Although other hemorrhagic diseases can have a prolonged thromboplastin time, due to the intensity of the lesion and the child's sex and family history, the most likely diagnosis is hemophilia.

An 18-month-old boy, with complete immunization schedule to date, who consults the Emergency Department for right knee swelling after playing in the park, without obvious trauma. In the directed anamnesis, the mother refers that an uncle of hers had similar problems. The ultrasound examination is compatible with hemarthrosis and in the analytical analysis only an APTT lengthening of 52'' (normal 25-35'') stands out. What is the most probable diagnostic hypothesis?

Further evidence for recessive inheritance of von Willebrand disease with abnormal binding of von Willebrand factor to factor VIII.

A new family with a bleeding diathesis and FVIII deficiency secondary to abnormal binding of von Willebrand factor (vWF) to factor VIII (FVIII) is described. Two propositi of this family, an 18-year-old male and a 33-year-old female, both with a history of epistaxis, bruising, bleeding from the gums, epistaxis, hemarthrosis, and hematoma, were analyzed. Also additional members of the same family with no bleeding history were also studied. The propositi showed normal vWF activities, low FVIII activity; one of them had been diagnosed as having hemophilia A and the other was a hemophilia A carrier. Both showed a very poor response to treatment with FVIII concentrates and desmopressin (DDAVP) but a good clinical response to cryoprecipitate. APTT was prolonged and no inhibitory activity was noticeable in their plasmas. Thirty-five units per kilogram body weight of Hemofil M was infused to both propositi and FVIII reached basal level within 60 minutes of the infusion. No FVIII response at all was observed in the female after intravenous DDAVP administration. However, the male who received the infusion of 35 U/kg body weight of Humate-P achieved a normal FVIII level that was maintained for 12 hours. Multimeric analysis of vWF was normal in all the members studied. Von Willebrand factor domain for FVIII binding was assayed in the two propositi and in six other members of the same family by using a non-isotopic and sensitive method, a modification of the one previously described, using the Hemofil M concentrate as exogenous FVIII. The data obtained showed that both propositi had similar binding to that observed by using plasma of a patient with severe von Willebrand disease. Furthermore, five siblings had a decreased binding of vWF to FVIII, when compared with plasma from normal individuals or patients with hemophilia A. We also observed that, for screening purpose, the ratio of bound FVIII/immobilized vWF (at saturation of the anti-vWF and offering of 1 U/ml of exogenous FVIII) distinguished two levels of abnormality (normal range 0.70-1.15, propositi 0.004-0.007, and remaining members affected 0.25-0.42). The most probable explanation is that the propositi are homozygous or double heterozygous, the other five siblings affected being heterozygous for a recessive vWF defect. This more accessible assay presented here may be of help in routine analysis for diagnosing this type of von Willebrand disease, which has important implications for therapy and genetic counseling.

Diagnostic Challenges in Children With Congenital Bleeding Disorders: A Developing Country Perspective.

To assess the frequency and characteristics of children with inherited bleeding disorders that were initially misdiagnosed, leading to inappropriate disease management. This study was conducted at the Haematology/Pathology Department of Fauji Foundation Hospital, Rawalpindi, Pakistan, from August 2014 to August 2018. Children who were diagnosed with an inherited bleeding disorder but did not respond to initial therapy were reevaluated. In total, 62 children were diagnosed with a bleeding disorder. Of these, 27 were diagnosed with an inherited bleeding disorder and 35 with an acquired bleeding disorder. Of the 27 children with inherited bleeding disorders, 18% (n = 5) were misdiagnosed and treated inappropriately. The median age of the misdiagnosed patients was 9 years (range, 5-13 years). Three patients with Bernard-Soulier syndrome had been misdiagnosed as having immune thrombocytopenic purpura, 1 patient with von Willebrand disease had been misdiagnosed as having hemophilia A, and 1 patient with haemophilia B had been misdiagnosed as having hemophilia A. There are chances of misdiagnosis and improper or invasive management if comprehensive laboratory evaluation and a thorough clinical evaluation are not performed in children with congenital bleeding disorders.

The dental patient with a congenital bleeding disorder.

Congenital bleeding disorders account for approximately one in 10,000 births. Dentists are often anxious about delivering treatment to this special group of patients. In the Irish Republic, patients with inherited bleeding disorders have their dental care co-ordinated centrally at the National Centre for Hereditary Coagulation Disorders (NCHCD), St James's Hospital, Dublin. Dental care is normally integrated with routine outpatient haematological appointments. This ensures regular monitoring of oral health and the early treatment of any hard/soft tissue pathology. This article describes, in simple diagrammatic form, the normal coagulation mechanism (Figures 1 and 2), explains common coagulation terms (Appendix 1), and examines the three most common congenital bleeding disorders: haemophilia A, haemophilia B, and von Willebrand disease. General recommendations based on the current literature are provided with respect to procedures that are appropriate to perform in a general dental practice setting. Although not discussed in this article, it is important to note that non-coagulation bleeding disorders also exist. These include: hereditary haemorrhagic telangiectasia; blood vessel wall defects resulting from connective tissue disorders such as Marfan syndrome and Ehlers-Danlos syndrome; and, platelet disorders such as Bernard-Soulier syndrome, resulting in defective platelet adhesion.

Screening bleeding disorders in adolescents and young women with menorrhagia.

Chronic menorrhagia causes anemia and impairment of life quality. In this study the aim was the screening of bleeding disorders in adolescents and young women with menorrhagia. The study was performed prospectively by pediatric hematologists. A form including demographic characteristics of the patients, bleedings other than menorrhagia, familial bleeding history, characteristics of the menorrhagia, and impairment of life quality due to menorrhagia was filled out by the researcher during a face-to-face interview with the patient. A pictorial blood assessment chart was also used for evaluation of blood loss. All patients underwent pelvic ultrasound sonography testing and women also received pelvic examination by gynecologists. Whole blood count, peripheral blood smear, blood group, serum transaminases, urea, creatinine, ferritin, PFA-100, PT, aPTT, INR, TT, fibrinogen, VWF:Ag, VWF:RCo, FVIII, and platelet aggregation assays were performed. Platelet aggregations were studied by lumiaggregometer. Out of 75 patients enrolled, 60 patients completed the study. The mean age was 20.68±10.34 (range: 10-48) years and 65% (n=39) of the patients were younger than 18 years. In 18 (46%) of the adolescents, menorrhagia subsided spontaneously. In 20% (n=12) of the patients, a bleeding disorder was detected (1 case of type 3 von Willebrand disease, 2 patients with low VWF:Ag, 1 case of probable von Willebrand disease, 3 cases of Bernard-Soulier syndrome, 2 cases of Glanzmann thrombasthenia, 2 cases of immune thrombocytopenic purpura, 1 case of congenital factor VII deficiency). In patients with menorrhagia, at least complete blood count, peripheral smear, aPTT, PT, VWF:Ag, VWF:RCo, FVIII, and fibrinogen assays must be performed. When there is history of nose and gum bleeding, platelet function assay by lumiaggregometer must also be performed. In nearly 50% of adolescents, menorrhagia is dysfunctional and transient. Detailed coagulation assays can be postponed in adolescents if bleeding history other than menorrhagia and/or family history of bleeding and/or parental consanguinity is absent. All subjects with menorrhagia must consult with gynecologists and hematologists. None declared.

Ehlers-Danlos syndrome, clotting disorders and muscular dystrophy.

Ehlers-Danlos syndrome includes 11 distinct entities. The diversity of this collagen dysplasia and its combination with other abnormalities make it difficult to understand physiopathologically. A case of Ehlers-Danlos syndrome is reported, which is novel owing to its combination with clotting abnormalities and especially with muscular dystrophy. To our knowledge this has not previously been reported. The patient was a young man aged 16 years who presented with Ehlers-Danlos syndrome satisfying Perelman's diagnostic criteria. His father and two brothers had comparable clinical symptoms, but his mother and sister were healthy. The four male subjects had an increased cephalin-kaolin time, reduced levels of factor VIII and Willebrand's factor (but without haemophilia A or Willebrand's disease), and, especially, an abnormal platelet ATP secretion. The proband alone had muscular disease with bilateral quadriceps fatigability and amyotrophy. The muscle enzyme levels were greatly increased, the electromyographic trace was myogenic, and the biopsy showed severe muscular dystrophy. This new observation poses the problem of the relation between clotting abnormalities and collagen abnormalities in the Ehlers-Danlos syndrome. It is difficult to classify this case within any of the 11 known types because of its muscular manifestations. It may perhaps be a fortuitous combination or an extension of the nosological framework of this syndrome.

Bernard–Soulier syndrome

Differential diagnosis The differential diagnosis for Bernard–Soulier syndrome includes both Glanzmann thrombasthenia and pediatric Von Willebrand disease. BSS platelets do not aggregate to ristocetin, and this defect is not corrected by the addition of normal plasma, distinguishing it from von Willebrand disease. Following is a table comparing its result with other platelet aggregation disorders: Treatment Bleeding events can be controlled by platelet transfusion. Most heterozygotes, with few exceptions, do not have a bleeding diathesis. BSS presents as a bleeding disorder due to the inability of platelets to bind and aggregate at sites of vascular endothelial injury. In the event of an individual with mucosal bleeding tranexamic acid can be given. The affected individual may need to avoid contact sports and medications such as aspirin, which can increase the possibility of bleeding. A potential complication is the possibility of the individual producing anti-platelet antibodies.

Erik Adolf von Willebrand

He published a Swedish-language article in 1926 about the disease, titled Hereditär pseudohemofili ("Hereditary pseudohemophilia"). He referenced six previous publications from the years of 1876 to 1922, totalling 19 cases on families with bleeding diatheses. The earlier authors attributed the condition to hemophilia (even in the cases of females) or to thrombopathy, which was discovered shortly before as the cause of what had previously been known as purpura hemorrhagica or Werlhof's disease. Von Willebrand also conducted hematological examinations on Hjördis and some of her family members. He recorded a normal or slightly reduced number of platelets and an undisturbed clot retraction, unlike Glanzmann's thrombasthenia. The bleeding time (Duke) was greatly prolonged, extending to more than 2 hours in some cases, while the clotting time was within the normal range. He concluded that the disease was either a new form of thrombopathy or a condition of the capillary endothelium.

List of MeSH codes (C15)

– hemorrhagic disorders – afibrinogenemia – bernard-soulier syndrome – disseminated intravascular coagulation – factor v deficiency – factor vii deficiency – factor x deficiency – factor xi deficiency – factor xii deficiency – factor xiii deficiency – hemophilia a – hemophilia b – hypoprothrombinemias – platelet storage pool deficiency – hermanski-pudlak syndrome – purpura, thrombocytopenic, idiopathic – thrombasthenia – thrombocythemia, hemorrhagic – vascular hemostatic disorders – cryoglobulinemia – ehlers-danlos syndrome – hemangioma, cavernous – hemangioma, cavernous, central nervous system – multiple myeloma – pseudoxanthoma elasticum – purpura, hyperglobulinemic – purpura, schoenlein-henoch – scurvy – shwartzman phenomenon – telangiectasia, hereditary hemorrhagic – waldenstrom macroglobulinemia – vitamin k deficiency – hemorrhagic disease of newborn – von willebrand disease – waterhouse-friderichsen syndrome

Rare and unusual bleeding manifestations in congenital bleeding disorders: an annotated review.

Epistaxis, superficial and deep hematomas, hemarthrosis, gastrointestinal bleeding, hematuria represent the most frequent hemorrhagic events in congenital coagulation disorders. Occasionally, bleeding manifestations occur in unusual sites or are peculiar. A clotting defect may alter the clinical aspect of skin conditions or infections (hemorrhagic scabies or varicella). Hemobilia may occur as a complication of transjugular liver biopsy in hemophilia or Bernard-Soulier syndrome. Hemarthrosis of small joints of feet and hands occur in patients with hemophilia treated with protease inhibitors. Intramedullary hematomas of long bones have been described in α2-plasmin inhibitor or fibrinogen deficiencies. Spleen fracture with consequent hemoperitoneum has been reported in patients with fibrinogen deficiency. Rectus muscle sheath hematoma may occur in patients with factor VII (FVII)or FX deficiency. Acute or subacute intestinal obstruction may be caused by intramural wall hematomas in hemophilia and von Willebrand (vW)-disease. Physicians should always keep in mind that a congenital hemorrhagic disorder may cause bleeding in any tissue of the body and therefore alter the normal clinical features of a given disease.

Von Willebrand Disease -- Differential Diagnosis

Factor X deficiency Factor XI deficiency Hemophilia A Hemophilia B Bernard-Soulier syndrome Platelet function defects Antiplatelet drug ingestion Fibrinolytic defects

Spectrum of inherited bleeding disorders in southern Iran, before and after the establishment of comprehensive coagulation laboratory.

The objective of the present study was to determine the pattern of inherited bleeding disorders in southern Iran and evaluate the effect of a comprehensive coagulation laboratory and related efforts. A total of 545 patients with inherited bleeding disorders were evaluated during 1992-2007 by a cross-sectional study. Data were collected by a data-gathering form. Statistical analysis was done using Statistical Package for the Social Sciences version 15. A P value less than 0.05 was considered statistically significant. Overall 411 patients had common bleeding disorders including 326 hemophilia A, 46 hemophilia B, and 39 von Willebrand disease. Seventy-nine patients had rare coagulation disorders including deficiency of factor VII (n = 26), factor X (n = 18), factor XIII (n = 9), factor I (n = 9), factor XI (n = 7), factor V (n = 4), combined factor VIII and factor V (n = 4), and combined factor X and factor VII (n = 2). Fifty-five patients had platelet disorders including 23 with Glanzmann's thrombasthenia, 15 with Bernard-Soulier syndrome, and 17 with other platelet disorders, most of which (45) were diagnosed after the establishment of the comprehensive coagulation laboratory. Annual mean number of new diagnosed patients with common and rare bleeding disorders increased from 29 +/- 4 to 38 +/- 17. The ratio of the patients diagnosed with rare bleeding disorders to common bleeding disorders significantly increased after the establishment of the comprehensive diagnosis laboratory (P < 0.001).It seems that implementation of collaborative projects by the Shiraz Hemophilia Society and the establishment of the comprehensive coagulation laboratory and treatment centers have been successful in increasing diagnosis of the inherited bleeding disorders and consequently better management of the patients.

List of MeSH codes (C15)

– blood coagulation disorders – coagulation protein disorders – activated protein c resistance – afibrinogenemia – factor v deficiency – factor vii deficiency – factor x deficiency – factor xi deficiency – factor xii deficiency – factor xiii deficiency – hemophilia a – hemophilia b – hypoprothrombinemias – von willebrand disease – disseminated intravascular coagulation – blood coagulation disorders, inherited – activated protein c resistance – afibrinogenemia – antithrombin iii deficiency – bernard-soulier syndrome – factor v deficiency – factor vii deficiency – factor x deficiency – factor xi deficiency – factor xii deficiency – factor xiii deficiency – hemophilia a – hemophilia b – hermanski-pudlak syndrome – hypoprothrombinemias – protein c deficiency – thrombasthenia – von willebrand disease – wiskott-aldrich syndrome – platelet storage pool deficiency – hermanski-pudlak syndrome – protein s deficiency

Von Willebrand disease

Diagnosis Basic tests performed in any patient with bleeding problems are a complete blood count-CBC (especially platelet counts), activated partial thromboplastin time-APTT, prothrombin time with International Normalized Ratio-PTINR, thrombin time-TT, and fibrinogen level. Patients with abnormal tests typically undergo further testing for hemophilias. Other coagulation factor assays may be performed depending on the results of a coagulation screen. Patients with von Willebrand disease typically display a normal prothrombin time and a variable prolongation of partial thromboplastin time.

Congenital bleeding disorders in Karachi, Pakistan.

To determine the frequency of inherited bleeding disorders, its complications, and treatment modalities available for its treatment. Cross-sectional study. Patients with a history of bleeding tendency were tested for confirmation of the diagnosis. History and clinical findings were recorded. Laboratory analysis included prothrombin time (PT), activated partial thromboplastin time (APTT), bleeding time (BT), and fibrinogen assay. Patients with prolonged APTT were tested for factors VIII (FVIII) and IX (FIX). If FVIII was low, von Willebrand factor: antigen (vWF:Ag) and von Willebrand factor:ristocetin cofactor (vWF:RCo) were performed. When PT and APTT both were prolonged, FV, FX, and FII were tested. Platelet aggregation studies were done when there was isolated prolonged BT. Urea clot solubility test was done when all coagulation tests were normal. All patients with hemophilia A and B were evaluated for inhibitors. Of the 376 patients, inherited bleeding disorder was diagnosed in 318 (85%) cases. Median age of patients was 16.4 years. Hemophilia A was the commonest inherited bleeding disorder that was observed in 140 (37.2%) followed by vWD 68 (18.0%), platelet function disorders 48 (12.8%), and hemophilia B in 33 (8.8%) cases. We also found rare congenital factor deficiencies in 13 (3.4%), low VWF in 11 (3.0%) participants and 5 (1.3%) in female hemophilia carriers. Hemarthrosis was the most frequent symptom in hemophilia A and B (79.7%) involving knee joint. Inhibitor was detected in 21 (15%) cases. Fresh frozen plasma/cryoprecipitate were the most common modality of treatment. In 58 patients, no abnormality was detected in coagulation profile. Hemophilia A and vWD are the most common congenital bleeding disorders in this study. Hemarthrosis involving knee joint was the most common complication. Inhibitor was detected in a significant number of patients. Plasma is still the most common modality of treatment.

Clinical profile of hemophilia patients in Jodhpur Region.

Hemophilia is widely distributed all over the world, but little is known about its clinical profile in resource-limited regions. An insight into its clinical spectrum will help in the formulation of policies to improve the situation in these areas. To study the clinical profile of hemophiliacs (age <18 years) in Jodhpur region and screen them for transfusion-transmitted infections. A cross-sectional study conducted in the Department of Pediatrics, Umaid Hospital, Dr. S. N. Medical College, Jodhpur, over a period of 12 months. Out of a total of 56 cases enrolled, 51 (91%) cases were diagnosed as hemophilia A while 5 (9%) were diagnosed as hemophilia B. Positive family history was found in 26 (46%) cases. According to their factor levels, 25 (44%) cases had severe disease, 20 (36%) had moderate disease, and 11 (20%) had mild disease. The mean age of onset of symptoms and diagnosis was 1.73 ± 1.43 and 3.87 ± 3.84 years, respectively. First clinical presentation was posttraumatic bleed in 20 (36%), gum bleeds in 17 (30%), epistaxis in 4 (7%), joint bleeds in 4 (7%), skin bleeds in 4 (7%), and circumcision bleed in 3 (5%) cases. Knee joint was the predominant joint affected by hemarthrosis in 38 (68%), followed by ankle in 29 (52%), elbow in 20 (36%), and hip joint in 7 (13%) cases. All patients had a negative screening test for transfusion-transmitted infections. Occurrence of posttraumatic bleeds and gum bleeds in an otherwise normal child should warn the clinician for evaluation of hemophilia.

Hemophilia A -- Differential Diagnosis

Acquired hemophilia Ehlers-Danlos syndrome Factor XI deficiency Glanzmann thrombasthenia Haemophilia C Haemophilia type B Physical child abuse Platelet disorders Von Willebrand disease

Bleeding time

Normal values fall between 3 – 10 minutes depending on the method used. A disadvantage of Ivy's method is closure of puncture wound before stoppage of bleeding. Duke's method With the Duke;s method, the patient is pricked with a special needle or lancet, preferably on the earlobe or fingertip, after having been swabbed with alcohol. The prick is about 3–4 mm deep. The patient then wipes the blood every 30 seconds with a filter paper. The test ceases when bleeding ceases. The usual time is about 2–5 minutes. This method is not recommended and cannot be standardized because it can cause a large local hematoma. Interpretation Bleeding time is affected by platelet function, certain vascular disorders and von Willebrand Disease—not by other coagulation factors such as haemophilia. Diseases that cause prolonged bleeding time include thrombocytopenia, disseminated intravascular coagulation (DIC), Bernard-Soulier disease, and Glanzmann's thrombasthenia.

A longitudinal prospective study of bleeding diathesis in Egyptian pediatric patients:  single-center experience.

Keeping an updated registry of bleeding disorders is crucial for planning care and documenting prevalence. We aimed to assess the prevalence of various bleeding disorders including rare inherited coagulation and platelet disorders concerning their clinico-epidemiological, diagnostic data and bleeding manifestations severity. Patients suffering from manifestations of bleeding or coagulation disorders presented to Hematology Clinic during 16 years were included and prospectively followed up. Demographics, clinical characteristics, complete blood count, bleeding, prothrombin and activated partial thromboplastin times, platelet aggregation tests and bone marrow aspiration were recorded. Overall 687 patients with bleeding disorders from total 2949 patients were identified. Inherited coagulation defects were found in 27.2%; hemophilia A (70.6%), hemophilia B (13.9%), factor I deficiency (2.3%), factor V deficiency (1.6%), factor X deficiency (4.2%), factor VII deficiency (2.6%), factor XIII deficiency (1.1%), combined factor deficiency (2.1%) and unclassified coagulation disorders in 1.6% of studied patients. Overall 72.7% had diagnosed with platelet disorders; immune thrombocytopenia was the commonest (74.8%), and inherited conditions represent (25.2%) in the following order: Glanzman's thrombasthenia (11.2%), von Willebrand disease (6.6%), Bernard-Soulier syndrome (1%) and Chediak Higashi in 0.4% and unclassified in 6%. Median age of diagnosis of coagulation and platelet disorders were 33 and 72 months. Presenting symptoms of coagulation disorders were: 25.1% post circumcision bleeding, 22.5% ecchymosis, 20.9% hemoarthrosis and 15% epistaxis. Symptoms of rare coagulation disorders were postcircumcision bleeding (20%), bleeding umbilical stump (20%), epistaxis (12%), hemoarthrosis (8%) and hematomas (4%). Presenting symptoms in rare inherited platelet disorders were purpura, ecchymosis, epistaxis and bleeding gums, respectively. Analysis of the clinico-epidemiological data of patients with bleeding disorders is a useful tool for monitoring and improving their quality of care.

Bleeding diathesis

Causes other than coagulation Bleeding diathesis may also be caused by impaired wound healing (as in scurvy), or by thinning of the skin, such as in Cushing's syndrome. Genetic Some people lack genes that typically produce the protein coagulation factors that allow normal clotting. Various types of hemophilia and von Willebrand disease are the major genetic disorders associated with coagulopathy. Rare examples are Bernard–Soulier syndrome, Wiskott–Aldrich syndrome and Glanzmann's thrombasthenia. Gene therapy treatments may be a solution as they involve in the insertion of normal genes to replace defective genes causing for the genetic disorder. Gene therapy is a source of active research that hold promise for the future. Diagnosis Comparing coagulation tests

Hemophilia -- Differential Diagnosis

Other conditions can also present similarly with bleeding after minor trauma or spontaneous bleeds and require exclusion before confirming the diagnosis of hemophilia. Some of these conditions include von Willebrand disease, scurvy, diseases of platelet dysfunction, deficiency of other coagulation factors like V, VII, X, or fibrinogen, Ehlers-Danlos syndrome, Fabry disease, disseminated intravascular coagulation, and child abuse. In von Willebrand disease, bleeding symptoms can be similar to mild hemophilia, but patients with von Willebrand disease have more mucosal bleeding compared to musculoskeletal bleeding seen in hemophilia. Von Willebrand disease is diagnosed by checking for von Willebrand factor antigen or von Willebrand factor multimers. [40] Similarly, in scurvy, Ehlers-Danlos syndrome, and Fabry disease; also, the bleeding is usually mucosal, unlike hemophilia, where it is musculoskeletal. In scurvy, there is a deficiency of vitamin C. [41] In Ehlers-Danlos syndrome, the skin is hyperextensible, and joints are hypermobile. The diagnosis is usually through clinical features, genetic testing, and tissue biopsy. [42] Similarly, in Fabry disease, patients may also have other organs being affected, including kidneys and heart, and have skin lesions called angiokeratomas. They also have pain in the extremities. Fabry disease is usually diagnosed with clinical findings and genetic testing. [43] In cases of platelet dysfunction disorders, bleeding is usually mucocutaneous, unlike hemophilia. Usually, these disorders are diagnosed by platelet aggregation studies or platelet electron microscopy. [44] In the deficiency of other coagulation factors, musculoskeletal bleeding is uncommon. In fact, sometimes thrombosis can occur, especially in patients with factor VII or fibrinogen deficiency or in patients with combined factor V and VIII deficiency. Specific coagulation factor assays usually confirm the diagnosis. Disseminated intravascular coagulation (DIC) that mimics hemophilia is hard to differentiate, but usually, there is an underlying condition in DIC, for example, acute promyelocytic leukemia. Diagnosis is usually carried out by blood tests that show decreased platelet count and the absence of factor VIII autoantibodies. Child abuse can sometimes be misidentified and confused with hemophilia, and it is essential to find inconsistencies in the history of how trauma has occurred. Other signs of malnourishment require vigilance, and x-rays may reveal evidence of fractures of different ages. [45] [46]

List of MeSH codes (C16)

– anemia, hypoplastic, congenital – anemia, Diamond–Blackfan – fanconi anemia – ataxia telangiectasia – blood coagulation disorders, inherited – activated protein C resistance – afibrinogenemia – antithrombin III deficiency – Bernard–Soulier syndrome – factor V deficiency – factor VII deficiency – factor X deficiency – factor XI deficiency – factor XII deficiency – factor XIII deficiency – hemophilia A – hemophilia B – Hermansky–Pudlak syndrome – hypoprothrombinemias – protein C deficiency – thrombasthenia – Von Willebrand disease – Wiskott–Aldrich syndrome – CADASIL – cardiomyopathy, hypertrophic, familial – cherubism

Bernard-Soulier Syndrome -- History and Physical

The International Society on Thrombosis and Haemostasis Bleeding Assessment Tool (ISTH-BAT) is useful for assessing bleeding disorders. Its utility was tested in a small study, including patients with known inherited platelet disorders. The study demonstrated a specificity of 100%, a positive predictive value of 90%, and a negative predictive value of 100% using this assessment tool. [17] In the setting of von Willebrand disease, a BAT score >6 repeatedly correlates to a 99% probability of an inherited platelet defect such as BSS. [8] ] Similarly, other bleeding assessment tools like Molecular and Clinical Markers for the Diagnosis and Management (MCMDM) of type 1 von Willebrand's disease (VWD) and the World Health Organization Bleeding Assessment Tool are similar tools. An electronic version of MCMDM-type-1 VWD was developed in 2010. [17]

InternalMed_Harrison

Hemophilia is a sex-linked recessive genetic disorder characterized by the absence or deficiency of factor VIII (hemophilia A, orclassic hemophilia) or factor IX (hemophilia B, or Christmas disease) (Chap. 141). Hemophilia A constitutes 85% of cases. Spontaneous hemarthrosis is a common problem with both types of hemophilia and can lead to a deforming arthritis. The frequency and severity of hemarthrosis are related to the degree of clotting factor deficiency. Hemarthrosis is not common in other disorders of coagulation such as von Willebrand disease, factor V deficiency, warfarin therapy, or thrombocytopenia. Hemarthrosis occurs after 1 year of age, when a child begins to walk 2241 and run. In order of frequency, the joints most commonly affected are theknees,ankles,elbows,shoulders,andhips.Smalljointsofthehands and feet are occasionally involved.

Hemarthrosis due to a rare cause of hemorrhagic diathesis: Ehlers-Danlos syndrome.

The authors report a case of hemarthrosis complicated by severe anemia related to a congenital connective tissue disease: Ehlers-Danlos syndrome. A boy fell down and suffered tumefaction of both knees with bilateral rupture of the rotula tendon. He underwent surgical reinsertion of each tendon on the rotula. He later showed an unexpected ongoing hematic effusion, with severe anemia. He was screened for coagulation disorders with no results. On taking a more detailed history and investigating the patient's phenotypical features, the authors diagnosed Ehlers-Danlos syndrome, hypermobile variant. The hemarthrosis and anemia were thus concluded to be consequences of excessive tissue fragility due to a congenital connective tissue disease.

The role of ultrasonography in the diagnosis of the musculo-skeletal problems of haemophilia.

Recurrent haemarthrosis is the final cause of haemophilic arthrosic disease in haemophilia patients. Therefore, it is essential to diagnose it early, both clinically and by imaging. In addition, haemophilia patients experience chronic synovitis, joint degeneration, muscle haematoma and pseudotumours. The objective of this article is to highlight the value of ultrasounds in the diagnosis and control of the evolution of musculo-skeletal problems in haemophilia patients. To this end, we have performed a literature search in the PubMed, Web of Science(®) (WOS) and SciVerse bases, using the following keywords: hemophilia or haemophilia and ultrasonography (US), ultrasound, echography and sonography. The search was limited to studies published in English between the years 1991 and 2011, finding a total of 221 references. After reviewing the title or abstract for evidence of the use of US for the diagnosis of musculo-skeletal lesions in haemophilia, we selected 24 of these references. We added data collected from our experience to the most important data found in the references. Our main conclusion is that US is highly valuable for the diagnosis of musculo-skeletal diseases in haemophilia. It is a fast, effective, safe, available, comparative, real-time technique that can help us confirm the clinical examination. It is particularly important in acute haemarthrosis, as it can be used to objectively identify the presence of blood in the joints, measure its size, pinpoint its location, assess its evolution and confirm its complete disappearance.

The value of ultrasonography in detecting early arthropathic changes and contribution to the clinical approach in patients of hemophilia.

PURPOSE\AIM: Hemophilia affects the blood clotting process, is a genetic disease characterized by recurrent bleeding. The hemophilia early arthropathy detection with ultrasound (HEAD-US) procedure and scoring method were designed for the detection of early changes in affected joints of patients. In this article, it was aimed to detect early arthropathic changes in the joints of hemophilia patients with the HEAD US scoring system and to investigate its clinical contribution. It was aimed to investigate the effectiveness of HEAD-US scoring in showing early joint damage in subclinical hemophilia cases and its contribution to treatment. The present study included 50 hemophilia patients who were admitted to Departments of Pediatric and Adult Hematology for routine follow-up. During routine follow-up controls, patients were scored by physical examination and HJHS 2.1 and by ultrasonography and HEAD US. Statistical tests were used to analyze joint health status and the results of US examination in the patient group. A total of 294 joints (elbow n = 100, knee n = 94, ankle n = 100) were evaluated by ultrasonography. The mean HJHS and HEAD-US scores of the patients were 14.94 ± 15.18 and 15.6 ± 12.6, respectively. HEAD-US is accepted to be more sensitive than HJHS in detecting early signs of arthropathy. Detection of early abnormalities by ultrasonography will enable the development of individualized treatment protocols and to the prevention of arthropathy development.

Nonsurgical synovectomy in the treatment of arthropathy in Von Willebrand's Disease.

Von Willebrand's disease is the most common inherited bleeding disorder, with an overall prevalence in the general population of 0.8% to 1.3%. Hemarthrosis occurs mainly in the severest forms of the disease (type III), with a frequency of 3.5% to 11%, and can cause severe arthropathy similar to that seen in hemophilia. We retrospectively reviewed our experience with nonsurgical synovectomy in the treatment of recurrent hemarthrosis with arthropathy in patients with von Willebrand's disease. Four of our six patients had type III disease and the remaining two had type II disease. The age range was 13 to 63 years. The frequency of hemarthrosis prior to synovectomy was one to four per month. One (n = 2) or both (n = 1) knees were treated in 4 cases, one (n = 1) or both (n = 1) ankles in 3 cases and an elbow in one case. We used yttrium 90 in a dose of 5 mCi for one knee, rhenium 186 in a dose of 2 mCi for two ankles and the elbow and osmic acid for two knees and one ankle. Clinical and radiological results were evaluated six months after synovectomy using the World Federation of Hemophilia score. Radiologic lesions remained stable and clinical manifestations improved in every case (p < 0.05). Five patients achieved a complete remission. Safety was satisfactory. The clinical efficacy of synovectomy done, using radiocolloids or osmic acid in arthropathy due to von Willebrand's disease, seems similar to that in hemophilia.

Joint assessment in von Willebrand disease. Validation of the Haemophilia Joint Health score and Haemophilia Activities List.

Assessment of clinical outcome after joint bleeding is essential to identify joint damage and optimise treatment, to prevent disability. However, disease-specific tools to assess the musculoskeletal status in patients with von Willebrand disease (VWD) are lacking. We aimed to determine validity and reliability of the Haemophilia Joint Health Score (HJHS) and Haemophilia Activities List (HAL) in patients with Von Willebrand disease (VWD). Ninety-six patients with VWD were included (mean age 46 years) of whom 27 had more than five documented joint bleeds. The HJHS was performed in all patients and all patients completed the HAL and Impact on Participation and Autonomy (IPA) questionnaires. Health-related quality of life (SF36) results were obtained from the prior 'Willebrand in the Netherlands' study. Joint X-rays of knees, elbows and ankles were scored according to Pettersson (PS). Internal consistency of the HJHS (Cronbach's α (α)=0.75) and HAL (α=0.89) were good. Inter-observer agreement of the HJHS was good (ICC 0.84; Limits of Agreement ± 10.3). The HJHS showed acceptable correlation with the X-ray PS (Spearman's r (r<subs</sub)>0.60 all joints) and HAL (r<subs</sub=0.71). The HAL also showed acceptable correlation with the SF36 physical functioning (r<subs</sub=0.65) and IPA (r<subs</sub=0.69). Hypothesis testing showed adequate discriminative power of both instruments: in patients with a history of >5 versus ≤ 5 joint bleeds (median HJHS 10 vs 2 (p<0.01); median HAL 77 vs 98 (p<0.01)), independent from age. In conclusion, both the HJHS and HAL are feasible to assess clinical outcome after joint bleeds in VWD.

Von Willebrand factor

Interactions von Willebrand Factor has been shown to interact with Collagen, type I, alpha 1. Recently, It has been reported that the cooperation and interactions within the Von Willebrand Factors enhances the adsorption probability in the primary haemostasis. Such cooperation is proven by calculating the adsorption probability of flowing VWF once it crosses another adsorbed one. Such cooperation is held within a wide range of shear rates. See also von Willebrand disease Bernard–Soulier syndrome References External links GeneReviews/NCBI/NIH/UW entry on von Willebrand Factor Deficiency. Includes: Type 1 von Willebrand Disease, Type 2A von Willebrand Disease, Type 2B von Willebrand Disease, Type 2M von Willebrand Disease, Type 2N von Willebrand Disease, Type 3 von Willebrand Disease Blood proteins Coagulation system Glycoproteins

Autosomal recessive inherited bleeding disorders in Pakistan: a cross-sectional study from selected regions.

Autosomal recessive bleeding disorders (ARBDs) include deficiencies of clotting factors I, II, V, VII, X, XI, XIII, vitamin K dependent clotting factors, combined factor V & VIII, Von Willebrand Disease (vWD) type 3, Glanzmann's thrombasthenia (GT) and Bernard-Soulier syndrome. Patients with primary bleeding disorders from all the major provincial capitals of Pakistan were screened for ARBDs. Prothrombin (PT), activated partial thromboplastin time (APTT), bleeding time (BT) and fibrinogen levels were measured. Cases with isolated prolonged APTT were tested for factors VIII and IX using factor assays This was followed by FXI:C level assessment in cases with normal FVIII and FIX levels. vWD was screened in patients with low FVIII levels. Factors II, V and X were tested in patients with simultaneous prolongation of PT and APTT. Peripheral blood film examination and platelet aggregation studies were performed to assess platelet disorders. Urea clot solubility testing was done to detect Factor XIII levels where platelet function tests were normal. Descriptive analysis was done using SPSS version 16. Of the 429 suspected bleeding disorder patients, 148 (35%) were diagnosed with hemophilia A and 211 (49.1%) patients had ARBDs. 70 patients (16.3%) remained undiagnosed. Out of 211 patients with ARBD; 95 (33.8%) had vWD type 3. Fibrinogen deficiency was found in 34 patients (12%), GT in 27 (9.6%), factor XIII deficiency in 13 (4.6%), factor VII deficiency in 12 (4.3%), factor V deficiency in 9 (3.2%). Eight patients (2.8%) had vitamin K-dependent clotting factor deficiency, Bernard-Soulier syndrome was diagnosed in seven patients (2.5%), factor X deficiency in 2 (0.7%), factor II deficiency in 2 (0.7%), factor XI deficiency and combined factor V and VIII deficiency in 1 (0.4%) patient each. vWD type 3 was the most common ARBD found in our sample of patients in Pakistan, followed by fibrinogen deficiency and GT in respective order.

Spectrum of Von Willebrand's disease in Punjab: clinical features and types.

Von Willebrand's disease (VWD) is a common inherited bleeding disorder caused by quantitative deficiency (Type-1 & Type-3 VWD) or qualitative defect of Von Willebrand's Factor (Type-2 VWD). Regarding VWD limited studies are available in Pakistan. The current study was aimed to determine the clinical presentation and frequency of types of VWD. A cross sectional study was carried out from 16th December 2012 to 15th December 2013 on fifty one patients of VWD. Patients were diagnosed on the basis of prolonged bleeding time, abnormal APTT, reduced level of VWF: Ag, FVIII, VWF: RCo and ratio of VWF: RCo/VWF Ag. Among them 26 (50.98%) were male and 25 (49.02%) were female. Type3 VWD (94.12%) was found to be the commonest type. Two (3.92%) cases of type-2 VWD and only one (1.96%) case of type-1 VWD were identified. Easy bruising was the most commonly observed clinical presentation, 21 (41.18%) patients, followed by epistaxis 7 (13.73%), gum bleed 4(7.84%) menorrhagia 5(9.80%), haemarthosis 2(3.92%), haematoma formation 5 (9.80%), bleeding after circumcision 2 (3.92%), bleeding after surgery 2 (3.92%) and umbilical cord bleeding 3 (5.88%). Consanguineous marriages were reported in parents of 42 (82.4%) patients. Family history of bleeding disorder was reported in 44 (86.27%) of cases. Type-3 VWD was found to be the commonest type which can be attributed to the fact that type-3 VWD is transmitted through autosomal recessive pattern of inheritance and consanguineous marriages are highly practiced in our society leading to high frequency of this form of VWD. Easy bruising and epistaxis were concluded to be the most common clinical presentation. Menorrhagia was found to be common in the females of child bearing age.

Abstracts of papers on haemophilia from other journals.

Surgical synovectomy in haemophilic arthropathy of the knee. Rodriguez Merchan EC, Galindo E, Ladreda JMM, Pardo JA Definition of the bleeding tendency in factor XI deficient kindreds: a clinical and laboratory study. Bolton-Maggs PHB, Patteson DA, Wensley RT, Tuddenham EGD. Rapid genotype analysis in type 2B von Willebrand's disease using a universal heteroduplex generator. Wood N, Standen G, Murray EW, Lillicrap D, Holmberg L, Peake IR, Bidwell J Biological effect of desmopressin in eight patients with type 2N ('Normandy') von Willebrand disease. Mazurier C, Gaucher C, Jorieux S, Goudemand M. Heterogeneity of hepatitis C virus genotypes in haemophilia: relationship with chronic liver disease. Preston FE, Jarvis LM, Makris M, Philp L, Underwood JCE, Ludlam CA, Simonds P.


Knowing that we have taken measures of sleep hygiene, we have explored what provokes him not to sleep, and he does not sleep nine hours and still wants to sleep more,...then the less harmful answer is the 2. Because it is the one with the shortest half-life and he does not want the lady to fall down the next day.

Knowing that we have taken measures of sleep hygiene, we have explored what provokes him not to sleep, and he does not sleep nine hours and still wants to sleep more,...then [HIDDEN]. [HIDDEN] and he does not want the lady to fall down the next day.

We are consulted by an 84-year-old woman for insomnia of conciliation. After failing sleep hygiene measures, it is decided to initiate pharmacological treatment. Which of the following drugs would you select for the patient?

[Insomnia therapy and withdrawal of hypnotics].

The aim of this study is to evaluate the efficiency of a treatment prescribed, in the course of an hospital consultation for sleep pathology, to patients suffering from chronic insomnia not improved by longstanding and sustained medication with hypnotic drugs. The basis of the treatment is a progressive but total withdrawal of hypnotics in so far taken regularly. The withdrawal of hypnotics was prescribed to 79 patients: 33 aged 17 to 39 years (group 1, mean age 30) and 46 aged 40 to 70 years (group 2, mean age 51). 41 showed primary psychophysiological insomnia and 28 showed insomnia associated with psychiatric disorders. In patients of group 1, the average durations were 8 years for insomnia and 3 years for sustained hypnotic use; these durations were 15 and 5 years respectively in patients of group 2. Hypnotic drug withdrawal was achieved without placebos in 3 months in group 1 patients and 5 months in group 2 patients. 65 patients completely stopped the continual use of hypnotics. Subjective improvement of insomnia was reported by 51 of these patients (as well as by 6 patients who were given simultaneous antidepressant therapy). 16 of the 51 improved patients have resorted to hypnotics occasionally (at intervals of 10 days or more). After complete withdrawal, patients went on consulting for various lengths of time: 5 months average for group 1, 14 months average for group 2. This study of a fairly large group of insomniacs shows the frequent ineffectiveness of a sustained use of currently available hypnotics. It also shows that two times out of three the complete stop of sustained hypnotic medication proved beneficial to the patient.

Studio Morfeo 2: survey on the management of insomnia by Italian general practitioners.

To carry out an observational epidemiological survey (Studio Morfeo 2) in order to define the management procedures of insomnia in a large Italian population presenting directly to the general practitioner (GP). Each GP recruited five insomniac subjects in the course of 1 week or 5 consecutive office days over a period of 2 weeks. On each office day, a brief questionnaire (Q1) including five questions investigating insomnia symptoms and current use of treatment was administered to the first 10 patients who referred to the GP office for reasons associated with their own health. The first patient of each day classified as insomniac underwent a second investigation based on a more detailed questionnaire (Q2) including demographic variables, socio-economic status, general medical conditions, severity, duration and clinical features of insomnia, daytime dysfunction, sleep satisfaction and therapeutic management. In a primary care setting, insomnia symptoms are often persistent (>1 year), recurrent (>1/week) and accompanied by daytime consequences. Two out of three patients with insomnia symptoms are dissatisfied with their sleep. In most cases, insomnia symptoms are underrated both by the patients, who cover the problem or reject treatment, and by the GP, who limits intervention on the sleep disorder (scarcely modifying ongoing therapy both in responders and in non-responders). In responders, treatment was confirmed in 91% of cases and discontinued in only 2%. When there was no improvement, or if insomnia symptoms became worse (non-responders), treatment was nevertheless continued in 74.5% of cases, either maintaining the same ineffective dose, increasing the dose, or adding another drug or a non-pharmacological procedure. Regardless of specific medication, the Italian GP privileges the pharmacological approach, which is fourfold more frequent than non-pharmacological therapy (78.6 versus 18.2%). Non-benzodiazepine hypnotic drugs are mostly prescribed when the GP decides to apply medication in previously untreated patients with insomnia symptoms. Self-administration is not unusual among the patients with insomnia symptoms and is more common among non-responders. Italian GPs tend to confirm the ongoing therapy and avoid re-evaluation of the treatment regimen. Limited use of non-pharmacological treatment in the Italian primary care setting is in line with this conservative approach of the GPs who tend to be problem-solvers rather than problem-seekers.

Perampanel in chronic insomnia.

Insomnia is the most prevalent sleep disorder in the general population, and one of the most frequent reasons for consultation in the Sleep Units. Perampanel is an antiepileptic also effective on the structure of sleep, and in restless legs syndrome. We describe the first study that evaluates perampanel in patients with chronic insomnia. Observational retrospective cohorts study of 66 patients with chronic resistant insomnia, 33 exposed to perampanel, other 33 as non-exposed group. All patients attended in Neurology or Psychiatry Consultation, from November 2017 to November 2018. Patients included had been treated with more than 4 different drugs in the previous 4 years. We reviewed age, sex, insomnia etiology, years of evolution, number of previously used drugs, and the results of perampanel for insomnia after 3 months of treatment in the exposed cohort, measured by the improvement of 3 or more points in the ISI and Pittsburgh scales, as well as the average of hours of sleep gained. Non-exposed patients were matched with this variables, but never treated with perampanel. We have included 66 patients. In the exposed cohort: we describe 33 patients with chronic resistant insomnia, 20 women (60 %), 13 men (40 %). Average age 53.48 years, average time of evolution: 11.25 years. Main etiology: depression 13 cases (40 %). After the combination of perampanel 2-4 mg (100 %) with antidepressants (17 cases, 51.5 %) or anxiolytics (12 cases, 36.36 %) along 3 months: the total number of hours of sleep improves in 2.5 h, the scale ISI improves by 6 points (± 2.1 SD, p = 0.02), and Pittsburgh scale improves in 4 points (± 1.7, p = 0.04). In non-exposed cohort, the improvement of the ISI scale was 2.2 points (±0.8, p = 0.06), on the Pittsburgh scale was 1.6 points (± 0.5, p = 0.01). The main adverse effect was irritability in 3 patients, without withdrawal perampanel. The treatment was abandoned by 4 patients (12.12%): 1 due to persistent irritability (3%), 2 due to lack of efficacy (6 %), 1 due to pregnancy wish (3 %). The combination of Perampanel with an antidepressant, or an anxiolytic, improves the quality of sleep measured by ISI and Pittsburgh scales (statistically significant), probably due to its antagonistic action on glutamate. A clinical trial compared with placebo would be necessary to corroborate these results.

Chlordiazepoxide

Tolerance Chronic use of benzodiazepines, such as chlordiazepoxide, leads to the development of tolerance, with a decrease in number of benzodiazepine binding sites in mouse forebrain. The Committee of Review of Medicines, who carried out an extensive review of benzodiazepines including chlordiazepoxide, found—and were in agreement with the Institute of Medicine (USA) and the conclusions of a study carried out by the White House Office of Drug Policy and the National Institute on Drug Abuse (USA)—that there was little evidence that long-term use of benzodiazepines were beneficial in the treatment of insomnia due to the development of tolerance. Benzodiazepines tended to lose their sleep-promoting properties within 3–14 days of continuous use, and in the treatment of anxiety the committee found that there was little convincing evidence that benzodiazepines retained efficacy in the treatment of anxiety after 4 months' continuous use due to the development of tolerance.

GABAA receptor positive allosteric modulator

Insomnia Barbiturates were introduced as hypnotics for patients with schizophrenia. It induced a state of deep and prolonged sleep. But this was not used for long because of adverse side effects. Anticonvulsant Phenobarbital was the first truly effective drug against epilepsy. It was discovered by accident when given to epileptic patients to help them sleep. The positive side effects were anticonvulsant properties that reduced seizure number and intensity. Sedation Pentobarbital is used as a hypnotic when analgesia is not required. It´s often used in CT imaging when sedation is needed. It is efficient, safe and the recovery time is short. In 2013 the barbiturates phenobarbital and butabarbital are still used as sedatives in certain cases as well as to antagonize the effects of drugs as ephedrine and theophylline. Phenobarbital is used in cases of drug withdrawal syndromes. It is used as normal and emergency treatment in some cases of epilepsy.

Somnology

Generally, these treatments are given after the behavioral treatment has failed. Drugs such as tranquilizers, though they may work well in treating insomnia, have a risk of abuse which is why these treatments are not the first resort. Some sleep disorders such as narcolepsy do require pharmacological treatment. See also Sleep disorder Sleep medicine Snoring References External links Sleep disorders sv:Somnologi

Somnology

Pharmacological treatments Pharmacological treatments are used to chemically treat sleep disturbances such as insomnia or excessive daytime sleepiness. The kinds of drugs used to treat sleep disorders include: anticonvulsants, anti-narcoleptics, anti-Parkinsonian drugs, benzodiazepines, non-benzodiazepine hypnotics, and opiates as well as the hormone melatonin and melatonin receptor stimulators. Anticonvulsants, opiates, and anti-Parkinsonian drugs are often used to treat restless legs syndrome. Furthermore, melatonin, benzodiazepines hypnotics, and non-benzodiazepine hypnotics may be used to treat insomnia. Finally, anti-narcoleptics help treat narcolepsy and excessive daytime sleepiness. Of particular interest are the benzodiazepine drugs which reduce insomnia by increasing the efficiency of GABA. GABA decreases the excitability of neurons by increasing the firing threshold. Benzodiazepine causes the GABA receptor to better bind to GABA, allowing the medication to induce sleep.

Clobazam

In India, clobazam is approved for use as an adjunctive therapy in epilepsy, and in acute and chronic anxiety. In Japan, clobazam is approved for adjunctive therapy in treatment-resistant epilepsy featuring complex partial seizures. In New Zealand, clobazam is marketed as Frisium In the United Kingdom clobazam (Frisium) is approved for short-term (2–4 weeks) relief of acute anxiety in patients who have not responded to other drugs, with or without insomnia and without uncontrolled clinical depression. It was not approved in the United States until October 25, 2011, when it was approved for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in patients 2 years of age or older. Contraindications Clobazam should be used with great care in patients with the following disorders: Myasthenia gravis. Sleep apnea. Severe liver diseases such as cirrhosis and hepatitis. Severe respiratory failure.

Effectiveness and safety of hypnotic drugs in the treatment of insomnia in over 70-year old people.

Good sleep is an important index of the quality of life in people and above all in old subjects. Among all the symptoms reported to general practitioner, insomnia is at the 3(rd) place and this is present in particular in the elderly. In elderly people high comorbidity and polytreatment are often present. We have studied 60 elderly people with history of insomnia and concomitant diseases: depression, dementia and behavioral disturbances. All the patients of the present study were visited in our outpatients' department. Three hypnotic drugs were used for the treatment of insomnia: zolpidem, or triazolam, or oxazepam, respectively at doses of 10mg/day, 0.125-0.25mg/day and 15.0mg/day. All the three drugs showed to be effective and safe; no paradoxical effects were observed.

Autism Spectrum Disorder and Mental Health Comorbidity Leading to Prolonged Inpatient Admission.

Sam is a 6-year-old boy with a diagnosis of autism spectrum disorder (ASD) who recently relocated and has an appointment with you, his new pediatric clinician, to establish care. He was previously followed by a psychiatrist for 2 years for additional diagnoses of insomnia, bipolar disorder, anxiety, attention deficit hyperactivity disorder, and intellectual disability. He has tried and (apparently) failed multiple psychotropic trials including stimulants, nonstimulants, mood stabilizers, atypical antipsychotics, and nonbenzodiazepine hypnotics. He has a delayed sleep onset and frequent night awakenings each night for the past 3 months, during which he "screams, cries, and thrashes and can stay up for over an hour." His behaviors are described as irritable, self-injurious, and aggressive with no clear pattern of triggers according to his mother. He is nonverbal and communicates by leading and rarely pointing. The patient's current medication regimen includes clonidine 0.2 mg at night, lorazepam 1.5 mg as needed at night, olanzapine 5 mg twice daily, and diphenhydramine as needed for sleep/agitation. His mother is concerned that he is developing "tolerance" to the regimen and wants to wean him off some of the medications. His mother is struggling to take care of the patient given his worsening behavior and body habitus (body mass index >99%; z = 3.41).There is a family history of depression, anxiety, bipolar disorder, and autism. He has a 3-year-old sister, who is also diagnosed with ASD, though she is not as severely impacted. His mother's partner recently moved in along with 2 children of his own, aged 3 and 4 years. Sam attends a specialized school, where he receives behavior therapy and occupational therapy. He has undergone inpatient pediatric hospitalization twice, 1 time for 3 weeks and the other for 6 days, for aggressive behavior, and in both instances, he was discharged before inpatient psychiatric placement because of a lack of available beds.After urgent consultation with your local developmental and behavioral pediatrician, a slight reduction was made in the lorazepam because of concerns about tolerance and side effects. However, within a week of this, he was brought to the emergency department for continued self-injurious behavior and increased trouble with sleeping. His mother voiced concerns about his safety in the home, which were particularly related to aggression toward his younger sister. He was admitted to the pediatric inpatient floor for observation, and medication adjustment (increasing olanzapine), which was initially helpful in improving behavior, but mostly behavioral/environmental strategies were used to soothe him, including frequent wagon rides through the hospital corridors.Despite the patient being stable from the medical standpoint, Sam's mother did not feel comfortable taking him home. Social work contacted local community mental health services to pursue outpatient resources and respite care options and sought inpatient pediatric psychiatry. After several failed attempts to find placement, he remained in pediatric inpatient care for 1 and a half months with no acute medical interventions other than his oral medications.He was finally accepted to the in-state pediatric psychiatric facility when a bed was available. During his week-long stay, he had further medication adjustments with a decrease in olanzapine and optimization of his clonidine dose. During his psychiatric hospital stay, care coordination succeeded in arranging center-based applied behavior analysis interventions and respite care and parent training for his family. Sam began to show improvement in his overall agitation and aggression, requiring less clonazepam, and his mother then maintained outpatient follow-up.The day before discharge, you visit him in the hospital, and a medical student asks you why he was in the hospital for so long. How would you answer the question?

[Clinical picture and therapy of sleep in aged, internal-medicine patients].

The management of sleep disorders in elderly patients with internal diseases consists in the first line in rectifying pathophysiological disregulations. Only in the second line, proper hypnotics are to be prescribed. When considered as indispensable, these medicaments are selected according to their toxicity and side effects. In present time, Benzodiazepines are definitely preferred, whereas neuroleptic, anti-depressant and the older drugs are to be taken secondarly in account.

[Sleep disorders--what can be done when hypnotics no longer help? Overview and case report].

We report on the case of a 45-year old female with chronic insomnia and refractory to hypnotics, who also has a - polygraphically documented - tolerance to the imidazopyridine "zolpidem". We discuss the main differential diagnosis and demonstrate a therapeutic regimen which allows a step-by-step replacement of hypnotics by sedative antidepressants. This interval replacement treatment reduces on the one hand the risk of developing a severe withdrawal syndrome. On the other hand the replacement by sedative antidepressants improves insomnia and insomnia-associated depressive symptoms. Finally, the clinical implications and rationale of a therapeutic approach with sedative antidepressants in chronic insomnia are discussed.

Chlordiazepoxide

Chlordiazepoxide, trade name Librium among others, is a sedative and hypnotic medication of the benzodiazepine class; it is used to treat anxiety, insomnia and symptoms of withdrawal from alcohol and other drugs. Chlordiazepoxide has a medium to long half-life but its active metabolite has a very long half-life. The drug has amnesic, anticonvulsant, anxiolytic, hypnotic, sedative and skeletal muscle relaxant properties. Chlordiazepoxide was patented in 1958 and approved for medical use in 1960. It was the first benzodiazepine to be synthesized and the discovery of chlordiazepoxide was by pure chance. Chlordiazepoxide and other benzodiazepines were initially accepted with widespread public approval but were followed with widespread public disapproval and recommendations for more restrictive medical guidelines for its use.

Behavioral treatment of chronic insomnia in psychiatrically ill patients.

Psychiatric patients often have residual intractable insomnia as a serious problem. Forty-eight psychiatrically ill patients (DSM-IV diagnoses) who had failed to respond to medicinal treatment for chronic insomnia were referred for and completed behavioral therapy as an adjunct to the pharmacologic treatment of their insomnia. The behavioral treatments included structured sleep hygiene, progressive muscle relaxation, stimulus control, and sleep restriction. The treatment program was accomplished in 6 sessions over 2 months. Follow-up evaluations were completed at 2, 6, and 12 months from the beginning of the treatment program. The outcome of the treatment program was evaluated in terms of the change in (1) self-reported specific sleep parameters, (2) self-ratings of sleep-related day-time state, (3) self-rating of quality of sleep, (4) the use of sleep medication, and (5) the therapist's global rating of improvement. There was a statistically significant change from the baseline in all self-reported specific sleep parameters after 2 months that was sustained after 6 and 12 months. Sleep-related characteristics of daytime state showed statistically significant changes after 2 and 6 months that were maintained after 12 months. Sleep quality had a statistically significant change after 2 months, continued to improve statistically after 6 months, and was maximum after 12 months. Over half the patients (52.7%; 20 of 38) either reduced their sleep medication by half or stopped it completely. The therapist's global rating showed an improvement in 29.2% (N = 14) of patients after 2 months, 56.2% (N = 27) after 6 months, and 68.7% (N = 33) after 12 months. The use of concomitant behavioral and pharmacologic treatment of chronic insomnia in psychiatrically ill patients results in improving sleep and sleep-related state and reduces the risk of return of insomnia for 10 months after finishing active treatment.

[Therapeutic trials in outpatients. Apropos of triazolam trials].

Clinical trials conducted in general practice are more especially interesting as they enable to test a drug in the real conditions of use. On the other hand, these trials are beneficial to the G.P. (new image, rupture of his loneliness, change in his prescription habits, contact with hospitals). The methodology, as for hospital studies, must be rigorous. As a matter of fact, these two types of studies are additional and the cooperation between the G.P.'s and the pharmaceutical industry can conduct to the solution of specific problems: drug interaction--long-term therapeutic effect--new indications. This double blind cross over study comparing triazolam and nitrazepam conducted by G.P.'s on insomniacs is the first French clinical study intended for the registration application and done according to this methodology. This work is an exemple of the new opportunity offered to G.P.'s in future. The results have shown that: on 54 patients (23 male and 31 female) of an average age: 48, 32 have preferred triazolam, 13 have preferred nitrazepam, 9 have had no preference.

Cabotegravir/rilpivirine

Contraindications and interactions Cabotegravir/rilpivirine must not be combined with drugs that induce the liver enzyme CYP3A4, because they accelerate the inactivation of rilpivirine, and/or the enzmye UGT1A1, because they accelerate the inactivation of cabotegravir. These mechanisms potentially result in loss of effectiveness. Examples for such drugs are rifampicin, rifapentine, carbamazepine, oxcarbazepine, phenytoin and phenobarbital. Adverse effects The most common side effects of the injectable combination therapy with rilpivirine are reactions at the injection site (in up to 84% of patients) such as pain and swelling, as well as headache (up to 12%) and fever or feeling hot (in 10%). Less common side effects (under 10%) are depressive disorders, insomnia, rashes, fatigue, musculoskeletal pain, nausea, sleep disorders, and dizziness. Pharmacology

Insomnia: often a therapeutic challenge.

Insomnia, a more or less chronic sleep disturbance, is a very common symptom in psychiatric patients but also relatively freguent in the general population to a lesser degree. Two broad types of insomnia may often be distinguished: (1) difficulty falling asleep and frequent wakening, characteristic of anxiety states or obsessive worrying; and (2) early morning wakening, sometimes in a panic, suggestive of endogenous depression. The first group of patients respond well to minor tranquilizers and psychotherapy, whereas the second do well with tricyclic anti-depressants. Many studies in sleep laboratories have declineated the stages and cycles of sleep physiology and pathology, especially the importance of REM or dreaming sleep. The clinician should be cautious in the use of hypnotics like barbiturates which suppress REM sleep and produce a rebound increase on withdrawal, as well as problems of dependence of habituation. Flurazepam and chloral hydrate are considerably safer in this respect. Understanding sleep neurophysiology and biochemistry permits appropriate individual clinical management for both psychiatric patients and medical patients with conditions like peptic ulcer and nocturnal angina pectoris.

Barbiturate

for anesthetic purposes, and are also sometimes prescribed for anxiety or insomnia. This is not a common practice anymore, however, owing to the dangers of long-term use of barbiturates; they have been replaced by the benzodiazepines and Z-drugs such as zolpidem, zaleplon and eszopiclone for sleep. The final class of barbiturates are known as long-acting barbiturates (the most notable one being phenobarbital, which has a half-life of roughly 92 hours). This class of barbiturates is used almost exclusively as anticonvulsants, although on rare occasions they are prescribed for daytime sedation. Barbiturates in this class are not used for insomnia, because, owing to their extremely long half-life, patients would awake with a residual "hang-over" effect and feel groggy.

[The use of olanzapine in sleep disorders. An open trial with nine patients].

The impossibility of treating patients with sleep disorders adequately means that, as specialists, we have to look for new pharmacological treatments and for this reason we examined the information in the paper by Salin Pascual (1999) about the increase in deep sleep when olanzapine is used as an antipsychotic drug. We decided to use this medication in six females and three males who were suffering from different sleep disorders that conditioned their chronic insomnia. The dosages of olanzapine used ranged from 2.5 and 10 mg in a single dose. The clinical history and progress were used to elaborate the results and conclusions. The result was positive in eight of the nine patients, five who were administered the medication as monotherapy and three as polytherapy. The population studied is insufficient to prove the effectiveness of the drug, but the fact that in eight of our patients the treatment clearly improved their symptoms leads us to think that this line of research must be continued.

Insomnia

Non medication based strategies provide long lasting improvements to insomnia and are recommended as a first line and long-term strategy of management. Behavioral sleep medicine (BSM) tries to address insomnia with non-pharmacological treatments. The BSM strategies used to address chronic insomnia include attention to sleep hygiene, stimulus control, behavioral interventions, sleep-restriction therapy, paradoxical intention, patient education, and relaxation therapy. Some examples are keeping a journal, restricting the time spent awake in bed, practicing relaxation techniques, and maintaining a regular sleep schedule and a wake-up time. Behavioral therapy can assist a patient in developing new sleep behaviors to improve sleep quality and consolidation. Behavioral therapy may include, learning healthy sleep habits to promote sleep relaxation, undergoing light therapy to help with worry-reduction strategies and regulating the circadian clock.

[Ambulatory treatment of sleep disorders in the aged].

An enquiry into the handling by medical practitioners of sleeping problems among elderly patients was conducted in southern Lower Saxony by personal interview, combined with a standard questionnaire. A typical case report had been drafted concerning a 70-year-old, previously healthy widow: her complaints were "nonspecific" and could be classified as an example of either depression, of the onset of senile dementia or as within normal limits for age. This case report was presented by two interviewers to 145 general practitioners (GPs) and 14 neurologists in private practice (response rate of 83.2%) who were asked how they would have treated the patient's sleeping disorder. 30.3% of the GPs and 14.3% of the neurologists would initially not have prescribed medication. Only GPs (19.5%) mentioned possible herbal medication. Sedative neuroleptics were preferred by 57.1% of neurologists and 26.2% of GPs, while benzodiazepines would have been given by 14% of both groups. Antidepressive drugs and chloral hydrate were chosen less often (5.7% and 2.5%, respectively). These data support the finding of a high frequency of neuroleptic prescriptions given to the elderly. They also make clear that the possibility of treatment without drugs is usually not sufficiently explored.

Sleep hygiene

There is support showing positive sleep outcomes for people who follow more than one sleep hygiene recommendation. There is however no evidence that poor sleep hygiene can contribute to insomnia. While there is inconclusive evidence that sleep hygiene alone is effective as a treatment for insomnia, some research studies have shown improvement in insomnia for patients who receive sleep hygiene education in combination with cognitive behavioral therapy practices.

[Pharmacotherapy of sleep disorders].

Benzodiazepines and related drugs are the hypnotics of first choice. They shorten sleep latency, enhance sleep continuity and may prolong sleep duration. Their undesired effects include a persistent day-time sedation and ataxia when getting up at night. There is some risk of habit formation and dependence. For treating an acute insomnia, the prescription of hypnotics should be limited to a short duration (smallest package size), for treating chronic forms of insomnia they should have only an adjuvant role in therapy.

Factors leading to dependence on hypnotic drugs.

Patients in general practice complaining of insomnia of recent origin have been studied in order to ascertain which factors may be of value in the detection of those more susceptible to drug dependence. The type of sleep disturbance was found to be of importance and a personal disturbance scale was found useful as a screening test in two-thirds of the patients. No difference was found in the development of dependence on amylobarbitone and nitrazepam. One of the most important factors in the prevention of drug dependence seems to be frequent review by the doctor after the first prescription and his cautionary advice to the patient.

Paradoxical reaction

Antipsychotics Chlorpromazine, an antipsychotic and antiemetic drug which is classed as a "major" tranquilizer, may cause paradoxical effects such as agitation, excitement, insomnia, bizarre dreams, aggravation of psychotic symptoms and toxic confusional states. Barbiturates Phenobarbital can cause hyperactivity in children. This may follow after a small dose of 20 mg, on condition of no phenobarbital administered in previous days. Prerequisity for this reaction is a continued sense of tension. The mechanism of action is not known, but it may be started by the anxiolytic action of the phenobarbital. Barbiturates such as pentobarbital have been shown to cause paradoxical hyperactivity in an estimated 1% of children, who display symptoms similar to the hyperactive-impulsive subtype of attention deficit hyperactivity disorder. Intravenous caffeine administration can return these patients' behaviour to baseline levels.

Cognitive-behavioral therapy for chronic insomnia.

Psychological and behavioral therapies should be considered the first line treatment for chronic insomnia. Although cognitive behavioral therapy for insomnia (CBT-I) is considered the standard of care [1], several monotherapies, including sleep restriction therapy, stimulus control therapy, and relaxation training are also recommended in the treatment of chronic insomnia [2]. CBT-I is a multimodal intervention comprised of a combination of behavioral (eg, sleep restriction, stimulus control) and cognitive therapy strategies, and psychoeducation delivered in 4 to 10 weekly or biweekly sessions [3]. Given that insomnia is thought to be maintained by an interaction between unhelpful sleep-related beliefs and behaviors, the goal of CBT-I is to modify the maladaptive cognitions (eg, worry about the consequences of poor sleep), behaviors (eg, extended time in bed), and arousal (ie, physiological and mental hyperarousal) perpetuating the insomnia. CBT-I is efficacious when implemented alone or in combination with a pharmacologic agent. However, because of the potential for relapse upon discontinuation, CBT-I should be extended throughout drug tapering [4]. Although the treatment options should be guided by the available evidence supporting both psychological therapies and short-term hypnotic treatment, as well as treatment feasibility and availability, treatment selection should ultimately be guided by patient preference [5]. Despite its widespread use among treatment providers [6], the use of sleep hygiene education as a primary intervention for insomnia should be avoided. Sleep hygiene may be a necessary, but insufficient condition for promoting good sleep and should be considered an adjunct to another empirically supported treatment.

Phenobarbital

The first-line drugs for treatment of status epilepticus are benzodiazepines, such as lorazepam or diazepam. If these fail, then phenytoin may be used, with phenobarbital being an alternative in the US, but used only third-line in the UK. Failing that, the only treatment is anaesthesia in intensive care. The World Health Organization (WHO) gives phenobarbital a first-line recommendation in the developing world and it is commonly used there. Phenobarbital is the first-line choice for the treatment of neonatal seizures. Concerns that neonatal seizures in themselves could be harmful make most physicians treat them aggressively. No reliable evidence, though, supports this approach. Phenobarbital is sometimes used for alcohol detoxification and benzodiazepine detoxification for its sedative and anti-convulsant properties. The benzodiazepines chlordiazepoxide (Librium) and oxazepam (Serax) have largely replaced phenobarbital for detoxification.

Drug treatment of insomnia: indications and newer agents.

Insomnia is a symptom that should be treated according to the underlying etiology. It is more common in elderly individuals and in women. Common causes of insomnia include acute situational factors, psychiatric disorders, use of various medications and illicit drugs, and medical disorders that cause pain, dyspnea or nausea. Pharmacotherapy should be generally restricted to use of the benzodiazepines, imidazopyridines (zolpidem) and occasionally tricyclic antidepressants. As a rule, hypnotic drugs should be used for less than two weeks to one month.

[A connection between insomnia and psychiatric disorders in the French general population].

Untreated insomnia often has repercussions on socio-professional or cognitive functioning of insomniacs. In industrialized countries, the prevalence of insomnia ranges between 10% and 48%, depending on the methodology and the measured time interval. However, few studies have examined the relationship between insomnia and mental disorder diagnoses. This epidemiological study on insomnia complaints was conducted on 5 622 subjects representative of the non-institutionalized French population aged 15 years or over. Sixteen interviewers using the Sleep-EVAL expert system performed telephone interviews. Insomnia complaints (defined as difficulty initiating or maintaining sleep, feeling unrefreshed at awakening accompanied by dissatisfaction with sleep quality or quantity, or use of sleep-promoting medication) were observed in 18.6% (95% confidence interval: 17.6% to 19.6%) of the sample. The median duration of insomnia complaints was five years. Regional variations in the prevalence of insomnia complaints were observed in France. In North 2 and Center 4 regions, the prevalence of insomnia complaints was higher compared to the rest of France with a relative risk of 1.4 (95% confidence interval: 1.1-1.6) time superior for the North region and 1.3 (95% CI: 1.0-1.6) for the Center 4 region. The lowest prevalence was registered in the Mediterranean area. In most regions, the prevalence of insomnia complaints was higher in women than in men with the exception of the South and West regions where the prevalence was similar. Subjects with insomnia complaints consulted more frequently compared to the rest of sample with an odds ratio of 3 to 1 [95% CI: 2.8 to 4.1]. Close to 20% of subjects were being treated for a physical disease at the time of the survey; subjects with insomnia complaints being twice more numerous (34.3%) than the rest of the sample (15.9%; p<0.001). To identify the main factors associated with insomnia complaints, socio-demographic and health variables were introduced in a multivariate model. Separated or divorced individuals (OR: 1.6); widowers (OR: 1.5); subjects aged between 45 and 65 years (OR: 1.4) or older than 65 (OR: 1.5); women (OR: 1.3); those with little or no education (OR: 1.4); and subjects living in the North region had higher reported insomnia complaints. Living in the East region (Mediterranean) was a protective factor (OR: 0.6). Furthermore, subjects with vascular diseases (OR: 2.0), musculo-skeletal diseases (OR: 2.0) or cardiac diseases (OR: 1.9) and those who had consulted a physician in the previous six months (OR: 2.7) had higher a probability of insomnia complaints. Subsequently, DSM IV insomnia diagnoses were examined in subjects who complained of insomnia. A diagnosis of primary insomnia was found in 7% of these subjects. A diagnosis of insomnia related to another mental disorder was found in 15.6% of insomnia complainers. A depressive disorder diagnosis was given in 10.8% of cases (mainly a major depressive disorder). This diagnosis was made more often among women and subjects of less than 65 years. An anxiety disorder diagnosis was given for 33.1% of insomnia complainers (an anxiety generalized disorder in about half the cases). About a quarter of insomnia complainers did not receive a diagnosis. This was the case more often for men and the subjects 65 years or older. If demographic and medical factors are relatively well documented at the epidemiological level, it is otherwise for psychiatric diagnosis associated with insomnia complaint. Very few studies in the general population have been done and still fewer of them have applied a positive and differential diagnosis process. In this study, we used the DSM IV classification to establish positive and differential diagnoses among subjects with insomnia complaints. Compared to other epidemiological studies, our study is distinguished by several aspects: 1) insomnia complaint had a narrower definition. It did not suffice that the subject reported insomnia symptoms, it was also necessary that the subject said s/he was dissatisfied with her/hr/his sleep or that s/he took measures to improve it (medication or sleep hygiene). This choice was motivated essentially by the fact that it is difficult, from a point of clinical point of view, to consider that an individual has insomnia solely based on the presence of symptoms, that, appreciated by a clinician, would resemble insomnia without that they make problem for the subject. 2) Several sleep habits were systematically collected. The majority of epidemiological studies are not centered on sleep problems, with the consequence that results do not allow a global view of factors that are associated with insomnia. 3) The various diagnostic categories of insomnia as well as elements of the differential diagnosis were applied. Thus, we can conclude that insomnia, as a diagnostic entity, including all its forms, is found in 5.6% of the French population. In the majority of cases, the insomnia complaint is part of the symptomatology of a mental disorder, mainly an anxiety disorder. This distinction is important since it helps the physician to determine therapeutic choices. To conclude, it is worthwhile to consider the number of insomnia complainers who had consulted a physician, mainly a general practitioner, in the six months prior to the study. This designates physicians as the first-line resource in the treatment and the prevention of sleep disorders.

What happens when doctors stop prescribing temazepam? Use of alternative therapies.

We investigated the withdrawal of temazepam in a single general practice using two alternative prescribing policies: an alternative benzodiazepine; or an alternative group of drugs recommended for short-term management of insomnia, including sedative antihistamines and chloral hydrate. The study showed that temazepam prescribing in general practice can be reduced or stopped by using a simple intervention. An alternative benzodiazepine is useful in helping patients to stop their use of hypnotic agents. The use of antihistamines as substitute hypnotics is not advocated on the basis of our findings.

Changes in insomnia subtypes in early Parkinson disease.

To examine the development of factors associated with insomnia in a cohort of originally drug-naive patients with incident Parkinson disease (PD) during the first 5 years after diagnosis. One hundred eighty-two drug-naive patients with PD derived from a population-based incident cohort and 202 control participants were assessed for insomnia before treatment initiation and were repeatedly examined after 1, 3, and 5 years. Insomnia was diagnosed according to the Stavanger Sleepiness Questionnaire. The Parkinson's Disease Sleep Scale was used to differentiate sleep initiation problems from problems of sleep maintenance. Generalized estimating equation models were applied for statistical measures. The prevalence of insomnia in general was not higher in patients with PD compared to controls at the 5-year follow-up. There were changes in the prevalence of the different insomnia subtypes over the 5-year follow-up. The prevalence of solitary problems in sleep maintenance increased from 31% (n = 18) in the drug-naive patients at baseline to 49% (n = 29) after 1 year and were associated with the use of dopamine agonists and higher Montgomery-Åsberg Depression Rating Scale scores. The prevalence of solitary sleep initiation problems decreased continuously from 21% (n = 12) at baseline to 7.4% (n = 4) after 5 years; these were associated with less daytime sleepiness. The prevalence rates of the different insomnia subtypes changed notably in patients with early PD. The frequency of sleep maintenance problems increased, and these problems were associated with dopamine agonist use and depressive symptoms, while the total number of patients with insomnia remained stable. Our findings reflect the need for early individual assessments of insomnia subtypes and raise the possibility of intervention to reduce these symptoms in patients with early PD.

Pharmacology_Katzung

Benzodiazepines can cause a dose-dependent decrease in both REM and slow-wave sleep, though to a lesser extent than the barbiturates. The newer hypnotics, zolpidem, zaleplon, and eszopiclone, are less likely than the benzodiazepines to change sleep patterns. However, so little is known about the clinical impact of these effects that statements about the desirability of a particular drug based on its effects on sleep architecture have more theoretical than practical significance. Clinical criteria of efficacy in alleviating a particular sleeping problem are more useful. The drug selected should be one that provides sleep of fairly rapid onset (decreased sleep latency) and sufficient duration, with minimal “hangover” effects such as drowsiness, dysphoria, and mental or motor depression the following day. Older drugs such as chloral hydrate, secobarbital, and pentobarbital continue to be used, but benzodiazepines, zolpidem, zaleplon, or eszopiclone are generally preferred. Daytime