بسم الله الرحمن الرحيم

1. بسم الله الرحمن الرحيم

2. Neurological Complications of Diabetes By Dr: Hazem El Hewage

3. Diabetic complication • Central • Peripheral

4. Sleep disorders

5. Excessive Daytime Sleepiness”EDS“ • The sleep disorder of excessive daytime sleepiness "EDS" requires proper diagnosis due to its important potential consequences • It leads to impaired performance and diminished intellectual capacity and can be a major factor or cause of accidents and catastrophes specially in old age • The incidence of EDS was doublicated in diabetic patients when copmered with normal individuals. • EDS occurring in diabetic patients was reversible with control of blood glucose level • there is no relations between age at onset of illness, duration of diabetes and EDS.

6. Theories that explain of EDS • Certain sleep disorders are common in DM • Sleep apnea as a consequence of diabetic autonomic neuropathy, or obesity associated with type II diabetes. • Narcolepsy, restless leg syndrome

7. Other main causes of EDS • Parasthesias: • Nocturia: • Type of treatment : patients treated with insulin are more commonly reported EDS than oral therapy due to rapid fluctuation of blood glucose .

8. Cognitive impairments and intelligence in DM

9. Intelligence in children and young adult • There are significant reduction of IQ in children and young adult with type 1 DM when compared with general populating • Also children of diabetic mothers who reported poor glycemic control or repeated hypoglycemic episodes

10. Cognitive impairment in adult diabetics • The quantitative meta-analysis showed that diabetes was a risk factor for any type of dementia and MCI. (Med J. May 2013) • New research has shown that cognitive decline in people with Type 2 Diabetes is likely due to brain atrophy, or shrinkage, that resembles patterns seen in the early stages of Alzheimer's disease. (Diabetes Care, September, 2013 ) • The World Health Organization reports that more that more than 347 million people worldwide live with diabetes and around 90 % of these cases are Type 2.

11. Site of brain atrophy in DM • Differing from type 1 diabetes, compounded by age and various risk factors ( HTN, Dyslipidemia, obesity, ….) which common in type 2 diabetes, a very wide range of functional damage is observed. • It is generally considered that vascular damage which more common in type 2 is closely associated with impairment of aspects of frontal lobe function, such as psychomotor speed, executive function and attention, and that atrophy of the hippocampus, which is related to memory, and reduced blood flow in the parietal lobe, the posterior portion of cingulated gyrus related togait affection

12. Site of brain atrophy in type 2 DM

13. Mechanisms of dementia in DM

14. Pattern of cognitive impairments in type1 and type 2 DM • In type 1 diabetes: impairment in information processing, psychomotor efficiency, attention, visuospecial abilities and mental flexibility are greatly impaired. • In type 2 diabetes: psychomotor speed and executive function, as well as memory, are greatly affected . • As a result of decrease walking speed, balance is impaired, risk of falls is increased and fractures are more frequent in elderly diabetic patients, reducing quality of life. • This differences explained by which the brain executive dysfunction has been reported to be associated with inability to carry out lower-extremity task.

15. Glycemic control and cognation • The ACCORD-MIND study observed a 0.14-point drop in Mini-Mental State Examination (MMSE) score for each 1% increase in HbA1c. (ACCORD-MIND trial. Diabetes Care 2009) In this studies : • Psychomotor speed assisted by ( Digital symbol substitution test” DSST”) • Memory assisted by (Rey Auditory Verbal Learning Test) • executive function assisted by(Stroop test) This study show significant negative association between HbA1c level and cognitive function

16. Type of drug therapy and cognition • Ryan  et al 2006 in a 24-week study in which rosiglitazone, a thiazolidinedione, a sulfonylurea, was combined with metformin, it was observed that both agents improved fasting blood glucose and also working memory •   Another study Haan et al 2003 found that oral hypoglycemic agents were more effective when the duration of disease was longer, and that multiple drug therapy was better at improving cognitive function than monotherapy. • Recently Himeno et al 2011 and Bomfim  2012 in animal studies reported that agents enhancing incretin effects will have beneficial effects on neuroprotection and disruption of brain insulin signaling, and they could be effective in preventing dementia in the future.

17. How we can prevent dementia in DM? • In conclusion, hyperglycemiaand hyperinsulinemia, as well as hypoglycemia, are associated with the progression of cognitive decline. • Diabetic control from an early stage would be useful in preventing the onset of vascular events, as well as cognitive decline. • Although the usefulness of intensive glycemic control has yet to be shown, good control that avoids hypoglycemia and hyperinsulinemia would suppress cognitive impairment. • However, at the current stage, lifestyle improvement with regard to diet, exercise habits, smoking and stress should help prevent diabetes and vascular complications, as well as the future development of dementia

18. Postural Instability in Diabetic Patients Posture and gait disturbances lead to limitations in the daily living activities with increase liability to fall. Postural instability are not only due to PN and impaired sensation in foot but also due to Spinal cord degeneration including degeneration of dorsal columns, spinocerebellar tracts, and anterior horn cell, which detected by SSEP and Motor evoked potential by using TMS

19. Cerebrovascular stroke and DM • Diabetics are at 2 to 4 fold risk increase to developing stroke than general population with significant increase of morbidity and mortality. • Increase the frequency cardio-embolic stoke after myocardial infarction in diabetic than non diabetic.

20. Cerebrovascular stroke and DM • Patients with TIA is concerned high risk patient in presences of DM (high risk TIA) according to ABCD2 Score (age, blood pressure, clinical presentation , diabetes , duration of attack) which incidence of developing stroke, fatal or non fatal myocardial infarction increase up to 34% within first week

21. Risk according to clinical features of TIA was assisted by ABCD2 score: (A) Age:> 60 years 1 point (B) Blood pressure:> 140/90 1 point (C) Clinical Features : weakness2point speech 1 point visual 0 point (D) Duration of Attack: < 10 min 0 point > 10 min 1 point > 60 min 2 point (D) Diabetes : If present 1 point The patient was higher risk if total score more than 5

22. Cholesterol ApoB Patients with Type 2 DM are more likely to have Small, Dense LDL LDL-C levels in people with diabetes can be misleading;Patients may have more LDL particles at a given LDL-C level Large, buoyant LDL Small, dense LDL Same LDL-C

23. Interrelation Between Atherosclerosis and Insulin Resistance Hypertension Obesity Hyperinsulinemia Diabetes Hypertriglyceridemia Small, dense LDL Low HDL Hypercoagulability InsulinResistance Atherosclerosis

24. DM and risk of CNS Infection • Diabetics are immunocompermized patients so developing of subacute cerebral or spinal cord symptoms, epidural abscess or meningitis must be considered. • A febrile facial pain with or without cranial nerve affection or proptosis, fugal sinusitis“mucromycosis” is most common cause due to direct intracranial extension or invasion of blood vessels and sinus thrombosis. • And this risk are duplicated with history of DKA

25. Diabetic peripheral neuropathy • DM is one of the most common causes of disableing polyneuropathy. • DPN was present in 66% of IDDM and 59% NIDDM. • However only 20% are symptomatic

26. Etiology of DPN • Hyperglycemic –polyol-myoinositol hypothesis: Glucose— Hexokinase Glucose 6 phosphate→ Krebs's cycle In diabetics glucose inter to polyol pathway with excess production of sorbitol and increase of intracellular myoinositol This result in defective of Na/ K ATPase activity leading to reduction of axonal transport

27. Other theories • Microangiopathy: • Structural change at the node of Ranvier: ATPase deficiency increase of Na lead to detachment of myelin and dying back of axon • Vsaculitic neuropathy: lymphocytic inflammatory vasculopathy as in painful proximal diabetic neuropathy. • Nerve growth factor deficiency: Skin of foot of diabetics show marked reduction of NGF which responsible on small sensory fiber neuropathy.

28. Classification of diabetic neuropathy • Two classification systems for diabetic neuropathy are the Thomas system and the symmetrical-versus-asymmetrical system. • The Thomas system (modified) is as follows:

29. The Thomas system classification • Hyperglycemic neuropathy • Generalized symmetrical polyneuropathies • Sensory neuropathy • Sensorimotor neuropathy • Autonomic neuropathy • Focal and multifocal neuropathies • Superimposed chronic inflammatory demyelinating polyneuropathy

30. Distal symmetrical sensorimotor polyneuropathy • Distal symmetrical sensorimotor polyneuropathy is most common for of diabetic neuropathy and defined according to the following 3 key criteria: • The patient must have diabetes mellitus consistent with a widely accepted definition. • Severity of polyneuropathy should be correlate with duration and severity of diabetes. • Other causes of sensorimotor polyneuropathy must be excluded

31. Asymmetrical neuropathies include the following: • Median neuropathy of the wrist (carpal tunnel syndrome) • Other single or multiple limb mononeuropathies • Thoracic radiculoneuropathy • Lumbosacral radiculoplexus neuropathy • Cervical radiculoplexus neuropathy

32. Another classification • Diffuse metabolic neuropathy (DPN) • Hyperglycemic neuropathy • Insulin neuritis • Hypoglycemic neuropathy • Vasculitic neuropathy • Demyelinating neuropathy

33. Subdivisions of Sensory Neurons

34. Risk factors that are associated with more severe symptoms • Poor glycemic control • Advanced age • Hypertension • Long duration of DM • Dyslipidemia • Smoking • Heavy alcohol intake • HLA-DR3/4 phenotype • Tall height

35. Clinical features of diabetic polyneuropathy • Mainly sensory :paraesthesiae and pain • Deep sensation affection and sensory ataxia • “Neuropathic Arthoropathy” most affected joint tarsometatarsal then metatharsophalengial joint • Unrecognized fractures • Ulcers • If prominent motor features must suspect CIDP

36. Staging of diabetic polyneuropathy • NO - No neuropathy • N1a - Signs but no symptoms of neuropathy • N2a - Symptomatic mild diabetic polyneuropathy: (sensory, motor, or autonomic symptoms) patient is able to heel-walk • N2b - Severe symptomatic diabetic polyneuropathy: patient is unable to heel-walk • N3 - Disabling diabetic polyneuropathy

37. Acute painful diabetic neuropathy • Acute or subacute burning lower limb pain with marked cutanous hyperalgesia, with no definite distal sensory loss, and slight reduction of ankle jerk • So may confusing as psychogenic condition specially that 70% of cases associated with depression • Most of cases associated with rapid weight loss • And usually follow tight gylcemic control

38. Diabetic truncal radiculoneuropathy • Attacks of truncal pain with no specific sensory disturbance of abdomen • Occur in fifth to seventh decades female with type2 DM • Focal abdominal wall paralysis and increase of abdominal protuberance • Marked weigh loss ?????

39. Diabetic proximal neuropathy • The disorders range from familiar extreme of acute asymmetrical painful proximal weakness within daystopainless symmetrical proximal weakness occur over weeks or months • The disorders carry many terms as: Diabetic (myelopahty, amyotrophy, myopathy, radiculopathy, lumber radiculopathy, or neuropahtic cachexia).

40. Clinical features • Occur in fifth to seventh decades in type2 DM • Anterior thigh muscle pain usually first presenting symptoms • Characteristic involvement of quadriceps weakness • Lost knee jerks • Extensor planter • In spite of unilateral onset 50% of cases bilateral affection within few weeks • Marked weight loss • Increase of CSF protein ???

41. Mononeuropathy and cranial neuropathy • Mononeuropathy: as CTS • Cranial neuropathy : Either ischemic or vasculitic ??? Most common affected nerves are ocular nerves third, sixths and less common fourth Other nerves may be affected specially facial and usually preceded by pain around ear ????

42. Autonomic neuropathy • Is the most serious and disabling neuropathy with DM • Most of functional abnormalities of organ as kidney, heart, retina , bladder ect…. Are due to sympathetic denervation of these organs .

43. Sweating abnormalities • Abnormal sweating is the first presenting symptoms of autonomic neuropathy which precede other symptoms by many years as: • Defective sweating in foot • Gustatory sweating which highly characteristic symptoms of diabetic autonomic neuropathy.

44. Blood vessels and blood flow • Sympathetic denervation of blood vessels lead to peripheral vasodilationand opening of arteriovenous shunts. With charcheristic features of foot: • Neuropahtic edema • Venous engorgement • Excessively warm foot • Paradoxical stimuli which warming of foot lead to vasoconstriction

45. Orthostatic hypotension • ↓of systolic Bp >30 mmHg or diastolic > 10 with setting position • Features: • Headedness, dizziness with longstanding or when patient awake from sleep • Gray mistiness of vision follow by curious pain in back of neck and shoulders “ coat hanger” distribution and later loss of consciousness • Orthostatic hypotension worse with of insulin due to reduction of peripheral vascular resistance with insulin

46. Diabetic cystopathy • Neurogenic blader must be suspected in long standing DM • Usually due to detrusor muscle dysenergia • Usually associated with sever polyneuropathy

47. Impotance • One of most common complication with DM and either due to: • Neurogenic due to impairment of central conduction of pudendal nerve though spinal cord which lead to defective nitric oxide delivery to cavernosal smooth muscles. • Vascular leakage or thrombosis of internal pudendal artery • So penile Doppler US are important

48. Other autonomic features • Diabetic diarhoea • Gastroparesis • Respiratory arrest

49. Thank you