5 years of age, significantly more have sonic post-fertilization, and in that period causes malformation or functional deficit than when evaluated at malformations of eyes and limbs, and other structures birth. The pre-implantation period may be sensitive to certain Congenital eye malformations are reputed to be less teratogens, but often ends in death to the zygote or no effect. Rarely docs an ously thought because the concept of susceptibility at the ophthalmologist participate in studies done that focus on time of development of an embryo is often quite compli obvious malformations in the first few weeks of life. An example is that infants were noted to have major and minor eye defects ocular colobomas were seen in thalidomide embryopathy (3. After more detailed exami closure is described in the textbooks as occurring at 5 to 6 nations, the most frequent (and most obvious) eye weeks. After the end of organogenesis, teratogenicity and malformations were anophthalmia/microphthalmia, cata lethality decline, but there is increasing evidence that a ract, and coloboma. The prevalence should be considered teratogen in the fetal period can cause functional and psy a minimal estimate, as many malformations would become chological changes that will be manifested in the infant. Based on available data, the total Warkany22refers to the concept of “termination period” eye malformations were estimated as 21. For example, an ocular coloboma cannot be caused were primarily intrauterine infections. Susceptibility to a teratogen m ay depend on the species during pregnancy, resulted in major changes in attitude and genotype o f the fetus. It is mate of over 10,000 affected pregnancies, and over 5,000 well appreciated that many fetuses exposed to the live births in Germany alone. Thalidomide was the terato same toxic agent will show a spectrum of effects, from gen that resulted in many rules and regulations to protect lethality to no effects, even with similar doses of the the fetus from the adverse effects of environmental agents teratogen. While there has been considerably more informa resistant to the drug, whereas humans and higher tion and modification of these principles, and the original mammals arc highly sensitive to it. Teratogenic agents act in a specific way on developing are often referred to in publications and are still worth review cells and tissues, causing abnorm al embryogenesis. Many changes are often not apparent because they occur at the subcellular and molecular levels, and do 1. Susceptibility to teratogenesis varies with the not result in obvious birth defects. Clinical research developmental stage at the tim e o f exposure to the gives some insight into these mechanisms. This certainly is a very important premise in evaluating the effects of teratogenic agents, 4. Thefinal manifestations are death, malformation, growth and also will apply to many genetic influences. Of these, only ionizing radiation is known field of teratology and developmental biology, the old princi to be clearly teratogenic.
As current surgical tech- believe that both the Alpha Centella tape and cream niques become more standardized and results more system marketed as ScarScience™ as well as Laser predictable order 40 mg sotalol amex, a fne scar may be the deciding factor therapy are two approaches of which yield a high level between acceptable and unacceptable aesthetic results purchase sotalol 40mg without a prescription. This chapter will go to the healing process order 40mg sotalol with amex, how the scar heals can vary on beneath the surface and explore how the surgeon the protocol taken to achieving benefcial wound heal- and patient alike can work in a symbiotic relationship ing. W ith each scar management approach itself is a with the natural process of scar formation to achieve multitude of nuances and variations among plastic the best results possible. There is no such thing as the perfect scar general overview of scar formation, different types management program; thus the task of which approach of scars, and the various elements that affect scar to use could be an arduous one. This will then lead to a discussion of the different modalities of scar management com- monly used. Lastly, a thorough discussion will be provided of the Alpha Centella (ScarScience™ ) Scar M anagement Program and Laser Therapy, both of which have clinically and experimentally been proven effective for improving the aesthetic appearance of G. George W ashington University School of M edicine and To remedy this, the normal wound healing process is Health Sciences, 1111 Army Navy Drive Appartment 1421, initiated in response to such injury. Craig is simply collagen beneath the skin that develops from George W ashington University School of M edicine and Health Sciences, 10661 Oakton Ridge Ct. Hypertrophic the infammatory phase is initiated frst with a scars often develop after thermal or traumatic injury duration being between 2 and 6 days . Although the proliferative phase follows a few days after the the collagen found in these scars is not unlike colla- infammatory phase with a duration being 3–4 weeks gen in a normally healing scar, the appearance of the . Collagen production continues with a slow pro- scar is raised, nodular and red in color. Hypertrophic scars are distinguished the fnal phase of scar formation, the maturation from keloid scars by their lack of growth beyond the phase, has a duration of many weeks to many years boarders of the original wound . As a slow process, more collagen forms to are hypertrophic but not all hypertrophic scars are strengthen the wound. Even after completed scar formation, usually younger than 30 years and have darker skin the scar tissue is not comprised of the same materials pigmentation . The two most important dif- thickened bundles of hyalanized acellular collagen ferences are the lack of dermal appendages and the arranged in a chaotic tangle with increased hyalurani- altered collagen composition. They result when the body overcompensates for or protein anchors found in the dermis, are destroyed dermal injuries including but not limited to surgery, in the line of the incision or wound and do not regener- acne or piercings. They are often extremely unsightly mary reasons why scared areas look and feel different and are removed for cosmetic reasons. They result after an acute infammation orientation of scars is something to be of concern when destroys the underlying structures supporting the skin, determining scar type. This type of scarring is 27 Scar Management 279 often associated with cystic acne or varicella. They often become hypopigmented and will exhibit a slower healing time, as well as a more fbrous overtime . This is due to the structural changes in the skin of an elderly per- son such as fattening of the dermal–epidermal junc- 27. On the contrary, younger patients tend to vide an optimum surrounding to support the cellular form thicker scars because their youthful bodies are activities involved for proper wound healing. The build of an indi- this, the surgeon attempts to remove or protect the vidual can also affect the availability of oxygen and wound from various factors that may have the potential nutrients to the wound site. Such factors that could weight individual will have reduced delivery of energy affect the cosmetic appearance of a scar fall into two as well as small protein reserves; both of which are categories: intrinsic factors and extrinsic factors. On the contrary, overweight Intrinsic factors include the following: a hereditary individuals may experience an increased risk of a spon- predisposition for scar formation, health status, age taneous rupture of a wound, hernia formation, and factors, body build, race, age, anatomical location of infection . Extrinsic factors include Overall, the supply of nutrients (proteins, fats, vita- the following: mechanical stress, temperature, infec- mins/minerals, and adequate fuid intake) plays a vital tion, medications, alcohol abuse, smoking, and psy- role in the cellular activity. For latory conditions, and anemias infuence the healing example, vitamin C is required for collagen synthesis, process. In addition, any condition associated with immune response, and fbroblast functions. A chronic circulatory condition, for example, can reduce blood fow thereby decreasing the oxygen available for normal tissue activity and replacement. Friction can also cause wound healing diffculties surgery can cause a deviation from the norm in blood by wearing down newly formed epithelium, thereby sugar levels . Shear mechanical stress has the scientifc evidence published over the past 25 years. On the other hand, a Temperature can also play a role in wound healing multi-directional or intermittent tension on a scar ini- because it plays a role in the activation/deactivation of tiates lymphocytes. This could result in a hypertrophic chemical and enzymatic processes as well as the scar [12, 14, 15]. The common initiating factor is the metabolism of cells and tissues engaged in the repair tension on the scar, and the critical element needed to process. In regards to dressings, those that promote a counteract this tension is scar support. Sun approaches have become the standard of care for exposure can cause darkening and thickening of scars hypertrophic scar control – both prevention and treat- for up to a year after surgery. Keloids in general respond minimally to these incisions or wounds should be covered during the day approaches . The clinical signs of a wound infection are the following: erythema, heat, local swelling, and pain. Systemic steroids commonly used M icroporous tape has been proven clinically to be a to treat infammation, pain, asthma, or allergies can reliable method of scar support. Chemo- has a benefcial effect on scar control and is the basis therapeutic agents can also affect scar formation via of silicone gel sheeting [12, 16]. The Alpha Centella the suppression of protein synthesis, inhibiting cell cream consists of two main components: an extract reproduction or the infammatory response. This plant extract nosuppressive drugs will naturally reduce infamma- leaves a layer of fatty vesicles of glycoprotein on the tory activities, thereby increasing the susceptibility of skin surface, thereby increasing hydration under the a wound infection [9, 10]. The the Alpha Centella Cream is the principal terpenoids surgeon should advise a patient to stop drinking at extracted from the Centella asiatica plant which least 1 week before surgery . Optimistic, positive personalities heal more rap- appears to be the stimulation of maturation of the scar idly than those depressed and/or anxious individuals. Thus these components have been incorporated into a formulation used in my offce called the Alpha Centella (ScarScience™) Scar 27. These factors have stemmed from nism of action is via a laser beam to cause a thermal tissue 27 Scar Management 281 reaction. This will thereby heat the injury or coagulate function of deep massaging is to stretch fresh scars and specifc tissues. For instance, the fash lamp-pumped thereby break down the cement or matrix holding the pulsed dye laser selectively decreases scar blood fow scar contracted. M assaging also stimulates fbroblast with a demonstrated improvement of more than 50% in synthesis of collagen, therefore this approach is com- over 50% of cases. Based upon clinical evidence results bined with an anticollagen synthesis approach [19–23]. ScarScience™ combination (18–24 h a day for at least 6 months) has been clini- of gel formula and microporous tape fulflls the fol- cally proven to have at least partial success in produc- lowing four criteria for an effective cosmetic scar man- ing a thinner, more mature/pliable scar.