Stephanie J. Estes, MD

• Assistant Professor
• Division of Reproductive Endocrinology and Infertility
• Department of Obstetrics and Gynecology
• Penn State Milton S. Hershey Medical Center
• Hershey, Pennsylvania

In myeloproliferative and myelodysplastic disorders insomnia gluten free cookies buy generic provigil 200 mg on line, platelets can function abnormally sleep aid quil discount provigil 100 mg on-line, leading to occlusion and/or hemorrhage sleep aid 3 ingredients discount provigil 200 mg fast delivery. When the platelet count is within the normal range in the setting of a myeloproliferative neoplasm sleep aid 263 buy provigil without prescription, the risk of thrombosis is uncertain insomnia pokemon order provigil 200 mg without a prescription. Epidemiology Both polycythemia vera and essential thrombocytosis occurs more often in women sleep aid overdose 100 mg provigil with visa. They are uncommon before the age of 50 years, but the incidence increases almost exponentially after age 60 years. Patients with polycythemia vera have an increased cardiovascular mortality risk (1. Clinical features Cutaneous lesions occur in ~20% of patients with essential thrombocytosis, including purpura, hematomas, livedo reticularis, erythromelalgia, Raynaud phenomenon, urticaria, cutaneous small vessel vasculitis, leg ulcers, gangrene, and recurrent superficial thrombophlebitis10. It is characterized by intense burning and paroxysmal bright erythema of the distal extremities. Most closely associated with essential thrombocytosis, and less often with polycythemia vera, erythromelalgia can occur with any myeloproliferative or myelodysplastic disorder if the platelet count is sufficiently elevated11,12. Because this form of secondary erythromelalgia is caused by platelet-mediated acral vasodilation, inflammation and microvascular occlusion, patients can also develop discrete areas of purpura or necrosis, often retiform in outline, as a unique manifestation. This version of erythromelalgia typically responds dramatically to aspirin administration, whereas idiopathic and other secondary forms generally show minimal or no benefit from aspirin. Other clinical features of patients with myeloproliferative neoplasms depend on the diagnosis. Chronic myelogenous leukemia patients have elevated neutrophil counts and, frequently, elevated eosinophil or basophil counts. The cause of venous thrombosis is multifactorial and is due in part to microparticle formation from platelets and other blood component membranes as well as depletion of nitric oxide related to hemolytic release of free hemoglobin. Clinical features this acquired clonal hematologic disorder classically presents with intravascular hemolysis, deficient hematopoiesis, and a thrombotic tendency. It may also occur in the setting of hematologic disorders such as aplastic anemia and myelodysplastic syndrome where it is often subclinical because of a limited number of mutated clones17. Depletion of nitric oxide related to chronic hemolysis can lead to smooth muscle dystonia with dysphagia, abdominal pain, and erectile dysfunction17. Pathology Microvascular occlusion of dermal vessels or subcutaneous arterioles is found in biopsy specimens from retiform purpura or necrotic lesions. Differential diagnosis Useful findings which suggest a myeloproliferative neoplasm include anemia or elevated hematocrit, an abnormal white blood cell count or differential, and an abnormal platelet count or platelet morphology. The differential diagnosis of reactive thrombocytosis, especially due to iron deficiency, infection or malignancy, must be considered when assessing the significance of an elevated platelet count. Prompt and lasting relief of burning pain by low-dose aspirin is a characteristic finding in thrombocythemic erythromelalgia. Treatment In the past, treatment was largely supportive, consisting of transfusions, iron and folic acid supplementation, and anticoagulation when needed. Eculizumab, which inhibits the terminal phase of the complement cascade at the C5 stage and can reduce intravascular hemolysis and venous thrombosis, is now routinely prescribed as a lifelong therapy17. Because eculizumab can increase the risk of meningococcemia via C5 inhibition, patients should ideally receive the meningococcal vaccine at least 2 weeks before instituting therapy. These proteins are responsible for protecting blood cells and platelets from complement-mediated injury. The relative lack of protection leads to red cell lysis and activation of platelets. The macular petechiae usually reflect simple hemorrhage, but occasionally may be attributed to platelet plugging. While platelet occlusion has been thought to occur primarily in visceral organs but not the skin, very few papers have addressed the histology of cutaneous lesions. Disease may remain subclinical unless triggered by factors such as drugs, pregnancy, autoimmune connective tissue disease, systemic infections, hematopoietic stem cell transplant, or malignant hypertension. All three groups can cause occlusive syndromes in the skin that are triggered by cold exposure. While cryofibrinogens and cold agglutinins can be detected in many patients in association with a variety of illnesses, they are rarely the cause of cold-related occlusion syndromes27. Clinical syndromes due directly to cryoprecipitation or cryoagglutination are uncommon. Pathogenesis Cryoglobulins change their configuration in the cold and become waterinsoluble, which increases blood viscosity leading to sludging and occlusion. However, many of these proteins transform only at refrigerator temperatures, not at skin temperatures typically seen with cold exposure of acral areas. Simple occlusion with minimal early inflammation and often retiform purpura/necrosis develops when cryoproteins precipitate upon cold exposure, and this is primarily a reflection of monoclonal immunoglobulins (IgG, IgM IgA, light chains), i. Cryofibrinogen precipitate is composed of fibrinogen, fibrin, fibronectin, and occasionally albumin, immunoglobulins, or other plasma proteins26,27. Cold agglutinins bind to red cells in the cold, often triggering complement activation and red cell lysis. Because of their ability to bind multiple red cells, pentameric IgM antibodies much more readily agglutinate red cells. Pathology Microvascular occlusion of visceral terminal arterioles and capillaries is expected, but is rare in the cutaneous microvasculature. Petechial (cutaneous) hemorrhage is most likely due to simple hemorrhage, but documentation is limited. Epidemiology the prevalence of cryofibrinogenemia varies from 0% to 7% in healthy individuals and from 8% to 13% in hospitalized patients26. Cryofibrinogenemia may be essential or secondary to a wide spectrum of disorders including infections, autoimmune diseases, and carcinomas. Other cutaneous findings include acral cyanosis, Raynaud phenomenon, and livedo reticularis. Because of the prevalence of cryofibrinogenemia (see above), clinical correlation is critical in judging the significance of its presence26,27. Cutaneous findings are similar to those induced by cryoglobulins and include both venous and arterial occlusion. Cryofibrinogens are fibrinogens which precipitate in the cold, are consumed in clotting, and are therefore detectable only in plasma samples26. Differential diagnosis the sudden onset of acral disease with cold exposure should suggest this group of disorders. Chilblains (pernio) must also be considered, but lesions are usually slow in onset and seldom progress to significant purpura or necrosis. Introduction/pathogenesis these syndromes share the feature of vessel invasion by organisms (see Chs 74 & 77), and they usually occur in severely immunocompromised patients. All but disseminated strongyloidiasis can have organism growth within the endothelium or vascular wall. The immunocompromised state is usually due to severe neutropenia and/or to the administration of multiple potent immunosuppressive agents, but may be due to chronic disease or malnutrition. Treatment For cryoglobulin occlusion, therapy is primarily directed at minimizing cold exposure and controlling the underlying plasma cell dyscrasia or lymphoproliferative disorder in order to reduce the titer of monoclonal cryoglobulin. Treatment of cryofibrinogenemia includes minimizing cold exposure in addition to systemic corticosteroids plus low-dose aspirin for patients with moderate essential disease; stanozolol represents an alternative maintenance therapy26. Immunosuppressants, plasmapheresis, and/or intravenous fibrinolysis may also be useful. Of note, long-term, up to half of patients with "essential" cryofibrinogenemia may develop a lymphoma26. In cold agglutinin disease, cold avoidance is recommended, but is ineffective in up to ~75% of patients26. Clinical features/pathology Ecthyma gangrenosum is the syndrome of occlusion by organisms (usually bacterial) proliferating in the adventitia of subcutaneous blood vessels. The classic organism is Pseudomonas aeruginosa, but ecthyma gangrenosum-like skin lesions have also been described with other organisms, including other Pseudomonas spp. Ecthyma gangrenosum begins as erythematous, painless macules, but typically progresses to purpuric or escharotic lesions which may be bullous or pustular, and frequently show retiform or branching features. There is extensive bacillary infiltration of the media, adventitia, and perivascular regions of blood vessels, typically with sparing of the lumen and intima. As the bacteria proliferate, gradual compression of the vessel wall narrows and then ultimately occludes the lumen of a subcutaneous arteriole that supplies an overlying cone of skin. Immediate antibiotic therapy is crucial, although the prognosis is poor if the neutropenia persists, antimicrobial agents are ineffective, or the disease process is advanced. Of note, many authors include cutaneous lesions and histopathologic findings in this category which might more properly be classified as septic vasculitis due to bacteremia from Gram-negative rods, when sufficient neutrophils exist to provide a local response. In severely immunocompromised patients, vessel-invasive fungi can result in necrotic lesions secondary to vessel invasion and thrombosis31. The most common opportunistic fungi in this group are Aspergillus, Rhizopus, Mucor, Rhizomucor, and Lichtheimia (formerly Absidia) spp. In diabetic patients, mucormycosis may present in the central face with cutaneous necrosis, presumably originating from a sinus cavity infection. Opportunistic fungi that produce retiform purpura tend to proliferate and invade from within the lumen into the vessel wall and into vascular branches. Thrombus develops around the hyphal elements within the vessels and presumably also on the altered endothelium. Disseminated strongyloidiasis can occur in patients infected with the human nematode Strongyloides stercoralis. Histologically, the purpuric lesions demonstrate extravasated erythrocytes and larvae within capillaries and between collagen bundles. When symptomatic, cold agglutinins lead to hemolysis post cold exposure, which can be severe28. Very rarely, cold exposure in patients with cold agglutinins can induce red cell agglutination, sludging, and vascular occlusion in cold-exposed sites29. Lesions may develop at infusion sites following administration of cold blood products30. Although skin lesions due to vascular occlusion are unusual, in one study 90% of patients with primary cold agglutinin disease had symptoms, ranging from moderate acrocyanosis to severe Raynaud phenomenon precipitated by even slight cold exposure28. The associated thrombotic lesions are distinguished from erythema nodosum leprosum (an immune complex-mediated neutrophilic vasculitis with variable involvement of the panniculus) by an absence of fever, leukocytosis, and tenderness; a poor response to thalidomide; and restriction to patients with diffuse non-nodular lepromatous leprosy. Acute lesions, described as having arcuate borders, seem to correspond to retiform purpura34. Extensive blanchable livedo reticularis of the extremities may also be present36, and concomitant antiphospholipid antibody syndrome has been reported34. Histologically, some cases have endothelial swelling and thrombus formation within dermal and some subcutaneous vessels whereas others show features of leukocytoclastic vasculitis in the superficial and mid-dermis with overlying epidermal necrosis. Acid-fast stains show aggregates of bacilli within the endothelial cells and dermal macrophages34. Initially, the eruption is not hemorrhagic, but by day 5, petechiae usually develop within lesions due to vascular hyperpermeability37. Early petechial lesions may be comma-shaped or linear, reflecting hemorrhage following the microvasculature. Other spotted fevers that often have a hemorrhagic component are Brazilian spotted fever, boutonneuse fever, and Japanese spotted fever38. The first is arterial or coronary catheterization, which may disrupt a plaque, leading to emboli within hours to days of catheterization. The second is prolonged anticoagulation, which slowly lyses the clot which may be reinforcing a friable plaque, leaving exposed areas of the plaque subject to the shear stress of arterial flow41. The anticoagulant-induced syndrome of cholesterol embolus typically occurs after 1 to 2 months of therapy. This "warfarin blue toe syndrome" is not restricted to warfarin anticoagulation and should not be confused with warfarin necrosis. The third trigger for cholesterol embolus is acute thrombolytic therapy given for myocardial infarction or stroke. Clinical features Clinical findings include fever, weight loss, myalgias, altered mental status, and a sudden onset of arterial hypertension. Transient ischemic attacks, strokes, renal failure, gastrointestinal ulcerations, and hemorrhagic pancreatitis may also occur. Patients with multisystem involvement can have significant morbidity, and occasionally may die from embolic complications. Because retiform purpura represents a purpuric accentuation of the livedo reticularis pattern, it may be included as livedo reticularis in some reports. Differential diagnosis the differential diagnosis includes other causes of non-inflammatory purpura due to cutaneous microvascular occlusion (see Table 23. Treatment Treatment is directed at mitigating the immunocompromised state where possible, and by selecting appropriate antimicrobial therapy based on identification of the invading organism. Areas of retiform purpura usually provide diagnostic findings in punch biopsy specimens and should be the first choice for biopsy when present.

The degree of difficulty depends upon the ability to substitute an unrelated but equally effective drug insomniaxnet purchase cheapest provigil. Although eosinophils were observed exclusively in the lichenoid drug eruptions sleep aid belsomra buy discount provigil online, they were found in only 2 of the 15 cases sleep aid taking cvs by storm cheap 200mg provigil with visa. Therefore sleep aid for pregnancy buy discount provigil 200 mg on-line, it would be ill-advised to make the diagnosis of lichenoid drug eruption solely on the basis of histologic criteria insomnia hours order 200mg provigil visa. In an openlabel sleep aid for diabetics order generic provigil on-line, randomized, controlled trial, topical calcipotriene (calcipotriol) and betamethasone valerate had equal efficacy. Rebound and relapses may occur, but long-term maintenance therapy with systemic corticosteroids should be avoided. One study demonstrated that the median time to clearing was 18 weeks in the corticosteroid-treated group and 29 weeks in the placebo group35. A therapeutic regimen consisting of acitretin 30 mg/day for 8 weeks resulted in significant improvement or remission in 64% of those in the treatment group, compared with 13% in the placebo group36. In particular, oral erosive lesions have been reported to respond favorably to this drug. More recently, in a retrospective study, hydroxychloroquine (200 mg twice daily) was shown to improve both lichen planopilaris and frontal fibrosing alopecia38; the latter is also treated with oral 5- reductase inhibitors. More recently, a randomized, double-blind, placebo-controlled trial utilizing a maximum of 2. A complete response was achieved in 10 of 11 patients within 1 month and the medication was well tolerated without adverse effects. Complete responses were observed with doses of cyclosporine ranging from 1 to 6 mg/ kg/day. The majority of patients did experience a relapse during follow-up periods of several months, but a rebound in disease activity can occur upon discontinuation of cyclosporine. Similar results were described in lichen planopilaris; alleviation of symptoms, resolution of clinical activity, and halting the progression of hair loss was achieved within 3 to 5 months42. It may be preferable to other immunosuppressive drugs such as cyclosporine because of its safer side-effect profile. However, resolution was observed in a few patients despite continued use of the drug. For mild disease, symptomatic treatment includes topical corticosteroids and oral antihistamines for reducing pruritus. Most patients experienced symptomatic improvement in less than 1 month following twice-daily application. However, in one study, the median relapse time was 5 weeks (range, 2 to 20 weeks), and patients often require intermittent therapy as maintenance to prevent subsequent flares34. To date, serious adverse effects from long-term use (>1 year) have not been reported. The eruption consists of a continuous or interrupted band composed of discrete or clustered pink, skin-colored or tan (hypopigmented) papules that are flat-topped, smooth or scaly, and range in size from 2 to 4 mm. There are reports of the eruption spreading distally from the trunk down an extremity, as well as observations of proximal extension along an extremity50. Although lichen striatus does not usually recur, relapses may occasionally occur, either in the same site or on the same side of the body48. The eruption usually appears suddenly, develops fully over days to weeks, and after several months to a year or more, undergoes spontaneous resolution. Postinflammatory hypopigmentation may be seen, particularly in those with more darkly pigmented skin. In the latter individuals, the eruption is often first noticed as linear hypopigmentation. When lesions involve the nail apparatus, onycholysis, splitting, fraying and total nail loss may result. The diagnosis is usually made clinically based upon the appearance of the primary lesions and the distinctive developmental pattern. Its distribution along the lines of Blaschko plus the age of the patient usually narrows the differential diagnosis rather quickly. Pathology the histologic features of lichen striatus are variable and depend upon the age of the lesion at the time the biopsy is performed. Even though the lichenoid inflammation that may be present around hair follicles is indistinguishable from that seen in lichen planopilaris, sweat gland and hair follicle involvement can still be a helpful diagnostic feature of lichen striatus49. Exocytosis, parakeratosis, dyskeratosis, and focal or diffuse vacuolar degeneration can be seen in the epidermis overlying the lichenoid infiltrate. Depending upon the age of the lesions, Langerhans cells were either decreased (earlier lesions) or increased (later phase due to an influx of precursor cells). History In 1898, Balzer and Mercier first described a peculiar linear papular eruption that they termed "lichenoid trophoneurosis". Ever since the condition was first described, the pathogenesis of its linearity has been the subject of debate. Epidemiology Lichen striatus is seen primarily in children between the ages of 4 months and 15 years, although the disorder occasionally occurs in adults. The median age of onset is 2 to 3 years and the vast majority of cases occur in preschool-age children48. Pathogenesis Although the distribution of lichen striatus along the lines of Blaschko points to somatic mosaicism (see Ch. The latter occurs, 201 Lichen Planus and Lichenoid Dermatoses patients after 12 weeks45. However, to date, a viral association has not been proven via serologic testing or cultures. Concurrent familial occurrence of lichen striatus in a mother and child has been touted as evidence for a viral trigger. In theory, during early fetal development, aberrant clone(s) of epidermal cells produced by somatic mutation migrate out along the lines of Blaschko. Lichen striatus may represent a manifestation of an atopic diathesis with the abnormal immune responses usually associated with atopy being a predisposing factor. The timing and relative infrequency of lichen striatus suggests that an infectious agent acts as a trigger in genetically predisposed individuals. Lastly, there are scattered reports of lichen striatus occurring at sites of injury. B Three linear streaks on the lower extremity composed of multiple pink papules, some of which are flat-topped with scale. In addition to hyperkeratosis with focal parakeratosis, both a lichenoid and a perivascular and periadnexal lymphocytic infiltrate extending into the deeper dermis is seen. The papules have a distinctive histology with a dense, wellcircumscribed, lymphohistiocytic infiltrate closely apposed to the epidermis. It is generally accepted that lichen nitidus has no relationship to any systemic illness. Only a few authors believe that it may be a cutaneous manifestation of Crohn disease51. Treatment Treatment of lichen striatus is usually not needed because it is selflimited, usually resolving within 1 to 2 years. Topical corticosteroids under occlusion can be used to hasten spontaneous resolution. In scattered case reports, topical calcineurin inhibitors have also been reported to be effective, including for the nail dystrophy. Obviously, with any purported therapy, the natural history of lichen striatus must be kept in mind. History In 1901, Pinkus first described a peculiar papular eruption he termed "lichen nitidus" and suggested that it was a distinct entity histologically. Epidemiology Reliable epidemiologic data are difficult to accumulate because of the relative rarity of lichen nitidus. Other authors have observed that lichen nitidus is more prevalent among children or young adults, and a female predominance has been described in the generalized variant. In darkly pigmented individuals, the papules tend to be hypopigmented, but sometimes they are hyperpigmented; marked hyperpigmentation has rarely been reported. The lesions are usually distributed on the flexor aspects of the upper extremities as well as the chest, abdomen, genitalia, and dorsal aspects of the hands. Less commonly, the face, neck, lower extremities, palms, soles, and mucous membranes are involved. Nail involvement is observed in up to 10% of patients (primarily adults) and the changes include pitting, rippling, longitudinal ridging, terminal splitting, and increased longitudinal linear striations. Lichen nitidus was initially thought to represent a tuberculous lesion or tuberculid because of its histologic features. However, no causative infectious agents have ever been demonstrated, even by repeated inoculations of tissue into animals. The possibility exists that the two conditions represent different responses to a similar triggering factor. In such cases, the lack of variation in size, the absence of a violaceous color or Wickham striae, and no deposits of immunoglobulin in dermal papillae would suggest the diagnosis of lichen nitidus. Periappendageal inflammation is more typical of lichen striatus, but patients with the latter have been described where both periappendageal inflammation and superficial features of lichen nitidus were present, suggesting a morphologic spectrum. The possibility of the spinous follicular variant of lichen nitidus should be kept in mind when a patient presents with spiny keratotic papules plus typical histologic features of lichen nitidus. Lastly, lichen nitidus-like lesions can be seen in a photodistribution in summertime actinic lichenoid eruption, also referred to as actinic lichen nitidus (see below). Note the typical "ball and claw" configuration for the infiltrate and epidermis, respectively. Vesicular and hemorrhagic lesions are found in some patients, and they are often admixed with the more typical papules. Several other clinical variants have been described, including palmoplantar, linear, and follicular spines. According to one study, the duration in two-thirds of the patients was 1 year or less and the longest duration was 8 years52. Since the majority of patients experience spontaneous clearing within one or several years, treatment is primarily symptomatic. When significant pruritus is present, topical corticosteroids and oral antihistamines may be helpful. Anecdotally, topical calcineurin inhibitors have been reported as an effective therapy in children with lichen nitidus. In most lesions, the infiltrate is confined to the width of two to three dermal papillae. The overlying epidermis is usually atrophic and frequently exhibits a parakeratotic "cap" centrally. Absence or thinning of the overlying granular layer is seen and vacuolar degeneration of the basal layer is consistently observed, often accompanied by incontinence of melanin pigment. The lichenoid infiltrate closely apposes the epidermis and is thought to play a role in inducing reactive epidermal hyperplasia of the surrounding rete ridges. The predominant cell types in the dermal infiltrate are lymphocytes and epithelioid cells, and in some cases, epithelioid cells predominate. These authors suggested calling the disorder "erythema chronicum figuratum melanodermicum" because they considered it to be a new variant of erythema perstans. Sulzberger then proposed a less cumbersome and more descriptive term, "erythema dyschromicum perstans". In general, no gender predilection exists, although a few authors reported that women were more commonly affected than men. Although the lesions of pityriasis rosea are often oval, the resultant hyperpigmentation is predominantly epidermal, not dermal. Less common entities in the differential diagnosis are macular urticaria pigmentosa, pinta and leprosy. In one patient, characteristic lesions occurred suddenly after a radiographic study using orally administered contrast medium (barium sulfate). However, to date, a rigorous epidemiologic study examining potential triggers has not been performed. On the basis of a case series, clofazimine was reported as a successful treatment. Spontaneous remission can occur, but unfortunately many patients have the disease for years. He used the term "lichen ruber acuminatus verrucosus et reticularis" to describe a patient with a linear, warty lichenoid eruption. Over time, keratosis lichenoides chronica has become the most consistently used name for this disorder.

In retrospective studies insomnia late pregnancy cheap 100mg provigil with amex, there was also a high rate of complete responses in symptoms in patients with inducible urticarias65 insomnia hypnosis purchase discount provigil online. For its urticaria indication sleep aid for dogs buy provigil canada, the adverse event profile for omalizumab appears very favorable sleep aid noise buy generic provigil 200 mg line. A very heterogeneous group of cutaneous disorders manifests as erythemas insomnia problems best purchase for provigil, ranging from palmar erythema of pregnancy to a diffuse scarlatiniform eruption sleep aid strips discount provigil 200mg with visa. In figurate erythemas, the lesions have an annular, arciform, or polycyclic appearance. While a wide range of cutaneous diseases can have an annular configuration (Table 19. In one series, an associated disease was identified in only one-third of patients7a. One explanation for this is that once the other three major figurate erythemas (with specific etiologies; see below) and the disorders listed in Table 19. Unfortunately, this has led to some confusion, but until a specific "trigger" can be identified for each individual patient, this situation will persist. An individual lesion can enlarge to greater than 6 cm in diameter over a period of 1 to 2 weeks. If expansion of the annular plaque is not uniform, incomplete arcs appear, as do polycyclic lesions, or simply festooned bands. In the superficial form, the lesions are minimally elevated, and there is desquamation at the inner margin, i. There may be associated pruritus, especially in lesions that histologically show spongiosis. In a figurate erythema, the lesions can assume an annular, arciform, or polycyclic configuration. However, oftentimes the underlying etiology of these reactive processes remains unknown or uncertain, especially in the case of erythema annulare centrifugum, also referred to as a gyrate erythema. Histologic examination, in addition to microbiologic and serologic evaluation, is often required to exclude specific etiologies prior to labeling the disorder as idiopathic. As lesions resolve, there is no residual scarring, but postinflammatory hyperpigmentation can be seen and, on occasion, purpura. Individual lesions can persist for weeks to months, but associated systemic manifestations are uncommon. While new lesions can appear just as older ones resolve, there may be prolonged intervals of time between flares. The advancing edge, which is slightly raised, may also show edema in the papillary dermis. Even in the absence of an identifiable cause, some authors have advocated the empiric use of antibiotics or antifungal agents. Although systemic corticosteroids can induce a clinical remission, recurrences are common when the medication is discontinued. Topical corticosteroids applied to the advancing border of the lesions may be of benefit. Two years later, Perry reported that rapid migration of the lesions was a characteristic finding13. It is estimated that in high-income countries, the incidence is 5 per 100 000, whereas in lowincome countries, it ranges from 100 to 1000 per 100 000. Pathogenesis the mechanisms that underlie the appearance of cutaneous lesions of erythema marginatum are unknown. Presumably, there is an abnormal humoral and cellular immune response to one or more antigens associated with group A -hemolytic streptococci. Antigenic mimicry may play a role in that epitopes that cross-react with group A streptococcal antigens have been identified in human myosin, actin, tropomyosin, keratin, laminin, N-acetylglucosamine, and vimentin17. Streptococcus pyogenes exotoxin B [SpeB], immunoglobulin G degrading enzyme of Str. Cutaneous manifestations include erythema marginatum and subcutaneous nodules, but they are seen in a minority of patients. In 2002, a group of international experts reaffirmed the validity of the major and minor Jones criteria and recommended no further revisions11. The lesions of erythema marginatum begin as erythematous macules that spread peripherally and become patches or plaques with no scale. The most common locations for erythema marginatum are the trunk, axillae and proximal extremities, with sparing of the face. New lesions usually last from a few hours to a few days and are often most noticeable during the afternoon. Of note, children less than 5 years of age appear to have a higher incidence of erythema marginatum as well as carditis and arthritis20. These lesions appear primarily over bony prominences, especially the wrists, elbows, knees and ankles, in patients with longstanding disease. Similar nodules can be seen in patients with polyarticular juvenile idiopathic arthritis (see Ch. In addition to the major and minor criteria (see Introduction), patients may also have malaise, chest or abdominal pain, epistaxis, tachycardia and anemia, as well as a nonspecific urticarial eruption18. History the first report of an annular erythema developing after a tick bite was by Afzelius in 1909 and he coined the term "erythema migrans". In the 1980s, Burgdorfer isolated a new spirochete in lesions of erythema migrans and the organism was subsequently named B. Pathology An interstitial and perivascular infiltrate composed predominantly of neutrophils without vasculitis is observed. Occasionally, eosinophils are seen and in later stages, there can be extravasation of erythrocytes. Direct immunofluorescence microscopy for immunoglobulin and complement deposits is negative. These histologic findings are not unique to erythema marginatum, and overlapping features with the neutrophilic variant of annular erythema of infancy (neutrophilic figurate erythema of infancy) may be observed. The competent hosts that serve as a reservoir for Borrelia include mice, chipmunks and birds, with deer playing a role in sustaining the life cycle27. Differential Diagnosis the differential diagnosis includes primarily annular urticaria. There is also an annular erythema with an appearance similar to erythema marginatum that precedes or accompanies episodes of hereditary angioedema22 and is seen only occasionally in patients with cat scratch disease or psittacosis23,24. In a patient receiving sorafenib, figurate lesions with associated scalecrust and hemorrhage developed and the name "erythema marginatum hemorrhagicum" was proposed, but clinically these lesions can easily be distinguished from erythema marginatum25. In addition, Salp15 inhibits adaptive immune responses against both Borrelia and tick antigens30. Once the Borrelia organisms have entered the body, spirochetal lipoproteins trigger an innate immune response, with cytokines being produced by macrophages31. In addition, a Th1 response is triggered and B-cell responses facilitate the synthesis of antibodies against different antigens of B. Spirochetemia is present in approximately 45% of patients at the time of their presentation with erythema migrans32, and these organisms can disseminate widely due to their ability to resist elimination by macrophages, adhere to brain and Treatment 326 There is no specific therapy for this dermatosis. The persistence of the spirochete in the skin after the tick bite may be due to an absence of the production of interferon- and an ineffective immune response31. While routine histology is often not specific, many specimens will show superficial and deep lymphoid infiltrates admixed with a few eosinophils and plasma cells. The eventual diameter is usually at least 5 cm, and the center may become darker red to violaceous in color, crusted, or even vesicular. Lesions of primary erythema migrans favor the trunk, axilla, groin and popliteal fossa. In Europe, this initial clinical phase is usually less severe, and the lesions of erythema migrans tend to last longer. If untreated, approximately 60% will go on to have monoarticular or oligoarticular arthritis (usually the knee) within weeks to months after the initial infection; approximately 10%, a neurologic manifestation (most commonly facial nerve palsy); and approximately 5%, a cardiac complication (usually varying degrees of atrioventricular block)32. For a discussion of borrelial lymphocytoma and acrodermatitis chronica atrophicans, see Chapter 74. Depending upon the geographic region, Ixodes ticks can be co-infected with the following microbes (in addition to B. The latter includes the isolation of Borrelia from tissues (including lesions of erythema migrans) or fluids, or more commonly, the detection of anti-Borrelia antibodies by the two-test approach of a sensitive enzyme immunoassay. During convalescence following antibiotic therapy, positive test results are still only observed in approximately half of those who did not have dissemination, presumably reflecting eradication of the spirochetes27. Erythema migrans must be distinguished from exaggerated local arthropod reactions (including to the tick bite), erysipelas, cellulitis, allergic contact dermatitis and non-pigmented fixed drug eruption, and less often, other entities outlined in Table 19. In theory, the cutaneous lesions arise as a result of an immune reaction against tumor-associated antigens with the subsequent recognition of similar antigens in the skin. In patients from endemic areas (>20% of ticks infected) in whom the tick, identified as a nymphal or adult I. The responsible antigen(s) is not known, but a curious finding is an accumulation of active Langerhans cells in the upper layers of the epidermis46. Pathology the histopathologic findings are nonspecific and include hyperkeratosis, focal parakeratosis, moderate patchy spongiosis and a mild, perivascular lymphohistiocytic infiltrate. Clinical Features Patients usually have multiple, annular or polycyclic, erythematous lesions that develop scale at their edges and advance at a rapid rate (up to 1 cm per day)47. The cutaneous lesions usually develop from 1 year prior to 1 year after the diagnosis of the neoplasm. There may be a return of cutaneous lesions in association with the development of metastases or local recurrences of the malignancy. By daily observation, von Hebra recognized that some of the original papules evolved into lesions with concentric zones of color change, which he termed "target" lesions. However, von Hebra described neither a prodrome nor the presence of mucosal lesions. He recognized that the condition could be recurrent and mentioned a "typus annuus" which recurred every spring. That said, because these are biologic processes, there can be patients where the distinction proves challenging. Both are characterized by the same type of elementary lesions (targets), but are distinguished by the presence or absence of mucosal involvement and systemic symptoms (Table 20. May be a pattern of cutaneous lesions in the disease rather than a precipitating factor. An "autoimmune" response is then thought to result from the recruitment of T cells that respond to autoantigens released by lysed/apoptotic viral antigen-containing cells. In particular, a severe acro-mucosal presentation with mucositis, conjunctivitis, and targetoid or bullous skin eruptions can be seen in patients with M. However, this association could also be explained by autoimmune molecular mimicry, as in M. These clinical criteria are as follows: (1) the type of elementary skin lesion; (2) the distribution of skin lesions (topography); (3) the presence or absence of overt mucosal lesions; and (4) the presence or absence of systemic symptoms (see Table 20. Given the possibility that only a few typical target lesions may be present, a complete skin examination is essential. The latter measures <3 cm in diameter, has a regular round shape and a well-defined border, and consists of at least three distinct zones. While early target lesions often have a central dusky zone and a red outer zone ("iris" lesion), they can evolve to three zones of color change. Each concentric ring within the target lesion most likely represents one of a sequence of events of the same ongoing pathologic process. This may explain why some patients have only a limited number of fully developed, typical targets amidst a number of target lesions that are Distribution of skin lesions (topography) Although there is considerable variation from individual to individual, numerous lesions are usually present9. Erosions of the anogenital mucosa are often large and polycyclic with a moist base. Arthralgias with joint swelling have occasionally been described, as has pulmonary involvement resembling atypical pneumonia. These individuals may have five or six episodes per year or even almost continuous disease in which one attack has not completely resolved before another occurs. The incidence of secondary bacterial infections also increases in the setting of prolonged corticosteroid use9,17. As the process evolves, mild spongiosis and focal vacuolar degeneration of basal keratinocytes are observed. Superficial dermal edema and a perivascular infiltrate of lymphocytes with exocytosis into the epidermis are also seen. New lesions appear daily May be associated with swelling of face, hands or feet (angioedema) *Can be documented by circling individual lesions with ink then observing over time.

These lesions result from faulty closure of the cephalic portion of the neural tube during development insomniax sleep pants order provigil visa, and they are much less common than their caudal counterparts insomnia 46 buy provigil 200mg low price. Occasionally insomnia used in a sentence discount 100 mg provigil with amex, small frontal lesions are misdiagnosed as deep infantile hemangiomas sleep aid light bulb order provigil without a prescription, vascular malformations insomnia 6 hours sleep order generic provigil on-line, hypertelorism insomnia wiki purchase 200 mg provigil with mastercard, or nasal polyps3,4; of note, the latter are almost never seen in children younger than 3 years of age. Cephaloceles typically appear as a soft, compressible, pulsatile mass with a bluish color. They may be covered with either normal skin or a thin, glistening epithelial membrane. The size of cephaloceles varies tremendously, from 1 cm nodules to lesions containing nearly half of the brain, and the size does not necessarily correlate with the extent of the underlying bony defect. Patients with intranasal cephaloceles often present with a broadened nasal bridge but no palpable mass, whereas lesions on the scalp may have an overlying capillary malformation and/ or a surrounding hair collar (see above, Midline lesions of the scalp)8. They are a separate entity from benign cystic teratomas, neoplasms that are also referred to as dermoids. Although dermoid cysts are congenital defects and may be recognized at birth, these lesions often escape notice until they become enlarged, inflamed, or infected. This typically occurs by early childhood, but diagnosis may be delayed until as late as the sixth decade of life. Dermoid cysts on the nose or midline scalp have a much higher likelihood of intracranial extension than those in a periocular location. Nasal lesions, which account for <10% of cervicofacial dermoid cysts, occur anywhere from the glabella to the tip of the nose (see above) and can result in a widened nasal bridge. The presence of a sinus ostium, which may be heralded by protruding hairs or a sebaceous discharge, increases the risk of intracranial involvement of a nasal dermoid cyst to almost 50%, versus ~25% overall3. A sinus ostium without an underlying subcutaneous mass may also connect with an intracranial dermoid cyst. These lesions favor the midline occipital area but can occur elsewhere on the face and scalp; recurrent drainage and inflammation may represent signs of deeper extension12. Intranasal gliomas may manifest as a widened nasal bridge or a polypoid nodule within the nasal cavity, sometimes protruding from a nostril. They occasionally cause nasal obstruction resulting in respiratory distress, and lesions involving the nasopharynx may be associated with a cleft palate16. Histologically, nasal gliomas demonstrate well-circumscribed nodules composed mostly of astrocytes, admixed with other glial cells and loosely textured intercellular glial substance interwoven with fibrous tissue. Neurons may or may not be present focally, and there are often prominent dilated blood vessels in the lesion and overlying skin. After imaging studies to determine whether an intracranial extension is present, nasal gliomas should be surgically excised. Nasal cephaloceles may develop in conjunction with facial clefts and other midline defects, while encephaloceles are often associated with neurologic abnormalities. On histologic examination, encephaloceles show mature neuroglial tissue embedded in varying amounts of fibrous stroma. When a patient is suspected of having a cephalocele, imaging studies and subsequent neurosurgical repair should be performed. Of note, the nasal glioma, a developmental anomaly with no malignant potential, is an entirely separate entity from the similarly named glioma, a malignant brain tumor. Nasal gliomas are present at birth, accounting for ~5% of congenital nasal midline masses3,15, and they typically enlarge in proportion to the growth of the child. However, in intermediate forms known as atretic encephaloceles and meningoceles, a fibrotic stalk that extends intracranially with some degree of luminal ablation remains8. Heterotopic brain tissue may be located in the scalp, orbit, lip and oropharynx, as well as in the nasal area (nasal glioma); rudimentary meningoceles are usually found on the scalp or overlying the spine10,17. Occasionally, rudimentary meningoceles have a bullous appearance and are clinically indistinguishable from membranous aplasia cutis17. Lesions are often located in the midline occipital or parietal scalp, where they can manifest with alopecia of the overlying skin and/or a surrounding hair collar. Histologic features of heterotopic brain tissue are as described for nasal glioma. Although classic findings such as cystic cavities lined by meningothelial cells are present in some cases of rudimentary meningocele, the histologic features are often subtle, with meningeal elements simulating the appearance of vascular or loose connective tissue. Because the presence or absence of an intracranial connection cannot be reliably determined by clinical examination, imaging studies should be performed prior to surgical excision. Approximately 100 cases have been reported to date in the English-language literature, with a female-to-male ratio of 2: 118. Midline cervical clefts may be isolated or found in association with other defects, including other midline clefts. Patients present at birth with a vertically oriented, linear cleft on the midline neck at any point between the inferior edge of the mandible and the sternum. The lesion is covered with atrophic skin, which is often weeping in the neonatal period. Additional features may include a blind mucosal sinus tract inferiorly and a skin protuberance superiorly. A subcutaneous fibrous cord deep to the latter may extend upward to the chin, resulting in progressive cervical contracture and/or webbing of the neck with extension (pterygium colli medianum). Histologically, midline cervical clefts consist of parakeratotic stratified squamous epithelium without normal adnexal structures. The subcutis often contains dense connective tissue, and fibrous cords may include bundles of skeletal muscle. Following ultrasonography to evaluate for an associated thyroglossal duct cyst (see Ch. Vertical primary closure is avoided to reduce the risk of cicatricial contracture. Midline Lesions of the Spine Spinal dysraphism refers to abnormal fusion of dorsal midline structures during embryologic development21. This term encompasses a wide variety of congenital spinal defects, ranging from myelomeningoceles (protrusion of the spinal cord and meninges with no overlying skin) and other overt anomalies in which neural tissue is exposed (open spinal dysraphism) to less obvious, skin-covered malformations (closed or "occult" spinal dysraphism). The latter include diastematomyelia (a split in the spinal cord), meningoceles, intraspinal lipomas, lipomyelomeningoceles (protrusion of the cord extraspinally into an attached lipoma), tight or fatty filum terminale, dermoid cysts, dermal sinuses, and isolated posterior spina bifida22. The degree of neurologic impairment associated with closed spinal dysraphism is variable. Any lesion that produces traction and/or pressure can cause progressive damage to the spinal cord, resulting in neurologic symptoms. Occasionally, an acute onset of symptoms is precipitated by childbirth, heavy lifting, or spinal trauma. Early diagnosis allows timely neurosurgical intervention that can halt progression and prevent potentially irreversible neurologic damage. Because the skin and the nervous system share an ectodermal origin, concurrent anomalies of these tissues are common. Midline cutaneous lesions thus serve as a valuable marker for spinal dysraphism, and in the majority of patients, they are the finding that leads to the diagnosis. Approximately 80% of individuals with closed spinal dysraphism have paraspinal skin abnormalities, and the majority of them have more than one type of skin lesion23,24. Most of the cutaneous lesions associated with spinal dysraphism are located in the lumbosacral area, reflecting the relative rarity of neural tube defects in the cervicothoracic region28. Hypertrichosis is the cutaneous marker of spinal dysraphism most often evident at birth. Overall, however, lumbosacral lipomas are the skin lesions most commonly associated with spinal dysraphism23,24. An intraspinal lipoma or lipomyelomeningocele often represents a portion of a larger subcutaneous lipoma, typically presenting as a soft mass located above the gluteal cleft and extending asymmetrically into one buttock. A curved gluteal cleft is suggestive of such a lesion, but clinical findings may be subtle initially, becoming more noticeable with time. Infantile hemangiomas and vascular malformations located on or near the dorsal midline may also be signs of dysraphism. These lesions most frequently involve the superior sternum, but inferior clefts and a complete bifid sternum can also occur. For sternal clefts associated with a substantial bony defect, surgical repair can be performed to protect the mediastinal organs and improve respiration as well as cosmesis. A supraumbilical raphe is a rare midline abdominal defect that presents as a firm, scar-like, linear protuberance extending cephalad from the umbilicus. Vascular malformations are most often an indicator of dysraphism when they occur together with other midline cutaneous lesions, most notably lipomas. The cutaneous component may mimic a capillary malformation or angiokeratomas, and neurologic manifestations of cord compression can develop (see Ch. Lumbosacral capillary stains often have rhomboidal or triangular shapes ("butterfly-like") and are frequently associated with additional nevus simplex lesions of the head, neck, and (occasionally) upper back. Many authors feel that regardless of spinal level, capillary stains alone are rarely a sign of dysraphism26,28. A prospective study of 3623 neonates found that 1 of the 25 individuals noted to have a sacral capillary stain in the absence of other lumbosacral skin lesions had a spinal abnormality revealed by imaging studies33. Cutaneous lesions of the spinal axis that should alert the clinician to the possibility of dysraphism are summarized in Table 64. The presence of two or more skin lesions is a particularly strong sign; in another series, 61% (11/18) of such patients had spinal dysraphism, compared to 8% (3/36) of those with only one skin lesion34. High-risk cutaneous stigmata overlying the spine represent an indication for radiologic evaluation, and superficial removal for cosmetic reasons is contraindicated until an underlying abnormality is excluded. Similarly, in a second series, ultrasound was 50% sensitive and 78% specific for detecting spinal anomalies (tethered cord, spinal lipoma > intraspinal hemangioma) in infants with lumbosacral infantile hemangiomas32. However, in infants with dysraphism associated with an anorectal malformation, spinal ultrasound had a sensitivity as low as 15%36. When infants are found to have anomalies with the potential to cause traction and/or pressure on the spinal cord, close follow-up is required and neurosurgical intervention may be recommended. It may occur as an isolated defect, in association with other developmental anomalies, or as a feature of a variety of disorders (Tables 64. The many possible etiologies include genetic factors, vascular compromise, trauma, teratogens, and intrauterine infections37. Along the embryonic fusion line between the maxillary and mandibular prominences of the first branchial arch. Membranous aplasia cutis typically presents at birth as a sharply marginated ("punched-out"), oval or round defect covered by a thin, translucent, glistening epithelial membrane. Dermoscopy typically shows a lack of follicular openings, telangiectatic vessels, and radially oriented hair follicles extending horizontally at the periphery ("starburst-like")38a. The latter likely result from the mechanical trauma of fetal movements in a setting of increased skin fragility. Approximately 25% of patients have more than one lesion, and multiple membranous lesions may occur in a linear arrangement. Large, irregular lesions are more likely to extend to deeper structures and may affect the dura and/ or leptomeninges. Cutaneous defects noted at birth may initially be erroneously attributed to obstetric trauma, such as injuries from forceps or fetal scalp electrodes. In such instances, daily cleansing and application of a topical antibiotic ointment or petrolatum until healing is complete are often the only interventions required. Because the risk of complications increases if the period of healing is prolonged, early surgical repair of large stellate scalp lesions or those associated with a dural defect or exposure of the sagittal sinus is recommended. Preoperative imaging studies are required to identify underlying vascular structures. Even without surgical intervention, residual scarred, hairless areas generally become less conspicuous as the child grows. If desired for cosmetic reasons, excision or hair transplants can be performed later in life. Lesions are sometimes associated with swelling of the lip or, particularly if located on the philtrum, recurrent infection. Although most often an isolated anomaly, they may be inherited in an autosomal dominant fashion along with preauricular pits and hearing impairment in patients with a form of branchio-otic syndrome linked to chromosome 1q3146. Commissural lip pits also have been described in association with alveolar synechiae, ankyloblepharon filiforme adnatum (congenital adhesions between the upper and lower eyelids), and ectodermal defects. Upper lip pits, also known as midline sinuses of the upper lip, are rare lesions that are typically located along the philtrum. Although usually an isolated defect, they may be associated with hypertelorism and other dysmorphic facial features. Lower lip pits may be an isolated finding or seen as a part of van der Woude syndrome, which is characterized by paramedian pits in the vermilion portion of the lower lip, cleft lip and/or palate, and hypodontia. Histologically, the sinus tracts associated with lip pits are lined by stratified squamous epithelium; associated salivary or mucous glands are occasionally observed. The evaluation of patients with lip pits should include a family history and a physical examination to exclude associated anomalies.

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