Antithyroid drugs in Graves' hyperthyroidism: differences between "block and replace" and "titration" regimes in frequency of euthyroidism and Graves' orbitopathy during treatment.

PURPOSE: Whereas antithyroid drugs (ATD) are the preferred treatment modality for Graves' hyperthyroidism (GH), there is still controversy about the optimal regimen for delivering ATD. To evaluate whether 'Block and Replace' (B + R) and 'Titration' (T) regimes are equivalent in terms of frequency of euthyroidism and Graves' Orbitopathy (GO) during ATD therapy. METHODS: A prospective multicentre observational cohort study of 344 patients with GH but no GO at baseline. Patients were treated with ATD for 18 months according to B + R or T regimen in line with their institution's policy. RESULTS: Baseline characteristics were similar in both groups. In the treatment period between 6 and 18 months thyrotropin (TSH) slightly increased in both groups, but TSH was on average 0.59 mU/L (95% CI 0.27-0.85) lower in the B + R group at all time points (p = 0.026). Serum free thyroxine (FT4) remained stable during the same interval, with a tendency to higher values in the B + R group. The point-prevalence of euthyroidism (TSH and FT4 within their reference ranges) increased with longer duration of ATD in both groups; it was always higher in the T group than in the B + R group: 48 and 24%, respectively, at 6 months, 81 and 58% at 12 months, and 87 and 63% at 18 months (p < 0.002). There were no significant differences between the B + R and T regimens with respect to the fall in thyrotropin binding inhibiting immunoglobulins (TBII) or thyroid peroxidase antibodies (TPO-Ab). GO developed in 15.9% of all patients: 9.1 and 17.8% in B + R group and T group, respectively, (p = 0.096). GO was mild in 13% and moderate-to-severe in 2%. CONCLUSION: The prevalence of biochemical euthyroidism during treatment with antithyroid drugs is higher during T compared to B + R regimen. De novo development of GO did not differ significantly between the two regimens, although it tended to be higher in the T group. Whether one regimen is clinically more advantageous than the other remains unclear.

Asymmetry indicates more severe and active disease in Graves' orbitopathy: results from a prospective cross-sectional multicentre study.

PURPOSE: Patients with Graves' orbitopathy can present with asymmetric disease. The aim of this study was to identify clinical characteristics that distinguish asymmetric from unilateral and symmetric Graves' orbitopathy. METHODS: This was a multi-centre study of new referrals to 13 European Group on Graves' Orbitopathy (EUGOGO) tertiary centres. New patients presenting over a 4 month period with a diagnosis of Graves' orbitopathy were included. Patient demographics were collected and a clinical examination was performed based on a previously published protocol. Patients were categorized as having asymmetric, symmetric, and unilateral Graves' orbitopathy. The distribution of clinical characteristics among the three groups was documented. RESULTS: The asymmetric group (n = 83), was older than the symmetric (n = 157) group [mean age 50.9 years (SD 13.9) vs 45.8 (SD 13.5), p = 0.019], had a lower female to male ratio than the symmetric and unilateral (n = 29) groups (1.6 vs 5.0 vs 8.7, p < 0.001), had more active disease than the symmetric and unilateral groups [mean linical Activity Score 3.0 (SD 1.6) vs 1.7 (SD 1.7), p < 0.001 vs 1.3 (SD 1.4), p < 0.001] and significantly more severe disease than the symmetric and unilateral groups, as measured by the Total Eye Score [mean 8.8 (SD 6.6) vs 5.3 (SD 4.4), p < 0.001, vs 2.7 (SD 2.1), p < 0.001]. CONCLUSION: Older age, lower female to male ratio, more severe, and more active disease cluster around asymmetric Graves' orbitopathy. Asymmetry appears to be a marker of more severe and more active disease than other presentations. This simple clinical parameter present at first presentation to tertiary centres may be valuable to clinicians who manage such patients.

[Alternative Methods of Local Therapy for Complicated Periocular Infections - Two Case Reports]. / Alternative Methoden der Lokaltherapie bei komplizierten periokulären Infektionen ­ 2 Fallberichte.

Background Wounds of the eyelid can usually be cured with common surgical measures and the use of local antibiotics. Here we present two cases to demonstrate that biological debridement and negative pressure vacuum therapy (NPWT), two second line therapies, are effective and possibly superior alternatives to conventional, antibiotic-based approaches. Methodology and Result A persistent infectious wound of the upper eyelid after surgical debridement of necrotising fasciitis and an upper eyelid abscess with multiple purulent entry points, which was refractory to a five-week antibiotic regimen, were treated with biological debridement and NPWT. The combination of these two therapies leads to an optimal outcome. Conclusion Our cases demonstrate that, in ophthalmology, uncommon methods such as biological debridement and NPWT are quite practicable and are valuable therapeutic options.

Charles Bonnet's syndrome: not only a condition of the elderly.

PURPOSE: To investigate whether the experience of visual hallucinations, namely Charles Bonnet's syndrome, in psychologically healthy people is a phenomenon solely of elderly, visually impaired people. METHODS: In a prospective controlled study, four groups of subjects (total 324) were formed: age ≤40 years, no visual impairment; age ≤40 years, visually impaired; age >40 years, no visual impairment; age >40 years, visually impaired. Visual impairment was defined as best-corrected visual acuity ≤0.3 (Snellen) in the better-seeing eye. Each group consisted of 81 subjects. Visual hallucinations were defined as complex visual perceptions. After ruling out psychiatric causes for visual hallucinations or medication related to the experience of visual hallucinations, affected subjects underwent a detailed interview about their visual hallucinations. RESULTS: The prevalence of visual hallucinations among young subjects with visual impairment was 4.9 %; among the elderly visually impaired subjects, it was 6.2 %. The difference was not statistically significant. No subject without visual impairment experienced visual hallucinations. CONCLUSIONS: Charles Bonnet's syndrome is not limited to elderly people suffering from visual impairment, though there tends to be a higher prevalence of visual hallucinations in this group.

Thyroid-stimulating immunoglobulins indicate the onset of dysthyroid optic neuropathy.

PURPOSE: Recognition of dysthyroid optic neuropathy (DON) requires sensitive diagnostic tools. Clinical assessment may fail to reliably evaluate the acuteness of DON especially if signs for inflammation are missing. Aim of this cross-sectional study was to assess the relationship between thyroid-stimulating immunoglobulins (TSI) and onset of DON. METHODS: At a multidisciplinary orbital center, serum TSI levels were measured in 180 consecutive patients with thyroid eye disease (TED) and 302 healthy controls with a FDA-cleared cell-based bioassay using a chimeric TSH receptor and a CRE-dependent luciferase. RESULTS: Thirty of 180 (16.7 %) patients with TED had DON of recent onset or a past history of DON (post-DON). Optic disk swelling was present and visual-evoked potentials were pathologic in all eyes with DON of recent onset, but in one of 13 (7.7 %) with post-DON, only (p = 0.005). 19/20 (96 %) patients with DON of recent onset were TSI-positive. TSI was associated with DON of recent onset (OR: 20.96; 95 % CI 1.064-412.85, p = 0.045). All controls were TSI negative. TSI correlated with the clinical activity score (R = 0.70, p < 0.001) and higher TSI-levels were noted in active vs. inactive TED (485.1 ± 132.3 vs. 277.7 ± 143.7 %, cut-off < 140 %; p < 0.001). Six of seven (85.7 %) patients with inactive TED with recent onset DON versus one of four (25 %) with active post-DON were TSI-positive (p = 0.006). A discriminatory cut-point of 377 SRR % for TSI was determined based on a ROC analysis (sensitivity: 0.95, specificity: 0.8). CONCLUSIONS: Serum TSI levels identify patients with DON of recent onset requiring urgent therapy.

[In-vivo Confocal Microscopy for the Diagnosis of Mucous Membrane Pemphigoid]. / In-vivo-Konfokalmikroskopie in der Diagnose des okulären Schleimhautpemphigoids.

BACKGROUND: An early diagnosis is crucial for the outcome of mucous membrane pemphigoid (MMP). The sensitivity of the so-called diagnostic gold standard, direct and indirect immune fluorescence (DIF/IIF) ranges from 30 to 80 %, and is thus lower than desirable. Moreover, conjunctival biopsy, mandatory in most cases, entails the risks of exacerbation. The purpose of this study is to establish the contribution of non-invasive in vivo confocal microscopy to the recognition of MMP. PATIENTS AND METHODS: We examined the conjunctiva of ten patients and ten control subjects with the confocal microscope Heidelberg Retina Tomograph II/Rostock Cornea Module and checked for differences in qualitative and quantitative structure of the connective tissue. RESULTS: Pemphigoid patients showed an increase and/or aggregation of reticular connective tissue with hyperreflective strands in the substantia propria, as well as an increased subepithelial fibrosis compared to controls. The basal membrane zone was thicker and more hyperreflective than in the healthy subjects. CONCLUSION: In-vivo confocal microscopy may serve as a useful additional diagnostic method in the detection of MMP.

Thyroid-associated orbitopathy is linked to gastrointestinal autoimmunity.

Common autoimmune disorders tend to co-exist in the same subjects and cluster in families. The objective of this study was to determine the prevalence of autoimmune co-morbidity in patients with autoimmune thyroid disease (AITD) with and without thyroid-associated orbitopathy (TAO). This was a cross-sectional study conducted at an academic tertiary referral centre. Of 1310 patients with AITD [n = 777 or 59% with Graves' disease (GD) and n = 533, 41% with Hashimoto's thyroiditis (HT)] followed at a specialized joint thyroid-eye out-patient clinic, 176 (13·4%) had an adult type of the autoimmune polyglandular syndrome, 129 (9·8%) type 1 diabetes, 111 (8·5%) coeliac disease, 60 (4·6%) type A autoimmune gastritis, 57 (4·4%) vitiligo and 25 (1·9%) Addison's disease. Coeliac disease and autoimmune gastritis were associated positively with GD [odds ratio (OR) = 2·18; P = 0·002 and OR = 6·52; P < 0·001], whereas type 1 diabetes, Addison's disease, autoimmune primary hypogonadism, alopecia areata, rheumatoid arthritis and Sjögren's syndrome were 'protective' for GD and thus linked to HT, OR = 0·49 (P < 0·001), 0·06 (P < 0·001), 0·25 (P < 0·001), 0·50 (P = 0·090) and 0·32 (P = 0·003), respectively. Of 610 (46·6%) AITD patients with TAO, 584 (95·7%) and 26 (4·3%) had GD and HT, respectively (P < 0·001). TAO was most prevalent in GD patients with coeliac disease (94%, OR = 1·87, P < 0·001). Multivariate analysis showed high OR for coeliac disease and autoimmune gastritis (3·4 and 4·03, both P < 0·001) pertaining to the association with TAO while type 1 diabetes, Addison's disease and alopecia areata were protective for TAO. In patients with TAO, coeliac disease is the most prevalent co-morbid autoimmune condition and rates are increased compared to GD patients without TAO.

[Patient satisfaction after transverse blepharotomy (Wies procedure) in the management of senile entropion - a postoperative analysis]. / Die horizontale Lidspaltung bei Involutionsentropium - eine Befragung zur postoperativen Zufriedenheit.

BACKGROUND: Senile entropion is a common pathology of the aging lid. Chronic irritation of the conjunctiva and/or cornea is bothersome to the patients and may cause severe complications. Surgical intervention is typically required. We present data from a postoperative telephone interview of 38 patients undergoing 43 entropion repairs, which were performed as transverse blepharotomy according to Wies in the modification of Collin. PATIENTS AND METHODS: In a retrospective study 43 surgeries were evaluated. Mean follow-up time was 34 (6-96) months. 8 entropions were recurrencies, one surgery was performed after ectropion. Patient satisfaction, complications and symptoms after surgery and frequency of repeated surgery were evaluated by sending a questionnaire with subsequent telephone survey. RESULTS: The transverse blepharotomy was successful in 31 cases (91.2 %) as a primary surgical intervention. In recurrencies, a successful result was obtained in 8 lids (88.9 %). 4 lids underwent further surgical procedures: 2/43 eyes developed another entropion (4.7 %), one exhibited overcorrection/ectropion and one developed a lid malposition which could not be exactly specified during telephone interview. 2 patients complained of newly appearing dry eye symptoms/foreign body sensation (4.7 %) and one each suffered from granuloma due to incompletely removed suture material and fistulation. CONCLUSION: Although being a historically "old" surgical technique to treat involutional entropion, horizontal blepharotomy according to Wies proved successful in the vast majority of our patients. The overall success rate in our series was 90.7 % and rose to 91.2 % in cases of primary surgery. Even in recurrent disease, 88.9 % of surgeries resulted in sustained correction of the lid malposition.

[Therapy for systemic metabolic disorders based on the detection of basic corneal landmarks in childhood]. / Hornhaut-Schlüsselbefunde im Kindesalter als Hinweis für therapierbare systemische Stoffwechselerkrankungen.

Many systemic lysosomal storage disorders show basic corneal opacities already in childhood. The lysosome is a cell organelle, produced by Golgi's apparatus, that is surrounded by a membrane and contains hydrolytic enzymes that break down food molecules, especially proteins and other complex molecules. The ophthalmologist's precise diagnosis of corneal clouding at the slit-lamp may reveal the correct interpretation of the specific lysosomal storage disorder. It is very important to diagnose such diseases as soon as possible because today the development of systemic enzymatic therapies has broadened the therapeutic armamentarium for the current standard of care. The following corneal landmarks of systemic storage diseases and of the modern systemic therapy are presented: cornea verticillata in Fabry's disease, periodic infusion of alpha-galactosidase a; Kayser-Fleischer's ring in Wilson's disease, zinc, trienetin, low copper diet; multiple, punctiform crystals in cystinosis, cysteamine, Raptor RP 103(DR cysteamine) that reduces the cytotoxity in form of continous dissolving of cystine from lysosome, renal transplantation, haematopoietic stem cell transplantation; peripheral ring, but not true lipid arc, and moderate stromal haze in LCAT-deficiency, injection of recombinant enzyme or of encapsulated LCAT-secreting cells; diffuse stromal haze in mucopolysaccharidoses (MPS). Enzyme replacement therapy is currently indicated for MPS I, MPS II, and MPS VI, haematopoietic stem cell transplantation; painful, bilateral pseudo-dendritic opacities in tyrosinemia type II (eponym: Richner-Hanhart syndrome), low phenylalanine and tyrosine diet result in complete disappearance of corneal alterations with a consecutive painfree period. Strict diet during the whole life is necessary to prevent corneal recurrences and the occurrence of palmo-plantar keratoses. Such therapies can enable the patient to lead an otherwise normal life for decades.

Dose of intravenous steroids and therapy outcome in Graves' orbitopathy.

BACKGROUND AND AIM: Several trials have proved the efficacy of intravenous (IV) steroids in Graves' orbitopathy (GO). However, the impact of administered dose and therapy schedule has not been assessed yet. SUBJECTS AND METHODS: Nine randomized and 14 non-randomized controlled trials of IV steroids in GO were evaluated according to the applied single and cumulative doses with respect to outcome, efficacy on clinically relevant issues and adverse events. RESULTS: High single (1 g per day) and cumulative (>6 g) doses of IV steroids are superior to lower single (0.5 g/d) and cumulative (<5 g) doses with respect to therapy response (84 vs 75%; p=0.034 and 83 vs 77%; ns, respectively), improvement of eye symptoms (87 vs 75%, p=0.052 and 85 vs 71%; ns, respectively) and disappearance of diplopia (32 vs 27%; ns and 48 vs 27%; p=0.08, respectively). Decrease of both clinical activity score (3 vs 2.5 points and 2.5 vs 3, ns) as well as proptosis (-1.4 vs -1.2 mm, ns and 1.5 vs 1.2, ns) are similar in both groups. However, high single and/or cumulative doses are accompanied with a 2-fold higher rate of adverse events (56 vs 28%; p<0.001 and 52 vs 33%; p=0.034, respectively). CONCLUSIONS: Tailoring the IV steroid dose to severity of GO can be concluded and implies that a prospective randomized trial comparing different doses of IV steroids in active/severe GO is keenly warranted.

[Lysosomal storage diseases - update and new therapeutic options]. / Lysosomale Speichererkrankungen - Update und neue therapeutische Optionen.

Lysosomal storage diseases represent a group of about 50 genetic disorders. The deficiencies of lysosomal and non-lysosomal proteins cause an accumulation of compounds which are normally degraded within the lysosome. There are currently no therapeutic options to cure patients suffering from a lysosomal storage disease. Due to their progressive nature there is considerable morbidity and mortality. Thus, an early treatment to maintain major systemic functions is of utmost importance. While so far only symptomatic therapies are in use, the newly available enzyme replacement therapies offer a real causal approach for selected storage diseases. Many of these disorders are characterised by pathognomonic eye findings. Therefore, the ophthalmological examination provides the opportunity for an early and non-invasive diagnosis and a chance to initiate early treatment. This review is intended to give a survey of the most common lysosomal storage diseases, particularly with regard to ophthalmological changes as well as illustrate new therapeutic options.

[Chronic eyelid oedema and rosacea (Morbus Morbihan): diagnostic and therapeutic challenges]. / Chronisches Lidödem assoziiert mit Rosazea (Morbus Morbihan): Differenzialdiagnostische Schwierigkeiten und Therapieoptionen.

BACKGROUND: Morbus Morbihan is a rare complication of rosacea, consisting of a persistent lymphoedema of the upper part of the face. It has typically a chronic course, unspecific histopathological findings and an extreme refractoriness to therapy. PATIENTS AND METHODS: Between February 2008 and January 2010, 5 patients with Morbus Morbihan were observed at the Department of Ophthalmology of the University Medical Centre Mainz. In the present cohort study, we describe the clinical, laboratory and histological findings that led to the diagnosis. The course of the affection and the results of different therapeutic options are also reported. RESULTS: Each patient underwent a complete ophthalmological examination, as well as general and dermatological consultations. All patients showed facial skin alterations typical for rosacea. 4 out of 5 subjects underwent a lid biopsy to confirm the diagnosis of Morbus Morbihan, one patient refused it. Initial treatment consisted of various systemic and local medical therapies, however, with poor success. One patient had intravenous therapy with corticosteroids elsewhere with no effect. We treated 3 cases with intralesional triamcinolone injections with good results. 2 patients underwent upper lid blepharoplasty. Results of surgery remained stable also due to manual lymph drainage and intralesional injections of triamcinolon. No complications or side effects were seen in patients treated with triamcinolone. CONCLUSIONS: Morbus Morbihan can be diagnosed only after excluding other conditions leading to chronic lid swelling. In our series, good results were achieved with intralesional injection of triamcinolone. Surgery also led to relevant improvements for a long period (13 months), with some adjuvant therapy. The treatment of chronic eyelid oedema associated with rosacea remains a challenge for the ophthalmologist and the oculoplastic surgeon.

[Significance of the horizontal lid split in the surgical therapy for involutional entropion]. / Stellenwert der horizontalen Lidspaltung nach Wies in der Entropiumchirurgie.

The horizontal blepharotomy or Wies procedure is a simple and quick surgical procedure for the correction of an involutional entropion. The procedure is directed against two of the at least three most important pathogenetic factors (horizontal lid loosening and overriding the preseptal orbicularis muscle). This article gives an overview of the literature and significance of this procedure gained in the 50 years since its first description.

Clinical features of pediatric Graves' orbitopathy.

Pediatric Graves' orbitopathy is rare, thus its clinical picture is less well defined in comparison with the adult population. Therefore it is our aim to describe the clinical spectrum at our tertiary referral center. We identified 11 patients under the age of 18 years (3♂, 8♀; range 3-16 years, mean age 14.5 years) with Graves' disease and signs of orbitopathy. Seven of them where reevaluated (mean follow-up 25 months, range 3-66 months). Eyelid retraction and proptosis were the predominant signs in 10/11 of our patients. In six patients, Hertel readings ranged from 22 mm or above. Mild ocular motility impairment was seen in four children. Active orbitopathy or severe impairment of visual acuity/ocular motility, corneal or optic nerve involvement was not observed in our study. Our series confirms that pediatric Graves' orbitopathy lacks significant inflammatory features; however, proptosis is common and may be marked. All seven patients who were reevaluated did not show any clinically significant change of ocular signs during the observation period. In particular, there was no improvement of proptosis despite restoration of euthyroidism.

[Bilateral ocular surface squamous neoplasia and neurodermatitis. Two cases with different courses]. / Bilaterale konjunktivale Plattenepithelneoplasie bei Neurodermitis. Zwei Fälle mit unterschiedlichem Verlauf.

Recent data suggest neurodermatitis as a risk factor for ocular surface squamous neoplasia (OSSN). We describe two cases of bilateral OSSN associated with chronic atopic keratoconjunctivitis. The cases support the hypothesis that neurodermatitis is a risk factor for OSSN. Additional risk factors may facilitate development and progression of the disease.

Graves' orbitopathy as a rare disease in Europe: a European Group on Graves' Orbitopathy (EUGOGO) position statement.

BACKGROUND: Graves' orbitopathy (GO) is an autoimmune condition, which is associated with poor clinical outcomes including impaired quality of life and socio-economic status. Current evidence suggests that the incidence of GO in Europe may be declining, however data on the prevalence of this disease are sparse. Several clinical variants of GO exist, including euthyroid GO, recently listed as a rare disease in Europe (ORPHA466682). The objective was to estimate the prevalence of GO and its clinical variants in Europe, based on available literature, and to consider whether they may potentially qualify as rare. Recent published data on the incidence of GO and Graves' hyperthyroidism in Europe were used to estimate the prevalence of GO. The position statement was developed by a series of reviews of drafts and electronic discussions by members of the European Group on Graves' Orbitopathy. The prevalence of GO in Europe is about 10/10,000 persons. The prevalence of other clinical variants is also low: hypothyroid GO 0.02-1.10/10,000; GO associated with dermopathy 0.15/10,000; GO associated with acropachy 0.03/10,000; asymmetrical GO 1.00-5.00/10,000; unilateral GO 0.50-1.50/10,000. CONCLUSION: GO has a prevalence that is clearly above the threshold for rarity in Europe. However, each of its clinical variants have a low prevalence and could potentially qualify for being considered as a rare condition, providing that future research establishes that they have a distinct pathophysiology. EUGOGO considers this area of academic activity a priority.

A questionnaire survey on the management of Graves' orbitopathy in Europe.

OBJECTIVE: To determine management patterns among clinicians who treat patients with Graves' orbitopathy (GO) in Europe. DESIGN AND METHODS: Questionnaire survey including a case scenario of members of professional organisations representing endocrinologists, ophthalmologists and nuclear medicine physicians. RESULTS: A multidisciplinary approach to manage GO was valued by 96.3% of responders, although 31.5% did not participate or refer to a multidisciplinary team and 21.5% of patients with GO treated by responders were not managed in a multidisciplinary setting. Access to surgery for sight-threatening GO was available only within weeks or months according to 59.5% of responders. Reluctance to refer urgently to an ophthalmologist was noted by 32.7% of responders despite the presence of suspected optic neuropathy. The use of steroids was not influenced by the age of the patient, but fewer responders chose to use steroids in a diabetic patient (72.1 vs 90.5%, P<0.001). Development of cushingoid features resulted in a reduction in steroid use (90.5 vs 36.5%, P<0.001) and increase in the use of orbital irradiation (from 23.8% to 40.4%, P<0.05) and surgical decompression (from 20.9 to 52.9%, P<0.001). More ophthalmologists chose surgical decompression for patients with threatened vision due to optic neuropathy, who were intolerant to steroids than other specialists (70.3 vs 41.8%, P<0.01). CONCLUSION: Deficiencies in the management of patients with GO in Europe were identified by this survey. Further training of clinicians, easier access of patients to specialist multidisciplinary centres and the publication of practice guidelines may help improve the management of this condition in Europe.

[Eye involvement in neurofibromatosis]. / Augenbeteiligung bei Neurofibromatose.

Neurofibromatosis 1 (NF1) and neurofibromatosis 2 (NF2) are characterized by an autosomal dominant pattern of inheritance with irregular penetrance and a broad spectrum of different clinical phenotypes. There are large variations in the age of onset, progression and prognosis. Symptoms are often manifested early in childhood. Characteristics which the two main forms NF1 and NF2 have in common are a positive family history, characteristic skin alterations, such as café au lait macules, axillary or inguinal freckling and neural tumors such as neurofibroma and optic glioma (NF1) as well as (bilateral) vestibular schwannomas (NF2). An interdisciplinary cooperation is necessary for the diagnostics and therapy.

[Optic disc swelling : A compilation of relevant differential diagnoses]. / Differenzialdiagnose der Papillenschwellung : Wichtige Differenzialdiagnosen im Überblick.

Optic disc oedema describes blurred optic disc margins. It describes an unspecific clinical sign with various possible underlying causal mechanisms. The correct diagnosis and the detection of the underlying disease is however of special clinical importance. This article summarizes the most important differential diagnoses and gives advice to find the correct diagnosis.