It will then depend on environmental factors (in the widest sense) or the interplay of various genes whether or not this predisposition will lead to manifest disease treatment bipolar disorder cheap 50mg naltrexone overnight delivery. A traditional method used to assess the contribution of genetic factors towards the development of a disease is the study of twins medications removed by dialysis naltrexone 50mg low cost. There are two types of twins medicine stick effective 50mg naltrexone, monozygotic twins who are genetically identical medications when pregnant buy 50mg naltrexone visa, and dizygotic twins who symptoms 2 order naltrexone pills in toronto, like ordinary siblings medications xanax buy generic naltrexone 50 mg on-line, on average share half of the genetic make-up treatment neuropathy naltrexone 50 mg sale. A comparison of the concordance rates in the two types of twins allows an assessment to be made of the relative role that genetic and nongenetic factors play in pathogenesis treatment example purchase naltrexone now. The rate of discordance in identical twins, for instance, is a measure of the importance of exogenous pathogenic factors. With most multifactorial diseases, the concordance rate in monozygotic twins is around 40 to 60 per cent, in dizygotic twins around 10 to 15 per cent. On the one hand, these findings point to the effects of genetic factors, but on the other hand they also show that it must be environmental factors which determine whether or not a multifactorial disease will become manifest. There is still little understanding of the type of genetic predisposition to most of these diseases. A predisposition may be based on a genotype which only under very specific circumstances leads to functional disorders, or on the combination of two or more genotypes which are passed on to the next generation independently of each other. Unlike monogenic genetic diseases, the gene changes which predispose a person to complex genetic diseases have a high incidence among the population. Often multifactorial diseases are not difficult to manage therapeutically since they are determined not only by genetic factors, but also by environmental factors which can be changed. But so far drugs have mostly been developed without any clear idea of the aetiology 19 of the diseases concerned. Consequently, understanding the underlying genetic mechanisms will be of far-reaching importance for the development of new therapies. The following consideration may serve to illustrate the therapeutic possibilities available: Monozygotic twins, as outlined above, often have a 40 to 60 per cent concordance for multifactorial diseases. Based on the example of schizophrenia, a realistic estimate shows that the power of molecular findings will be limited. Twin studies have demonstrated that both genetic and environmental factors play an important part in the development of this psychiatric disease. If one of a pair of monozygotic twins develops schizophrenia, the risk for the other twin to develop the same condition is not 1 per cent which would be the basic risk of the population at large, nor is it 100 per cent which would be the case if this disease were exclusively genetically determined. Rather, the initially healthy twin will develop symptoms in about 50 per cent of the cases. This goes to show that genetic predisposition indeed plays a key role; but even if in future every single factor accounting for the genetic contribution to pathogenesis were known (several dozen rather than a few genes are expected to be involved), one simply could not say whether or not an affected person will actually develop the disease, because non-genetic factors also contribute substantially to the process of disease development. Consequently, there must be exogenous factors which either prevent a genetic predisposition from turning into a full-fledged disease or further this process. The manifestation of a genetic predisposition can be modified by exogenous influences. If scientists knew the exact mechanisms involved, they should be able to use this knowledge for developing appropriate therapies. In order to understand the role played by genetic risk factors and environmental influences and their interaction it is necessary to study large groups of patients and healthy persons and even conduct epidemiological studies among the population at large. In future, research will increasingly depend on such collections which is why they have to be made available to science. A better understanding of the interactions between genotype and environment will also permit new preventive strategies to be developed. Even if mutations have been identified which predispose a person to a multifactorial disease, the link with the disease will always have only a statistical, i. It is possible to determine the "relative risk" of the carrier of the mutation of developing a certain disorder. Even if all 20 genetic risk factors are known which, taken together, account for the genetic predisposition to a disease, the level of predictability of this disease will at most reach the concordance rate of monozygotic twins. Consequently, it will never be possible definitively to predict or preclude the occurrence of a multifactorial disease by employing genetic methods. This is why it is wrong to assume that there is such a thing as genetic determinism, and concerns along those lines are unfounded. The situation is even more complicated when it comes to functions of the human brain such as intelligence, creativity or sexual preference. It is true that studies of family members and especially monozygotic twins suggest that here, too, genetic influences can play a certain role and may be responsible for some of the differences between different people. But it is still open whether it will ever be possible to establish a clear and unambiguous correlation between such phenotypes and specific genes. These include the physical examination of a patient and the classification of, for example, skeletal deformities or dermatological symptoms as being associated with a certain clinicalcondition. Various test procedures may be used to confirm or disprove the diagnosis of a suspected disorder. A case in point would be the use of colour perception tables to diagnose X-linked red/green blindness. Imaging procedures such as ultrasonography can show pathological organic structures. Laboratory tests offer a wide range of additional diagnostic possibilities, with different types of specimens being analysed. Biochemical procedures make it possible to examine gene products and thus establish the presence of certain metabolites indicating a hereditary metabolic disorder. Specific molecular genetic studies are of great importance for basic biomedical research and are playing an ever greater role in the diagnostic process. They permit a better subclassification of disorders and a more precise prognosis. Moreover, it is possible, based on the knowledge of the pathomechanisms underlying a clinical picture, to develop new therapeutic concepts specifically geared to the disorder concerned. Methodological progress such as chip technology enables a host of data to be collected in a single experiment; without such developments it would be necessary to perform a large number of individual analyses. But in qualitative terms the information they yield does not differ from that produced by conventional procedures. As a result of the technical developments of the last few years it is possible today to arrange more than 250,000 different oligonucleotides on a chip 2 with a surface of 1 cm. The molecules on the chip make it possible to identify the specific bonding partners in the mixture of the analysed sample. This miniaturisation goes hand in hand with automation which permits a high throughput of samples to be analysed and evaluated. Quite apart from the fact that so far not even the exact number of human genes has been determined, their functions and complex interactions in different tissue and developmental phases are very little understood. The method used for genetic diagnosis does not per se determine the diagnostic depth or power. The diagnosis of dyschromatopsia by means of molecular genetic procedures does not have to be assessed differently from a conventional examination using colour perception tables simply because the genotype and not the phenotype is analysed. What is of great importance here is the context in which the genetic examination is performed. Different mutations in a single gene, for instance, can trigger different symptoms. The clinical consequences of these mutations range from severe life-shortening pulmonary disease to digestion problems due to loss of the pancreatic function to infertility in males as a result of a constitutional disorder of the seminal ducts. Establishing the correlation between specific genotype and phenotype will contribute to individualising medicine. It is not only that different mutations in a gene cause different clinical pictures, but conversely a specific clinical picture may be triggered by different genetic defects. A heterogeneous group of diseases of this type is retinitis pigmentosa, a retinal disorder which causes a progressive loss of vision and eventual blindness. In the case of type I neurofibromatosis, possible clinical findings range from pigmented brownish patches on the skin to benign, but cosmetically undesirable tumours consisting of connective tissue and nerve cells, to skeletal deformations and even to malignant brain tumours. It is not possible to infer the symptoms of one family member from those of another. Such differences are due to the fact that other, still unknown genes also influence the phenotype. This means that monogenic diseases, too, are actually complex in nature and that they can be considerably modulated by other genes and also by environmental factors. At about 5 per cent, the risk of disease in male carriers of the same mutation is even lower. Such phenocopies are not associated with an increased risk of repetition if the teratogenic agent (the substance damaging the embryo) is discontinued. In other words, a clear distinction between environmental influences and genetic causes is of essential importance. But this applies even more to diseases which are caused by a wide variety of genetic disorders and their interactions with environmental factors. Conversely, it is becoming more and more obvious that almost all diseases also depend on the genetic constitution of the person concerned. On the other hand, the susceptibility to , and mortality caused by, infectious diseases such as tuberculosis or streptococcal pneumonia may be increased for genetic reasons. Another interaction which is more and more shifting into the focus of medicine is the response of an individual to drugs, i. Various components which recognise, transport or metabolise chemical compounds decide on whether a particular drug will produce the desired effect, whether it will be not efficacious at all or whether it will cause lethal complications. Knowledge of the hereditary predisposition to complex diseases of different organ systems is growing rapidly as a result of human genome research. Scientists today feel that they have succeeded also in identifying some of the genes involved in the development of psychiatric diseases such as schizophrenia. Depending on the type of disease concerned, it is possible to make predictions based on simple clinical examinations, imaging or biochemical procedures and genetic methods. Among these, genetic methods have the greatest importance due to their universal applicability. When a genetic predisposition has been identified, all that is possible in many cases is to predict the probability of disease manifestation. The time of the potential future onset of the disease cannot be precisely derived from the findings, either. Many years or even decades may elapse between obtaining the test results and the occurrence of the first signs of the disease, involving a phase of uncertainty which may vary in length. On the other hand, predictive diagnosis can provide the opportunity to identify a disease at an early stage and start a therapy or take preventive measures. A stressful situation can be relieved when it is possible to exclude an assumed higher risk of disease which, for instance, was derived from a family history. But predictive genetic diagnosis may also entail certain dangers as a result of 26 wrong, contradictory or undesirable information. This is why in any case the performance of predictive tests should be subject to special conditions, as discussed in detail below. Contrary to a common notion, there are no search procedures which would cover all genetic risks across the board. This is why it is necessary to determine in advance which person is to undergo which test to identify which risk. There are several areas of application for predictive tests to which different conditions apply. But the implementation of such a diagnostic scheme which affects all neonates in a given country has to meet a number of criteria. It should only be considered if the disease in question causes severe harm, if untreated, and if the test helps to diagnose it in time before it becomes manifest. What is of particular importance, however, is the availability of an effective therapy. Since newborn screening was introduced about 30 years ago, it has been possible to save several thousands of children in Germany from this fate. But the protein hydrolysate used in this diet has such a revolting taste that the affected children and adolescents are eager to end the diet as soon as possible. Their phenylalanine level would rise again and in case of pregnancy severely damage the unborn child. This teratogenic effect of phenylalanine, an amino acid, had previously not been known. This example demonstrates that the introduction of meaningful diagnostic and therapeutic strategies can lead to unforeseeable problems at a later stage. This is why it is of fundamental importance that even after they have been 27 introduced into regular patient management regimes, such procedures are evaluated by means of accompanying scientific studies. Since the 1980s it has been possible to establish a genetic diagnosis as early as the 10th week of gestation by studying placental cells (obtained by means of chorionic villus sampling). There is an ongoing highly controversial debate on the legal and especially the ethical admissibility of this technique in Germany where so far it has been prohibited. These debates focus on issues such as the protection of embryos, the problem of selection and the limitation of indications. These specific and complex aspects would require a separate discussion which is not intended in this statement. In these instances the carriers themselves are clinically healthy; however, there is a 25 per cent probability that two carriers will produce children in whom the clinical picture is manifest. Some countries where the incidence of specific mutations is high offer population screening programmes. As at-risk couples underwent prenatal testing or decided not to have any children of their own there was a clear decline in the incidence of this disease in those countries. The problem lies in the information about the test result and in how it is taken into account. A few years after having been told about the test result, many carriers of cystic fibrosis, for example, were no longer aware of the significance of the findings (they felt that they themselves had a health impairment) or of their own status as carriers. Also in the case of autosomal recessive predispositions to diseases the penetrance of a mutation may vary considerably. Genetic haemochromatosis, for instance, leads to an increased absorption of iron from the diet. The clinical symptoms are caused by the progressive functional loss of various organs (liver, heart, pancreas) due to an increasing iron overload which may even cause hepatocellular carcinoma. On the other hand, pilot studies for population screening showed that only 1 per cent of all persons with this genetic constellation had clinical symptoms at the time of analysis and that their lifetime risk of clinical manifestation was 10 to 40 per cent at most. Although there is a simple and effective method to prevent organic lesions in patients with hereditary haemochromatosis, i. These studies will help to clarify the benefits of an extensive genetic screening programme. Similar considerations also apply to a mutation in the factor V gene (factor V disorders) which, with a prevalence of 1 to 5 per cent, is common in Europe. This mutation leads to a predisposition to venous thrombosis and its sequelae such as embolisms. In this case, too, the activities of other coagulation factors and exogenous risk factors. This means that often the first symptoms occur when the patients already have children who have a 50 per cent risk of being a carrier of the mutation themselves and of then almost inexorably developing the disease as well. There are easily understandable arguments for and against testing; the decision to undergo such tests can only be taken individually by each member of an affected family. But it is important to make sure that the individual is aware of the implications of his or her decision. It is also necessary to point out the possibility of paradoxical reactions after the findings have been communicated. For instance, a person may develop a depressive disorder after learning that their own test results are normal, because they feel guilty that other members of the family are affected by the disease. Counsellors should also address issues that are outside the actual medical context, such as the right time to take out a life insurance policy. This is why it is important to couch the genetic diagnosis in a comprehensive counselling and care concept covering the period both before and after the actual testing phase. It is estimated that an inherited predisposition to tumours is underlying 10 to 15 per cent of all manifest cancers; many of the genes responsible are already known. These examples prove that there is a positive side to predictive diagnosis as it permits cancer prevention in an affected carrier. For the time being, it is not possible to establish a precise correlation of genotype and phenotype and a clear-cut risk definition. Furthermore, the clinical evaluation of the options for the prevention or early detection of breast cancer such as imaging procedures, prophylactic medication and surgical intervention has not yet been completed. Before a molecular genetic test is performed, the patient must be informed of this situation. If it turned out that individual medical aspects need to be included in the interpretation of such test results, these tests should be performed on the initiative of a physician. They differ in terms of objectives, accuracy, predictive power, possible applications, reliability and effort required. There are such a variety of providers and such a broad range of genetic testing procedures that the situation is rather confusing. Each laboratory offering genetic tests can only provide a limited number of testing procedures due to the complexity of the tests involved. Genetic tests and the laboratories performing these tests must meet the currently valid professional standards. They have to inform patients or family members seeking advice of the possible presence of a genetic disease, the diagnostic means available, the basic biological aspects of inheritance and whether there is a special genetic risk within the family. Counselling physicians have to explain about genetic testing in such a way that the person tested can easily understand its significance. They must explicitly draw attention to uncertainties involved in the interpretation of results and in the prognosis of consequences. In addition, it is necessary to assist the person tested and, if so required, their family in dealing with the test result and its implications.
A few people may get psychotic symptoms such as hallucinations (seeing or hearing things that are really not there) symptoms kidney failure purchase naltrexone 50 mg mastercard, delusions (false or strange thoughts or beliefs) and unusual behavior symptoms of colon cancer buy generic naltrexone online. Medication Guides for trade bottles will be affixed to the outside of the bottle and may also be provided in tear-off pads distributed to U medications images buy generic naltrexone pills. Medication Guides for professional samples will be included inside the carton dispensed to the patient illness and treatment order cheap naltrexone on line. Serial seizures and status epilepticus are common in childhood; 40% of status epilepticus occurs in children under two years of age3 and 75% of status epilepticus is the first seizure presentation in a child medications you can crush buy 50 mg naltrexone mastercard. The diagnosis of epilepsy is often straightforward but medicine man dr dre purchase generic naltrexone on-line, on occasion medications going generic in 2016 buy discount naltrexone, immensely difficult medications 44 175 cheap 50 mg naltrexone with mastercard. There is a wide differential diagnosis in assessing whether a seizure is epileptic or non-epileptic and this is particularly the case for children and young people. Misdiagnosis is a significant problem and there has also been much debate in the literature regarding the appropriate investigation of epileptic seizures. The epilepsies are a heterogeneous group of childhood conditions that have differing diagnostic criteria, management and widely differing outcomes. It is important to identify the specific epilepsy syndrome wherever possible to refine the choice of medication to maximise benefit and minimise adverse effects. Children and their parents deserve information appropriate to their particular type of epilepsy. Teenagers with epilepsy are a group who very often have particular needs not well addressed by more traditional paediatric and adult services. The guideline is aimed at healthcare professionals involved in the diagnosis and management of the epilepsies of childhood, and it is hoped that it will also be used by children and their families. It tries to reflect the issues often raised by families, for example, with a section on learning and behaviour in children who have epilepsy. The guideline does not cover seizures in newborn babies, infants under one month of age, the management of non-epileptic seizures nor surgical or other specialised treatment for intractable seizures. Issues relating to contraception and reproduction have been covered in the adult guideline. A convulsion or convulsive seizure refers to a particular type of seizure involving motor movements and this again may be epileptic or non-epileptic. An epileptic seizure is a clinical manifestation presumed to result from an abnormal and excessive discharge of a set of neurones in the brain. Consciousness may or may not be retained or there may be partial loss of awareness. Generalised epileptic seizures involve large areas of brain from the outset, usually both hemispheres, and are associated with early impairment of consciousness. They range from absences characterised only by impairment of consciousness, to generalised tonic-clonic seizures in which widespread convulsive activity takes place. The likelihood of arriving at an epilepsy syndrome diagnosis is very much more likely in children than in adults. Adherence to guideline recommendations will not ensure a successful outcome in every case, nor should they be construed as including all proper methods of care or excluding other acceptable methods of care aimed at the same results. The ultimate judgement must be made by the appropriate healthcare professional(s) responsible for clinical decisions regarding a particular clinical procedure or treatment plan. Five per cent of medical paediatric accident and emergency attendances follow a seizure. This may be a febrile seizure, but there is an important group of children whose apparent febrile seizure is due to bacterial meningitis or other central nervous system infection, and for whom early recognition and treatment is required. Blood glucose should be checked (near-patient testing is preferable to blood analysis to ensure that hypoglycaemia is recognised and treated promptly). The clinician should be aware of the signs and symptoms of meningitis, other intracranial infection or covert injury and maintain a high index of suspicion, especially if recovery does not ensue rapidly. In some circumstances, urgent brain imaging may be indicated to identify other underlying causes. Criteria for admission from A&E to an acute care paediatric unit, developed using a formal consensus process, are listed in Table 1. This might include discussion on risk of recurrence, what action should be taken in the event of a further seizure and appropriate reassurance about the nature of febrile seizures. Where there is diagnostic uncertainty, possible causes and the interim management should be discussed. The accurate diagnosis of one of the epilepsies of childhood can be very difficult. The differential diagnosis of a paroxysmal event in childhood is extensive and non-epileptic seizures are common. In a birth cohort long term follow up study at 11 years, nearly 7% of children had a history of seizures or other episodes of loss of consciousness. Two per cent had a history of febrile convulsions and in a similar number the diagnosis of epilepsy was refuted. By contrast, only 7 of 124 children with multiple unclear episodes at intake later received a diagnosis of epilepsy. The misdiagnosis of epilepsy has significant implications for the iatrogenic adverse effects of medication and adverse psychosocial impact. The inappropriate treatment of young pregnant women with antiepileptic medication risks subsequent damage to an unborn child. Given these concerns regarding misdiagnosis, the breadth of epilepsy syndromes and the range of differential diagnoses, a service for children with epilepsy should have specialists with skills and interest in the management of epilepsy and other paroxysmal disorders. The history taking 4 skills required to ascertain comprehensive witness accounts of events are built upon through training, continuing education and experience. They can be acquired only with an understanding of the range and complexity of the differential diagnosis that exists in children. Staring or blank spells, particularly in children with learning difficulties, often cause diagnostic difficulty. Key historical features will help select those seizures likely to be non-epileptic. Factors more likely to be indicative of non-epileptic staring include: n staring interrupted by voice or touch n staring associated with rocking n staring initially noticed by a professional carer rather than the family. There can be appropriate diagnostic uncertainty, particularly after a first seizure. A false negative diagnosis of epilepsy is probably less harmful than a false positive diagnosis. It is appropriate to share the uncertainty surrounding diagnosis and the importance of making a correct diagnosis with the child and family until a definite diagnosis is made. A list of non-epileptic paroxysmal disorders seen at different ages in childhood is shown in Annex 2. D An accurate history of the event should be taken from first-hand witnesses and the child. Overinterpretation of normal 3 variants as epileptiform abnormalities is a recognised pitfall in adult recordings. It contributes to: n identification of features of a focal or of a generalised epilepsy n syndromic diagnosis n choice of further investigation n the therapeutic management of epilepsy n prognosis of epilepsy. It should not be used to guide a decision on whether or not to commence antiepileptic drug medication. The evidence that children with complex febrile seizures have an increased chance of developing epilepsy is contradictory. Sodium valproate, ethosuxamide and benzodiazepines suppress the typical three per second spike-wave activity in childhood absence epilepsy. Sodium valproate significantly suppresses photic induced discharges (paroxysmal responses). Among the 2+ epilepsies for which this is particularly useful are juvenile myoclonic epilepsy, infantile 3 spasms52,53 and absence seizures. When used appropriately, sleep recordings may contribute 4 significantly to epilepsy classification and particularly in syndromes such as benign rolandic epilepsy with centrotemporal spikes,55 juvenile myoclonic epilepsy56 and infantile spasms. There is no clear evidence 34,57-59 2 that one method of obtaining sleep is significantly more productive than another. In situations of continuing clinical uncertainty where epilepsy is suspected, the next steps depend on the circumstances of the event, its frequency and availability of 2+ investigations. This may require only a few hours as an outpatient if events are very + 53,65 2 frequent or are inducible. The International League Against Epilepsy has published recommendations on cranial imaging 72 73 44 in epilepsy. Children with the following epilepsy syndromes (which are following a typical course) do not need brain imaging: nnnnn idiopathic (primary) generalised epilepsies (eg childhood absence epilepsy, juvenile myoclonic epilepsy or juvenile absence epilepsy) nnnnn benign childhood epilepsy with centrotemporal spikes (benign rolandic epilepsy). A preliminary classification of diseases frequently associated with epileptic seizures is shown in Annex 5. Studies aimed at finding genetic defects underlying the common forms of epilepsy have identified many different ion channel, neuronal receptor and synaptic abnormalities. Facilities for mutation testing are currently limited but testing may be indicated where three or more family members have idiopathic epilepsy. While there are typical neonatal presentations, children 4 may present up until the third year of life. There may be diagnostic issues when specialist investigations are required such as videotelemetry or for clarification of a syndromic diagnosis. Initial management of the child with a first seizure in primary care and A&E settings is covered in section 2. Detailed pharmacological management of the child with epilepsy is considered in section 5. The management of serial seizures and status epilepticus is dealt with in section 6. Surveys of people affected by epilepsy have reported that up to 90% of them wanted more information about the cause of epilepsy, effects and interactions 4 of drugs and the avoidance of potentially dangerous situations. Almost as important as the quality of information is the manner in which it is given. People with epilepsy place great importance on having a doctor who is approachable, communicative and knowledgeable. A checklist is useful in giving a structure to discussion and ensuring important points are covered. Sensitivity to the needs of individual families should guide the clinician on how much information to give at the first consultation. Information for families should be suited to their understanding, making adjustments for different sociocultural contexts. Parents of young children value written or video material to share with relatives and others who look after their children. D Families should be given information to take home in the most suitable format making adjustments for different sociocultural contexts, eg leaflets, fact sheets, videos. School staff are keen to provide a safe environment for the child but this can lead to the child not being allowed to participate fully in some activities. Some voluntary organisations have leaflets on epilepsy safety specifically written for teachers. Discussions about any possible restrictions on activities within the school should always involve the parents, the child, school staff and a health professional/voluntary sector worker who is knowledgeable about epilepsy. There may be additional risk of minor injuries for some children who have epilepsy but inclusion and independence should be prioritised and joint decisions made about risk and safety. Many children feel that more open discussion about epilepsy and education of their peers is the best way of reducing stigma and dispelling myths leading to greater acceptance of them and their seizures. Epilepsy awareness training can be provided by health professionals, field workers or staff from voluntary organisations. Children with epilepsy which is difficult to control may require extra support to enable them to participate in all aspects of the curriculum. Educational and clinical psychologists can be helpful in supporting school staff and the child and family throughout school life. If seizures are not controlled or treatment is causing adverse effects, this should be taken into account at exam time. When children have a history of prolonged seizures, training on administration of emergency (or rescue) medication should be given to school staff who are willing to do this, and a care plan agreed with the school and family. Training of school staff (usually by the school nurse) in the administration of emergency medication should be updated regularly. Provision should be made for children with a short recovery period to be allowed to stay in school and rejoin the class when able. Children may be inappropriately restricted from participating in some sports, social activities and school 2trips. Supervision during water activities (swimming, bathing, showering) reduces the risk of accidental drowning. These are most commonly sustained during cooking, consuming hot drinks,97 during showering98 or by falling against radiators. Children with learning difficulties have an increased risk of injury compared with the general 99 3 population and epilepsy may compound this. Bathing and showering are best undertaken with the bathroom door unlocked and with someone nearby. The level of supervision required for an individual child should be based on the environment and the type of epilepsy. Crossing at traffic lights where possible should minimise the risk of being knocked down should a seizure occur. When cycling, children with epilepsy should avoid traffic and cycle with a friend if possible. Rubberised flooring in play areas and crash mats in gymnasiums allow most children with epilepsy to participate in climbing activities with their peers. Abseiling and climbing can often be undertaken as long as those in charge of the activity are aware of the possibility of a seizure occurring and feel it can be managed safely. Only around 5% of children with epilepsy have seizures triggered by flickering light and this is commonest between the ages of 7 and 19 years. Antiepileptic treatment usually abolishes the photosensitive response and families should be given written information on strategies to minimise risk. D Children with epilepsy should be encouraged to participate in normal activities with their peers. Supervision requirements should be individualised taking into account the type of activity and the seizure history. The vast majority of children with epilepsy who die do so for reasons relating to a severe underlying neurological impairment rather than the epilepsy itself. In some situations, the death of someone with epilepsy cannot be adequately explained. For people with idiopathic epilepsy and without additional severe neurological impairments, the risk of sudden unexpected death appears to be very low and may not exceed that of the general population. Factors associated 2+ with this are early age of onset of epilepsy, number of seizures, severe learning difficulty and 3 seizure type. Responses to individual drugs vary considerably according to seizure and syndrome type and the diagnosis should be reviewed at each clinical contact. Risk factors for recurrence are a first seizure before the age of 15 months; epilepsy or febrile seizures in a first degree + 1 relative; or a prolonged focal seizure. While phenobarbital and sodium valproate may reduce + 2 recurrence rates, the risk of adverse effects does not justify their routine use. B Children with febrile seizures, even if recurrent, should not be treated prophylactically with antiepileptic drugs. This early treatment is ineffective in reducing mortality or preventing the later emergence of epilepsy. In a large randomised study, around three quarters of children did not experience seizure recurrence within seven days following a first unprovoked, tonic-clonic epileptic seizure. The benefit of early treatment appears to be confined to a short term reduction in seizure recurrence risk but has no effect on long term remission rates. A Antiepileptic drug treatment should not be commenced routinely after a first, unprovoked tonic-clonic seizure.
Characteristics of gene therapies that merit consideration for amortized payment strategies in treatment 2 generic naltrexone 50 mg visa. Options for the Amortization of Gene Therapy Payment the options for amortization can be divided into categories dependent on who bears the financial risk and who provides the financing medicine and technology buy naltrexone with mastercard. The major categories are: 1) consumer loans to pay large up-front prices to manufacturers; 2) third-party financial institution financing for payers to obtain financing for large up-front prices to manufacturers; 3) government financing for payers to pay large up-front prices to manufacturers; and 4) manufacturer managed financing medicine dispenser discount 50mg naltrexone fast delivery, in which long-term payment plans are negotiated with payers as part of outcomes-based agreements medicine 5443 discount 50 mg naltrexone mastercard. The pros and cons of these different mechanisms are described in detail in the body of the paper symptoms ms buy naltrexone in india. The Policy Summit discussion did not favour consumer loans treatment yellow tongue discount naltrexone 50 mg without prescription, viewing them as being inadequate to provide fair and affordable patient access to these treatments treatment with chemicals or drugs purchase naltrexone online now. The focus thus fell upon financing by third-parties medicine lake mn cheap naltrexone amex, such as Wall Street financial institutions, the government, or manufacturers. The risk and high costs of gene therapies may prove very difficult to manage within the fragmented private insurance system, and some stakeholders believe that the federal government will need to intervene and take over coverage, much as it did with renal dialysis. Among the forms of amortization it is felt unlikely that Wall Street institutions will of their own volition come forward with a financing option for payers, and payers expressed limited interest in this option. It became clear through the discussion of the Policy Summit that if private insurers were going to consider some kind of payment through amortization, the proposal and the vehicle for doing so would have to come from the manufacturer. Some manufacturers might have the size and financial resources to provide the financing themselves, and offer the payer some form of instalment payment plan; others would most likely need to work with third-parties to come up with some kind of financial instrument that they could then offer to payers. Unfortunately, time is short, with the first gene therapies expected to receive regulatory approval within the next year. To sustain future innovation in gene therapies while managing the very real concerns regarding affordability, all stakeholders will need to take vigorous and collaborative action to establish clear outlines for a comprehensive approach to evidence generation, assessment, pricing, and payment. Policy Recommendations Incorporating the discussion of this topic at the Policy Summit, the following specific policy recommendations reflect a combination of analysis and opinion of multiple stakeholders. These recommendations should be viewed in the larger context of the need for a broad and ongoing collaboration among manufacturers, payers, patients, and policymakers. Only with collaborative efforts can the opportunities presented by gene therapies be realized while addressing the significant challenges related to evidence generation, value assessment, and payment. Central to this broad dialogue will be continued discussion of how best to assess the clinical value of new treatments that offer a potential cure, and how to create new pricing and payment structures that can support innovation in a way that is stable and affordable for patients, payers, and society. Work with clinicians, patient groups, regulators, and payers to establish robust Patient Registries to facilitate collection of real world evidence before and after regulatory approval. Providing input on the scoping parameters of assessments is helpful, and special consideration should be given to sharing patient-level clinical and economic data when possible. For gene therapies whose characteristics make them good candidates for possible amortized payment options, be prepared to come to payers with a specific manufacturer-financed mechanism for instalment payments combined with an outcomes-based agreement. Work with clinicians, patient groups, regulators, and manufacturers to establish robust Patient Registries to facilitate collection of real world evidence following regulatory approval. Develop categorizations of different types of gene therapies based on their method of delivery, mechanism of action, and other key characteristics so that coverage policies can be clearly tailored to meet distinctive types of therapies. Outcomes-based agreements can be combined with different potential methods of amortized payments when health benefits are expected over a long time horizon. This raises concerns about the sustainability of this model of innovation for health systems. What challenges do these therapies give rise to , and how should payers and manufacturers address themfi They included payers, industry representatives and academics, all of whom were experienced in thinking through the implications of gene therapy research. However, these therapies are likely to face a higher concentration of these hurdles than conventional therapies. Some gene mutations result in these proteins not being made correctly (or not being made at all) and can lead to genetic disorders. Once delivered to the human tissue, either by injection, intravenously or outside of the human body in a lab, the virus then integrates its genetic material into the human cells. As a consequence, gene therapies are typically invasive in nature (the majority via intravenous, subcutaneous, intraperitoneal or intramuscular injection). Assuming treatment is successful, the new gene will make a functioning protein (Genetics Home Reference, 2016). Therefore the promise of successful treatment with gene therapy could positively affect millions of lives. However there are many challenges to be overcome: the science is complex, particularly when we move away from single gene disorders. In the European Union, seven regenerative medicine products have been granted marketing authorization. However, only one of these (ChondroCelect, a tissue-engineered therapy) has achieved national reimbursement, and this has only been achieved in three countries (Spain, Belgium and the Netherlands) (Abou-El-Enein et al. The Gene Therapy Pipeline Gene therapy is an attractive area for drug development because with the right target and approach, it can address the root cause of a severe disease. Cystic fibrosis has long been a target for gene therapy development because of the potentially devastating nature of the condition and the known biology underlying the disease. A cure could mean improved quality of life, quantity of life, and avoidance of healthcare costs (medications, physical therapy, lung transplantation, etc. As understanding of the human genome advances, the number of potential molecular targets for gene therapy grows as does the anticipation of rectifying genetic pathways of diseases that have seen only incremental advances or no advanced at all. Furthermore, in Europe it has to date only been paid for use in one patient, most likely due to its $1. Figure 1: Number of gene therapies per disease group Source: Pharmaprojects, 2016 Note: the treatments in the rare disease category are double counted in the graph as they also appear in the numbers for the relevant therapy area. We can see that rare diseases (501) account for 30% of the total of 1671 therapies. Others may also be for orphan indications, albeit within larger disease categories. Results from a pivotal phase 3 study indicate that this therapy has the potential to provide clinically meaningful and long-lasting improvements in retinal sensitivity, which allows for patients to have improved functional vision, leading, for example, to improvements in mobility. In the next sections we look at three key areas: evidence generation; assessing value; and affordability. This is a process that is usually followed for breakthrough drugs to expedite the review. The personalised nature of gene therapies, along with limited shelf life and stability (Bailey et al. Therefore, even if the manufacturer does manage to secure market authorization and reimbursement, there may still be practical delivery challenges to address. Concerns have also been raised that a lack of clarity around manufacturing and quality standards may result in inefficient product development and act as a barrier for development. This is likely to be particularly problematic in rare diseases where no precedents exist (van Schothorst et al. There may be a trade-off between allowing flexibility in the manufacturing process to account for the patient-specific nature of the products whilst establishing good manufacturing practice (Abou-El-Enein et al. The ethical dilemmas associated with gene therapy are similar to those for cancer treatments for small populations and include: (i) the challenge of denying coverage on grounds of cost for an apparently effective therapy for patients with substantial morbidity; (ii) the difficulty of running a randomised clinical trial with a poor current standard of care, when the new therapy appears to be performing well. In such cases where no alternative treatments exist, and when the intervention is for a life-threatening condition, it may be deemed unethical to withhold experimental treatment from participants within a trial, due to the lack of clinical equipoise. Note that not all of the challenges listed will be applicable to all gene therapies. The potential issues should not be thought of as insurmountable barriers, and will not apply uniformly across all gene therapies. In addition, some of the challenges are likely to be much more common than others. Because of the small numbers of patients, the regulator may deem it appropriate to give all of the patients the active comparator, in order to ensure that the maximum possible is learned about the new gene therapy. Such sham operations can be unethical and may prevent fully blinded placebo-controlled trial designs (van Schothorst et al. It can also be difficult to identify the appropriate comparator for the gene therapy to be assessed against, particularly where the therapy leads to marked changes in clinical practice or where there is no existing treatment. Trials are short, typically limited to a few years at most, and thus do not provide long term data. Many include a longer follow up period through which patients are monitored, but, as one interviewee pointed out, in order for manufacturers to provide data that these cures last a lifetime, or at least that the length of clinical benefit outweighs the short-term risks, they would need to observe patients for an extended time. Due to small patient numbers and perceived ethical and statistical benefits of crossover trials, it may be difficult to power studies adequately to evaluate the health outcomes ultimately being sought. As a result, key trials may necessarily depend on surrogate outcomes requiring extrapolation to estimate the key clinical and health endpoints. Additionally, appropriate surrogate outcomes may not exist for gene therapies, requiring development and validation of outcome measures currently unfamiliar to patients, clinicians and payers. As mentioned earlier, if adaptive licensing with surrogate markers is used, there will be substantial uncertainty requiring confirmatory studies post regulatory approval. Complicating evaluation of clinical effectiveness further, the risks and benefits of a product may in some cases vary depending on the delivery protocol and, if relevant, the skill of the surgical team (Abou-El-Enein et al. This could generate high variation in response across individuals and centres, leading to implications for the generalizability of efficacy and safety estimates. Safety evidence Gene therapies come with their own set of safety concerns; when delivered through viral mechanisms they can be tumorigenic and can give rise to proliferation in tissues which have not been intentionally targeted (van Schothorst et al. They can also stimulate immune reactions, requiring immunotherapy, adding to overall risks (Abou-ElEnein et al. As gene therapies are new to medicine, there is no long-term experience with which to gauge the potential for serious safety consequences that might emerge years after the initial treatment phase. Ultimately there is an uncertainty around the potential for harm given that we have incomplete knowledge about the consequences of manipulating the gene. There are concerns over immune response in the short term, in addition to the possibility for significant severe side effects in the longer term. The majority are biologics, although some may be medical devices or combination products. The regulatory approach for gene therapies is similar to other medical products, but does include flexibility related to the biological and technical complexity of the products. For example, phase I studies for gene therapies are typically conducted in a population who has the disease being studied (rather than in healthy volunteers). This is mainly due to unknown risks, but also allows sponsors to look for preliminary evidence of bioactivity on the characteristics of the disease. There is an acknowledgement that large confirmatory studies may not be feasible due to small population sizes, and evaluation may need to be based on a limited amount of data. The document aims to provide guidance on the development and evaluation of gene therapies, focusing on quality. Collection of post-launch Real World Evidence Collection of real world evidence via post launch registries tracking treated patients will usually be a safety requirement of obtaining regulatory approval. Observational level evidence is generally less well received by payers as it has greater risk of bias unless potential confounding can be addressed. Potential partnership between payers and manufacturers, with agreement on the outcomes to be collected, might mitigate some of these concerns. The design of post-launch evidence collection is likely be crucial for establishing medium to long term evidence of effectiveness and comparative effectiveness. In a delayed cross-over approach, patients are monitored for a period of time before crossing over to receive the other treatment. Use of Centers of Excellence for Diagnosis and Treatment the potential problems with accurate diagnosis of patients may require centralization of diagnostic processes at Centers of Excellence. Centers of Excellence could also be formed in a way to manage provider payments in a way that eliminates any concern about large provider margins being added to therapy delivery costs. For example, Spark Therapeutics is proposing to limit administration of voretigene neparvovec to Centers of Excellence that meet strict capabilities and training requirements to support appropriate patient care. This could be through a direct adjustment of the value assessment; through separate consideration of how to finance gene therapy; or both. The value of a potential cure Gene therapies are expected to offer greater clinical gains than conventional therapies: Bubela et al. On the other hand, one of the interviewees commented that we are often assuming that these therapies provide cures, but in reality we do not have long term data, and there is no guarantee that the effects will not wane. However, an insurer could also be on the receiving end of a new member whose disease has already been cured, having been paid for by another insurer. Early cures or substantial benefits at a young age could help produce significant gains in work productivity for patients compared to treatments that bring marginal gains over many years. Identifying Relevant Elements of Value Payers typically focus primarily on health gain for the patient and net direct costs to the health system when looking at their willingness to pay for a therapy in particular circumstances. There is evidence that society expects some priority to be given to addressing the health needs of people with severe unmet need. There is also evidence that society expects priority to be given to children, over and above that already factored into an estimate of life long health gain from treatment. It is likely that several early gene therapies will be aimed at young patients with severe conditions. These elements are likely to be important for gene therapies due to the offer of a cure which means that the individual is able to contribute to society in ways that may not have been possible before. The authors shows health interventions not only reduce morbidity and mortality, but can also have a variety of positive economic effects through: Individual non-health effects (see above); Impacting economic growth at a macro level; Impacting the non-health public sector (for example, education, social care, and criminal justice). High production and R&D costs the two gene therapies that have been marketed to date have been associated with high per patient prices. The price for Srimvelis agreed with the Italian Medicines Agency is 594,000 (Abou-El-Enein et al. Given these experiences, and similar ones with conventional ultraorphan therapies, we expect that high per patient prices will be the case for many gene therapies. Some argue that the same value assessment or willingness to pay criteria should be used, with no special considerations given for small patient numbers or the attributes of the technology. Others have noted that without higher prices, and/or longer-term market exclusivity as is provided in Europe, these therapies will not be developed; incentives to promote innovation should be recognised as part of the problem requiring long-term solutions. In addition to the usual information presented to panels (evidence of clinical and costeffectiveness), the review team also presented quantitative estimates of population health benefits and the consequences of decision uncertainty. This was done so that the panel focussed on the elements of evidence, uncertainty, and payment that would make the technology acceptable or not acceptable for reimbursement.
