Severe delayed posttonsillectomy haemorrhage due to a pseudoaneurysm of the lingual artery A 3.5-year-old child is presented with severe , recurrent haemorrhages after a tonsillectomy . The haemorrhages were caused by a pseudoaneurysm of the lingual artery , which was visualised more than 2 weeks postoperatively by angiography . The pseudoaneurysm was successfully embolised by coils . Coiling is an adequate therapeutic option for severe posttonsillectomy haemorrhage due to arterial damage . Introduction Postoperative haemorrhage is the most common serious complication of adenotonsillectomy and its incidence is around 3 % -LSB- 1 -RSB- . Intraoperative bleeding -LRB- < 24 h -RRB- may be related to the surgical technique or a bleeding diathesis . Delayed postoperative haemorrhage -LRB- > 24 h -RRB- predominantly occurs on the fifth to seventh-day postoperatively when the slough separates from the granulating fossa . The most critical posttonsillectomy haemorrhages are due to arterial dissections and aneurysms . In this report we present a boy with a severe , delayed posttonsillectomy haemorrhage due to a pseudoaneurysm of the lingual artery . Case report An otherwise healthy 3.5-year-old boy was brought in with severe oral bleeding . Nine days prior to the presentation he had undergone an adenotonsillectomy for chronic adenotonsillitis in another hospital . The tonsils had been removed with cold dissection and sutures had been placed in both tonsil areas . The procedure and the immediate postoperative period went uncomplicated . On the fifth postoperative day he had been admitted for a one-night observation because of haemorrhage from the mouth . During the admission no active bleeding was observed and his haemoglobin level of 4.9 mmol/l -LRB- normal values : 6.5 -- 8.4 mmol/l -RRB- was treated conservatively . The second postoperative bleeding started 9 days postoperatively , late at night when the patient was lying in bed . There were no provoking events . The bleeding lasted around 10 min but had already stopped at arrival in our emergency room . We saw a pale and restless boy . Intra-oral examination in general anaesthesia showed lacerated pharyngeal muscles in the left tonsillar fossa and a loose suture was removed . The right tonsillar fossa revealed diffuse bleeding from the pharyngeal muscles without pulsating masses . The nasopharynx and tongue base showed no abnormalities . The haemoglobin was increased from 2.9 to 8.2 mmol/l by transfusion with two units of packed red blood cells . The coagulation values were within the normal range . The postoperative period was uncomplicated , so he was discharged after 5 days , 15 days after the primary intervention , with dietary advices . One day later the boy arrived by ambulance with heavy bleeding from the mouth . He was pale , shivering and drowsy . Again , the severe bleeding started without a provoking moment and persisted for about 15 min . Immediately , after arrival at our emergency department , he was re-explored intra-orally under general anaesthetics . We saw a bluish , pulsating mass of 5 by 12 mm low in the right tonsillar fossa without active bleeding . The faucial pillars on the right side were approximated without tearing the mucosa or induration of the aneurysm . However , during extubation a massive bleeding occurred . The boy was re-intubated , and with digital oral pressure during 15 min haemostasis was achieved . The patient was stabilised and an arteriography was performed . A pseudoaneurysm of the right lingual artery was visualized with selective catheterisation using a vertebral catheter -LRB- Fig. 1 -RRB- . The pseudoaneurysm was coiled distally and proximally using a microcatheter -LRB- Excelsior 10 , Boston scientific , Natick , MA , USA -RRB- and microcoils -LRB- GDC 10 , Boston Scientific , Natick , MA , USA -RRB- . The close relation of the proximal part of the pseudoaneurysm to the entrance of the facial artery made coiling of the facial artery inevitable . The pseudoaneurysm was coiled successfully and no bleeding focus was seen on the control arteriography -LRB- Figs. 2 , 3 -RRB- . During the procedures blood transfusion was needed to restore the low haemoglobin level . Fig. 1Pseudoaneurysm of the right lingual artery seen from right-anterior side -LRB- 3D-surface rendering -RRB- Fig. 2Arteriography of pseudoaneursym of the right lingual artery seen from right-anterior sideFig . 3After coiling of the pseudoaneurysm , including the facial artery ; compare to Fig. 2 The boy was extubated without any bleeding and 4 days after the embolisation he was discharged in a good clinical condition . At a follow-up examination , he did not report any intra-oral or neurological abnormalities . Discussion True aneurysms develop through congenital or acquired weakness of all three layers of the vascular wall . False or pseudoaneurysms may arise due to localised arterial wall laceration caused by blunt or penetrating trauma . The intima or adventitia layer of the vessel wall is dissected , which creates a periarterial haematoma . Pseudoaneurysms after tonsillectomy may be triggered by blunt or direct trauma during dissection or due to placing ligation sutures . Haemorrhages from posttonsillectomy pseudoaneurysms of the lingual , facial and internal carotid artery have been observed within 5 h postoperatively to the eighth postoperative day in a few cases -LSB- 2 , 3 -RSB- . In those reports no intra-oral pulsating masses were observed . The pseudoaneurysms were shown with angiography and treated with embolisation . Mitchell et al. reported a case of fulminant bleeding during the tonsillectomy procedure from an aberrant lingual artery with a pseudoaneurysm , which was treated with embolisation -LSB- 4 -RSB- . A pulsating neck mass can also be the first symptom of a pseudoaneurysm , which has been seen in two cases without any bleeding -LSB- 5 , 6 -RSB- . It is striking that the above-mentioned cases of posttonsillectomy pseudoaneurysms concerned children under the age of 10 years . No cases of posttonsillectomy haemorrhage due to pseudoaneurysms in adults have been reported . This suggestive higher incidence of pseudoaneurysms in children might result from the smaller anatomy and thinner pharyngeal muscles , and a subsequent higher risk of damaging the large vessels . Since the angiography of our patient did not show any aberrant courses of arteries , trauma to the artery during dissection or placing the suture in the tonsillar fossa could have caused the pseudoaneurysm in our patient . In the two first oral inspections no masses were observed , only after the third bleeding -LRB- 16th day postoperatively -RRB- a pulsating mass was seen . This suggests a gradual development of the aneurysm . False aneurysms are known to expand when the periarterial clot dissolves and more blood flows into the periarterial space -LSB- 5 -RSB- . The size of the lesion to the vessel wall might determine the amount of blood and whether the pseudoaneurysm is large enough to be observed . Maybe the vessel lesion in our patient was small , which made the pseudoaneurysm grow slowly . Although no real provoking events seem to have initiated the bleedings , lying down in bed might have raised the blood pressure in the carotid artery , which made the aneurysm leak . A new clot made the severe short lasting bleeding stop . Severe posttonsillectomy haemorrhage is treated with external ligation of the internal or external carotid artery or endovascular coiling of the injured artery . Although a randomized controlled trial has not been performed , embolisation seems to have advantages over external ligation -LSB- 7 -RSB- . Firstly , the diagnostic evaluation can be combined with direct therapeutic intervention . Furthermore , coiling is more selective . This is especially convenient in posttonsillectomy haemorrhages , where several branches of the external or internal carotid artery could be damaged . The third advantage is that embolisation is less mutilating and has less risk of damaging the vagal and accessory nerves . The potential complications of embolisation are perforation of the vessel with leakage of coils , ischemia of mucosa or nerves , or vasospasm . External ligation seems to be the only quick option in massive bleeding and unstable patients . Conclusion Pseudoaneurysms are life-threatening and should be considered in severe posttonsillectomy haemorrhage . Pseudoaneurysms do not always present as intra-oral or cervical pulsating masses , and can develop gradually . If the technique and technical crew are available , interventional arteriography is strongly recommended in severe posttonsillectomy haemorrhage . It is diagnostic and therapeutic at the same time and more selective than surgical ligation .

O O B I O O O B O O B I O O O O O O O O O O O O O O O O O O O O B O O B I O O O O O O O O O O O O O B O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O B O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B I O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O B I O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B I O O B O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O

pseudoaneurysm
lingual artery
posttonsillectomy haemorrhage
embolisation


Metabolic and vascular determinants of impaired cognitive performance and abnormalities on brain magnetic resonance imaging in patients with type 2 diabetes Aims/hypothesis The determinants of cerebral complications of type 2 diabetes are unclear . The present study aimed to identify metabolic and vascular factors that are associated with impaired cognitive performance and abnormalities on brain MRI in patients with type 2 diabetes . Introduction Diabetes mellitus is associated with slowly progressive changes in the brain -LSB- 1 -RSB- . Neuropsychological studies show that patients with type 2 diabetes mellitus have mild to moderate impairments in attention and executive functioning , information processing speed and memory -LRB- for reviews see -LSB- 2 , 3 -RSB- -RRB- . Patients with type 2 diabetes also show changes on brain magnetic resonance imaging -LRB- MRI -RRB- , such as cortical and hippocampal atrophy -LSB- 4 , 5 -RSB- . We have recently shown that cognitive dysfunction in patients with type 2 diabetes was associated with white matter lesions -LRB- WML -RRB- , -LRB- silent -RRB- brain infarcts and to a lesser extent with atrophy -LSB- 6 -RSB- . The determinants of changes in cognition and abnormalities on brain MRI of patients with type 2 diabetes are uncertain -LSB- 2 -RSB- . Some studies report associations with hypertension -LSB- 3 , 4 , 7 , 8 -RSB- , but this was not supported by others -LSB- 5 , 9 , 10 -RSB- . Associations between impaired cognition and chronic hyperglycaemia have also been noted -LSB- 9 -RSB- . Studies on other diabetic complications may provide leads for potentially relevant determinants . Complications like nephropathy , retinopathy and neuropathy are thought to be due to hyperglycaemia-induced microangiopathy -LSB- 11 , 12 -RSB- , with additional involvement of hypertension and macrovascular disease -LSB- 13 -- 15 -RSB- . Since atherosclerosis and hypertension are established risk factors for age-related cognitive decline and brain MRI changes in the general population -LSB- 16 -- 19 -RSB- , we hypothesised that the combined effects of atherosclerotic macrovascular disease , chronic hyperglycaemia and hypertension are involved in the development of cognitive impairments in patients with type 2 diabetes . The aim of the present study was to identify possible metabolic and vascular determinants of cognitive dysfunction and changes on brain MRI in patients with type 2 diabetes . Given the uncertainty about these determinants , an exploratory design was chosen . A detailed neuropsychological examination and brain MRI were obtained from a large cross-sectional sample of type 2 diabetes patients and related to different measures of glucose metabolism , vascular risk factors , microvascular complications and macrovascular disease . Methods Participants The Utrecht Diabetic Encephalopathy Study aims to identify determinants of cognitive impairment in patients with diabetes -LSB- 6 -RSB- . Therefore , patients were not selected for the presence or absence of diabetic complications , co-morbid conditions -LRB- e.g. hypertension -RRB- or exposure to other risk factors -LRB- e.g. smoking -RRB- . For inclusion patients had to be 55 to 80 years of age , functionally independent and speakers of Dutch , with a minimal diabetes duration of 1 year . Exclusion criteria for all participants were : a psychiatric or neurological disorder that could influence cognitive functioning ; a history of alcohol or substance abuse and dementia ; and , for the control group , a fasting blood glucose ≥ 7.0 mmol/l -LSB- 20 -RSB- . Participants with a history of stroke who were still fully functionally independent were classified as eligible . To increase statistical power for within-group analyses in the type 2 diabetes group , twice as many patients as controls were enrolled.Overall , 122 patients with type 2 diabetes -LRB- age 56 -- 80 years -RRB- and 56 controls -LRB- age 57 -- 78 years -RRB- were included in the present study . Patients were recruited through their general practitioners ; controls were spouses or acquaintances of the patients . Groups were comparable for age , sex and educational level . The study was approved by the local medical ethics committee and each participant signed an informed consent form . All participants underwent a 2 day protocol , which included brain MRI , a neurological and neuropsychological examination , retinal photography and ultrasonography of the carotid arteries . Fasting blood and urine samples were collected and blood pressure was recorded . In one control person and two type 2 diabetes patients it was not possible to perform the neuropsychological examination . Similarly , MRIs could not be obtained in five controls and nine type 2 diabetes patients , mostly due to MRI contraindications -LRB- claustrophobia , pacemaker -RRB- . Neuropsychological examination The neuropsychological examination tapped the major cognitive domains in verbal and non-verbal ways . Eleven tasks were administered in a fixed order , taking about 90 min to complete . These tasks were divided into five cognitive domains , as described previously -LSB- 6 -RSB- : -LRB- 1 -RRB- attention and executive functioning ; -LRB- 2 -RRB- information processing speed ; -LRB- 3 -RRB- memory ; -LRB- 4 -RRB- abstract reasoning ; and -LRB- 5 -RRB- visuoconstruction . For analysis the test scores were standardised into z scores for each of the five domains , based on the means of the whole group . The mean performance from each participant across the domains is expressed as the composite cognitive z score.Premorbid IQ was assessed with the Dutch version of the National Adult Reading Test . To control for possible effects of mood disturbances or affective disorders a Beck depression inventory -LSB- 21 -RSB- was performed . Brain MRI The MRI investigation -LRB- 1.5 T ; Philips Medical Systems , Best , the Netherlands -RRB- consisted of an axial T1-weighted and an axial T2 and T2 fluid-attenuating inverse recovery -LRB- FLAIR -RRB- scan -LRB- TR/TE/TI : 6000/100/2000 , field of view 230 mm , matrix 180 × 256 , slice thickness 4.0 mm , contiguous , 38 slices -RRB- . WML were rated according to the Scheltens scale -LSB- 22 -RSB- with slight modifications -LSB- 6 -RSB- . Periventricular WML -LRB- PWML -RRB- were rated on a severity scale -LRB- 0 -- 2 -RRB- at the frontal and occipital horns and the body of the lateral ventricle on both sides -LRB- sum score 0 -- 12 -RRB- . For the rating of deep -LRB- subcortical -RRB- WML -LRB- DWML -RRB- the brain was divided into six regions : frontal , parietal , occipital , temporal , basal ganglia and infra-tentorial . Per region the size and number of WML were rated on a scale ranging from 0 to 6 . The total score thus ranged from 0 to 36 . Cortical atrophy was evaluated by the frontal interhemispheric fissure ratio and the Sylvian fissure ratio -LSB- 23 -RSB- . Subcortical atrophy was evaluated by the bifrontal ratio and by the bicaudate ratio -LSB- 23 -RSB- . These ratios were converted to z scores : a cortical atrophy z score -LRB- mean of z frontal fissure ratio and z Sylvian fissure ratio -RRB- and a subcortical atrophy z score -LRB- mean of z bicaudate ratio and z bifrontal ratio -RRB- . All MRI scans were rated by two investigators -LRB- S. M. Manschot and G. J. Biessels -RRB- blinded for presence or absence of diabetes or other characteristics . In case of disagreement of more than 1 point on the WML scales in a particular region or more than 5 mm -LRB- actual size -RRB- on any of the atrophy measurements -LRB- 2 mm for fissure widths -RRB- , a consensus reading was held -LRB- 0 % of PWML , 4 % of DWML and 4 % of atrophy ratio readings were thus affected -RRB- . In all other cases the readings of both raters were averaged . Diabetes characteristics and glucose metabolism A standardised questionnaire addressed medical history , medication use , diabetes duration and the life-time occurrence of severe hypoglycaemic episodes -LRB- defined as episode of hypoglycaemia severe enough to require the assistance of another person , hospitalisation or emergency room visit -RRB- . BMI was calculated as weight divided by height square.Blood was drawn by venepuncture to assess HbA1c , fasting glucose and insulin levels . Insulin resistance was estimated with the homeostasis model assessment of insulin resistance -LRB- HOMA-IR -RRB- . The HOMA-IR is calculated as fasting glucose -LRB- mmol/l -RRB- × fasting insulin -LRB- mU/l -RRB- / 22.5 -LSB- 24 -RSB- . Because insulin was expressed in pmol/l we used the formula fasting glucose -LRB- mmol/l -RRB- × fasting insulin -LRB- pmol/l -RRB- / -LRB- 22.5 × 6.945 -RRB- -LSB- 24 -RSB- . Vascular risk factors Blood pressure was measured at home at nine fixed time points during the day with an automatic blood pressure machine -LRB- 705CP ; Omron , Mannheim , Germany -RRB- . These measurements were averaged . In the primary analysis hypertension was defined as a mean systolic blood pressure > 160 mmHg or a mean diastolic pressure > 95 mmHg or the use of antihypertensive medication . In a second analysis cut-off values for systolic and diastolic blood pressure of 140 and 90 mmHg were used.Smoking habits were classified as ` current ' and ` past or never ' . Total cholesterol , HDL-cholesterol , LDL-cholesterol and triacylglycerol were assessed in a fasting venous blood sample . Microvascular disease Following mydriasis with phenylephrine and tropicamide , single-field photographs were taken of both eyes with a 50-degree retinal camera -LRB- Zeiss FF 450 , Carl Zeiss B.V. , Sliedrecht , the Netherlands -RRB- , centred on the macula . Retinopathy was rated on slides , according to the diabetic retinopathy severity scale -LRB- grades 1 -- 7 -RRB- as used in the Wisconsin Epidemiologic Study of Diabetic Retinopathy -LSB- 25 -RSB- . Photocoagulated eyes were rated at grade 5 or higher -LRB- severe non-proliferative diabetic retinopathy -RRB- . Ratings were performed by two investigators , blinded to patient characteristics . In case of disagreement -LRB- 2 % -RRB- , a third investigator was involved and a consensus was made . Retinopathy was defined as a grade of 1.5 or higher.Neuropathy was rated with the Toronto Clinical Neuropathy Scoring System -LSB- 26 -RSB- , with a slight modification . A sensory test for temperature was not performed , so that the maximum score was 18 points -LRB- severe polyneuropathy -RRB- instead of 19 . A score of 0 -- 5 indicated no neuropathy , 6 -- 8 indicated mild neuropathy , 9 -- 11 moderate neuropathy and ≥ 12 severe neuropathy . Neuropathy was defined as a score of ≥ 6 . Urine was collected overnight . Albuminuria was defined as microalbuminuria -LRB- albumin 0.03 -- 0.25 g/l -RRB- or macroalbuminuria -LRB- albumin 0.25 g/l or positive protein dipstick test -RRB- . Macrovascular disease Several composite measures of macrovascular disease were defined . ` Any peripheral arterial disease ' was defined as current complaints of intermittent claudication -LRB- assessed with the Rose questionnaire -LSB- 27 -RSB- -RRB- or a history of surgery or endovascular treatment for arterial disease of the legs or the abdominal aorta . ` Ischaemic heart disease ' was defined as a history of myocardial infarction or surgery or endovascular treatment for coronary artery disease . ` Any vascular event ' was defined as a history of myocardial infarction or stroke , or a history of operative or endovascular treatment for coronary , carotid or peripheral -LRB- legs , abdominal aorta -RRB- artery disease.Brain infarcts were rated on brain MRI , by location -LRB- cortical and subcortical -RRB- , size -LRB- lacunar -LSB- < 1.5 cm -RSB- or large -RRB- and number . A lesion was considered an infarct if it was hypo-intense on T1 and FLAIR images and if its appearance was unlike a perivascular space.Carotid intima-media thickness -LRB- CIMT -RRB- was measured in both common carotid arteries as described previously -LSB- 28 -RSB- with an ATL Ultramark 9 -LRB- Advanced Technology Laboratories , Bothell , WA , USA -RRB- equipped with a 10-MHz linear-array transducer . Scanning was performed at three different longitudinal projections -LRB- anterior-oblique , lateral and posterior-oblique -RRB- . The CIMT was measured in a 1 cm section proximal to the beginning of the dilatation of the carotid bulb in all three projections , in both carotid arteries . CIMT was calculated as the average of these six measurements . CIMT readings were not available in six type 2 diabetes patients and one person in the control group . Statistical analysis The differences between patients and the control group were examined with t test for means , Mann -- Whitney U was used for non-parametric data and χ2 test for proportions . In the text and tables , data are shown as mean ± SD or proportions , unless stated otherwise.Within the type 2 diabetes population , cognition -LRB- five domains -RRB- and brain MRI findings -LRB- cortical and subcortical atrophy z scores , PWML , DMWL and infarcts -RRB- were related to the different measures of glucose , insulin and lipid metabolism , and to microvascular complications and macrovascular disease by linear or logistic regression analyses , adjusting for age , sex and estimated IQ . In order to limit the number of analyses the ` composite cognitive z score ' was used as the primary cognitive outcome measure in the regression analyses . For significant associations , post hoc tests were performed per domain . Secondary analyses were performed with information processing speed , the domain most markedly affected by type 2 diabetes . The results were essentially the same as for the composite cognitive z score -LRB- data not shown -RRB- . In the regression analyses , B values > 0 indicate that a variable is associated with more severe MR abnormalities ; for cognition B values < 0 indicate that a variable is associated with more pronounced performance impairments . For the between and within-group analyses , p < 0.05 was considered statistically significant . All variables that reached a significance level of p ≤ 0.1 in the adjusted univariate risk factor analyses were included in a multivariate model that also included age , sex and estimated IQ . Results Participant characteristics The age , sex , level of education and estimated IQ in the groups were comparable -LRB- Table 1 -RRB- . Table 1Participant characteristicsCharacteristicType 2 diabetes groupControl groupParticipants -LRB- n -RRB- 12256Sex -LRB- male/female -RRB- 62/6025/31Age -LRB- years -RRB- 66.0 ± 5.865.1 ± 5.2 Level of education -LRB- 1 -- 7 -RRB- a4 -LRB- 3 -- 5 -RRB- 4 -LRB- 3 -- 5 -RRB- Estimated premorbid IQ99 ± 15101 ± 14Diabetes duration -LRB- years -RRB- b8 .7 ± 6.1 Diabetes treatment -LRB- % -RRB- Diet10 Oral medication alone61 Insulinb29HbA1c -LRB- % -RRB- b6 .9 ± 1.2 ** , d5 .5 ± 0.3 Fasting glucose levels -LRB- mmol/l -RRB- b8 .6 ± 2.9 ** 5.5 ± 0.6 Fasting insulin levels -LRB- pmol/l -RRB- b , c120 ± 110 ** , e -LRB- n = 82 -RRB- 76 ± 50 -LRB- n = 54 -RRB- HOMA-IRb , c6 .6 ± 6.4 ** , f2 .6 ± 1.8 BMI -LRB- kg/m2 -RRB- b28 .1 ± 4.427.3 ± 5.3 Data are given as number or percentage -LRB- as indicated -RRB- , mean ± SD or ranges ** p < 0.01 for type 2 diabetes vs control groupaLevel of education was expressed in seven categories -LSB- 49 -RSB- bEntered as explanatory variable in the regression analyses within the type 2 diabetes groupcOnly from participants who were not treated with insulin and did not have antibodies against insulinStatistically significant associations within the type 2 diabetes group : with composite cognitive z scores -- dp < 0.05 ; with MRI abnormalities -- ep < 0.01 , fp < 0.05 Detailed neuropsychological and MRI data have been reported previously -LSB- 6 -RSB- . In short , performance of patients with type 2 diabetes was worse than that of the control group across all five cognitive domains , with statistically significant differences on attention and executive functioning -LRB- difference mean z scores 0.23 -LSB- 95 % CI 0.03 , 0.43 -RSB- ; p = 0.02 -RRB- , information processing speed -LRB- 0.40 -LSB- 0.17 , 0.63 -RSB- ; p = 0.001 -RRB- and memory -LRB- 0.20 -LSB- 0.05 , 0.36 -RSB- ; p = 0.01 -RRB- . Patients with type 2 diabetes had more pronounced cortical atrophy -LRB- difference mean z scores 0.62 -LSB- 95 % CI 0.33 , 0.91 -RSB- ; p < 0.001 -RRB- and subcortical atrophy -LRB- 0.38 -LSB- 0.07 , 0.68 -RSB- ; p = 0.01 -RRB- . They also had more severe DWML -LRB- controls , median -LSB- range -RSB- : 5 -LSB- 0 , 18 -RSB- ; type 2 diabetes : 7 -LSB- 0.5 , 27.5 -RSB- ; p = 0.02 -RRB- , but PWML severity in the two groups was similar -LRB- control : 6 -LSB- 4 , 10 -RSB- ; type 2 diabetes : 6 -LSB- 3 , 12 -RSB- ; p = 0.13 -RRB- . Patients with type 2 diabetes also had more -LRB- silent -RRB- cerebral infarcts than controls -LRB- type 2 diabetes 22/113 , control 4/54 ; p = 0.06 -RRB- . Glucose metabolism HbA1c , fasting glucose and insulin levels were higher -LRB- all p < 0.01 -RRB- in patients with type 2 diabetes than in the control group . BMI was similar in both groups . Only a small proportion -LRB- 6 % -RRB- of type 2 diabetes patients had ever experienced a severe hypoglycaemic event -LRB- Table 1 -RRB- . In the regression analyses within the type 2 diabetes group , HbA1c levels were significantly related to cognition -LRB- composite z score : B -LSB- per % HbA1c -RSB- : − 0.07 -LSB- − 0.14 , 0 -RSB- p = 0.047 ; post hoc per domain : information processing speed : B -LSB- per % HbA1c -RSB- : − 0.15 -LSB- 95 % CI : − 0.27 , − 0.2 -RSB- , p = 0.02 ; abstract reasoning : B : − 0.15 -LSB- − 0.29 , − 0.01 -RSB- , p = 0.04 -RRB- . Elevated fasting insulin levels and HOMA-IR were related to increased DWML severity -LRB- B -LSB- per 10 pmol/l insulin -RSB- : 0.14 -LSB- 0.04 , 0.26 -RSB- , p = 0.009 ; B -LSB- HOMA-IR -RSB- : 0.21 -LSB- 0.04 , 0.39 -RSB- , p = 0.02 -RRB- . Vascular risk factors Table 2 shows that patients with type 2 diabetes had higher systolic blood pressure -LRB- p < 0.01 -RRB- and pulse pressure -LRB- p < 0.05 -RRB- than controls . They also had hypertension more often -LRB- p < 0.01 -RRB- . Total cholesterol was lower in the type 2 diabetes group -LRB- p < 0.01 -RRB- , but the proportion of individuals taking lipid-lowering drugs was higher in that group -LRB- p < 0.01 -RRB- . There were no statistically significant differences between type 2 diabetic patients and the control group in the proportion of participants who smoked or had dyslipidaemia -LRB- Table 2 -RRB- . Table 2Vascular risk factorsCharacteristicType 2 diabetes group -LRB- n = 122 -RRB- Control group -LRB- n = 56 -RRB- Mean arterial pressure -LRB- mmHg -RRB- a103 ± 11 * , b98 ± 10Pulse pressure -LRB- mmHg -RRB- a65 ± 15 * 59 ± 16Hypertension -LRB- % -RRB- a73 ** 34Antihypertensive drugs -LRB- % -RRB- 70 ** 32Current smoking -LRB- % -RRB- a2214Total cholesterol -LRB- mmol/l -RRB- a5 .0 ± 0.9 ** 5.8 ± 1.1HDL-cholesterol -LRB- mmol/l -RRB- a4 .3 ± 1.24.4 ± 1.5 Triacylglycerol -LRB- mmol/l -RRB- a1 .9 ± 1.01.6 ± 1.1Lipid-lowering drugs -LRB- % -RRB- a54 ** , c21Data are given as percentage or mean ± SD * p < 0.05 , ** p < 0.01 for type 2 diabetes vs control groupaEntered as explanatory variable in the regression analyses within the type 2 diabetes groupbp < 0.05 for association with more severe MRI abnormalitiescp < 0.05 for reverse associationIn the regression analyses within the type 2 diabetes group there were no statistically significant associations with the composite cognitive z score . Non-significant trends -LRB- p ≤ 0.10 -RRB- were observed for associations between both hypertension and current smoking and impaired cognitive performance -LRB- hypertension B : − 0.19 -LSB- − 0.38 , 0 -RSB- , p = 0.053 ; smoking B : − 0.21 -LSB- − 0.43 , 0 -RSB- , p = 0.051 -RRB- , and between the use of lipid-lowering drugs and better performance -LRB- B : 0.15 -LSB- − 0.03 , 0.32 -RSB- , p = 0.10 -RRB- . Reanalysis with cut-off values for hypertension of 140/90 mmHg made the association with the composite cognitive z score less strong . Mean arterial pressure was associated with more severe PWML -LRB- B -LSB- per 10 mmHg -RSB- : 0.28 -LSB- 0.03 , 0.53 -RSB- , p = 0.03 -RRB- . The use of lipid-lowering drugs -LRB- statins in all but one patient -RRB- was associated with less severe MRI abnormalities -LRB- PWML : B : − 0.68 -LSB- − 1.25 , − 0.12 -RSB- , p = 0.02 ; cortical atrophy : B : − 0.36 -LSB- − 0.69 , − 0.03 -RSB- , p = 0.03 -RRB- . These effects were not affected by additional adjustment for the actual cholesterol levels -LRB- Table 2 -RRB- . Microvascular disease In 20 patients with type 2 diabetes and 8 control individuals it was not possible to perform retinal photographs . Mostly due to logistical reasons , overnight urine samples could not be obtained from 21 diabetic patients and 13 controls . Patients with type 2 diabetes had more retinopathy and neuropathy than the control group -LRB- both p < 0.01 -RRB- . Although albuminuria was more common in the type 2 diabetic than in the control group , this difference was not statistically significant -LRB- Table 3 -RRB- . Table 3Microvascular diseaseCharacteristicType 2 diabetes group -LRB- n = 122 -RRB- Control group -LRB- n = 56 -RRB- Retinopathy -LRB- diabetes n = 112 ; control n = 48 -RRB- a37 -LRB- 33 -RRB- ** , b1 -LRB- 2 -RRB- Background 33 1 Severe non-proliferative4 Neuropathya47 -LRB- 39 -RRB- ** 7 -LRB- 13 -RRB- Mild neuropathy25 7 Moderate neuropathy18 0 Severe neuropathy4 0Albuminuria -LRB- diabetes n = 101 ; control n = 43 -RRB- a16 -LRB- 16 -RRB- 3 -LRB- 7 -RRB- Microalbuminuria93 Macroalbuminuria7 0Any microvascular diseasec72 -LRB- 59 -RRB- ** 11 -LRB- 20 -RRB- Data are given as values -LRB- percentage -RRB- ** p < 0.01 for type 2 diabetes vs control groupaEntered as explanatory variable in the regression analyses within the type 2 diabetes groupbp < 0.05 for association with MRI abnormalitiescIncludes all patients with albuminuria , neuropathy or retinopathyIn the regression analyses within the type 2 diabetes group , there were no statistically significant associations with the composite cognitive z score . Retinopathy was associated with more pronounced cortical atrophy -LRB- B : 0.48 -LSB- 0.11 , 0.85 -RSB- , p = 0.01 -RRB- -LRB- Table 3 -RRB- . Macrovascular disease Patients with type 2 diabetes were more likely to have had intermittent claudication -LRB- p < 0.01 -RRB- or a history of ischaemic heart disease -LRB- p < 0.01 -RRB- . There was no difference between the two groups in the CIMT -LRB- Table 4 -RRB- . Table 4Macrovascular diseaseCharacteristicType 2 diabetes group -LRB- n = 122 -RRB- Control group -LRB- n = 56 -RRB- Any peripheral arterial diseasea18 -LRB- 15 -RRB- ** 0 Claudicatio intermittens14 -LRB- 11 -RRB- ** 0 Vascular surgery femoral artery4 -LRB- 3 -RRB- 0 Vascular surgery -LRB- AAA -RRB- 3 -LRB- 3 -RRB- 0Ischaemic heart diseasea23 -LRB- 19 -RRB- ** , b2 -LRB- 4 -RRB- Myocardial infarction15 -LRB- 12 -RRB- * 1 -LRB- 2 -RRB- CABG13 -LRB- 11 -RRB- * 1 -LRB- 2 -RRB- Brain infarct on MRIa22 -LRB- 20 -RRB- * , b , c4 -LRB- 8 -RRB- History of brain infarcta7 -LRB- 6 -RRB- 2 -LRB- 4 -RRB- Carotid surgerya2 -LRB- 2 -RRB- 1 -LRB- 2 -RRB- Any vascular event a33 -LRB- 27 -RRB- ** , b , c4 -LRB- 7 -RRB- CIMTa0 .093 ± 0.0180.092 ± 0.023 Data are given as value -LRB- percentage -RRB- or mean ± SDAAA , abdominal aortic aneurysm ; CABG , coronary artery bypass grafting * p < 0.05 , ** p < 0.01 for type 2 diabetes vs control groupaEntered as explanatory variable in the regression analyses within the type 2 diabetes groupStatistically significant associations : with MRI abnormalities bp < 0.05 ; with impaired cognition cP < 0.05 In the regression analyses within the type 2 diabetes group , a history of ` any vascular event ' and the presence of brain infarcts on MRI were associated with an impaired composite cognitive z score as follows : -LRB- 1 -RRB- vascular event : composite z score B : − 0.25 -LRB- − 0.44 , − 0.05 -RRB- , p = 0.01 ; post hoc per domain : information processing speed B : − 0.46 -LRB- − 0.80 , − 0.12 -RRB- , p = 0.008 ; and memory B : − 0.23 -LRB- − 0.41 , − 0.06 -RRB- , p = 0.01 ; -LRB- 2 -RRB- infarct on MRI : composite z score B : − 0.28 -LRB- − 0.50 , − 0.06 -RRB- , p = 0.01 ; post hoc per domain : information processing speed B : − 0.77 -LRB- − 1.14 , − 0.39 -RRB- , p < 0.001 ; and abstract reasoning B : − 0.41 -LRB- − 0.82 , 0.01 -RRB- , p = 0.06 . A history of ` any vascular event ' was also associated with more pronounced DWML -LRB- B : 2.0 -LSB- 0 , 4.1 -RSB- , p = 0.05 -RRB- and with an increased occurrence of infarcts on MRI -LRB- odds ratio : 2.9 -LSB- 1.1 , 7.9 -RSB- , p = 0.04 -RRB- . Patients with a -LRB- silent -RRB- infarct on MRI tended to have more pronounced PWML -LRB- B : 0.7 -LSB- 0 , 1.4 -RSB- , p = 0.06 -RRB- and cortical atrophy -LRB- B : 0.51 -LSB- 0.10 , 0.92 -RSB- , p = 0.02 -RRB- relative to type 2 diabetes patients without infarcts on MRI -LRB- Table 4 -RRB- . Exclusion of patients with a history of stroke attenuated the association between ` any vascular event ' and the cognitive z score , but not that between ` any vascular event ' and DWML . Multivariate analysis For the majority of risk factors the values of the standardised regression coefficients ß were similar in the single risk factor and multivariate models , indicating that interaction between factors was limited . Values for ß for individual factors varied between 0.15 and 0.30 , indicative of modest associations -LRB- Table 5 -RRB- . Table 5Multivariate risk factor analyses within the type 2 diabetes group Single factors β -LRB- 95 % CI -RRB- Full model β -LRB- 95 % CI -RRB- Final model β -LRB- 95 % CI -RRB- Cognition Age − 0.30 -LRB- − 0.44 , − 0.16 -RRB- *** − 0.29 -LRB- − 0.43 , − 0.14 -RRB- *** Sex − 0.12 -LRB- − 0.24 , 0.02 -RRB- Estimated IQ0 .65 -LRB- 0.50 , 0.79 -RRB- *** 0.65 -LRB- 0.50 , 0.80 -RRB- *** HbA1c − 0.14 -LRB- − 0.28 , − 0.002 -RRB- * − 0.11 -LRB- − 0.25 , 0.02 -RRB- Hypertension − 0.14 -LRB- − 0.26 , 0.002 -RRB- − 0.12 -LRB- − 0.26 , 0.01 -RRB- − 0.14 -LRB- − 0.27 , − 0.001 -RRB- * Current smoking − 0.14 -LRB- − 0.29 , 0.001 -RRB- − 0.15 -LRB- − 0.29 , − 0.02 -RRB- * − 0.14 -LRB- − 0.27 , 0.001 -RRB- Lipid-lowering drugs0 .12 -LRB- − 0.02 , 0.26 -RRB- 0.17 -LRB- 0.03 , 0.31 -RRB- * 0.17 -LRB- 0.03 , 0.31 -RRB- * Any vascular event − 0.18 -LRB- − 0.32 , − 0.03 -RRB- * − 0.18 -LRB- − 0.32 , − 0.03 -RRB- * − 0.19 -LRB- − 0.34 , − 0.05 -RRB- ** Brain infarct on MRI a − 0.18 -LRB- − 0.32 , − 0.04 -RRB- * Cortical atrophy Sex − 0.005 -LRB- − 0.23 , 0.22 -RRB- Age0 .35 -LRB- 0.18 , 0.52 -RRB- *** 0.34 -LRB- 0.18 , 0.51 -RRB- *** Estimated IQ − 0.07 -LRB- − 0.24 , 0.10 -RRB- Lipid-lowering drugs − 0.20 -LRB- − 0.37 , − 0.02 -RRB- * − 0.19 -LRB- − 0.36 , − 0.03 -RRB- * − 0.18 -LRB- − 0.35 , − 0.02 -RRB- * Retinopathy0 .24 -LRB- 0.05 , 0.43 -RRB- * 0.21 -LRB- 0.04 , 0.39 -RRB- * 0.22 -LRB- 0.06 , 0.39 -RRB- ** Brain infarct on MRI0 .22 -LRB- 0.04 , 0.39 -RRB- * 0.23 -LRB- 0.06 , 0.40 -RRB- ** 0.23 -LRB- 0.06 , 0.40 -RRB- ** DWML Sex0 .13 -LRB- − 0.05 , 0.30 -RRB- Age0 .20 -LRB- 0.02 , 0.35 -RRB- * 0.22 -LRB- 0.04 , 0.39 -RRB- * Estimated IQ − 0.14 -LRB- − 0.31 , 0.04 -RRB- Insulin level0 .29 -LRB- 0.08 , 0.51 -RRB- ** 0.26 -LRB- 0.04 , 0.47 -RRB- * 0.24 -LRB- 0.03 , 0.45 -RRB- * Any vascular event0 .19 -LRB- − 0.002 , 0.37 -RRB- 0.15 -LRB- − 0.03 , 0.34 -RRB- PWML Sex0 .16 -LRB- − 0.02 , 0.34 -RRB- 0.16 -LRB- − 0.02 , 0.34 -RRB- Age0 .25 -LRB- 0.07 , 0.43 -RRB- ** 0.24 -LRB- 0.07 , 0.42 -RRB- ** Estimated IQ − 0.12 -LRB- − 0.30 , 0.06 -RRB- Mean arterial pressure0 .20 -LRB- 0.02 , 0.38 -RRB- * 0.15 -LRB- − 0.03 , 0.33 -RRB- 0.17 -LRB- − 0.004 , 0.35 -RRB- Lipid-lowering drugs − 0.22 -LRB- − 0.35 , − 0.001 -RRB- * − 0.20 -LRB- − 0.38 , − 0.02 -RRB- * − 0.18 -LRB- − 0.35 , 0.001 -RRB- * Brain infarct on MRI0 .17 -LRB- − 0.006 , 0.35 -RRB- 0.18 -LRB- 0.01 , 0.36 -RRB- * 0.18 -LRB- 0.009 , 0.36 -RRB- * β is the standardised regression coefficient B . The first column contains the values of β for all variables that reached a significance level of a least p = 0.10 in the univariate risk factor analyses within the type 2 diabetes patient group , adjusted for age , sex and estimated IQ . These variables were included in a multivariate model that also included age , sex and estimated IQ -LRB- second column , full model -RRB- . The final model -LRB- third column -RRB- is based on backward elimination of non-significant factors . This final model shows which variables that were related to the outcome measures in the univariate model remained significantly associated with the outcome measures independently of the other factors in the full modelFor cognition β values < 0 indicate that a variable is associated with more pronounced performance impairments ; for MRI β values > 0 indicate that a variable is associated with more severe MRI abnormalities * p < 0.05 ** p < 0.01 *** p < 0.001 aBecause ` infarct on MRI ' and ` history of any vascular event ' were interrelated in the univariate analyses -LRB- see Macrovascular disease section -RRB- only ` history of any vascular event ' was entered in the multivariate modelIn the multivariate model , hypertension and a history of vascular events were associated with worse cognitive performance and statin use with better performance . Retinopathy and brain infarction on MRI were associated with more severe cortical atrophy and statin use with less atrophy . A higher insulin level was associated with more DWML , brain infarction on MRI with more PWML and statin use with less PWML . Overall , macrovascular disease -LRB- history of macrovascular events or infarct on MRI -RRB- were most consistently associated with the different outcome measures -LRB- Table 5 -RRB- . Discussion Patients with type 2 diabetes had more cortical and subcortical atrophy and more DWML than control participants and their overall performance in the five cognitive domains was worse . As expected , patients with type 2 diabetes had more microvascular complications , more macrovascular -LRB- atherosclerotic -RRB- disease and more hypertension than the control group . In multivariate regression analyses within the type 2 diabetes group , hypertension and a history of vascular events were associated with worse cognitive performance , while statin use was associated with better performance . Retinopathy and brain infarcts on MRI were associated with more severe cortical atrophy and statin use with less atrophy . Insulin level and brain infarcts were associated with more severe WML and statin use with less severe WML . Cognitive function in patients with type 2 diabetes has been studied extensively -LRB- for reviews see -LSB- 2 , 3 -RSB- -RRB- . Performance in the domains verbal memory and information processing speed , and probably also executive functioning and non-verbal memory , is moderately impaired . Our results are in keeping with these findings . Thus far , relatively few studies have specifically addressed brain MRI abnormalities in patients with type 2 diabetes . In agreement with our observations , modest cortical and subcortical atrophy and symptomatic or asymptomatic infarcts have been found more often in type 2 diabetes patients than in control individuals -LSB- 4 , 5 , 29 -RSB- . Results of previous studies on the association between type 2 diabetes and WMLs are less consistent -LSB- 30 -RSB- . This might be due to the study populations involved and the use of relatively insensitive WML rating scales -LSB- 30 -RSB- . Chronic hyperglycaemia might be a determinant of cerebral changes in patients with type 2 diabetes . In the present study , HbA1c levels were related to the composite cognitive z score , but only in de univariate analysis . Moreover , retinopathy , which is generally considered to be a consequence of chronic exposure to hyperglycaemia -LSB- 11 -RSB- , was related to cortical atrophy . Previous studies on cognition in patients with type 2 diabetes have also reported an association with HbA1c levels -LSB- 2 , 9 , 31 -RSB- . The relation with fasting blood glucose or duration of diabetes is , however , inconsistent -LSB- 31 , 32 -RSB- . No previous studies have provided detailed data on the association between glycaemic control and MRI changes in type 2 diabetes . Studies in type 1 diabetes mellitus , however , have shown an association between diabetic retinopathy -LRB- as a proxy of chronic hyperglycaemia -RRB- and both brain atrophy -LSB- 33 , 34 -RSB- and cognitive functioning -LSB- 35 -RSB- . There are no previous studies on the relation between insulin levels and cerebral complications in type 2 diabetes . The association with WML severity , observed by us in the present study , is of particular interest in the light of recent studies in the general population , which link insulin to vascular abnormalities and degenerative changes in the brain -LSB- 36 , 37 -RSB- . Previous studies in the general population indicate that risk factors for vascular disease , such as hypertension , dyslipidaemia , increased BMI and smoking , are associated with an increased risk of cognitive decline and dementia and with brain MRI changes , including WML -LRB- e.g. -LSB- 38 -- 41 -RSB- -RRB- . Previous studies on the modulating effect of hypertension on cognitive function in type 2 diabetes show conflicting results -LSB- 7 , 9 , 42 , 43 -RSB- . In the present study , hypertension was related with impaired cognitive performance and mean arterial pressure with PWML severity . To our knowledge , the relation between other vascular risk factors and both cognition and brain MRI in patients with type 2 diabetes has not been examined previously . The reverse association between the use of statins and both cognition and MRI findings is intriguing . Nevertheless , this observation can not be regarded as proof of a possible treatment effect . It should be noted that the association between statin use and both cognition and age-related brain MRI changes in the general population is still being debated -LSB- 44 -RSB- . The present findings will need to be confirmed by further studies . Macrovascular atherosclerotic disease appeared to be the most consistent determinant of impaired cognition and brain MRI abnormalities in the type 2 diabetes patients in the present study . We have not found any previous studies that presented detailed data on the relation between macrovascular disease and cerebral changes in people with type 2 diabetes . In the general population , however , several studies have shown that macrovascular atherosclerotic disease is associated with age-related cognitive impairment and changes in brain MRI . In a large cross-sectional study , for example , previous vascular events , presence of plaques in the carotid arteries and presence of peripheral arterial atherosclerotic disease were negatively associated with cognitive performance -LSB- 17 -RSB- . In another study , the association between the number of cardiovascular disease conditions and cognitive impairment appeared to show a ` dose -- response ' relationship -LSB- 18 -RSB- . With regard to brain MRI changes , a history of stroke or myocardial infarction has been associated with the presence of WML -LSB- 19 -RSB- and plaques in the carotid artery with PWML -LSB- 16 , 45 -RSB- . The strength of our study is that we combined detailed data on cognitive function and brain MRI with detailed data on metabolic and vascular risk factor clusters , thus allowing an accurate assessment of the relation between these factors . Possible limitations include patient selection , the cross-sectional design and the large number of explanatory variables addressed . With regard to patient selection , we aimed to obtain a representative sample of functionally independent patients with type 2 diabetes from the general population . Although the rather demanding testing protocol may have deterred patients with relatively severe mental or physical limitations , the prevalence of microvascular and macrovascular disease , hypertension and smoking habits , as well as the level of metabolic control in our study sample is comparable with those found in other population-based studies in the Netherlands -LSB- 46 -- 48 -RSB- . To minimise the effects of lifestyle and socioeconomic factors , control participants were recruited from the direct environment of the type 2 diabetic patients . Consently , the prevalence of risk factors such as hypertension and high BMI was higher than would be expected in the general population in the Netherlands . If anything , this would have decreased the differences in cognition and MRI ratings between the groups . The cross-sectional design of our study precludes inferences about causal relationships . Moreover , the cognitive and imaging outcome measures were probably influenced by a large number of factors , some of which are specific to type 2 diabetes mellitus -LRB- e.g. chronic hyperglycaemia , diabetes treatment -RRB- and some not -LRB- e.g. age , hypertension , atherosclerosis -RRB- . Our exploratory analysis included a large number of explanatory variables , which has certain drawbacks . First , different explanatory variables might be interrelated . The relatively small regression coefficients and effect sizes affect the evaluation of these interrelations and limit statistical power . This may also explain why some of the variables that reached statistical significance in the univariate analyses dropped out of the multivariate model . Nevertheless , the multivariate analysis as presented in Table 5 does indicate which variables were the strongest independent determinants of cognition and MRI abnormalities in the model used . The second drawback is that the large number of regression analyses can lead to type I errors . Nevertheless , we feel that this first detailed study of cognition and brain MRI in type 2 diabetes patients in relation to metabolic and vascular risk factors does provide important leads that could be further evaluated in future studies . Such studies should : -LRB- 1 -RRB- preferably have a longitudinal design ; -LRB- 2 -RRB- include assessment of cognition and brain MRI in relation to chronic hyperglycaemia and atherosclerotic vascular disease ; and -LRB- 3 -RRB- allow the assessment of potential confounders -LRB- e.g. hypertension -RRB- . Type 2 diabetes is associated with modest impairments in cognition , as well as with atrophy and vascular lesions on MRI . This ` diabetic encephalopathy ' is a multifactorial condition , for which atherosclerotic -LRB- macroangiopathic -RRB- vascular disease is an important determinant . Chronic hyperglycaemia , hypertension and hyperinsulinaemia may play additional roles . Electronic supplementary material Below is the link to the electronic supplementary material . ESM The Utrecht Diabetic Encephalopathy Study Group -LRB- PDF 12.8 kb -RRB-

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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O B I I O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O

brain atrophy
brain mri
cerebral complications
cognitive performance
diabetic encephalopathy
type 2 diabetes mellitus
vascular risk factors
white matter lesions

metabolic risk factors
neuropsychological investigation


Dilatation

tracheoscopy

for

laryngeal

and

tracheal

stenosis

in

patients

with

Wegener

's

granulomatosis

Wegener

's

granulomatosis

-LRB-

WG

-RRB-

frequently

involves

the

subglottis

and

trachea

and

may

compromise

the

upper

airway

The

objective

of

this

study

is

to

evaluate

retrospectively

the

effect

of

treatment

of

subglottic

stenosis

-LRB-

SGS

-RRB-

and

tracheal

stenosis

-LRB-

TS

-RRB-

by

dilatation

tracheoscopy

-LRB-

DT

-RRB-

in

patients

with

WG

We

performed

a

cohort

study

on

all

patients

who

underwent

DT

between

February

and

September

in

our

institution

From

this

cohort

we

identified

a

total

of

nine

WG

patients

In

all

patients

clinical

serological

and

histopathological

data

had

been

prospectively

collected

by

a

standardized

protocol

from

the

time

point

of

diagnosis

In

the

nine

patients

that

were

identified

with

SGS

or

TS

due

to

WG

-LRB-

eight

women

and

one

man

-RRB-

a

total

of

DT

's

were

performed

Two

patients

needed

a

tracheostoma

-LRB-

one

temporarily

-RRB-

The

mean

follow-up

after

the

first

DT

was

months

Two

patients

did

not

experience

a

recurrence

of

SGS

or

TS

Six

patients

required

a

second

DT

without

recurrence

of

local

disease

The

remaining

patient

underwent

DT

's

in

a

period

DT

can

offer

a

simple

and

repeatable

solution

to

SGS

and

TS

due

to

WG

Seven

of

the

nine

patients

required

more

than

one

dilatation

and

some

patients

experience

a

functional

restriction

One

patient

has

a

definitive

tracheostoma

Introduction

Wegener

's

granulomatosis

-LRB-

WG

-RRB-

first

described

by

Friedrich

Wegener

in

Stuttgart

in

is

multi-system

disease

characterized

by

a

necrotizing

granulomatous

arteritis

of

the

upper

and

lower

respiratory

tract

and

a

necrotizing

crescentic

glomerulonephritis

-LSB-

-RSB-

Vasculitis

may

also

affect

other

organs

such

as

the

eyes

skin

joints

heart

and

the

nervous

system

-LSB-

-RSB-

Upper

respiratory

tract

manifestations

particularly

sinusitis

ulcerations

of

the

nasal

mucosa

and

epistaxis

are

common

and

debilitating

presentations

Subglottic

stenosis

-LRB-

SGS

-RRB-

and

tracheal

stenosis

-LRB-

TS

-RRB-

however

are

potentially

life

threatening

presentations

of

WG

SGS

has

been

found

to

occur

in

approximately

in

patients

carrying

a

diagnosis

of

WG

-LSB-

-RSB-

This

narrowing

of

the

upper

airway

at

the

level

of

cricoid

cartilage

and/or

upper

tracheal

rings

presents

a

management

dilemma

Dilatation

tracheoscopy

-LRB-

DT

-RRB-

is

one

of

the

possible

options

for

treatment

of

SGS

and

TS

The

long-term

effects

of

DT

in

patients

with

WG

have

never

been

reported

DT

is

a

minimally

invasive

self-standing

procedure

It

can

be

used

for

elective

and

emergency

intervention

in

patients

with

subglottic

and

tracheal

stenosis

This

has

been

described

elsewhere

-LRB-

G.B.

Halmos

F.G.

Dikkers

Dilatation

tracheoscopy

in

treatment

of

subglottic

and

tracheal

stenosis

submitted

for

publication

-RRB-

Patients

suffering

from

WG

present

differences

-LRB-

age

sex

response

to

treatment

-RRB-

compared

to

other

aetiologies

which

justifies

separate

publication

The

objective

of

this

study

is

therefore

to

evaluate

the

effect

of

the

treatment

of

SGS

and

TS

by

DT

in

patients

with

WG

Methods

We

retrospectively

identified

all

patients

from

our

institution

that

underwent

a

DT

between

February

and

September

The

total

cohort

of

benign

grade

II

-LRB-

Myer-Cotton

-RRB-

subglottic

or

tracheal

stenosis

consisted

of

patients

with

a

history

of

posttraumatic

tracheal

stenosis

thermal

tracheal

stenosis

posttracheotomy

cicatricial

stenosis

tracheal

rupture

postintubation

stenosis

and

WG

amongst

others

As

stated

before

the

cohort

is

described

elsewhere

From

the

cohort

we

identified

a

total

of

nine

WG

patients

These

nine

patients

had

been

diagnosed

with

WG

between

May

and

August

During

this

period

a

total

of

patients

in

our

institution

were

diagnosed

as

having

WG

-LRB-

including

the

nine

patients

who

underwent

DT

-RRB-

From

this

cohort

one

additional

patient

underwent

a

DT

for

SGS

in

Three

other

patients

were

diagnosed

with

relatively

mild

SGS

or

TS

that

did

not

necessitate

DT

The

reference

group

for

the

comparison

of

demographic

and

serological

data

consisted

of

the

total

cohort

minus

the

patients

who

underwent

DT

and

minus

the

three

patients

with

mild

tracheal

stenosis

who

did

not

undergo

DT

Differences

in

age

between

the

DT

group

and

the

reference

group

were

tested

with

the

Mann

Whitney

U

test

differences

in

the

male/female

ratio

and

antineutrophil

cytoplasmatic

autoantibodies

-LRB-

ANCA

-RRB-

specificity

were

tested

with

chi-square

test

Although

this

was

a

retrospective

study

the

clinical

serological

and

histopathological

data

of

both

the

DT

group

and

the

control

group

had

been

prospectively

collected

by

a

standardised

protocol

starting

at

the

time

of

the

diagnosis

of

Wegener

's

granulomatosis

Extrarenal

organ

involvement

was

categorized

as

described

previously

-LSB-

-RSB-

ANCA

was

assayed

with

indirect

immunofluorescence

Sera

from

all

patients

were

assayed

for

the

presence

of

antibodies

against

proteinase

-LRB-

ANCA

-RRB-

myeloperoxidase

-LRB-

MPO

ANCA

-RRB-

and

elastase

as

described

previously

-LSB-

-RSB-

DT

was

performed

when

patients

complained

of

progressive

dyspnoea

in

combination

with

decrease

of

peak

flows

DT

is

an

endoscopically

performed

intervention

An

intubation

laryngoscope

a

Groningen

optical

dilatation

tracheoscope

-LRB-

Karl

Storz

-RRB-

-LRB-

Fig.

-RRB-

telescope

and

suction

tubes

are

required

for

this

procedure

The

tracheoscope

has

a

length

of

cm

The

proximal

end

of

the

tracheoscope

is

designed

in

such

a

way

that

customary

ventilation

tubes

and

a

cm

Hopkins

straight

forward

telescope

-LRB-

Karl

Storz

-RRB-

can

be

connected

The

distal

end

of

the

instrument

contains

numerous

lateral

tiny

openings

which

enable

air

to

come

through

in

the

centre

of

the

stenosis

The

dilatation

tracheoscope

is

available

with

a

diameter

of

and

mm

The

appropriate

size

of

the

instrument

is

determined

by

the

size

of

the

patient

's

larynx

and

the

healthy

portion

of

the

trachea

Fig.

dilatation

tracheoscope

The

intervention

is

carried

out

under

general

anaesthesia

Following

the

administration

of

the

anaesthesia

with

ventilation

taking

place

via

an

anaesthesia

mask

the

dilatation

tracheoscope

is

introduced

under

endoscopic

control

The

stenosis

is

then

visible

through

the

vocal

cords

-LRB-

Fig.

-RRB-

The

bevelled

design

of

the

tip

which

can

be

advanced

forward

through

the

stenosis

ensures

that

the

ventilation

is

maintained

during

the

process

The

conical

construction

of

the

tip

enables

the

instrument

to

be

advanced

up

to

the

wider

section

of

the

tracheoscope

-LRB-

Fig.

-RRB-

after

which

the

tracheoscope

remains

in

place

for

to

min

Fig.

nr

pre

dilatation

During

laryngotracheoscopy

a

subglottic

stenosis

is

clearly

visible

The

vocal

cords

can

be

seen

bilaterallyFig

nr

during

DT

The

dilatation

tracheoscope

is

introduced

through

the

stenosis

Parts

of

the

tissue

protrude

through

the

tiny

distal

openings

of

the

tracheoscope

The

constellation

of

the

tracheoscope

is

suitable

for

most

grade

II

-LRB-

Myer-Cotton

-RRB-

subglottic

or

tracheal

stenosis

The

intervention

can

be

repeated

after

any

time

interval

Typically

no

antibiotics

or

corticosteroids

are

used

The

use

of

mitomycin-C

was

considered

in

each

case

but

it

was

never

used

because

mitomycin-C

should

be

used

in

fresh

wounds

Patients

are

dismissed

the

day

after

DT

Peakflows

were

measured

three

times

-LRB-

Respironics

Healthscan

Inc.

Cedar

Groove

NJ

USA

-RRB-

in

an

upright

position

The

mean

of

the

three

measurements

was

taken

Results

Patients

The

total

cohort

of

patients

who

underwent

DT

because

of

SGS

and

TS

was

Nine

of

them

were

identified

as

patients

with

WG

Eight

were

female

one

was

male

The

other

patients

did

not

have

vasculitis

as

cause

of

their

stenosis

The

causes

in

these

patients

were

posttraumatic

-LSB-

-RSB-

postintubation

-LSB-

-RSB-

idiopathic

-LSB-

-RSB-

post

tracheotomy

-LSB-

-RSB-

and

post

thermal

-LSB-

-RSB-

injury

The

mean

age

of

the

patient

group

at

first

presentation

of

WG

was

years

-LRB-

Table

-RRB-

The

interval

between

the

presentation

of

WG

and

the

first

symptoms

of

laryngeal

and

tracheal

stenosis

varied

between

and

months

-LRB-

mean

-RRB-

The

average

age

at

of

the

time

of

presentation

of

the

stenosis

was

years

-LRB-

Table

-RRB-

Table

characteristics

of

nine

patients

with

Wegener

's

Granulomatosis

-LRB-

WG

-RRB-

and

subglottic

stenosis

-LRB-

SGS

-RRB-

or

tracheal

stenosis

-LRB-

TS

-RRB-

Clinical

and

laboratory

findings

ANCA

antineutrophil

cytoplasmatic

autoantibodies

proteinase

MPO

myeloperoxidasePatient

No.SexAge

at

presentation

of

WGOrgans

involved

at

first

presentation

of

WGANCA

specificityNumber

of

relapses

of

WGOrgans

involved

at

first

relapse

of

WGFollow-up

after

diagnosis

of

WG

-LRB-

years

-RRB-

Age

at

first

presentation

of

SGS

or

TSInterval

between

diagnosis

of

WG

and

first

treatment

of

TS

or

SGS

-LRB-

months

-RRB-

eye

kidney

-LRB-

concha

inferior

-RRB-

ear

-LRB-

septum

and

concha

-RRB-

joints

At

diagnosis

all

WG

patients

had

additional

organ

involvement

outside

the

otorhinolaryngologic

area

The

kidneys

lungs

and

eyes

were

affected

three

times

The

joints

were

affected

two

times

The

skin

was

affected

once

-LRB-

Table

-RRB-

As

shown

in

Table

the

number

of

relapses

of

WG

varied

between

and

There

was

no

relation

between

the

number

of

relapses

and

the

occurrence

of

TS

or

SGS

In

only

one

of

the

DT

procedures

there

was

endoscopic

and/or

histopathological

evidence

of

vasculitis

activity

The

TS

or

SGS

occurred

in

in

periods

where

the

disease

appeared

to

be

less

active

In

Table

the

patient

characteristics

of

the

patients

who

underwent

DT

for

SGS

or

TS

are

compared

with

those

patients

who

were

diagnosed

with

WG

in

the

same

time

frame

but

who

did

not

have

evidence

of

SGS

or

TS

In

the

DT

group

were

female

whereas

of

patients

in

the

reference

group

were

female

-LRB-

P

-RRB-

In

the

DT

group

the

age

at

diagnosis

of

WG

was

significantly

lower

in

comparison

with

the

reference

group

-LRB-

P

-RRB-

Table

characteristics

of

nine

patients

with

Wegener

's

granulomatosis

who

underwent

DT

for

SGS

or

TS

compared

with

the

reference

group

of

patients

who

were

diagnosed

with

WG

in

the

same

period

without

evidence

of

SGS

or

TSWG

patients

who

underwent

DT

-LRB-

n

-RRB-

WG

patients

without

evidence

of

SGS

or

TS

-LRB-

n

-RRB-

P

valueMale

female

number

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Age

at

diagnosis

of

WG

-LRB-

years

mean

SD

-RRB-

ANCA

n

-LRB-

-RRB-

MPO-ANCA

n

-LRB-

-RRB-

n

-LRB-

-RRB-

MPO-ANCA

n

-LRB-

-RRB-

HNE-ANCA

n

-LRB-

-RRB-

ANCA-negative

n

-LRB-

-RRB-

Not

significantWG

Wegener

's

granulomatosis

DT

dilatation

tracheoscopy

SGS

subglottic

stenosis

TS

tracheal

stenosis

ANCA

antineutrophil

cytoplasmatic

autoantibodies

proteinase

MPO

myeloperoxidase

HNE

human

neutrophil

elastase

Follow-up

of

the

DT-group

In

the

nine

patients

identified

with

SGS

or

TS

due

to

WG

a

total

of

DT

's

were

performed

-LRB-

Table

-RRB-

The

mean

follow-up

after

treatment

was

months

-LRB-

Table

-RRB-

Two

patients

-LRB-

numbers

and

-RRB-

did

not

experience

a

recurrence

of

significant

stenosis

Six

patients

-LRB-

numbers

-RRB-

required

a

second

DT

without

recurrence

of

local

disease

activity

after

the

second

DT

One

of

these

patients

-LRB-

patient

number

-RRB-

had

acute

WG

in

the

trachea

proven

by

biopsy

-LRB-

Fig.

-RRB-

She

was

treated

with

high

dose

prednisolone

-LRB-

intravenous

methylprednisolone

mg

on

three

consecutive

days

-RRB-

and

intubation

for

a

week

She

could

be

detubated

a

week

later

-LRB-

Fig.

-RRB-

Two

patients

needed

a

tracheostoma

-LRB-

patient

numbers

and

-RRB-

One

patient

-LRB-

number

-RRB-

developed

a

cricoid

stenosis

years

after

the

diagnosis

of

WG

Initially

the

stenosis

was

treated

with

two

DT

's

During

a

pregnancy

the

patient

required

an

emergency

tracheotomy

because

of

a

threatened

airway

After

pregnancy

she

was

treated

with

a

laser

and

three

DT

's

Unfortunately

however

she

required

a

definitive

tracheostomy

Currently

the

process

of

decannulation

is

taking

place

One

patient

-LRB-

number

-RRB-

became

respiratory

insufficient

at

diagnosis

of

WG

and

had

a

tracheotomy

for

months

She

subsequently

developed

a

cicatricial

SGS

but

she

has

enough

lumen

to

live

without

a

tracheostomy

-LRB-

Table

-RRB-

Table

after

last

DTPatient

numberLocation

of

stenosisNumber

of

DT

sFollow-up

after

last

treatment

-LRB-

months

-RRB-

Tracheotomy

nr

with

acute

WG

during

biopsy

of

a

subglottic

stenosisFig

nr

after

pulse

therapy

and

intubation

The

picture

was

taken

one

week

after

Fig.

The

effect

of

DT

on

peakflows

was

evaluated

in

five

patients

In

these

patients

the

mean

-LRB-

SD

-RRB-

peakflow

increased

from

l/min

before

DT

to

l/min

after

dilatation

An

example

of

the

effect

of

DT

on

the

peakflow

is

shown

in

Fig.

Two

months

after

this

patient

had

been

diagnosed

with

WG

she

developed

complaints

of

dyspnoea

Tracheoscopy

revealed

a

SGS

with

signs

of

active

vasculitis

After

treatment

with

high-dose

corticosteroids

she

had

a

regression

of

the

WG

activity

Fourteen

and

months

after

first

diagnosis

of

SGS

a

dilatation

tracheoscopy

was

performed

successfully

Fig.

flow

measurements

after

dilatation

of

patient

number

The

arrows

indicate

the

DT

procedures

Discussion

There

are

multiple

causes

of

benign

laryngeal

or

tracheal

stenosis

the

most

common

being

traumatic

However

if

there

is

no

prior

history

of

tracheal

trauma

the

aetiology

of

the

stenosis

may

be

obscure

and

difficult

to

determine

necessitating

a

systematic

approach

to

make

the

diagnosis

Excluding

trauma

the

differential

diagnosis

of

TS

can

be

subdivided

into

four

categories

congenital

neoplastic

infectious

and

inflammatory

Congenital

TS

is

really

quite

rare

and

is

often

the

result

of

posterior

fusion

of

the

tracheal

rings

thereby

forming

complete

rings

Other

causes

of

congenital

stenosis

include

vascular

rings

and

other

congenital

cardiovascular

anomalies

such

as

an

anomalous

subclavian

artery

These

patients

typically

present

at

young

age

Primary

benign

tumours

of

the

trachea

such

as

chondromas

fibromas

squamous

papillomas

hemangiomas

and

granular

cell

tumours

are

also

unusual

causes

of

stenosis

In

addition

extrinsic

compression

of

the

trachea

can

occur

by

thyroid

neoplasms

and

goiters

A

number

of

infections

of

the

bronchopulmonary

tree

can

lead

to

TS

Fungal

infections

such

as

histoplasmosis

and

blastomycosis

should

always

be

considered

when

the

aetiology

of

the

stenosis

is

unclear

Serologic

testing

and

histopathologic

examination

can

be

helpful

in

this

regard

Other

infectious

causes

of

TS

include

rhinoscleroma

tuberculosis

syphilis

and

diphtheria

Non-infectious

inflammatory

causes

of

TS

include

sclerosing

mediastinitis

primary

amyloidosis

and

sarcoidosis

WG

and

relapsing

polychondritis

can

also

cause

TS

but

they

are

almost

always

seen

in

combination

with

other

more

classic

hallmarks

of

these

diseases

A

laryngeal

or

tracheal

stenosis

is

optimally

diagnosed

via

tracheal

visualization

which

is

generally

performed

by

an

otorhinolaryngologist

Indirect

and

fiberoptic

laryngoscopy

are

non-invasive

examination

techniques

that

can

be

performed

in

the

office

but

usually

do

not

show

the

entire

trachea

A

subglottic

stenosis

is

not

always

visible

therefore

direct

rigid

tracheoscopy

in

general

anaesthesia

is

indicated

in

cases

suspect

of

WG

Recurrent

SGS

is

a

well

recognized

but

uncommon

feature

of

WG

Patients

with

WG

who

develop

laryngotracheal

disease

have

usually

already

been

diagnosed

as

such

because

of

the

presence

of

disease

in

other

organs

at

the

same

time

or

at

a

previous

occasion

-LSB-

-RSB-

Isolated

involvement

of

the

subglottic

larynx

is

conspicuously

rare

only

a

few

cases

have

been

reported

in

the

literature

-LSB-

-RSB-

In

our

series

however

three

patients

had

SGS

or

TS

as

presenting

symptom

of

their

WG

We

do

not

have

an

explanation

for

this

rare

presentation

Another

particular

finding

is

that

eight

of

our

nine

patients

were

female

This

contrasts

significantly

with

the

male/female

ratio

in

the

reference

group

that

consisted

of

WG

patients

that

were

diagnosed

in

the

same

period

as

the

DT

group

but

who

did

not

have

evidence

of

SGS

or

TS

It

is

difficult

to

speculate

on

the

reason

for

this

female

preponderance

Anatomically

the

female

airway

is

narrower

than

the

male

making

it

more

prone

for

post-intubation

stenosis

However

we

even

had

females

presenting

with

a

SGS

or

TS

More

research

in

larger

series

has

to

be

performed

to

explain

this

phenomenon

In

cases

where

the

diagnosis

of

WG

is

suspected

ANCA

testing

should

be

part

of

the

routine

laboratory

evaluation

-LSB-

-RSB-

C-ANCA

has

been

shown

to

be

a

specific

marker

for

WG

with

rare

false-positive

results

p-ANCA

testing

is

much

less

specific

Only

the

particular

laboratory

findings

of

c-ANCA

reacting

with

and

p-ANCA

reacting

with

myeloperoxidase

-LRB-

MPO

-RRB-

are

specific

for

the

autoimmune

vasculitides

-LSB-

-RSB-

Notably

seven

of

our

nine

patients

that

underwent

DT

were

positive

and

one

patient

was

MPO-ANCA

positive

All

patients

had

involvement

of

additional

organs

In

three

patients

the

disease

presented

as

a

stenosis

and

laryngotracheoscopy

revealed

the

size

and

site

of

the

lesion

Organs

involved

showed

no

pattern

in

which

there

should

be

additional

suspicion

for

the

development

of

SGS

or

TS

There

was

no

relation

between

the

number

of

relapses

and

the

development

of

TS

or

SGS

The

TS

or

SGS

occurred

more

often

in

periods

where

the

disease

appeared

to

be

less

active

Remarkably

TS

or

SGS

predominantly

became

manifest

in

periods

in

which

WG

appeared

to

be

inactive

Interestingly

seven

out

of

our

nine

patients

who

developed

TS

or

SGS

had

not

been

diagnosed

previously

with

tracheal

involvement

of

WG

neither

at

first

presentation

nor

at

relapse

-LRB-

s

-RRB-

We

speculate

that

during

active

disease

a

subclinical

tracheal

involvement

occurs

which

may

subsequently

heal

with

scar

formation

To

examine

this

hypothesis

in

patients

elective

tracheoscopy

should

be

performed

in

all

patients

with

WG

The

time

interval

between

presentation

of

clinical

stenosis

in

these

seven

patients

-LRB-

mean

months

median

range

-RRB-

favours

watchful

waiting

DT

with

the

Groningen

dilatation

tracheoscope

is

a

safe

minimally

invasive

procedure

for

the

treatment

of

Cotton-Myer

grade

II

subglottic

or

tracheal

stenosis

of

various

origin

It

is

an

elegant

self-standing

surgical

intervention

where

no

additional

interventions

are

needed

For

an

overview

of

the

effect

of

DT

the

reader

is

referred

elsewhere

-LRB-

G.B.

Halmos

F.G.

Dikkers

Dilatation

tracheoscopy

in

treatment

of

subglottic

and

tracheal

stenosis

submitted

for

publication

-RRB-

Nowadays

mitomycin-C

an

alkylating

agent

that

inhibits

cell

division

protein

synthesis

and

fibroblast

proliferation

-LSB-

-RSB-

is

increasingly

used

as

adjuvant

treatment

in

the

management

of

selected

cases

of

laryngeal

and

tracheal

stenosis

for

example

luminal

obstruction

in

fresh

circular

sutured

wounds

However

the

laryngeal

and

tracheal

stenoses

of

WG

patients

are

almost

always

of

older

age

and

display

advanced

scarring

at

the

time

of

diagnosis

Dilating

such

mature

stenoses

will

inevitably

lead

to

damage

of

tracheal

epithelium

However

this

damage

is

considerably

different

from

granulomatous

scarification

in

sutured

lumina

and

therefore

we

do

not

expect

an

additional

favourable

response

to

mitomycin

Therefore

we

have

not

applied

mitomycin-C

in

our

WG

patient

cohort

In

cases

where

TS

or

SGS

develops

there

is

always

the

question

whether

or

not

to

intervene

and

the

question

of

timing

of

the

intervention

There

are

two

main

parameters

in

these

patients

complaints

and

physical

signs

One

might

see

this

as

a

two-by-two

table

with

complaints

on

the

x-axis

and

peakflow

values

on

the

y-axis

Progressive

complaints

and

progressive

decline

of

peakflow

values

-LRB-

-RRB-

indicate

intervention

by

DT

Absence

of

progressive

complaints

and

unchanged

peakflow

values

-LRB-

-RRB-

indicate

watchful

waiting

Absence

of

progressive

complaints

with

decline

of

peakflow

values

-LRB-

-RRB-

need

to

be

addressed

when

the

values

reach

a

critical

level

in

which

it

can

be

expected

that

a

common

cold

might

lead

to

severe

stenosis

of

the

airways

Finally

progressive

complaints

with

unchanged

peakflow

values

-LRB-

-RRB-

indicate

that

pulmonary

function

tests

should

be

performed

and

if

negative

indicate

that

the

patient

has

an

incorrect

perception

of

his

physical

potentials

This

can

then

be

addressed

Unfortunately

in

only

five

of

the

nine

patients

in

this

retrospective

study

we

have

peak

flow

measurements

A

reason

is

that

two

patients

have

or

had

a

tracheostomy

We

have

registered

no

complications

or

deaths

during

or

because

of

DT

We

have

three

reasons

to

regard

dilatation

tracheoscopy

as

a

minimally

invasive

intervention

We

have

experienced

no

complications

related

to

dilatation

tracheoscopy

It

requires

short

hospitalization

-LRB-

generally

days

-RRB-

The

intervention

is

not

straining

for

the

patients

A

variety

of

surgical

techniques

has

been

used

to

treat

SGS

or

TS

of

other

aetiologies

-LSB-

-RSB-

The

success

of

these

surgical

techniques

in

upper

airway

stenosis

related

to

WG

has

been

variable

-LSB-

-RSB-

In

our

series

two

out

of

nine

patients

were

treated

once

for

upper

airway

stenosis

with

dilatation

without

any

re-stenosis

because

of

WG

Unfortunately

two

patients

required

a

tracheostomy

One

was

temporary

but

one

patient

needed

a

permanent

tracheotomy

-LRB-

-RRB-

this

was

the

pregnant

woman

needing

an

emergency

procedure

This

number

equals

that

of

Gluth

et

al.

-LSB-

-RSB-

Conclusion

WG

as

such

is

a

rare

disease

and

SGS

and

TS

are

rare

symptoms

in

patients

with

WG

DT

can

offer

a

simple

and

repeatable

solution

to

this

very

serious

symptom

Patient

complaints

and

monitoring

of

peakflow

values

offer

simple

tools

for

the

decision

whether

or

not

to

intervene

However

a

causative

solution

to

WG

should

be

the

ultimate

goal

B I O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O B I O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O B I O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O B I O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O B I O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

subglottic stenosis
tracheal stenosis
dilatation tracheoscopy