This is the fourth in a series of five articles

This article reviews our current understanding of the cognitive processes involved in diagnostic reasoning in clinical medicine. It describes and analyses the psychological processes employed in identifying and solving diagnostic problems and reviews errors and pitfalls in diagnostic reasoning in the light of two particularly influential approaches: problem solving1, 2, 3 and decision making.4, 5, 6, 7, 8 Problem solving research was initially aimed at describing reasoning by expert physicians, to improve instruction of medical students and house officers. Psychological decision research has been influenced from the start by statistical models of reasoning under uncertainty, and has concentrated on identifying departures from these standards.

#### Summary points

Problem solving and decision making are two paradigms for psychological research on clinical reasoning, each with its own assumptions and methods

The choice of strategy for diagnostic problem solving depends on the perceived difficulty of the case and on knowledge of content as well as strategy

Final conclusions should depend both on prior belief and strength of the evidence

Conclusions reached by Bayes's theorem and clinical intuition may conflict

Because of cognitive limitations, systematic biases and errors result from employing simpler rather than more complex cognitive strategies

Evidence based medicine applies decision theory to clinical diagnosis

### Diagnosis as selecting a hypothesis

The earliest psychological formulation viewed diagnostic reasoning as a process of testing hypotheses. Solutions to difficult diagnostic problems were found by generating a limited number of hypotheses early in the diagnostic process and using them to guide subsequent collection of data.1 Each hypothesis can be used to predict what additional findings ought to be present if it were true, and the diagnostic process is a guided search for these findings. Experienced physicians form hypotheses and their diagnostic plan rapidly, and the …

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Clinical problem solving and diagnostic decision making: selective review of the cognitive literature

Today, the average life expectancy in developed nations is over 80 years and climbing. And yet, the quality of life during those additional years is often significantly diminished by the effects of age‐related, degenerative diseases, including age‐related macular degeneration (AMD), the leading cause of blindness in the elderly worldwide. AMD is characterized by a progressive loss of central vision attributable to degenerative and neovascular changes in the macula, a highly specialized region of the ocular retina responsible for fine visual acuity. Estimates gathered from the most recent World Health Organization (WHO) global eye disease survey conservatively indicate that 14 million persons are blind or severely visually impaired because of AMD. The disease has a tremendous impact on the physical and mental health of the geriatric population and their families and is becoming a major public health burden.Currently, there is neither a cure nor a means to prevent AMD. Palliative treatment options for the l...

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Age-related macular degeneration--emerging pathogenetic and therapeutic concepts.

Ophthalmoscopic evaluation of the optic nerve head.

The cystathionine beta synthase (CBS) gene is localized on chromosome 21 (21q22.3). This enzyme is one of three enzymes able to produce hydrogen sulfide. CBS is overexpressed in Down syndrome with levels 166% of normal values in fibroblasts [Chadefaux et al., 1985] and 1,200% in myeloblasts [Taub et al., 1999]. The CBS overexpression could induceanoverproduction ofhydrogen sulfide in Down syndrome patients, and this overproduction is potentially able to induce some of the clinical signs of Down syndrome such as hypotonia and mental retardation. As thiosulfate is the main catabolite of hydrogen sulfide [Kangas and Savolainen, 1987], we compared the levels of this molecule in the urine of Down syndrome patients and control subjects. Human erythrocytes containvarious formsofhemoglobin.These include sulfhemoglobin, which is formed by transformation of the ferric derivative of hemoglobin, methemoglobin. Sulfhemoglobin production requires hydrogen sulfide (or another sulfide) andmethemoglobin [Nichols et al., 1968]. The determination of sulfhemoglobin in erythrocytes was therefore also used to assess hydrogen sulfide production in Down syndrome. Informed consent was obtained from Down syndrome patients and their parents and from controls. The subjects were assigned to three groups. Group 1 (diet-matched pairs) consisted of 21 pairs of subjects (17 of them were included in a previously published study [Belardinelli et al., 2001]. In each volunteer family, one Down syndrome subject and one relative (mother or father in most families, brother or sister in rare cases) were given identical diets. This group consisted of 13 male and 8 female Down syndrome subjects and matched controls (10 male and 11 female). Sulfur compounds were excluded from the daily treatments of Downsyndromepatientsandcontrols.Group2consisted of 30 patients with Down syndrome (19 male and 11 female) and 20 controls (volunteers from the laboratory; 10 male and 10 female). In this group, age distribution was similar for Down syndrome patients and controls (Table I). The first urine produced in the morning was collected from the subjects of groups 1 and 2 in vials containing boric acid used as a preservative. Thiosulfate was determined in urine by colorimetry after chromatographic separation [Voroteliak et al., 1993]. Creatinine was determined by the manual Jaffe method. Group 3 consisted of 60 Down syndrome patients (33 male and 27 female) and 60 age-matched controls (35 male and 25 female). Venous blood was withdrawn in fasting subjects of group 3; erythrocytes were separated by centrifugation and hemolysates were frozen until use. Sulfhemoglobin was determined by spectrophotometry and the results are expressed as ratio of absorbance (A) at various wawelengths: (A622 nm A636 nm)/(A535 nmþA560 nm) 0.5 10. This ratio was used because it is not affected by differences between the respective concentrations of oxygenated and unoxygenated hemoglobin. A significant difference was observed in the urinary excretion of thiosulfate between Down syndrome patients and relatives of group 1 (diet-matched pairs) (Table I). In group 2, statistical analysis indicates that the differences in thiosulfate excretion persisted. To confirm that hydrogen sulfide was overproduced in Down syndrome patients, we studied erythrocyte sulfhemoglobin content in subjects of group 3. The wawelength ratios were 2.51 0.04 and 2.00 0.08 (SEM) for patientswithDownsyndrome and controls, respectively (P<0.001). We obtained two different types of evidence for the overproduction of hydrogen sulfide in Down syndrome patients. The main function of CBS is to catalyze the first step of transsulphuration pathway, producing cysteine from homocysteine. In vivo, the high level of CBS activity in Down syndrome results in low concentrations of the substrate of CBS (homocysteine) in plasma [Chadefaux et al., 1988]. CBS also has another enzymatic activity: the production of hydrogen sulfide from cysteine [Stipanuck and Beck, 1982]. The endogenous productionofhydrogensulfidecanbeestimatedbymonitoring thiosulfate excretion in urine (31 mmoles/day in control adults) [Sorbo and Ohman, 1978]. After hydrogen sulfide poisoning, the excretion of thiosulfate in urine increased significantly [Kangas and Savolainen, *Correspondence to: Pierre Kamoun, Biochimie B–Tour Lavoisier, Hôpital Necker Enfants Malades, 149, rue de Sèvres, 75743 Paris Cedex 15, France. E-mail: pierre.kamoun@nck.ap-hop-paris.fr

Endogenous hydrogen sulfide overproduction in Down syndrome.

Natural History of Central Retinal Vein Occlusion: An Evidence-Based Systematic Review

Infantile type of so-called neuronal ceroid-lipofuscinosis

• The multiple-dose, dose-response relationship and duration of action of the novel topical carbonic anhydrase inhibitor dorzolamide (previously known as MK-507) were investigated in a doublemasked, randomized, placebo-controlled, parallel study in 73 patients with bilateral primary open angle glaucoma or ocular hypertension. Dorzolamide (0.7%, 1.4%, or 2%) or placebo was administered every 12 hours for 5 days and then every 8 hours for 7 days. Intraocular pressure was investigated with multiple 12-hour diurnal curves. All concentrations of dorzolamide demonstrated substantial lowering of intraocular pressure throughout the day when given twice daily (9% to 21%) or three times daily (14% to 24%). Although a dose-dependent response was observed immediately following the first dose, there were no significant differences between concentrations or dose response at either the twice or three times daily dosing regimen. Three times daily administration of 2% dorzolamide demonstrated a mean percent decrease in intraocular pressure of 18% to 22% throughout the day (mean decrease, 4.5 to 6.1 mm Hg). Dorzolamide appears to have substantial potential in the treatment of glaucoma and ocular hypertension.

Dose Response and Duration of Action of Dorzolamide, a Topical Carbonic Anhydrase Inhibitor

Six new patients with the Cohen syndrome are reported from Finland and 25 published cases from elsewhere are reviewed. New findings are consanguinity among two pairs of parents, granulocytopenia, and marked ophthalmological changes: decreased visual acuity, hemeralopia, constricted visual fields, chorioretinal dystrophy with bull's-eye-like maculae and pigmentary deposits, optic atrophy, and isoelectric electroretinogram. Previously known features of the Cohen syndrome (non-progressive mental retardation, short stature, microcephaly, peculiar facies, slender hands and feet, floppiness, delayed puberty) are confirmed or revised.



The ophthalmological features merit attention in the previous and future suspected cases of the Cohen syndrome. Autosomal recessive inheritance can be taken for granted.

Further delineation of the Cohen syndrome; report on chorioretinal dystrophy, leukopenia and consanguinity.

The intra-operative difficulties and post-operative complications after posterior chamber lens implantation are described in 30 eyes with exfoliation syndrome (including 19 eyes with capsular glaucoma (CG), 30 age- and sex-matched patients with non-exfoliative eyes comprised a comparison group. Three eyes of the control group had simple glaucoma. The highest risk rate for intra-operative difficulties and post-operative complications was found in the CG group. 8/19 eyes had intra-operative difficulties and 7/19 post-operative complications corresponding 3/11 eyes and 2/11 eyes, respectively, in the exfoliation (E) group. Eyes in the control group had a low rate of complications, 3/30 intra-operatively and 2/30 post-operatively. In 63% of the CG and E eyes the visual acuity was 0.5-1.0 1 month post-operatively compared with 70% in the control group. Exfoliation syndrome is not a contraindication for posterior chamber lens implantation. Special attention should be paid to IOL selection. Complications due to insufficient mydriasis, weak zonules and possible undiagnosed lens subluxation, should be taken into account on planning the operation.

Christina Raitta

Papers

Infantile type of so-called neuronal ceroid-lipofuscinosis

Dose Response and Duration of Action of Dorzolamide, a Topical Carbonic Anhydrase Inhibitor

Further delineation of the Cohen syndrome; report on chorioretinal dystrophy, leukopenia and consanguinity.

Intraocular lens implantation in exfoliation syndrome and capsular glaucoma.

n-hexane-induced changes in visual evoked potentials and electroretinograms of industrial workers