Michael Vincent Boland, M.D., Ph.D.

• Director of Information Technology, Wilmer Eye Institute
• Associate Residency Program Director, Wilmer Eye Institute
• Associate Professor of Ophthalmology

https://www.hopkinsmedicine.org/profiles/results/directory/profile/0020165/michael-boland

Incidental brain abnormalities have been described in 3% of children with idiopathic epileptic syndrome and 10% of children with nonidiopathic epilepsy treatment lupus generic 15 mg primaquine free shipping, normal neurologic exams medicine in the civil war order primaquine 7.5mg on-line, and nonpharmacoresistant epilepsy [20] treatment 4 letter word buy primaquine canada. Thus symptoms xanax overdose buy primaquine 7.5 mg overnight delivery, the definition of refractory epilepsy is necessary but not indispensable for the referral for epilepsy surgery medicine 101 primaquine 15mg. Clinical Aspects: Semiology symptoms inner ear infection purchase line primaquine, Exam Findings, Weight, and Age Semiology the semiology of the seizures, specifically early in the course of seizures, is very important when considering epilepsy surgery. The presence of focal features can point to a specific brain region or location [15],[28], [29], [30], [31], [32]. Auras, lateralizing signs, and postictal symptoms are also very important in assigning both hemispheric and lobar localizations [28],[30],[33]. Semiology is even more critical in patients with multilobar or multilesional substrates. In multilobar cases, semiology may help predict early seizure spread in relationship to a large lesion. For example, in patients with posterior quadrant dysplasia, limb clonic or versive seizures at the onset may suggest anterior ictal spread. In multilesional patients, semiology may help narrow down the inventory of lesions that could possibly result in the semiology. Seizures characterized by arrest of activity with very subtle limb movements and/or automatisms are also seen in this group, and some seizures with clear asymmetric features fail to point to a generalized or a focal epilepsy [15],[36]. Clinical Exam the clinical exam is equally important when determining the type of brain surgery to be performed. In addition to the proximity of the lesion to the eloquent area, the presence of motor deficit, hemianopsia, 1827 neglect, etc. The possibility of a new neurologic deficit is a deterrent to patients and relatives when considering epilepsy surgery, and worsening of an existing neurologic deficit is also not desired. Risk of neurologic deficit was the cause for refusing resection in seven of nine children with subdural grids who were studied at the Cleveland Clinic [37]. In these cases, an early consent discussion that includes clearly defined risks and benefits could lead to alternative or palliative treatments. In some patients, assessment of hemiparesis may be difficult because it fluctuates with acute worsening and recovery over weeks to months. Infants as young as 1 month and weighing 4 kg have undergone surgery for catastrophic epilepsy [14],[15],[38]. Although operative risks are greater in very small infants or the elderly, there are no absolute age or weight limitations for epilepsy surgery if seizures are difficult to control. The expertise and comfort of the neurosurgeon and the hospital team are the ultimate determining factors. The Selection of the Surgical Procedure Listen Multilobar Resection/Disconnection Patients with multilobar and multilesional epilepsy involving contiguous lobes and located in or near eloquent cortex are candidates for multilobar resection or disconnection, assuming the absence of a significant preexisting neurologic deficit. These cases may require additional invasive evaluation if a more tailored surgery is possible or desired. A variety of multilobar resections or disconnections can be performed, depending upon the location of the lesion and information provided from the presurgical and invasive evaluations. The most common type of multilobar resection or disconnection is the occipital plus or posterior quadrant surgery. It is also the procedures of choice when there is need to preserve the motor and sensory cortex. The decision to perform a multilobar resection versus a disconnection depends on the experience and expertise of the center. Peri-insular posterior quadrantectomy has been described as the latest approach for posterior quadrant epilepsy [43]. Variations of focal resections with or without multiple subpial transections have been described in patients with perirolandic epilepsy [44]. Nevertheless, seizure outcome with complete seizure freedom has been reported only in 31% of the cases with new neurologic deficits present in up to 23% of the cases. Random cases with multifocal epilepsy can have improved quality of life when the resection is targeted toward the region producing more disabling or frequent seizures [46]. Hemispherectomy, Procedures Hemispherotomy, and Other Disconnective Patients with epilepsy secondary to large multilobar brain lesions generally undergo hemispherectomy, although there are some exceptions, particularly when the surgical procedure is risking a new neurologic deficit. Hemispherectomy or other disconnective procedures may be indicated for patients with multilobar and multilesional epilepsy involving contiguous lobes and located in or near the eloquent cortex who have a preexisting significant, complete or nearly complete neurologic deficit [47],[48]. In some patients with this scenario, the benefits from hemispherectomy may outweigh the risks of continuing seizures, hence favoring a more aggressive approach. In some patients with Rasmussen syndrome, hemispherectomy may be preemptively done due to anticipated deficits. Etiologies for patients with epilepsy who require hemispherectomy include Rasmussen encephalitis, vascular or posttraumatic encephalomalacia, in particular perinatal infarction, cortical dysplasia, and hemimegalencephaly. Pathologic analysis of samples from 34% of patients with encephalomalacia found additional abnormalities consistent with cortical malformation [48]. Functional or anatomical hemispherectomy is a procedure that is very well tolerated in infants and young children with catastrophic epilepsy [49]. Surgery in these cases has a short-term positive outcome of 79% compared to results in patients who did not have contralateral abnormalities [23]. Multilesional/Multifocal Resections and Multistage Surgeries Following a complete presurgical evaluation, multilesional and multifocal resections are performed in patients with multiple epileptogenic lesions or multiple ictal onset zones. The medical literature covering this topic is limited because patients with multilobar surgeries are often lumped together with those requiring multifocal/multilesional surgeries. The indications for evaluation and outcomes of the surgical procedures are, therefore, difficult to determine. Another limitation is that documentation of the success of multifocal epilepsy surgery is sometimes limited to case reports. Other etiologies include cortical dysplasias, postinfectious encephalitis, posttraumatic epilepsy, vascular injuries, tumors (in particular, brain metastases), postradiation epilepsy, etc. Some patients have dual pathologies that include malformations of cortical development and mesial temporal sclerosis [52],[53]. Multiple pathologies are reported in up to 10% of the specimens from patients with medically refractory epilepsy studied in one anatomopathology laboratory [54]. In the past, patients with multifocal ictal onset zones were considered nonsurgical candidates. Multifocal ictal onset zones were the reason for not performing resections in four out of nine children studied with subdural electrodes and reported by Pestana Knight et al. One study in adult patients with epilepsy documented that resections were not performed after invasive evaluation in 10 out of 22 patients because of diffuse or multifocal ictal onset zones [52]. Another study reported poorly localized epilepsy in 9 out of 17 cases in which resections were not performed after invasive monitoring [55]. These include the possibility of studying epileptogenicity in deep gyri, sulci, and bilateral brain structures when noninvasive or invasive studies had failed to localize the epileptogenic zone [57],[58]. Some patients with multifocal or multilesional epilepsy may also benefit from multistage procedures. Multistage procedures have been performed in patients who require up to four admissions and two to three operations at each admission [55], with a relatively low complication rate [45],[55],[59]. Other Surgical Procedures Multiple Subpial Transections 1830 Some patients are candidates for limited brain resection as a palliative, more than a curative, treatment. Multiple subpial transection is another technique that has been used in cases with lesional or nonlesional epilepsy. The technique has been used alone or in combination with lesionectomies, lobectomies, or multilobar resections [61],[62] and is discussed further in Chapter 86. All patients became free of seizures after the surgery and remained so after a mean follow-up period of nearly 3 years. The researchers concluded that patients with ictal symptoms that are consistent with temporal lobe epilepsy have excellent seizure outcomes following temporal lobectomy, regardless of the size or extent of the brain lesions. This study analyzed only a limited number of patients with a very specific seizure semiology. Seizure outcome of 75% at follow-up was also described in a series of four patients with infrasylvian multilobar polymicrogyria who underwent partial resection of the polymicrogyria (3/4 patients) combined with anterior mesial temporal resection. These patients had complex malformations that include polymicrogyria, squizencephaly, focal cortical dysplasia, and hippocampus malrotation [64]. Nonsurgical Candidates Some patients do not receive epilepsy surgery because of the extent of the lesion, high risk for new postsurgical deficits, or the suspicion of multifocal epilepsy. Twenty-one percent of the patients were seizure free at follow-up; others reported reduced seizure frequency. Particular cycling of the epilepsy could possibly explain the findings that seizure freedom in these two different patient groups is possible in some refractory cases. Some other cases considered not surgical candidates could benefit from palliative procedures such as corpus callosotomy or neurostimulation. Outcome of Multilobar and Multifocal Epilepsy Listen There are data supporting the position that complete resection obtains the best seizure control after surgery and that incomplete resection of the lesion is a predictor of poor outcome. Seizure outcomes in patients with epilepsy due to large hemispheric or multifocal lesions who underwent small or limited resections are not well known. Seizure-free outcome was reduced to 52% at 5 years and 41% at 10 years after surgery. They did not study patients with extensive brain lesions who underwent limited resections. This population included patients who had invasive evaluation only, which is not representative of current trends in pediatric epilepsy surgery in some tertiary care centers. Long-term seizure outcome after resective surgery in patients evaluated with intracranial electrodes. Refractory epilepsy is common in these cases and catastrophic epilepsy is commonly seen in younger children. Some of these cases need presurgical and invasive evaluations tailored to individual needs. Novel surgical strategies and improved perioperative care have improved seizure outcome and lowered surgical risk in these patients. Although it is difficult to group these cases for outcome analysis, further understanding of the epilepsy outcomes is needed. Each case is color coded in the figure key: Case 1 in dark red, Case 2 in yellow orange, Case 3 in dark green, and Case 4 in dark orange. At the time of the presurgical evaluation, he was having multiple daily seizures described as behavioral arrest (hypomotor seizures) and bilateral asymmetric tonic seizure. On examination, there was evidence of delayed cognition for age, left hemineglect, mild left hemiparesis, and a possible left hemianopia. There were generalized polyspikes during sleep and continuous slow activity over the right hemisphere. Hypomotor seizures had an ictal onset in the right occipital region or right hemisphere. The figure documents the presence of severely dysmorphic brain with massive right hemisphere cortical dysplasia, callosal dysgenesis, and complex supraventricular midline cyst. His initial and ongoing seizures were hypomotor seizures that often time were not identified by his relatives. He also had left arm clonic status epilepticus lasting several hours to a day and occurring around three times per year. On examination, he had a left hemiparesis with no fine motor movements in the left hand and left hemineglect. He had a ventriculoperitoneal shunt placed at birth due to complex midline cyst and hydrocephalus. Several hypomotor seizures were recorded with onset in the right centroparietal region. In this case, the complexity of the malformation did not allow for a functional hemispherectomy. Before surgery, she had multiple seizures per day that were described as complex motor behavior evolving to hypomotor seizures (behavioral arrest) and then followed by epileptic spasm. On examination, she has cutaneous tuberous sclerosis stigmata and clinical/behavioral features consistent with cognitive impairment and pervasive developmental disorder. At the time of the presurgical evaluation, she was taking zonisamide, valproic acid, levetiracetam, and clonazepam. Typical clinical seizures and electrographic seizures were recorded with an ictal onset in the right centroparietal region. At last outcome, 5 years after the surgery, Case 3 has had a seizure reduction of 80% compared to her presurgical baseline. On examination, he has clinic features consistent with moderate cognitive impairment and spastic quadriparesis with lower extremity predominance. Previous medications included lacosamide, lamotrigine, levetiracetam, rufinamide, valproate, and ketogenic diet. In patients like Case 4, palliative procedures such as callosotomy could be considered to reduce the daily seizure burden. Focal cortical resections for the treatment of extratemporal epilepsy in children.

Important features of several stem cell niches are basement membrane matrix molecules and proximity of mesenchymal cells medicine overdose cheap 7.5 mg primaquine with mastercard, chemokines and specific growth and differentiation factors symptoms rectal cancer generic primaquine 7.5mg with mastercard. The mere presence of adult stem cells or progenitor cells is not sufficient for tissue regeneration when tissue is damaged symptoms 5-6 weeks pregnant cheap 15mg primaquine amex. The method of repair is also influenced by the environment of the injury medications requiring prior authorization cheap primaquine 7.5 mg overnight delivery, that is medications that cause dry mouth buy primaquine without a prescription, the growth factors treatment nurse 15 mg primaquine with visa, Cells Can Be Classified by Their Proliferative Potential Cell populations divide at different rates. However, stable cells are also constituents of labile tissues with high rates of cell turnover. Labile epithelial tissues that typically form physical barriers between the body and the external environment self-renew constantly. Examples include epithelia of the gut, skin, cornea, respiratory tract, reproductive tract and urinary tract. Polymorphonuclear nucleocytes and reticulocytes are terminally differentiated cells that are rapidly renewed. Under appropriate conditions, tissues composed of labile cells regenerate after injury, provided enough stem cells remain. The potential to replicate, not the actual number of steady state mitoses, determines the ability of an organ to regenerate. For example, the liver, a stable tissue with less than one mitosis for every 15,000 cells, rapidly recovers through hepatocyte hyperplasia after loss of up to 75% of its mass. Traditionally, neurons, chondrocytes, cardiac myocytes and cells of the lens were considered permanent cells. If lost, cardiac myocytes and neurons may be replaced from progenitors, but not from division of existing cardiac myocytes or mature neurons. Every lens cell generated during embryonic development and postnatal life is preserved in the adult without turnover of its constituents. Systemic Factors No specific effect of age alone on repair has been found, although there is evidence that stem cell reserves are reduced with aging (see Chapter 10). Local thrombosis decreases platelet activation, reducing the supply of growth factors and limiting the healing cascade. The decrease in tissue oxygen that accompanies severe anemia also interferes with repair. Exogenous corticosteroids retard wound repair by inhibiting collagen and protein synthesis and by suppressing both destructive and constructive aspects of inflammation. Fibrosis and Scarring Contrasted Successful wound repair that leads to localized, transient scarring promotes rapid resolution of local injury. Scars reflect altered deposition of matrix compared to normal, surrounding tissue. Scars may vary in size and may be larger than the wound site, depending on the nature of the wound or its treatment. This occurs particularly where there exists greater mechanical movement and tension, such as over limb joints. Scarring is a typical response to tissue ischemia or infarction, where resident cells cannot be replaced. By contrast, in many chronic diseases of skin and parenchymal organs, including many autoimmune diseases. It then progresses to diffuse and progressive fibrosis, or continued and excessive deposition of matrix proteins, particularly collagen. Innate and adaptive immune-mediated inflammation, such as that of joints in rheumatoid arthritis, leads to differentiation and activation of fibroblasts. Both inflammatory and noninflammatory factors cause cardiac, hepatic, lung and kidney fibrosis. By example, glomerulosclerosis in the kidney results from infection, hypertension or diabetes. Resolution of a fibrogenic response is associated with M2 macrophages and, in some studies, Th1 and T regulatory cells. The fibrotic reaction, once initiated, may resolve with early removal of the inflammatory or noninflammatory triggers. Fibrosis itself further alters matrix composition, stiffness and mechanical stress, propagating fibroblast conversion to myofibroblasts and further matrix production. The composition of matrix changes from provisional matrix during fibrogenesis and remodeling, providing opportunities for a matrix that supports continued fibrosis. Uncontrolled fibrosis selfperpetuates, despite absence of continued inflammation; it features myofibroblast production of extracellular matrix. Skin lesions in such areas, particularly burns, often require skin grafts because their edges cannot be apposed. Complications or other treatments, like infection, obesity, diabetes, chemotherapy, glucocorticoids or ionizing radiation, also slow repair processes. Blood Supply Lower extremity wounds of diabetics often heal poorly or may even require amputation because advanced atherosclerosis in the legs (peripheral vascular disease) and defective angiogenesis compromise blood supply and impede repair. Varicose veins of the legs, due to failure of the venous valves to ensure venous return, can cause edema, formation of thick (fibrin) cuffs around microvessels, ulceration and nonhealing (venous stasis ulcers). Bed/pressure sores (decubitus ulcers) result from prolonged, localized, dependent pressure, which diminishes both arterial and venous blood flow and results in intermittent ischemia. Joint (articular) cartilage is largely avascular and has limited diffusion capacity. Often it cannot mount a vigorous inflammatory response, so that articular cartilage repairs poorly in the face of progressive, age-related wear and tear. Regardless of the underlying mechanism, fibrosis of parenchymal organs such as the heart, lungs, kidney or liver disrupts normal architecture and impedes function. The functional unit (smooth muscle, alveolus, hepatic lobule or renal glomerulus or tubule) is replaced by disordered collagen. Correction requires removing the inciting stimulus by treatment, as in rheumatoid arthritis, to suppress inflammation and so minimize tissue damage. Otherwise, tissue architecture and mechanics are so impaired that regenerative processes cannot reverse the injury. Fibrosis is the pathologic consequence of persistent injury and causes loss of function. Fibrosis is an abnormal process that develops from persistent or impaired normal processes. Often it is the final common result of diverse diseases or injuries, the causes of which cannot be ascertained from the end result. As an example, in scars of former glomeruli damaged following bacterial or immunologic injury to the kidney, the specific cause is no longer identifiable. Scarring, however, is often beneficial; it restores structural (if not necessarily functional) integrity to the injured area. Prevention of fibrosis requires either blocking the stimulus of matrix production or increasing the level of matrix degradation. Matrix deposition in the glomerulus is reduced, protecting the glomerulus from scarring and obliteration. These adhesions are initiated by fibrin deposition when mesothelial lining is disrupted or heals ineffectively. If the fibrin matrix is not dissolved by plasmin within a few days, the provisional matrix is invaded by fibroblasts and eventually transformed into a permanent fibrotic adhesion, with collagen, capillaries and nerves. There is accumulating evidence that resolution of the fibrotic process may not derive merely from reducing activating signals or developing an appropriate level of tensile strength and elasticity. Increases in these proteins are associated with reduced fibrosis, while their absence can lead to exaggerated scarring. Primary healing occurs when the surgeon closely approximates the edges of a wound. The actions of myofibroblasts are minimized owing to the lack of mechanical strain, and regeneration of the epidermis is optimal, since epidermal cells need migrate only a minimal distance. Secondary healing proceeds when a large area of hemorrhage and necrosis cannot be totally corrected surgically. The success and method of healing following a burn wound depends on the depth of the injury. If it is superficial or does not extend beyond the upper dermis, stem cells from sweat glands and hair follicles regenerate the epidermis. If deep dermis is involved, the regenerative elements are destroyed and surgery with epidermal or keratinocyte grafts is necessary to cover or heal the wound site and reduce scarring and severe contractures. In this case, epidermal appendages (follicles, sweat glands) are not regenerated, but cytokines produced by the grafted epidermis may contribute to the improved outcome. Cornea the cornea differs from skin in its stromal organization, vascularity and cellularity. Like skin, corneal stratified squamous epithelium is continually renewed by a stem cell population, at the periphery of the corneal limbus. Epithelial damage that does not involve stroma heals by keratinocyte migration and replication without scarring. Chemical, infectious, surgical or traumatic injury to the cornea results in scarring, owing to the distortion of the precisely arranged collagen fibers, effectively blinding the eye. Parenthetically, the cornea, because of its relative avascularity, was the first organ or anatomic structure to be successfully transplanted. Liver the liver has tremendous regenerative capacity, even though the normal liver almost totally lacks mitoses and virtually all hepatocytes are in cell cycle phase G0. Suffice it to say here that regeneration ceases when the normal ratio of liver to total body weight is reestablished; the molecular switch that regulates this ratio is unknown but may involve the Hippo pathway, a kinase cascade that controls organ size. Acute chemical injury or fulminant viral hepatitis causes widespread necrosis of hepatocytes. An initial open, incised wound (B) with closely apposed wound edges is held together with a suture, leading to minimal tissue gaping or loss. Such a wound requires only minimal cell proliferation and neovascularization to heal. The healing process requires wound contraction (mechanical strain), extensive cell proliferation, matrix accumulation and neovascularization (granulation tissue) to heal. The wound is reepithelialized from the margins, and collagen fibers are deposited throughout the granulation tissue. Granulation tissue is eventually resorbed, leaving a large collagenous scar that is functionally and esthetically imperfect. There is evidence for liver stem cells capable of supporting regeneration at the canal of Hering, within or peripheral to intralobular bile ducts, and among peribiliary hepatocytes (Table 3-8). Hepatocytes form regenerative nodules that lack central veins and expand to obstruct blood vessels and bile flow. Despite adequate numbers of regenerated hepatocytes, architectural disarray impairs liver function and patients eventually suffer hepatic insufficiency. Although the kidney has limited regenerative capacity, removal of one kidney (nephrectomy) is followed by compensatory hypertrophy of the remaining kidney. If renal injury, such as acute kidney injury due to nephrotoxins or ischemia, is not extensive and the extracellular matrix framework, in particular the basement membrane, is not destroyed, tubular epithelium will regenerate. In most renal diseases, however, the matrix is disrupted, leading to incomplete regeneration with scar formation. Fibroblasts proliferate, increased extracellular matrix is deposited and tubular lumina collapse. Some tubules will regenerate and others will become fibrotic, with consequent focal losses of functional nephrons. Medullary Renal Tubules Medullary diseases of the kidney are often associated with extensive necrosis, which involves tubules, interstitium and blood vessels. Although there is some epithelial proliferation, there is no significant regeneration. Mesangial cells are related to smooth muscle cells and seem to have some capacity for regeneration. Following unilateral nephrectomy, glomeruli in the remaining kidney enlarge by both hypertrophy and hyperplasia. The consequence of chronic hepatic injury is the formation of regenerating nodules separated by fibrous bands. A microscopic section shows regenerating nodules (red) surrounded by bands of connective tissue (blue). Podocyte hypertrophy or regeneration appears to be a possibility in some diseases like diabetes or chronic nephropathy, in which scarring and disease are reversed with pancreatic transplants or inhibition of angiotensin-converting enzyme. Cortical Renal Tubules Tubular epithelium normally turns over and cells are shed into the urine. No reserve cell has been identified, and simple division accomplishes replacement. As long as the basement membrane is continuous, surviving tubular cells in the vicinity of a wound flatten, acquire a squamous-like appearance and migrate into the injured area Lung the epithelium lining the respiratory tract can regenerate to some degree, if the underlying extracellular matrix framework is not destroyed. Superficial injuries to tracheal and bronchial epithelia heal by regeneration from adjacent epithelium. Mitoses are frequent, and occasional clusters of epithelial cells project into the lumen. The flattened cells soon become more cuboidal, and differentiated cytoplasmic elements appear. If the basement membrane remains intact following lung damage, there is rapid reepithelialization and return to normal lung architecture. Though small numbers of cardiac stem cells have been described, regeneration of myocardium is rarely observed. By and large cardiomyocytes are terminally differentiated and not capable of renewal. Myocardial damage due to infarction and acute inflammation is repaired by fibrosis and scar formation, increasing chances of arrhythmia or heart failure.

Not only does myocardial scarring result in the loss of contractile elements symptoms neuropathy purchase cheap primaquine line, but also the fibrotic tissue decreases the effectiveness of contraction in the surviving myocardium medications and mothers milk 2016 buy primaquine in united states online. A section through a healed myocardial infarct shows mature fibrosis (*) and disrupted myocardial fibers (arrow) medicine ketoconazole cream purchase primaquine 15 mg without a prescription. The nerve is surrounded by dense collagenous tissue medicine etymology cheap generic primaquine uk, which appears dark blue with this trichrome stain x medications order genuine primaquine on-line. Failure of the venous valves in the lower leg leads to tissue edema medications 500 mg discount generic primaquine canada, the formation of pericapillary fibrin cuffs and the generation of venous stasis ulcers, often on the inner aspect of the lower leg. Severe atherosclerosis or peripheral arterial disease can evoke the formation of arterial ulcers on the outer part of the lower leg or the foot. Diabetic foot ulcers are brought about by a combination of poor arterial and capillary blood supply that may be accompanied by a diabetic peripheral neuropathy that renders the patient insensitive to the progressing ulcer. Diabetes also reduces expression of and cellular responsiveness to growth factors, making it difficult to stimulate the healing process. This form of ulceration, if left unchecked, proceeds to infection of the underlying bone (osteomyelitis) and progressive loss of the extremity. Nonhealing wounds also develop in areas devoid of sensation because of trauma or pressure. Such decubitus ulcers are commonly seen in patients who are immobilized in either beds or wheelchairs. These ulcers can be both broad and deep, with infection penetrating deep into connective tissue. Effects of Scarring In the absence of the ability to form scars, mammalian survival would hardly be possible. Yet scarring in parenchymal organs modifies their complex structure and never improves their function. For example, in the heart, the scar of a myocardial infarction serves to prevent rupture of the heart, but it reduces the amount of contractile tissue. If extensive enough, it may cause congestive heart failure or lead to a ventricular aneurysm (see Chapter 17). Similarly, an aorta that is weakened and scarred by atherosclerosis is prone to dilate as an aneurysm (see Chapter 16). Scarred mitral and aortic valves injured by rheumatic fever are often stenotic, regurgitant or both, leading to congestive heart failure. Persistent inflammation within the pericardium produces fibrous adhesions, which result in constrictive pericarditis and heart failure. Infection in the peritoneum or even surgical exploration may create adhesions and intestinal obstruction. Immunologic injury generates replacement of renal glomeruli by collagenous scars and, if it is extensive, renal failure. Scarring in the skin after burns or surgery produces unsatisfactory cosmetic results and may severely limit mobility. An important goal of therapeutic intervention is to create optimum conditions for "constructive" scarring and prevent pathologic "overshoot" of this process. Excessive Scar Formation in the Skin Excessive deposition of extracellular matrix, mostly excessive collagen, at the wound site results in hypertrophic scars and keloids. Keloids are unsightly, and attempts at surgical repair are always problematic, the outcome likely being a still larger keloid. Keloids are generally restricted to adolescence and early adulthood and to the upper trunk, neck and head, with the exception of the scalp. This aspect reflects the (epigenetic) heterogeneity of fibroblast populations in different locations. Dark-skinned persons are more frequently affected, suggesting a genetic basis for this condition. Unlike normal scars, these keloids do not reduce collagen synthesis if glucocorticoids are administered. By contrast, hypertrophic scars are not associated with race or heredity, but the severity of scarring can decline with age. The scar is confined within the wound margins, and the development of the scar is often associated with unrelieved mechanical stress. Hypertrophic scars often have a reddened appearance indicative of hypervascularity, and they are pruritic, which suggests activation of mast cells producing histamine. Histologically, both types of scars exhibit broad and irregular collagen bundles, with more capillaries and fibroblasts than is normal for a scar of the same age. This situation suggests a "maturation arrest," or block, in the healing process, a hypothesis that is supported by the overexpression of fibronectin. Wound Repair Is Often Suboptimal Abnormalities in any of the three healing processes-repair, contraction and regeneration-result in unsuccessful or prolonged wound healing. Deficient Scar Formation Inadequate formation of granulation tissue or an inability to form a suitable extracellular matrix gives rise to deficient scar formation and its complications. Wound Dehiscence and Incisional Hernias Dehiscence (a wound splitting open) is most frequent after abdominal surgery and can be life-threatening. Increased mechanical stress on an abdominal wound from vomiting, coughing, pathologic obesity or bowel obstruction may cause dehiscence of that wound. Systemic factors predisposing to dehiscence include metabolic deficiency, hypoproteinemia and the general inanition that often accompanies metastatic cancer. Incisional hernias of the abdominal wall are defects caused by weak surgical scars owing to insufficient deposition of extracellular matrix or inadequate cross-linking in the collagen matrix. An exaggeration of these processes is termed contracture and results in severe deformity of a wound and surrounding tissues. A light-skinned black woman developed a keloid as a reaction to having her earlobe pierced. Microscopically, the dermis is markedly thickened by the presence of collagen bundles with random orientation and abundant cells. Contractures are particularly conspicuous when serious burns heal, and they can be severe enough to compromise the movement of joints. In the alimentary tract, a contracture (stricture) can obstruct the passage of food in the esophagus or block the flow of intestinal contents. Several diseases are characterized by contracture and irreversible fibrosis of the superficial fascia, including Dupuytren contracture (palmar contracture), Lederhosen disease (plantar contracture) and Peyronie disease (contracture of the cavernous tissues of the penis). In these diseases, there is no known precipitating injury, even though the basic process is similar to contracture in wound healing. Toxins, chemicals, drugs, viruses, microorganisms, multicellular parasites and transplanted foreign tissues can all elicit immunity. Responses are characterized by their capacity to distinguish self from nonself, discriminate among invaders (specificity) and generate immune memory and amplification loops. The adaptive system also encompasses generative lymphoid organs (bone marrow, thymus) that produce immune cells, secondary lymphoid structures (lymph nodes, spleen, regionally adapted lymphoid tissues) that facilitate the colocalization and concentrated exposure of foreign antigens to immune cells via a system of cell trafficking and recirculation (via the lymphatics and vascular system) orchestrated by soluble chemotactic factors, and location-specific intercellular adhesion molecules. These integrated systems enable the relatively few lymphocytes that express a particular antigen receptor to efficiently interact with individual specific target molecules among the wide variety of incoming antigens. Immune responses are involved in tissue- and organ-specific pathology whether in the context of infections, hypersensitivity reactions, autoimmune diseases or transplantation. Unlike adaptive responses, which develop over a period of several days, cells and soluble mediators of the innate system are either already completely functional or rapidly activated (minutes to hours) upon exposure to invaders. The innate system appeared early in evolution and evolved in concert with microorganisms as the latter developed novel mechanisms to circumvent host defenses. Epithelial barriers and surface defense molecules retard microbial entry into the host. Both resident and recruited phagocytes respond quickly to agents that have penetrated the outer defense, and a redundant set of soluble mediators and circulating phagocytes attack agents that have entered. The innate system distinguishes self from nonself in a manner that is far less fine-tuned than occurs in adaptive immunity. Finally, the innate system is functionally linked to many levels of the adaptive system. As noted, the first levels of innate immunity encompass mechanical epithelial barriers, chemical defenses and resident host defense cells. Whether cutaneous, respiratory, gastrointestinal or urothelial, barrier epithelial cells are held together by tight junctions and exhibit region-specific adaptations. Defensins are 18- to 45-amino-acid cationic peptides, classified into, and families based on the locations of six conserved cysteine residues that form internal disulfide bonds. They are produced by a variety of leukocytes and epithelial cells (skin, respiratory, gastrointestinal) and bind microbes in which they form pore-like surface defects. Cathelicidins are 12to 80-amino-acid peptides made by neutrophils and activated macrophages and barrier cells. The physical and chemical barriers of innate immunity are backed by phagocytes (neutrophils, monocytes, macrophages and antigen-presenting cells [e. These are biochemical moieties expressed by microbes but not by mammalian cells and thus "seen" as nonself (Table 4-1). Various lipopolysaccharides exhibit chemical differences, but all have a similar categorical structure and are found on the surfaces of essentially all gram-negative bacteria. In both cases, signal transduction leads to a variety of proinflammatory and/or antiviral cellular responses. Dectin-1 and dectin-2 bind -glucan and mannose-rich oligosaccharides, which are expressed by the yeast and hyphal forms, respectively, of Candida albicans. Diverse scavenger receptors bind a range of cell surface moieties, mediate uptake of oxidized lipoproteins and carry out microbe phagocytosis. They monitor the cytosolic compartment (Table 4-2) and are linked to activation pathways for inflammation and/or type I interferon generation. Other functional domains allow formation of oligomers and the formation of multiunit signaling complexes. Thymus and bone marrow are "generative" lymphoid organs, while peripheral lymphoid tissues (lymph nodes, spleen and regionally adapted areas) are "secondary. The colonization of peripheral lymphoid tissues by mature B and T lymphocytes and the rapid deployment and recirculation of mature lymphocytes to different, often remote, parts of the immune system is anatomically specific. Lymphocyte homing and recirculation are orchestrated by a series of complementary leukocyte and endothelial surface molecules that include site-specific selectins and addressins (see below). The processes of lymphocyte development and homing/recirculation are important in understanding immune responses, immunodeficiency states, regional host defense and the underpinnings of modern therapeutics. Cells of the immune system express a vast array of surface molecules important in differentiation and cell-to-cell communication. Natural immunoglobulin M (IgM) antibodies and the complement protein complex C1qrs are most familiar. C1qrs spans adjacent Fc domains of surface-bound immunoglobulin molecules, thus initiating the classical complement pathway and functionally linking the adaptive immune system (antibodies) to the complement system. C1qrs and C3 also directly bind microbial structures and thus serve as components of innate immunity. Activated innate system pathways facilitate the acute inflammatory response, which plays an important role in host defense. Acute inflammation is characterized by a stereotyped set of vascular changes including vasodilatation, slowing of blood flow, leakage of fluid into the extravascular space, concentration of leukocytes and an ordered set of leukocyte-endothelial activation, binding and recruitment/ extravasation events (see Chapter 2). The innate immune system also participates in host defense via the antiviral response. Finally, the activated innate immune system also facilitates the adaptive immune response through induction of the "second signal". Prevailing models of hematopoiesis/lymphopoiesis suggest that primitive stem cells give rise to committed progenitors (the hierarchical model) or that stem cells can develop either into progenitor cells or back to stem cells (the cell cycle or continuum model). At 6 weeks, the primary site of hematopoiesis shifts to fetal liver and then to bone marrow. The latter process begins at 2 months and by 6 months has completely shifted to bone marrow. While sequential changes in the primary site of hematopoiesis are well defined, there are periods of overlap. The relative proportions of lymphocytes in the peripheral blood and central and peripheral lymphoid tissues vary. Lymphocytes destined to become T lymphocytes migrate to the thymus where they become either / or / T cells. As thymocytes percolate through the cortex and then medulla, they are positively and negatively selected. Lymphoid progenitor cells destined to become T cells exit the bone marrow and migrate to the thymus. The early thymus is colonized by progenitors that give rise to T cells, macrophages and dendritic cells. Much of the positive selection of thymocytes occurs in the cortex; negative selection tends to occur through exposure of developing thymocytes to corticomedullary dendritic cells. Lineage-specific differentiation and thymic selection of T lymphocytes are fundamental to understanding the immune response and autoimmunity, respectively. B-1 and marginal zone B cells develop from immature B lymphocytes via a different program than do B cells that coexpress IgM and IgD. B cells differentiate in the bone marrow into mature B cells and in some cases further into antibody-secreting plasma cells. Similar to T-lymphocyte development, the microenvironments of fetal liver and bone marrow are critical to B-cell development. In both sites, only B lymphocytes that survive pass through the multiple steps necessary to produce surface immunoglobulin. Conversely, when surface immunoglobulin binds too avidly to self-antigens, developing B cells are negatively selected and eliminated.

White matter abnormalities at a regional and voxel level in focal and generalized epilepsy: a systematic Vollmar C in treatment 1 discount primaquine 15mg amex, et al medications with codeine discount 15mg primaquine visa. Altered microstructural connectivity in juvenile myoclonic epilepsy: the missing link medications you can take while nursing buy primaquine online now. Altered thalamocortical functional connectivity in idiopathic generalized epilepsy medicine cabinet home depot discount primaquine online mastercard. Generalized tonic-clonic seizures: aberrant interhemispheric functional and anatomical connectivity medicine plus cheap primaquine 15mg free shipping. Disrupted brain functional organization in epilepsy revealed by graph theory analysis medicine to stop vomiting generic primaquine 7.5mg with mastercard. Differences in graph theory functional connectivity in left and right temporal lobe epilepsy. The impact of age on prefrontal cortex integrity during spatial working memory retrieval. Evolution of functional connectivity of brain networks and their dynamic relationships. Correlation of widespread preoperative magnetic resonance imaging changes with unsuccessful Bonilha L, et al. Presurgical connectome and postsurgical seizure control in temporal lobe epilepsy. Evaluation of machine learning algorithms for treatment outcome prediction in patients with epilepsy Bonilha L, et al. The brain connectome as a personalized biomarker of seizure outcomes after temporal lobectomy. Connectome reorganization associated with surgical outcome in temporal lobe epilepsy. Preoperative automated fibre quantification predicts postoperative seizure outcome in temporal lobe Gleichgerrcht E, et al. Detecting possible underlying structural abnormalities or causes of epilepsy is one important aspect of such advances, and currently pathologic lesions are identified in about 80% of all refractory focal epilepsies [2]. In addition, novel imaging results are being explored to inform about cortical function or dysfunction in patients with epilepsy, as well as correlates of the ictal-onset zone [3], and to predict postoperative deficits and odds of seizure freedom. The objective of epilepsy surgery in pharmacoresistant focal epilepsies is the complete resection or at least disconnection of the epileptogenic zone while preserving eloquent cortex [2],[4]. This article focuses on the contribution of two novel imaging technologies to optimize surgical results. In addition, white matter architecture and tract morphology can be interrogated allowing to reconstruct major tracts in vivo. Together, both technologies may allow for novel insights in understanding the ictal-onset zone, irritative zone, and functional deficit zone. In a medium without any boundaries, the random translational motion or Brownian motion of water molecules results from the thermal energy carried by these molecules. In the brain, however, such diffusion is restricted by intra- and extracellular boundaries. Various animal models have been used to assess the most important boundaries affecting diffusion in the brain, revealing that myelin is the main barrier to water diffusion [6], [7], [8], [9]. Taking measurements in at least three directions allows for characterization of the mean diffusion properties within a voxel in the image. By applying diffusion gradients in six or more directions, the diffusion tensor, a mathematical construct, can be calculated. This allows assessing not only the amplitude of diffusional motion but also the directionality [13], [14], [15]. The fact that diffusion is not the same in the three main spatial directions, but is asymmetric in the brain and restricted in certain directions, gave rise to the concept of "anisotropy" [13],[16]. Diffusion in different directions, such as parallel (main direction of diffusion) and perpendicular to the main fiber tract orientation, can be studied. Together, these quantitative measures help characterize the integrity of the underlying white matter and facilitate the understanding of the pathophysiologic mechanisms consistent with such diffusion abnormalities. The tensor model has, however, several important limitations: With the crude image resolution of approximately 2 mm3, it cannot resolve distinct fibers that cross within a voxel. Further, water motion within a voxel is assumed to be gaussian, which is not the case. Exploring white matter changes in epilepsy, how they relate to epileptogenicity, and whether they may be a surrogate marker for cognitive difficulties is a matter of ongoing research. Using an in vitro model of wallerian degeneration in frog sciatic nerve, axonal and myelin degeneration causes a decrease in diffusion anisotropy due to reduced parallel and increased perpendicular diffusivity [9]. Myelin has been shown to modulate perpendicular diffusivity [7],[8], although it is not the only factor involved [20]. In humans, reductions in the principal direction and increases in radial diffusivities have been shown in chronically degenerated white matter tracts [21]. An initial decrease in parallel diffusivities evidencing the breakdown of the axons [22],[23] is followed in the chronic stage (2 to 4 months later) by an increase of the radial diffusivities as myelin sheath degeneration is noted. Water molecules become more mobile perpendicular to the axons, resulting in an increase in radial diffusivities. Tractography 1678 Lastly, anisotropy information forms the basis of reconstructing tracts. Anisotropy in white matter results from the organization of tissue as bundles of axons and myelin sheaths run in parallel, and the diffusion of water is freer and quicker in the long axis of the fibers than in the perpendicular direction [20]. The three-dimensional reconstruction of tract trajectories, or tractography, is an extension of such vector fields [24]. However, tractography only came into use in the late 1990s, due to the complexities to develop reliable computer algorithms to reconstruct the tracts. Various acquisitions and postprocessing analysis techniques have been proposed [24], and methods continue to evolve. White matter tractography is generally done in two different ways, either with a method known as "deterministic" tractography or with a "probabilistic" method. Using deterministic methods, seed points are placed, and the tract grows in both directions along the dominant diffusion direction. As the main direction of water diffusion is used for tract reconstruction, crossing fibers will not be represented, and only the main tracts and its main direction will be displayed. The probabilistic methods probe fiber orientation distributions at each voxel and are computationally more intensive but can more reliably reconstruct crossing fibers. There is no doubt that validation is of central importance for the development of tractography; how to validate and against what gold standard is a matter of debate. Subsequently, peri-ictal and postictal changes in diffusivity have been observed in animal models of status epilepticus and in patients both after status epilepticus and after single short seizures. Furthermore, such changes are dynamic, leading initially to restricted diffusion due to cytotoxic edema and, after several days, to normalization or facilitated diffusion [28], [29], [30], [31]. Diffusion imaging may, therefore, provide an opportunity to directly image the areas involved in seizure generation and possibly spread. The first report of diffusion changes in a patient with focal status epilepticus was published in 1997 [32]. Status consisted of clonic jerking of the right leg, which continued for 22 days and was followed by transient paresis. This was explained by a shift of water into cortical neurons at the site of the seizure focus, that is, cytotoxic edema that is associated with restricted diffusion and vasogenic edema with a shift of water in the extracellular space in the underlying white matter [33]. Overall, the presence of dynamic diffusion changes has been documented in the majority of cases, but the correlation between the presumed epileptogenic zone and the diffusion changes is quite variable [34], [35], [36], [37], [38]. Correlations seem closer in patients with longer seizures (or status) and short duration between seizure end and scan [34],[36]. A single case report in man confirms that restricted diffusion is a marker of the ictal-onset zone: An area of restricted diffusion adjacent to the lesion in the right frontal lobe in a patient with repetitive prolonged focal motor seizures corresponded to the region of focal electrocorticographic seizures that was mapped intraoperatively [39]. The results remain rather disappointing, and it has become apparent that dynamic changes affected the diffusivity to a much higher degree than the directionality [35]. Peri-ictal mean diffusivity reductions are seen in about half of the patients investigated, but only a relatively small proportion (20%) colocalized with the presumed ictal-onset zone, even when patients were scanned within 45 minutes after the seizure [38]. Peri-ictal imaging changes occur in cortical areas related to the likely seizure onset but also in remote areas and in addition have been described in deep structures, particularly commonly in the thalamus [40]. In order to minimize delays between seizure and scanning, flumazenil was used to induce seizures in patients assessed for epilepsy surgery [41]. Therefore, it seems possible that diffusion changes after single seizures are more transient and require immediate access to scanning. In addition, in patients without lateralizing differences between the hippocampal formations, both hippocampi often showed increased apparent diffusion coefficient compared to a control population, indicating bilaterality of the disease. Such bilateral abnormalities are present throughout the limbic system, including fornix and cingulum in both adults [48],[49] and children [50]. Such more widespread changes have been confirmed using voxel-based approaches, which compare one individual to a group of normal controls and thus do not have selection bias to a particular region of interest [54]. An increase in mean diffusivity was most often reported for the corpus callosum and temporal lobe [57]. Using a tract-based segment analysis, a centrifugal pattern of mean diffusion increases in major tracts carrying temporal lobe connections was detected; the degree of abnormalities tapered off as the tracts exited the temporal lobe [58]. These changes are not reversible after successful temporal lobectomy, which may suggest structural abnormalities as opposed to functional changes due to seizures [59]. Future studies may elucidate their contribution to clinical or neuropsychological profiles and help quantify the burden of overall network abnormalities on clinical progression and outcomes after epilepsy surgery. Extratemporal Lobe Epilepsy Case numbers of extratemporal epilepsies in the presurgical epilepsy workup are rising, and these cases are often challenging as precise localization of the epileptogenic zone in relation to cortical function is mandatory. In addition, distant anisotropic changes can also be observed, possibly due to wallerian degeneration of tracts or gliosis resulting from chronic seizures. Investigations on the impact of cortical dysplasia on connectivity and adjacent tracts showed decreased tract size and displacement of tracts in larger dysplasias, as well as rarefaction of subcortical connections surrounding cortical dysplasia [62]. Future studies on larger samples are needed to assess how these findings relate to extent of the lesion and epileptogenicity. Studying the Structural Connectome to Predict Seizure Outcome A ter Epilepsy Surgery Over recent years, great attention has been given to understand epilepsy as a disorder affecting networks. Graph analysis has been widely used to describe the properties of such networks in health and disease. Superficial white matter diffusion changes directly underlying the cortex were shown in an ipsilateral temporolimbic distribution and interestingly were unrelated to cortical thinning, but rather related to hippocampal atrophy [71]. In another study, the structural connectome based on pre- and postoperative diffusion imaging was interrogated to establish predictors of failure after temporal lobectomy. The change in connectivity assessed for a given resection could "retrospectively" predict seizure outcome [73]. Preoperative automated fibre quantification predicts postoperative seizure outcome in temporal lobe epilepsy. Excitingly, the structural connectome based on diffusion imaging has also been used to inform neural field models and applied to questions regarding the diversity in spatiotemporal dynamics of seizure initiation, propagation, and termination and their multiple time scales [74]. Future studies are needed to explore how connectome analysis and modeling approaches can be used for surgical planning and prediction of seizure outcomes in individuals and how findings relate to postoperative 1683 functioning. Analysis of water diffusivity changes reveals a pattern of increase in perpendicular diffusivity and not of parallel diffusivity. Such abnormal areas in patients with intractable epilepsy, therefore, probably represent structural disruption, possibly reflecting either an underlying pathology or gliosis due to secondary damage. Intracranial recordings in a patient with cryptogenic focal epilepsy showed seizure onset in the right orbitofrontal region, colocalizing with an area of abnormal diffusivity [75], and postresection pathology revealed gliosis. Few papers have evaluated in detail the concordance between diffusion abnormalities and irritative zone and ictal-onset zone as evaluated using invasive recordings. Overall, the limited data available suggest that diffusion changes correlate better with areas of interictal spiking than the ictal onset. A recent study using a surface-based laminar analysis of gray and white matter showed differential findings regarding diffusivity in the seizure-onset zone [78], compared to healthy controls. In 18 children with nonlesional extratemporal lobe epilepsy, such analysis revealed increased diffusivity in the cortical gray matter, most pronounced in the outer fraction of the gray matter, also involving the white matter underlying the epileptic cortex. The electrographically normal cortex, in contrast, showed decreased diffusivity in inner and middle cortical fractions compared to controls. In conclusion, data remain sparse, and correlating electroclinical abnormalities using invasive recordings with diffusion changes may allow for better insights in the future. Anterior temporal lobectomies can cause a contralateral superior quadrantanopsia in up to 10% of patients by disrupting Meyer loop. The anterior extent of Meyer loop has large interindividual variability and cannot be visualized using conventional imaging [79]. Tractography has been used to demonstrate the optic radiation in normal subjects [80], and its use was subsequently explored for temporal lobectomies [81],[82], and the anteroposterior extent of the damage to Meyer loop as determined postoperatively correlated well with the degree of visual field loss [82]. These data provide evidence that tractography has the potential to inform about risks of epilepsy surgery procedures. Once successfully implemented into neuronavigation systems, this information may also be used intraoperatively to tailor resections [84]. Aside from the technical issues of performing tractography in health and disease, the intraoperative brain shift after craniotomy is another significant impediment. Extratemporal surgeries will also benefit from visualizing crucial connections and tracts such as the pyramidal tract. For this purpose, short epileptiform discharges such as single spikes have been likened to , and represented mathematically as, brief stimuli. In one study [105], the authors identified patterns of signal change in the absence of any overt ictal activity, and these changes were consistent with invasive localization. In another case report, ictal signs identified in relation to scan acquisition times were used to plot T2* signal changes relative to a baseline value voxel by voxel, revealing regions of signal increase and decrease preceding and during the motor seizure [106]. Regions of signal change were identified by comparing blocks of scans immediately preceding the seizures to blocks acquired 3 to 5 minutes before ictal onset. In a series of patients recruited specifically for the purpose of studying preictal and ictal hemodynamics, typical seizures were captured in 20/55 cases [113].

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