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TTD 13. Annual Congress, 5-9 May 2010 Lütfi Kırdar Uluslararası Kongre ve Sergi Sarayı- İstanbul OSAS Related Organ SystemComplicationsNeurologicandophthalmologic Doç.Dr.Sadık ARDIÇ SB Dışkapı Yıldırım Beyazit Eğitim ve Araştırma Hast, GöğüsHastalıkları Kliniği Uyku Hastalıkları Merkezi
OSAS,Neurologic, andOphthalmologicDiseases • NeurologicComplications • CognitiveFunctionImpairment • Stroke, • CerebrovascularDisease, • ExecessiveDaytimeSleepness. • OphthalmologicComplications • Glaucoma, • Nonarteriticanteriorischemicopticneuropathy, • Visualfielddefects, • Papilledema, • Centralserouschorioretinopathy, • Floppyeyelidsyndrome.
OUAS da Nöropsikiyatrik Sonuçlar • Morningheadache • Sleepfragmentionanddeprivation • İnsomnia • ExcessiveDaytimeSleepness, • Fatigiue • Badworkingperformance, • Mooddisorders, • CognitiveFunctionsİmpairment • CerebrovascularDisease, • Stroke
Executivefunctions • Executivefunctionsarecognitive control processes that include; • Flexibility in problem solving, • Planning, • Response inhibition, • Allocationof attention, • Maintenance and manipulation of informationover time, • Self-regulation of goal-directed behavior • Fuster JM. Executive frontal functions. Exp Brain Res 133: 66–70, 2000. • Elliott R. Executive functions and their disorders. Br Med Bull 65: 49–59,2003..
Jet Lag Shift Work DSPS ASPS İrreguar sleep-wake Patern Narcolepsy Focal leison Klein-Levin Prader-Willi Miyotonik Distrofi Ensefalit İMSS Hypersomnia Serebral Palsy Head İnjury Serebral Radyoterapy Methabolic Disorders Endocrine Disorders Neurologic Disorders Systhemic Disorders Circadien rythim Disorders Excessive Daytime Sleepness Sleep Fragmentation Drugs Light OUAS UARS PLMS Drugs Pshyiatric Disorders Sleep deprivation Şizofreni Seasonal Affective Disorders Social factors Circadien rythim Disorders Drugs
Cognitive Functions in OSAS • Workingmemoryspeed in OSDB was significantly slower than in healthy subjects, • A group average map showed absence of dorsolateral prefrontalactivation, regardless of nocturnal hypoxia. • ThomasR.J., et all.Functional imaging of working memory in obstructivesleep-disorderedbreathing.J ApplPhysiol 2005; 98:2226-2234.
Cognitive Functions in OSAS • After treatment, resolutionof subjective sleepiness, • Contrasted with no significant change inbehavioral performance, • Persistent lack of prefrontal activation, • Partial recovery of posterior parietal activation. • ThomasR.J., et all.Functional imaging of working memory in obstructivesleep-disorderedbreathing.J ApplPhysiol 2005; 98:2226-2234.
Cognitive Functions in OSAS • These findings suggestthat working memory may be impaired in OSDB, • Thisimpairment is associated with disproportionate impairment of functionin the dorsolateral prefrontal cortex. • Nocturnal hypoxia may notbe a necessary determinant of cognitive dysfunction, • Sleep fragmentationmay be sufficient. • ThomasR.J., et all.Functional imaging of working memory in obstructivesleep-disorderedbreathing.J ApplPhysiol 2005; 98:2226-2234.
OSAS da Histogram (Pre and Post CPAP) Sleep fragmentation In OSAS, pre CPAP Histogram In OSAS, post CPAP Histogram
Cognitive Functions in OSAS • There may be dissociations betweenrespiratory vs. cortical recovery and objective vs.subjective recovery. • Hypofrontality may provide a plausible biological mechanism for aclinical overlap with disorders of mood and attention. • ThomasR.J., et all.Functional imaging of working memory in obstructive sleep-disordered breathing.J Appl Physiol 2005; 98:2226-2234.
Cognitive Functions in OSAS • Theydemonstrateabsentdorsolaterallateralprefrontalactivationin OSDB patients performing a working memory taskregardless of the presence of nocturnal hypoxia. • After positiveairway pressure therapy, there was a complete subjectiveclinical recovery but activation remained impaired. • ThomasR.J., et all.Functional imaging of working memory in obstructivesleep-disorderedbreathing.J ApplPhysiol 2005; 98:2226-2234.
Cognitive Functions in SleepDeprivation • After sleep deprivation, subjects demonstrate impaired executive control,such as ; • Increased rate of forgetting, • Slow responses tosimple mathematical calculations, • False responses during avigilance task . • It is thus possible that impaired workingmemory is animportant abnormality in pathological sleepystates including obstructive sleep-disordered breathing (OSDB) or narcolepsy. • Van Dongen HP, et all.Sleep 26: 117–126, 2003.
Sleep Fragmentation in OSAS • Experimentalauditorysleepfragmentation, which can be induced by using , • Anauditory stimulus to disrupt sleep, • Sleepiness, • Impairs mood, • Decreasesmental flexibility, • Decreases sustained attention, • Martin SE, et all.The effect ofsleep fragmentation on daytime function. Am J RespirCrit Care Med 153: 1328–1332, 1996.
Cognitive Function and Behavior of Children With Adenotonsillar Hypertrophy. • Childrenwithadenotonsillarhypertrophy who are suspected of having OSDB, nightly • snoring, higher AHI values, • High sleep efficiencies, • Short sleep latencies (in the sleep laboratory) • Predictimpaired cognitive performance, especially with;generalverbal, abstract reasoning, and verbal memory tasks. • Thedegree of impairment of intellectual function in particularwas profound • Suratt P.M.etall. Suspected of Having Obstructive Sleep-Disordered BreathingCognitive Function and Behavior of Children With AdenotonsillarHypertrophy. Pediatrics 2007;119;320-329
Cognitive Function of PreschoolersChildren • Thesleep-disorderedbreathingmay be associatedwithimpairedexecutivefunction in preschoolers, • Itsstrongestimpact on theinhibitiondimension, • Furtheremphasizingtheimportance of earlyinterventionforsleep-disorderedbreathing in thisearlyage.
SDB and Cognition in older women • SDB is an important risk factor for cognitive impairment in older women, • Especially those with the APOE epsilon4 allele. • Mechanisms linking these disorders need to be identified. • Spira AP.et all SDB and cognition in older women. J Am Geriatr Soc. 2008;56(1):45-50.
Cognitive dysfunction, and OSA in Children • APOE epsilon4 allele is morefrequent in childrenwithobstructivesleepapnea, • Particularly in thosewhodevelopneurocognitivedeficits, • Suggestingthatthe APOE epsilon4 allele is associatedwith not onlyincreasedodds of havingsleep-disorderedbreathing, • But alsowith an increased risk forneurocognitivedysfunction. • Gozal D. et all.APOE epsilon 4 allele, cognitivedysfunction, andobstructivesleepapnea in children. Neurology. 2007 Jul 17;69(3):243-9
Truck Drivers in Hypersomnolence • Three hundred male truck drivers were studied. • The mean daily sleep duration was 5.6+/-1.3 h, and poor quality of sleep was found in 46.3% of the individuals. • Hypersomnolence was found in 46% of the drivers and was associated with younger age, snoring, and working >10 h without rest. • A positive correlation between hypersomnolence and previous accidents was detected (p=0.005).
Cognitive Dysfunction and OSA in Children • Childrenscheduledforadenotonsillectomyoftenhavemild-to-moderate SDB andsignificantneurobehavioralmorbidity, includinghyperactivity, inattention, attention-deficit/hyperactivitydisorder, andexcessivedaytimesleepiness, all of whichtendtoimproveby 1 yearaftersurgery. • However, thelack of bettercorrespondencebetween SDB measuresandneurobehavioraloutcomessuggeststheneedforbettermeasuresorimprovedunderstanding of underlyingcausalmechanisms. Chervin RD, et all.Sleep-disorderedbreathing, behavior, andcognition in childrenbeforeandafteradenotonsillectomy. Pediatrics. 2006 Apr;117(4):e769-78.
Cognitive Dysfunction and OSA in Children • On theneuropsychologyassessmentbattery (NEPSY), childrenwith SDB scoredsignificantlylowerthanthecontrolgroup on , • Theattention/executivefunction domain and • Twosubtestswithinthat domain, • Onemeasuringvisualattention , • Theotherexecutivefunction. • Inaddition, childrenwith SDB scoredsignificantlylowerthanthecontrols on onesubtestfromthe NEPSY language domain: PhonologicalProcessing. • O'BrienLM, etall .Neurobehavioralcorrelates of sleep-disorderedbreathing in children.J SleepRes. 2004 Jun;13(2):165-72.
Cognitive Dysfunction and OSA in Children • (devam) • Childrenwith SDB weresignificantlysleepierthancontrols. • Furthermore, total arousalindexwasnegativelycorrelatedwithneurocognitiveabilities, • Suggestinga role forsleepfragmentation in pediatric SDB-inducedcognitivedysfunction • O'Brien LM, etall .Neurobehavioralcorrelates of sleep-disorderedbreathing in children.J SleepRes. 2004 ;13(2):165-72.
Cognitive changes and sleep disordered breathing in elderly • Decliningcognitivefunction in olderpersonswithmildtomoderate SDB is relatedtotheamount of respiratorydisturbancesoccurring at night, • Suggestthattheeffect of SDB on cognitivedecline is unrelatedtoraceandmeasuredhypoxemia. • Thelargenumber of community-dwellingelderlywithmildtomoderate SDB mayaccrueconsiderablebenefits (bothcognitivelyandmedically) fromthetreatment of SDB, • iftheyare not markedlyhypoxemic. • Cohen-Zion M. et all.Cognitivechangesandsleepdisorderedbreathing in elderly: differences in race. J PsychosomRes. 2004 ;56(5):549-53.
Effect of CPAP Treatment on Cognitive Function in OSAS • It is concludedthat in patientswith severe OSA, CPAP treatmentresults in a significantearlyimprovement in cognitivefunction but not in emotionalstatus. • Borak J, et all.Effects of CPAP treatment on psychologicalstatus in patientswith severe obstructivesleepapnoea. J SleepRes. 1996;5(2):123-7
In OSAS Cognitive Functions • OUAS lılar, normal bireylerle karşılaştırıldığında,hareketi (motor fonksiyon) başlatma ve bitirmede daha yavaş kalmakta. • İnhibituvar motor kontrol eksekutif bir fonksiyondur, oksihemoglobin desaturasyonuna bağlı gelişir. • P. Sagaspe et al. Inhibitory motor control in apneic and insomniac patients.J.Sleep Res.2007;16 :381–387
In OSAS Cognitive Functions • Motor inhibisyon fonksiyonu, bozulduğunda bireyde trafik yada iş kazası yapma riski artar. • OUAS olan bireylerin kaza yapma risklerini artıran faktörlerden biriside bu fonksiyonun bozuk olmasıdır. • P. Sagaspe et al. Inhibitory motor control in apneic and insomniac patients.J.Sleep Res.2007;16 :381–387
OSAS ,CPAP treatment and Cognitive Functions • CPAP treatmenteffect on cognitivefunctions; • Afterlongterm CPAP treatment, attention,visiuallearningand motor skillsimprove, • But anyimprovmentwas not seenexecutivefunctions. • Ferini-StrambiL. et all. Cognitive dysfunction in patients with obstructive sleep apnea (OSA): partial reversibility after continuous positive airway pressure (CPAP)Brain Research Bulletin, 2003; 61 : 87-92
In OSAS, Brain Structural Changes • In OSAS, disease especially effects WM. • Lymbic system, pons, frontal, temporal and parietal cortexs and cerebellum(in and out neural patway) • Macey et al.Brain Structure in OSA— Sleep, 2008;31(7):967-977
In OSAS, Brain Structural Changes • In OSAS,neurobehavioral and pshycologic impairments belong to neural fiber destructions. • Hypoxia, oxidative stress, choronic inflammation, small vessel disease and local ischemia play role this structural changes • Macey et al.Brain Structure in OSA— Sleep, 2008;31(7):967-977
CPons: caudal pons; MCP: middle cerebellar peduncle; CST: corticospinal tract.
In OSAS, Brain Structural Changes • This pathologies would not be improved by conventional treatment methods and could be permenant. • Because of then,in OSAS,treatment modalities have to be preventive treatment options. • Macey et al.Brain Structure in OSA— Sleep, 2008;31(7):967-977
OSAS, Cognitive functionandBrain Figure 2. Significant hypometabolism (P < 0.005 uncorrected for multiple comparisonsfor voxels and P-corrected <0.05 forclusters) in the apneic group compared withcontrols, as shown by superimposition ontoaxial slices of the customized template (righthemisphere corresponds to the right side of figure). K. Yaouhi et al.Cognitive and brain imaging study of OSA patients.J. Sleep Res. 2009;18, 36–48
OSAS, Cognitive FunctionandBrain • In elderly OSAS patients, cognitive impairments are shown very early. • In young patients have severe OSAS,that they compansate, cognitive impairment is not happened. • Alchanatis et al., 2008
OSAS, Cognitive FunctionandBrain • There is very important amount regional gray matter loss in OSAS patients. • Frontal ,temporo–parieto–occipital cortex, thalamus, basal ganglions and cerebellar region • Hypometabolism restrict more than GM density changes. • These evidence prefrontal cortex, precuneus, parieto–occipital cotex and cingulate gyrus (mid and posterior regions) are seen. K. Yaouhi et al.Cognitive and brain imaging study of OSA patients.J. Sleep Res. 2009;18, 36–48
(a) Regional gray matter loss in OSAS patients. (b) Task-related activation in OSAS patients. 1 = left anterior cingulate cortex, 2 = posterior lateral parietal cortex, 3 = inferior temporal gyrus, 4 = parahippocampal gyrus, 5 = right quadrangular lobule, 6 = left hippocam-6 = left hippocam-pus, 7 = dorsolateral prefrontal cortex, 8 = inferior/middle frontal, 9 = thalamus, 10 = cingulate gyrus, 11 = cerebellum.*BOLD Blood oxygen level dependent Desseilles et al. Functional Brain Imaging in Sleep Disorders.Sleep 2008;31(6):777-794.
Sleepand Cerebral blood flow • Sleep-related breathing disorders are strongly associated with increased risk of stroke independent ofknown risk factors. . • The mechanisms underlying this increasedrisk of stroke are multifactorial and include reductionin cerebral blood flow, altered cerebral autoregulation, andincreased platelet aggregation and plasma fibrinogen level. • Mohsenin V. Stroke and Sleep Apnea,Stroke 2001;32;1271-1278
Sleepand Cerebral blood flow • Doppler USG,133Xe inhalation, Single-photon emission CT;have shown • 5% to 28% reduction in cerebral blood flow during non–rapideye movement (Non-REM) sleep, • 4% to 41% increase in REMsleep, • Compared with wakefulness in normal persons. • Mohsenin V. Stroke and Sleep Apnea,Stroke 2001;32;1271-1278
Sleepand Cerebral blood flow • Changes in cerebral blood flow parallel changes in the brainmetabolic rate and oxygenconsumption in both non-REMand REM sleep. • Madsen PL.ActaNeurol Scand Suppl. 1993;148:3–27. • These changes in cerebral blood flow areindependent of extracerebral hemodynamic factors • Lenzi P, et all.Cerebralbloodflowregulationin REM sleep: a model for flow-metabolism coupling. Arch ItalBiol. 1999;137:165–179.
Sleep and Cerebral blood flow • Several cross-sectional studies have demonstrated an agerelatedreduction in regional cerebral blood flow in the rangeof 20% to 24% in normal aging individuals. • This reduction in regional blood flow has been attributed toage-related brain atrophy and increased cerebral vascular resistance secondary to cerebral arteriosclerosis. • Naritomi H, Arch Neurol.1979;36:410–416. • Melamed E,Stroke. 1980;11:31–35.
Stroke, Transiet Ischemic Attack and OSAS • In a larger study of 128 patients with transient ischemicattack and stroke, Bassetti and Aldrich25 found obstructive sleepapnea in 62.5% of the patients compared with 12.5% in thenormal control group. • They observed a high frequency ofobstructive sleep apnea disorder in patients with transient ischemicattack, suggesting preexisting obstructive sleep apnea disorderbefore cerebrovascular events rather than as a consequenceof it. • This latter observation strongly supports the role of sleep apnea as an independent risk factor for cerebrovascular accident • Bassetti C, Aldrich MS. Sleep apnea in acute cerebrovascular diseases: final report on 128 patients. Sleep 1999; 22: 217-223.
Stroke, Transiet Ischemic Attack and OSAS • Taken together, the combination ofcerebral hypoperfusion and hypercoagulability in sleep apneadisorder is possibly the mainpathophysiological mechanismfor increased risk of stroke in this population. • The mechanisms underlying this increasedrisk of stroke are multifactorial and include reductionin cerebral blood flow, altered cerebral autoregulation, andincreased platelet aggregation and plasma fibrinogen level. • Mohsenin V. Stroke and Sleep Apnea, Stroke 2001;32;1271-1278
Table 3. Predictors of Stroke Unadjusted HR (95% CI) P Adjusted HR (95% CI)* P Apnea-hypopnea index < 5 1 1 Apnea-hypopnea index ≥5 3.92 (1.90–8.11) 0.001 2.89 (1.37–6.09) 0.005 Age, y 1.07 (1.02–1.12) 0.006 1.07 (1.02–1.13) 0.010 Body mass index, kg/m2 1.05 (0.97–1.13) 0.2471.04 (0.96–1.14) 0.340 Male gender 2.18 (1.05–4.50) 0.036 2.90 (1.27–6.58) 0.011 Left ventricular function Good 1 1 Fair 2.41 (1.30–4.47) 0.005 2.00 (1.04–3.83) 0.038 Poor 4.86 (1.86–12.7) 0.001 6.65 (2.37–18.7) 0.001 Coronary artery intervention 1.30 (0.61–2.79) 0.496 0.76 (0.33–1.77) 0.525 Diabetes mellitus 2.90 (1.55–5.42) 0.001 1.86 (0.94–3.71) 0.076 Hypertension 1.95 (1.10–3.45) 0.023 1.88 (1.01–3.51) 0.047 Previous stroke/TIA 1.72 (0.53–5.54)0.364 1.40 (0.40–4.87)0.602 Atrial fibrillation 2.11 (0.51–8.68) 0.303 2.19 (0.48–10.1) 0.314 Current smoking 0.84 (0.41–1.74) 0.639 1.25 (0.57–2.70) 0.578 TIA indicates transient ischemic attack. *Adjusted for apnea-hypopnea index 5, age, body mass index, gender, left ventricular function, coronary artery intervention, diabetes mellitus, hypertension, previous stroke/TIA, atrial fibrillation, and current smoking Valham F. et all.Circulation 2008;118;955-960;