Box 4.1 Relative risk, absolute risk, and the number needed to treat An important value to calculate from RCTs is the number needed to treat (NNT). The NNT aros e because of limitations with the terms rela- tive risk (RR) and absolute risk reduction (A RR). Imagine you have an intervention for schizophrenia: Nopixol. You locate a trial in Medline, which \201 nds the following results: 200 people with schizophrenia were randomized to p lacebo or Nopixol. 120 people received Nopixol, of which 30 relapsed at 6wks; 80 were rando mized to placebo, of which 60 relapsed over the same time. A \200\2302 \227 2 \200\231 ta ble helps to clarify the numbers: Relapse No relapse Nopixol 30 90 120 Placebo 60 20 80 The risk or probability of relapse in the Nopixol group is 30/120 or 0.25. This is called t he experimental event rate (EER). The risk or probability of relapse in the placebo group i s 60/80 or 0.75. This is called the control event rate (CER). The relative risk ( This mean s the risk of relapse on Nopixol is 0.33 times the risk on placebo. Another way of saying t his would be to say that the relative risk of relapse is reduced by 67% on Nopixol. This is sometimes called the relative risk reduction (RRR). This is usually not a good measure of clinical usefulness since if relapse was 100 times less common in both groups, the RR and R RR would stay the same. This would not re \202 ect the fact that clinically the treatment effect had diminished considerably. The absolute risk reduction ( which is 0.5. This means that for every person treated with Nopixol, the risk of relapse is reduced by about 50%. If the risk for each person is reduced by 50% by Nopixol instead of placebo, then it is intui tive that we need to treat two people to prevent, on average, one relapse. This is called t he number needed to treat (NNT). More generally, the NNT is equal to 1/ARR, or 1/0.5. In th is case the NNT = 2. RR) is the EER/CER = 0.25/0.75, which is 0.33. ARR) is the CER \200\223 EER = 0.75 \200\223 0.25, 1 Pocock SJ (1983) Clinical trials: a practical approach. Chichester: John Wiley and Sons L td. 04_Semple_Chap04.indd 115 12/7/2012 6:09:01 PM CHAPTER 4 Evidence-based psychiatry 116 Case \200\223control studies Exposed Population: with outcome Sample: outcome Not exposed Exposed Population: without outcome Sample: no outcome Not exposed Fig. 4.3 Case \200\223control studies appraisal \202 owchart Appraisal criteria (see Fig. 4.3) \200 Exposure when the outcome is rare. Cases The sample cases (those with the outcome) should i deally be a random sample of all cases from the population. Investigators should say how th e sample was selected. You should decide what effect this will have on the sorts of cases i ncluded in the study. Controls The sample controls (those without the outcome) should ideal ly be a random sample of all controls from the population and be as similar to the cases as possible (except for the exposure of interest). In practice this is dif \201 cult. Select ion of cases and controls Ideally should also be independent of exposure. For example, the selection of depressed people from a psychiatric hospital and controls from a community new sletter to assess whether child sexual abuse is associated with depression may introduce bi as because people with childhood sexual abuse are possibly more likely to be admitted to ho spital in general. Assessment of exposure objectively and blind to outcome status. In pract ice this is often dif \201 cult to accomplish as raters may be affected by their expectati ons and those with the outcome may be more likely to recall an exposure in a \200\230searc h for meaning \200\231 (recall bias). Confounding respects (apart from the exposure of inte rest), correction for this may be made in the statistical analysis. Correction should be ma de only when differences exist in a characteristic which is associated with the exposure an d outcome (e.g. age may confound an association between intravenous drug use and depression ). Case \200\223control studies are an alternative to cohort studies Measurement should be conducted Where the controls and cases differ in important 04_Semple_Chap04.indd 116 12/7/2012 6:09:01 PM CASE \200\223CONTROL STUDIES 117 Analysis from a case \200\223control study directly since the proportion of people developi ng the outcome in exposed/non-exposed populations has not been assessed. Odds ratios are of ten used and may be given, along with a 95% con \201 dence interval. A chi-square test wil l usually be used. If the investigators have examined to see if increasing levels of exposu re are more strongly associated with the outcome, a chi-squared test (for linear trend) or Mantel \200\223Haenszel test may be reported. It is not possible to calculate absolute and relative risks 04_Semple_Chap04.indd 117 12/7/2012 6:09:01 PM CHAPTER 4 Evidence-based psychiatry 118 Cohort studies Drop-out Exposed Outcome Measurement Controls Outcome Drop-out Fig. 4.4 Cohort studies appraisal \202 owchart Appraisal criteria (see Fig. 4.4) \200 Exposure strati \201 ed into levels of increasing dose. The controls should not be exposed but be similar to the exposed group. Bias will be introduced if controls differ in many wa ys apart from the exposure (e.g. drug users differ from non-drug users in many respects: em ployment, criminal record, etc.). Drop-out Drop-outs are virtually inevitable. The effects may bias the results, especially if drop-outs >20% or unequal. Some studies minimize attrit ion by consulting several sources, sending reminders, consulting government statistics (e.g . records of hospital admissions), and other methods of tracking people. Measurement status . In practice this is sometimes dif \201 cult. Retrospective/prospective notes (retrospect ively) or at interview (prospectively). Cohort studies often have retrospective and prospec tive components. Analysis then: Pa \200\223 Pb = absolute risk, pa/pb = relative risk, NNH = 1/absolute risk. If results are \200\230time to an event \200\231, then a survival anal ysis may be conducted. Correction for confounding is usually accomplished using ANCOVA, lin ear regression (outcomes measured on a scale), or logistic regression (where the outcome is an event). The exposure should be clearly de \201 ned and may be Should be conducted objectively and blind to exposure Exposure may be ascertained from case Pa,b \200\224proportion in group a or b who have the outcome, 04_Semple_Chap04.indd 118 12/7/2012 6:09:01 PM COHORT STUDIES 119 Comparing ways of measuring the importance of an intervention There are many ways in which the bene \201 t of an intervention can be measured. Cynically, one might expect the author s of an article to present the method which shows their intervention in the best light, so the reader will need to be aware of the main methods by which the utility of an interventio n can be measured and their conse- quent strengths and limitations (see Table 4.2). Table 4.2 Treatment bene \201 t Method Explanation Advantages Disadvantages Clinically insigni \201 cant treatments may still be statistically signi \201 cant. Gives little indication of precision. Provides a clear test of an investigator \200\231s hypothesis and is provided with all majo r statistical packages. P-value Gives the probability that the observed difference between the treatments is due to chance. Relative risk Gives the risk of an event in one group divided by the risk in the other group. Provides a clear indication of how many times better or worse a treatment is compared to an other. May mislead when outcomes are rare, e.g. a relative risk of 10 would be unimpressive if the event occurred only once in 10 000 patients. Absolute risk Gives the risk of an event in one group minus the risk in the other group. Provides a clearer indication of clinical signi \201 cance. The \201 gure in itself may not seem very meaningful either to clinicians or to patients. Takes appropriate account of baseline risk. Number needed to treat (NNT) States the number of patients required to be treated with the experimental intervention in order to prevent one additional adverse outcome. Relatively intuitive. In spite of obvious advantages, has not come into universal use. Provides a clear indication of how much therapeutic effort is required to bring about one a dditional \200\230good \200\231 outcome. NNTs published in meta-analyzes may be misleading unless the patients included in the prima ry studies are very like your own. Note: Con \201 dence intervals are a welcome addition to any published \201 gure about t reatment bene \201 t because they convey information about precision and statistical signi \201 cance. 04_Semple_Chap04.indd 119 12/7/2012 6:09:02 PM CHAPTER 4 Evidence-based psychiatry 120 Diagnostic studies Test +ve People in whom the diagnosis is in doubt Test \200\223ve Sample: diseased Sample: not diseased Test +ve Test \200\223ve Fig. 4.5 Diagnostic studies appraisal \202 owchart Appraisal criteria (see Fig. 4.5 and Table 4.3) \200 Sample doubt and in whom the test would be used in practice? Gold standard test results? Te st the gold standard and vise versa? Reliability between raters? Diagnostic test performanc e \200 Did the sample consist of people in whom the diagnosis was in Was a suitable gold standard applied regardless of the Was the test applied blindly without knowledge of the results of Could the diagnostic test be applied reliably over time or What are the sensitivity and speci \201 city? They are portable properties, but less clini cally useful than the positive and negative predictive values (PPV and NPV). What are the P PV and NPV? These are useful when you have a test result and you want to know its meaning. Other considerations our setting? What is our patients \200\231 post-test probability for a PPV? \200 \200 Is the test affordable, accurate, and feasible in Post-test odds = Likelihood ratio x Pre-test odds The likelihood ratio (LR) is: Probability of the test result in someone with the disease LR= Probability of the test result in someone without the diseases 04_Semple_Chap04.indd 120 12/7/2012 6:09:02 PM DIAGNOSTIC STUDIES 121 Table 4.3 Ways of measuring diagnostic utility Method Explanation Advantages Disadvantages Not very useful in clinical practice unless very high. Easily calculated and intuitive. Sensitivity Measures the proportion of people with a disorder correctly classi \201 ed by a test. When sensitivity is very high, a negative test will tend to rule out the disorder (SnNOut). Usually supplied in published papers. Does not depend on prevalence. Speci \201 city Measures the proportion of people without a disorder correctly classi \201 ed by a test. Easily calculated and intuitive. Not very useful in clinical practice unless very high. Usually supplied in published papers. Does not depend on prevalence. When speci \201 city is very high, a positive test will tend to rule in the disorder (SpPI n). Positive predictive value Measures the proportion of people with a positive test result who actually have the disorde r. Clinically useful. Tends to fall as the prevalence of the disorder falls. Easy to understand and communicate to colleagues and patients. May mislead if the pre valence of the disorder in your practice is lower than that of the s tudy. Likelihood ratio for a positive test A ratio of the probability of a positive test coming from someone with the disorder compare d with one without the disorder. Does not depend on the prevalence. More dif \201 cult to calculate than the above. Can be adapted to a variety of other situations. May not seem intuitively very meaningful. Calculating useful values Target disorder Present Absent Diagnostic test result Positive a b Negative c d Sensitivity = a/(a + c) Speci \201 city = d/(b + d) Likelihood ratio for a positive test = Sensitivity/(1 \200\223 Speci \201 city) Likelihood ratio for a negative test = (1 \200 \223 Sensitivity)/Speci \201 city Note: Further details on how to calculate these values a re provided in several texts1 and on a number of websites.2 Positive predictive value (PPV) = a/(a + b) Negative predictive value (NPV) = d/(c + d) 1 Lawrie SM, McIntosh AM and Rao S (2000) Critical appraisal for psychiatry. Edinburgh: Chu rchill Livingstone. 2 For example M http://www.cebm.net.tvt 04_Semple_Chap04.indd 121 12/7/2012 6:09:02 PM CHAPTER 4 Evidence-based psychiatry 122 Qualitative studies Purpose Qualitative studies are usually used to measure beliefs or atti tudes in situa- tions where quantitative research would be less meaningful or impractical. Results are usually presented as text without numbers or \201 gures in a way that is inte nded to preserve the richness of the data in its rightful context. For example, \200\230Wh at are the attitudes of patients with borderline personal- ity disorder to their diagnosis? \200\231 might be answered better by describing what the patients actually said than by pe rforming a survey and summariz- ing attitudes on a scale with medians and inter-quartile ra nges. Appraisal criteria \200 Clear question topic or question. Unlike quantitative research, h ypotheses may emerge in the course of the study and be tested out. Patient selection a repr esentative sample, qualitative researchers often \200\230purposively sample \200\231 patie nts in order to obtain \200\230typical \200\231 or exemplar cases. Information gathering s tandardized. Therefore, the study should describe exactly how this was performed. Material engagement their subject material? Did they check reactions? Did investigators seek non-con \201 rming data? Iteration them with their sample? Grounding interpretations? Did investi gators examine their Disclosure of investigators \200\231 prejudice own attitudes/beliefs/v alues/preconceptions as they embarked on the study? Coherence internally consistent? Testim onial validity investigator \200\231s interpretations? Re \202 exive validity understandin g of theory? Catalytic validity participants? Triangulation using another method (e.g. by o btaining another sample or by observation of the same sample using a different method)? Like all studies, the research should address a clear Unlike quantitative research which should address The gathering and analysis of information is not Did investigators make intense contact with Did investigators cyclically develop hypotheses and then test Were there systematic ways of linking observations with Are the results coherent? Was the interpretation Did the study subjects agree with the Did the observations change the investigator \200\231s Did the investigator reorient, focus, and energize Was there an attempt to con \201 rm the investigations 04_Semple_Chap04.indd 122 12/7/2012 6:09:02 PM This page intentionally left blank CHAPTER 4 Evidence-based psychiatry 124 Economic studies Types of studies \200 Cost analysis \200 Effectiveness analysis \200 Economic analyzes Costs only. Consequences only. Costs and consequences of \211 2 interventions. Types of analyzes \200 Consequences equal intervention). Consequences unequal (e.g. rating scales or admission/rea dmissions) = cost effectiveness analysis. Cost minimization analysis ( \201 nd cheapest Outcomes measured in same natural units If consequences unequal, and bene \201 ts measured in different units (e.g. comparing CBT for schizophrenia with ECT for depression) then convert consequences: \200 \200 to monetary units = cost \200\223bene \201 t analysis, or to patient preferences = cost \200\223utility analysis Costs and perspective Costs should be considered from a broad perspective. Interventions wh ich appear to be less expensive and equally effective at a hospital level may shift costs t o other areas (e.g. social work, criminal justice system), which were not apparent because of too narrow a perspective. \200 \200 \200 \200 \200 Direct costs Indirect costs Intangible costs Incremental cost Opportunity cost intervention over another (a concept of economic analysis rather than an actual cost). Salaries, drugs, buildings, etc. Usually gains/losses in productivity. , e.g. cost of improved health. Cost of each additional unit of production. Bene \201 ts forgone by using capital to provi de one Discounting In order to take into account (1) the preference to pay for things later rather than sooner and (2) the devaluation in currency over time, future costs should be discount ed so they appear at current prices. Occasionally economists argue that future consequences should also be discounted. Consequences The consequences of an intervention should be measured alongside the study use d to measure costs (usually a clinical trial). The more rigorous the study design (SRs > RC Ts > CTs) and the more valid, the more likely the results of the economic analysis are to b e true. 04_Semple_Chap04.indd 124 12/7/2012 6:09:02 PM ECONOMIC STUDIES 125 Dominance If one intervention is more effective and cheaper than an alternative, then choic e is easy. In all other situations, consider the incremental cost- effectiveness ratio: Incremental cost-effectiveness ratio (ICER)= Differences in costs Differences in consequences For example, an intervention causing two extra remissions in schizophre- nia at an extra co st of 100 000 has an ICER of 50 000 per additional remission. ICER gives a measure of t he extra cost for each additional unit of bene \201 t. There \200\231s no cut-off; the ICE R should help compare different interventions and come to a decision. Non-parametric statis tics are used to give p-values and 95% con \201 dence intervals for the ICER (randomizatio n tests, Monte Carlo analyzes). Sensitivity analysis Economic analyzes make assumptions about costs and consequences of dif ferent treatments. To test the robustness of an economic analysis, esti- mated bene \201 t s and costs can be varied one at a time or simultaneously to see if they alter the results of the analysis: \200 \200 \200 \200 One-way Extreme case Multi-way Monte Carlo analyzes simultaneously without assuming normali ty. (one variable at a time). (alter a variable to the extremes of its plausible range). (vary two or more variables simultaneously). are a way of varying several parameters 04_Semple_Chap04.indd 125 12/7/2012 6:09:02 PM CHAPTER 4 Evidence-based psychiatry 126 Applying the evidence to patients Having found valid and important new evidence about a par ticular prob- lem, a couple of further questions need to be asked: \200 \200 What is the likely bene \201 t for my patient? Does my patient actually want it? Diagnosis Diagnostic tests shown to be effective in a research setting may be of little uti lity in your clinical practice for two main reasons. First, the prevalence of the condition may be different in your setting. If the prevalence of the condition is lower in your sett ing, the PPV will be lower, although a nega- tive result will actually be more likely to in dicate an absence of the condi- tion. Secondly, the test itself may be too costly in terms of the \201 nancial, staff, and training resources required. Patients \200\231 values and expectations may also be very important in the context of a di sease for which there is no effective intervention (e.g. Huntington \200\231s disease) or w here the test is itself harmful or unpleasant. Treatment Chronic intractable conditions and mild and very benign conditions may fail to sh ow the bene \201 ts of therapy demonstrated in clinical trials because the patient \200 \231s baseline risk differs from those patients initially randomized. In either situation, it is possible simply to \200\230guess \200\231 what the likely bene \201 t for your patient will be, or one of several numerical methods may be used instead. The simplest numerical method involves an educated guess as to how likely your patient is t o bene \201 t compared to the average patient in the trial. If your patient is half as lik ely to bene \201 t, then the NNT from the trial is doubled. Other techniques are available that are both more accu- rate and more time-consuming.1 Finally, the decision to start a new treatment depends on other things apart from ef \201 cacy. First, and most importantly, your patient may actu- ally not want it because of undue side-effects or perhaps the regime (e.g. thrice-daily dosing) may be excessively inconveni ent for them. As well as potential harms, the decision to adopt a treatment or service at a health service level may also take account of economic evaluations. Note: Guard against drug company information! Although drug repre- sentatives will extol th e virtues of their medication over the competition, often on the basis of ef \201 cacy, li ttle evidence exists to suggest, for example, that one antipsychotic is more effective than another.2 Although doctors do not feel pharmaceutical representatives in \202 uence them, evidence from marketing research suggests otherwise. 1 Lawrie SM, McIntosh AM, Rao S (2000) Critical appraisal for psychiatry. Edinburgh: Church ill Livingstone. 2 Lieberman JA, Stroup TS, McEroy JP, et al. (2005) Effectiveness of antip sychotic drugs in patients with chronic schizophrenia. N Engl J Med 353: 1209 \200\22323. 04_Semple_Chap04.indd 126 12/7/2012 6:09:03 PM MEASURING PERFORMANCE AND IMPLEMENTING PRACTICE 127 Measuring performance and implementing evidence-based practice In the last few years there has been a proliferation in evidence-based guide- lines1 and attempts to audit our performa nce against those guidelines.2 Guidelines Guidelines can be thought of as a top-down approach to evidence-based practice. They are particularly useful where there is clear evidence that an intervention is effectiv e in a given condition, but for some reason isn \200\231t being given. They can also be use ful when there are wide national variations in practice, as is often the case in mental hea lth (e.g. ECT, clozapine). The process of guideline development is a bit like EBM in miniature. Relevant representativ es from all groups (patients, doctors, nurses, phar- macists, etc.) ask key questions which will form the basis for a system- atic review. A systematic review is then conducted and t he articles are appraised by the guideline group. Articles are graded according to their ri gor and members use their clinical judgment in assessing how directly relevant they are to clinical practice in the UK. The group makes recom- mendations on the evidence, which are t hen put into a guideline. The adherence to the guideline is then assessed, usually by audit . Unfortunately, although many good guidelines have been developed, many have not been implem ented. This may be because the methodology of guideline development was faulty or, more lik ely, because the imple- mentation was inadequate. Strategies for guideline implementation include:3 Educational outreach Advertisement Local opinion leaders Written and computerized reminders Reminders at the point of patient care \200 \200 \200 \200 Audit Audit is an attempt to measure actual clinical practice against a number of standards of good clinical care. Standards are sometimes drawn from guidelines, where the strength o f evidence is overwhelming in a given area. Alternatively, standards of good medical practi ce are set based on com- mon sense and good medical practice (e.g. we should discuss treatm ent with patients in a collaborative way). There is some evidence that audit improves adherence to clinical guide- lines and also impr oves individual patient outcomes. It is a cyclical process, with re-audit every few months/ years when standards should be reviewed and changed if necessary. 1 E.g. NICE M http:// www.nice.org and SIGN M http://www.sign.ac.uk 2 E.g. CHI M http://www .chi.nhs.uk and CSBS M http://www.nhshealthquality.org/ 3 See M http://www.york.ac.uk/inst/ crd/ehc51.pdf for further details. 04_Semple_Chap04.indd 127 12/7/2012 6:09:03 PM This page intentionally left blank 129 Chapter 5 Organic illness Presentations of organic illness 130 Dementia: general overview 132 Alzheimer \200\231s dis ease 1 134 Alzheimer \200\231s disease 2 136 Alzheimer \200\231s disease 3: pharmacological treatments 138 Dementia with Lewy bodies (DLB) 140 Fronto-temporal dementia (FTD) (Pick \200\231s disease) 142 Vascular dementia 144 Prion diseases 146 Amnestic disorders 148 Norm al pressure hydrocephalus (NPH) 150 Chronic subdural haematoma (SDH) 151 Psychiatric sequel ae of CVA 152 Psychiatric aspects of head injury 154 Psychiatric aspects of epilepsy 1 156 Psychiatric aspects of epilepsy 2 158 HIV/AIDS and psychiatry 1 160 HIV/AIDS and psychiatry 2: clinical presentations 162 Neuropsychiatric aspects of CNS infections 164 Autoimmune di sorders and psychiatry 166 Movement disorders in psychiatry 167 Parkinson \200\231s disease (PD) and psychiatry 168 Huntington \200\231s disease (HD) 170 Wilson \200\231s disease (WD ) 171 Other movement disorders 172 05_Semple_Chap05.indd 129 12/7/2012 3:28:32 PM CHAPTER 5 Organic illness 130 Presentations of organic illness All psychiatric illnesses are by their nature organic \200 \224that is, they involve abnormalities of normal brain structure or function. The term \200\230organic illness \200\231 in modern psychiatric classi \201 cation, however, refers to those con- ditions with demonstrable etiology in central nervous system (CNS) pathology . Organic disorders related to substance misuse are dealed with in Chapter 15. This chapter deals with those disorders that are caused by traumatic, in \202 ammatory, degenerative, infective, and metabolic conditions. Many psychiatric syndromes can have an organic etiology. For this rea- son, every patient w ho presents with psychiatric symptomatology requires a thorough physical examination (inclu ding neurological examination and in some cases special investigations) before a diagnosis of functional ill- ness is made. While psychiatrists do not have to be expert neurologists, a sound knowledge of those conditions that bridge neurology and psychiatry is essential. H istorically, these disciplines have not always been separated and, in this era of biologica l psychiatry, they are once again converging as increasing evidence emerges of brain dysfun ction underlying most psychi- atric disorders. Having said this, it is important to remembe r that biologi- cal, psychological, and social factors interact in a dynamic two-way proces s in the generation of psychiatric symptoms. Listed here (p. 130) are common organic causes of psychiatric syn- dromes (delirium, dement ia, and amnestic disorders are discussed later): Organic causes of psychosis \200 Neurological (epilepsy; head injury; brain tumor; dementia; encephalitis e.g. herpes simple x virus [HSV], human immunode \201 ciency virus [HIV]; neurosyphilis; brain abscess; CVA). Endocrine (hyper/hypothyroidism; Cushing \200\231s; hyperparathyroidism; Addison \200\231s disease). Metabolic (uraemia; sodium imbalance; porphyria). Systemic lupus erythematosus ( SLE) ( \200\230lupus psychosis \200\231). Medications (steroids; levodopa [L-dopa]; isoniaz id; anticholinergics; antihypertensives; anticonvulsants; methylphenidate). Drugs of abuse (cocaine; LSD; cannabis; PCP; amfetamines [including mephadrone and \200\230legal highs \200\231]; opioids). Toxins. \200 \200 Organic causes of depression \200 Neurological (CVA; epilepsy; Parkinson \200\231s disease; brain tumor; dementia; multiple s clerosis [MS]; Huntington \200\231s disease; head injury). Infectious (HIV; Epstein \200 \223Barr virus [EBV]/infectious mononucleosis; brucellosis). Endocrine and metabolic (hypot hyroidism; Cushing \200\231s; Addison \200\231s disease; parathyroid disease; vitamin de \201 ciency [B12 and folate]; porphyria). Cardiac disease (myocardial infarction [MI]; cong estive cardiac failure [CCF]). SLE. 05_Semple_Chap05.indd 130 12/7/2012 3:28:32 PM PRESENTATIONS OF ORGANIC ILLNESS 131 \200 \200 Rheumatoid arthritis. Cancer. Medications (analgesics; antihypertensives; levodopa [L-dopa] ; anticonvulsants; antibiotics; steroids; combined oral contraceptive [OCP]; cytotoxics; ci metidine; salbutamol). Drugs of abuse (alcohol; BDZs; cannabis; cocaine; opioids). Toxins. \200 Organic causes of mania \200 \200 \200 Neurological (CVA; epilepsy; brain tumor; head injury; MS). Endocrine (hyperthyroidism). Me dications (steroids; antidepressants; me \202 oquine; interferon, isoniazid; cytotoxics). Drugs of abuse (cannabis; cocaine; amfetamines). Toxins. \200 Organic causes of anxiety \200 Neurological (epilepsy; dementia; head injury; CVA; brain tumor; MS; Parkinson \200\231s di sease). Pulmonary (chronic obstructive airways disease [COAD]). Cardiac (arrhythmias; CCF; angina; mitral valve prolapse). Hyperthyroidism. Medications (antidepressants; antihyperten sives; \202 umazenil; yohimbine; fen \202 uramine). Drugs of abuse (alcohol; BDZs; caffe ine; cannabis; cocaine; LSD; MDMA [ecstasy]; amfetamines). \200 \200 \200 05_Semple_Chap05.indd 131 12/7/2012 3:28:32 PM CHAPTER 5 Organic illness 132 Dementia: general overview Essence Dementia is a syndrome characterized by progressive, usu ally irreversible, global cognitive de \201 cits. Often memory impairment is the \201 rs t symptom with progression to other de \201 cits including dysphasia, agnosia, apraxia, im paired executive function, and personality disintegration. For a diagnosis to be made there must be signi \201 cant impairment of normal functioning and other possible diagnoses (se e Differential diagnosis b p. 133), particularly delirium or depression, should be excluded . Common causes Alzheimer \200\231s disease (62%), vascular dementia (15%), mixed (10%), Le wy body dementia (4%), fronto-temporal dementia (2%), other (3%). Reversible causes (15%): subdural haematoma, NPH, vitamin B12 de \201 - ciency, metabolic causes, hypothyroidism. Etiology \200 Parenchymal/degenerative fronto-temporal dementia (including Pick \200\231s disease); Parki nson \200\231s disease; Huntington \200\231s disease; Wilson \200\231s disease; MS; motor n euron disease (MND); Lewy body disease; progressive supranuclear palsy; corticobasal degene ration. Intracranial pressure hydrocephalus (NPH). Infection HIV-associated dementia; tuber culosis (TB); subacute sclerosing panencephalitis (SSPE); other. Endocrine Addison \200\231 s disease. Metabolic imbalance; magnesium imbalance; electrolyte imbalance. B12; folate; pe llagra (niacin); thiamine. Vitamin de \201 ciency Prolonged alcohol misuse; heavy metal po isoning. Toxins Alzheimer \200\231s disease; vascular dementia; Tumor; head trauma; subdural haematoma; CVA; normal Creutzfeldt \200\223Jakob disease (prion disease); neurosyphilis; Hypothyroidism; hyperparathyroidism; Cushing \200\231s and Uraemia; hepatic encephalopathy; hypoglycaemia; calcium \200 Clinical features (see Box 5.1) \200 Memory impairment: starts with short-term and progresses to long- term. History of personal ity change, forgetfulness, social withdrawal, lability of affect, disinhibition, \200\230s illiness \200\231, diminished self-care, apathy, fatigue, deteriorating executive functioni ng. Other speci \201 c cognitive de \201 cits are seen in cortical dementias (see b p. 13 3). Hallucinations and delusions often paranoid (20 \200\22340%) and poorly systematized. A nxiety and/or depression in 50%. Neurological features (e.g. seizures, focal de \201 cits, primitive re \202 exes, pseudobulbar palsy, long-tract signs). Catastrophic reaction, ( P athological emotion \200\224spontaneous lability. Sundowner syndrome \200\224as evening app roaches confusion increases and falls become common. \200 \200 \200 b p. 88). 05_Semple_Chap05.indd 132 12/7/2012 3:28:32 PM DEMENTIA: GENERAL OVERVIEW 133 Differential diagnosis Delirium; depression (pseudodementia b p. 520); amnestic disorders ( b p. 148); learning disability (LD); psychotic disor- ders; normal ageing (b p. 514). Inves tigations Include: FBC; LFT; U&E; glucose; erythrocyte sedimenta- tion rate (ESR); thyroid- stimulating hormone (TSH); calcium; magnesium; phosphate; Venereal Disease Research Laborat ory (VDRL) test for syphi- lis; HIV; vitamin B12 and folate; C-reactive protein; blood cult ure; LP; EEG; chest X-ray (CXR); ECG; CT (optima and axial protocol); MRI; SPECT. Principles of management \200 \200 Assessment Cognitive enhancement donepezil; rivastigmine); antioxidants (selegiline, vitami n E); ? hormonal (estrogen; HRT). Treat psychosis/agitation Treat depression/insomnia Treat medical illness . Psychological support Functional management with self-care, toilet, and feeding; assist with communication. Social management matters (power of attorney, wills, an d curatorship). : diagnostic, functional, and social. : acetylcholinesterase inhibitors (tacrine; \200 \200 \200 \200 : consider antipsychotics. : SSRIs; hypnotics. : to both patient and care-givers. : maximize mobility; encourage independence : accommodation; activities; \201 nancial matters; legal Box 5.1 Clinical syndromes of dementia Dementias may be classi \201 ed in terms of primary site of pathology. Since site of patho logy in the brain correlates with neuropsychiatric symp- tomatology, this is a useful syste m of classi \201 cation. 1. Cortical dementias involve primarily the cortex and are divide d into: Fronto-temporal prominent personality change which may manifest as a frontal lobe syndrome. A common cause of early-onset dementia, it is often undiagnosed. Language impairments tend to involve reduction in content (semantic anomia). CT shows fronto-temporal atrophy and SP ECT shows fronto-temporal metabolism. Posterior \200\223parietal by early memory loss and f ocal cognitive de \201 cits. Personality changes are later manifestations. Language impair ments involve problems with word- \201 nding (lexical anomia). CT (optima protocol) shows thinning (<12 mm) of the cortex of the medial temporal lobe. 2. Subcortical dementias Parki nson \200\231s disease (p. 168); Huntington \200\231s dis- ease (p. 170); Wilson \200\231s disease (p. 171); Binswanger encephalopathy (p. 144); progressive supranuclear palsy (PSNP) (p. 167); HIV-associated dementia (p. 163); NPH (p. 150). Clinical features: gross psychom otor slowing; depressed mood; movement disorders; mild amnesia; and personality changes. 3. Cortical \200\223subcortical dementias e.g. Lewy body dementia (p. 140). Clinical features : cortical and subcortical symptoms. 4. Multifocal dementias e.g. CJD (p. 146). Clinical fe atures: rapid onset and course; involves cerebellum and subcortical structures. e.g. Pick \200\231s disease (p. 142). Characterized by e.g. Alzheimer \200\231s disease (p. 134). Characterized 05_Semple_Chap05.indd 133 12/7/2012 3:28:33 PM CHAPTER 5 Organic illness 134 Alzheimer \200\231s disease 1 Also termed \200\230dementia of the Alzheimer type \200\231 (DAT), this is the most common cause (70%) of dementia in older people. It is a degenerativ e disease of the brain with prominent cognitive and behavioral impairment that is suf \201 ciently severe to interfere signi \201 cantly with social and occu- pational function. It affects approximately 500 000 people in the UK and more than 30 million worldwide. A large r number of people have less severe impairments that usually evolve into the full disorder with time. The percentage of the total population aged over 65 is increasing in the develop ed world, meaning that the burden of DAT-related health care is likely to increase. Epidemiology Risk of DAT increases with age: 1% at age 60yrs; doubles every 5yrs; 40% of th ose aged 85yrs. Age-speci \201 c incidence is the same for men and women \200\224approxima tely 50% excess prevalence in women (explained by the greater number of at-risk women given their longer lifespan). Risk factors include: Down \200\231s syndrome, previous head injur y, or hypothyroidism; family history of Down \200\231s syndrome, Parkinson \200\231s diseas e, or DAT. Possible protective factors Smoking; estrogen (e.g. hormone replace- ment therapy [HRT]); n on-steroidal anti-in \202 ammatory drugs (NSAIDs); vitamin E; higher level of pre-morbid e ducation. Pathophysiology \200 -amyloid peptide deposits as senile Amyloid plaques \200\224insoluble plaques or -pleated sheets in the hippocampus, amygdala , and cerebral cortex. Increased density with advanced disease. Neuro \201 brillary tangle s (NFTs) \200\224consist of phosphorylated tau protein and are found in the cortex, hippoca mpus, and substantia nigra. (NFTs also found in normal ageing, Down \200\231s syndrome, dem entia pugilistica, and progressive supranuclear palsy.) However, even low densities of NFTs in the cortices of the medial temporal lobes should be considered abnormal. The co-occurre nce of amyloid plaques and NFTs was described by Alois Alzheimer in his original descriptio n of the disorder and is now accepted universally as a hallmark of the disease. Up to 50% l oss of neurons and synapses in the cortex and hippocampus. Genetics : 40% have a positive f amily history of DAT (esp. early onset: <55yrs). Autosomal dominant inheritance \200\224aff ects <1% of those with dementia. \200 Chromosome 21 \200\224the gene for amyloid precursor protein (APP) is found on the long arm . Also implicated in Down \200\231s syndrome. Chromosome 19 \200\224codes for apolipoprotei n E4. Presence of E4 alleles increases risk of DAT; some 15% of Europeans carry the allele. 05_Semple_Chap05.indd 134 12/7/2012 3:28:33 PM ALZHEIMER \200\231S DISEASE 1 135 B-amyloid Chromosome 14 \200\224codes for presenilin 1 (implicated in peptide). Chromosome 1 \200\224 codes for presenilin 11 (implicated in peptide). B-amyloid Cholinergic hypothesis : the pathological changes lead to degeneration of cholinergic nucle i in the basal forebrain (nucleus basalis of Meynert). This results in dcortical acetylchol ine (ACh). Pray, do not mock me: I am a very foolish fond old man, Fourscore and upward, not an hour m ore or less; And, to deal plainly, I fear I am not in my perfect mind. Methinks I should kn ow you and know this man; Yet I am doubtful: for I am mainly ignorant what place this is, a nd all the skill I have remembers not these garments; nor I know not where I did lodge last night. Do not laugh at me; For as I am a man, I think this lady to be my child Cordelia. Shakespeare: King Lear, Act II Scene 7 05_Semple_Chap05.indd 135 12/7/2012 3:28:33 PM CHAPTER 5 Organic illness 136 Alzheimer \200\231s disease 2 Clinical features Symptoms usually start insidiously but \201 rst presenta- tion may be related to an identi \201 able life event. \200 