Diabetic Cranial and Autonomic Neuropathies Clinical spectrum and Treatment

1. Diabetic Cranial and Autonomic NeuropathiesClinical spectrum and Treatment Sanjeev Kelkar Medical Director Novo Nordisk Education Foundation Bangalore India

2. Diabetic Neuropathy General: Incidence – 30 to 50% Recent Diabcare Asia Statistics – 37% Diabetic State is the trigger Uncontrolled diabetes – worsening over time Good control of diabetes - not the guarantee for – cure, arrest, reversal

3. Diabetic Neuropathy: Schema Cranial Neuropathies Peripheral Neuropathies Sensory, motor, mixed Autonomic Neuropathies Parasympathetic / Sympathetic Sudomotor Organ system related Radiculo-myelopathies with or without muscle involvement

4. Diabetic Cranial Neuropathies - 1 Isolate involvement known Older individuals with long standing diabetes May co-exist with other neuropathies Groups affected: Cranial Nerves III, IV & VI Facial Nerve Single / Multiple involvement associated with serious infections

5. Diabetic Cranial Neuropathies - 2 Oculomotor Nerves III, IV and VI Wide variations on incidence reported. No hard data. Gender ratio not reported. Oculomotor Nerves: Acute ipsilateral head ache Refractory to analgesics Diplopia, ptosis Pupilary abnormalities +

6. Diabetic Cranial Neuropathies - 3 Pathogenesis: Focal ischemia Segmental demyelination Aberrant remyelination as in any nerve regrowth

7. Diabetic Cranial Neuropathies - 3 Recovery over few days to few months Recurrence in frequent Aberrant regeneration uncommon Laboratory, all cranial imaging and CSF – Normal Treatment: Good diabetes control Treatment for the neuropathy – Analgesia, Stop smoking, vasodilators, omega fatty acids, anticonvulsants, anti depressants, antioxidants

8. Diabetic Cranial Neuropathies - 4 Facial Neuropathy – Bell’s Clinical unilateral weakness on the face, upper and lower Sensory symptoms in ear less often – pain and hyperacusis Gustatory disturbance variable Complete paralysis supposedly more frequent in diabetics

9. Diabetic Cranial Neuropathies - 5 Bell’s Palsy: Treatment control DM Steroid do not help, merely destabilizes control. Exposure ketatopathy: Dry cornea due to DM? Appropriate lubrication Night taping Marginal Tasorrhaphy in severe cases Prognosis: Proportional to initial deficit

10. Diabetes Autonomic Neuropathy: 1 • Must always look for AN • Development and its worsening to be tracked • Important to explain – • Organ system related symptoms • Avoids unnecessary investigations, • Help focused treatment • Scientific explanations help patient reassurance, relieves doubts • Has prognostic / danger signal significance

11. Diabetes Autonomic Neuropathy: 2 Pupillary abnormalities: • Clinically - small sized pupils • Reduced light reflex - sympathetic dysfunction • Severe reduction both PNS / SNS involved

12. Diabetes Autonomic Neuropathy: 3 Cardiovascular phenomena – Sympathetic dysfunction • Frequent in diabetics • Responsible for morbidity and higher mortality rates, can be early in diabetic life • The balance between the PNS / SNS tones affects several characteristics of cardiac function. • Sometimes PNS abnormalities progresses simultaneously

13. Diabetes Autonomic Neuropathy: 4 Clinical clues to diagnosis: Basal Tachycardia 90 – 120 / min. PNS degeneration SNS overtone Basal Bradycardia SNS dysfunction (in patients not on cardiovascular drugs, with heart failure, CHD or hypertension)

14. Diabetes Autonomic Neuropathy: 5 • Absence of beat to beat variations in inspiration / expiration, change of posture, stress and mild exercise suggest total denervation of heart • Postural hypotension: Fall of 30/10 mm in supine blood pressure on standing suggests sympathetic dysfunction

15. Diabetes Autonomic Neuropathy: 6 Cardiac Denervation explains: Painless MI, vague thoracic abdominal symptoms be suspect Sudden cardiac death due to adrenergic super sensitivity Important to submit to TMT before putting on exercises as cardiac output, vascular reflexes affected Minor stress variations required in daily life,

16. Diabetes Autonomic Neuropathy: 7 • Gastrointestinal Tract: Symptoms • Prevalence is high • Parasympathetic cause peristalsis • Sympathetic cause sphincter tightening • Symptoms depend on tonal integrity and balance of PNS – SNS • Dominant degeneration decides • Both PNS / SNS could be involved

17. Diabetes Autonomic Neuropathy: 8 • Gastrointestinal tract – 2 • Gastroparesis – commonest, bloating, discomfort, heart burn, vomiting • Vagal denervation critical • Motor dysfunction due to both ANS degeneration likely • Sensory perceptions from gut, increased first, then bluuted

18. Diabetes Autonomic Neuropathy: 8 • Diabetic Diarrhea, explosive non infective, painless, abnormal mucosal fluid absorption due to loss of adrenergic nerve • Sphincter laxity • PNS tonal dominance • Denervation hypersensitivity or loss of sympathetic brake

19. Diabetes Autonomic Neuropathy: 9 • Gastrointestinal tract – 4 • Diabetic constipation • Vagal denervation critical • SNS overtone due to ↓ PNS tone, sphincteric tightening • Very common • Laxative unresponsive • Erythromycin, cisapride

20. Diabetes Autonomic Neuropathy: 11 • Gastrointestinal tract – 5 • Other mechanisms: • Pancreatic, exocrine insufficiency • Insulin deficiency – atrophy of acinar cells • Reduced enzymatic & bicarbonate output • Acute hyperglycemia delays gastric emptying if ANS disturbance is present

21. Treatment Gastroparesis - 1 Restore hydration, electrolyte imbalance Control hyperglycemia IV / oral erythromycin Cisapride orally 5 mg BD to 20 mg thrice – Patient dependant, now withdrawn. Enquire for excessive flatulence and frequent bowel movement Phenothiazines

22. Treatment Gastroparesis - 2 In severe forms – Nasogastric decompression I.V. fluids, correction in metabolic states, hypos, Removal / disruptions of bezoars through endoscopy I.V. Erythromycin – 3 mg / kg body weight / 8 hrly Oral Erythromycin 250 mg to 500 mg 4 times a day

23. Treatment Gastroparesis - 3 • Liquids initially • Then blendorised meals, small, frequent ones • Low fat, low fiber diets • Paretic stomach also empties liquid, homogenized meals, vitamins • Affected is the distal trichurated action for solid particles • Jejunostomy feeding in unresponsive gastroparesis, • TPN in pan motility disorders

24. Treatment Gastroparesis - 4 Cisapride: Piperidinyl Benzamides Activates serotonin type 4 receptors, stimulates Ach relase, smooth muscle contraction. Not blocked by atropine. Hence other mechanisms likely No antidopaminergic effects: EPS, galactorrhoea, anxiety like metoclopromide

25. Treatment Gastroparesis - 5 Cisapride: No cholinomimetic effects outside gut, thus better than bethanocol for bladder frequency. Dosage: Acute paresis l0 mg QID x 4 weeks Chronic 10 – 20 mg TDS half hour before meals, bed time. Consistent moderate to good symptom relief score. Excellent safety. No tolerance.

26. Erythromycin • Inhibits metabolism of other drugs by inhibiting P-450 cytochrome pathway. • Should not be co-administered with – • Cisapride, guanidine, lovastatin, nifedipine, midazolam, carbomazepine etc. • High dose – induces ventricular tachycardia • Non antibiotic, prokinetic macrolides are in the pipeline

27. Treatment Gastroparesis Erythromycin: • Stimulates motilin receptors due to structural homology with it. • Stimulates cholinergic mechanism. • Activates calcium channel • Raises intracellular calcium and thus contraction. • Absorption is formulation dependant

28. Treatment Gastroparesis • Action Force – Dose dependant – 40 mg to 25 mg close contractions are strong but emptying can be still poor. • I.V. doses empty the stomach better with solids, bezoars help push N.G. tubes in small bowel. • Help develop migratory motor activity in the lower bowel.

29. Erythromycin Doses • IV 3 mg / kg body wt. 8 hrly generally 5 to 7 days • Tachyphylaxis develops • Then oral – 250 mg – 500 mg • Long term efficacy doubted • Abdominal cramping + ototoxicity in CRF • Pseudomembranous colitis

30. Diabetes Autonomic Neuropathy: 11 • Sudomotor dysfunction: (Abnormalities of sweating) • Sympathetic fiber with cholinergic nerve ending • Distal loss of sweating 65% • Dry scaly cracked feet important • Body segmental loss – 25% • Single or multiple dermatomes sweat loss – 25%

31. Diabetes Autonomic Neuropathy: 12 • Sexual dysfunction : M : F • Urinary dysfunction : M : F • Both SNS PNS denervations common to • Etiology diabetic • Tremendous impact on diabetic patients life • Urinary dysfunction late in realization in males than sexual dysfunction

32. Diabetes Autonomic Neuropathy: 13 Male sexual dysfunction – 1 • Somatosensory input • Dorsal nerve of penis • Perineal nerve to CNS • Autonomic Nerve supply cavernous nerve from pelvic plexus, sends afferent impulses • NO, Ach, VIP released • Cavernous spaces relax and fill

33. Diabetes Autonomic Neuropathy: 14 Ejaculation: • Emission – seminal fluid from male adnexa in posterior urethra • Needs contraction of the smooth muscles in male adnexa - sympathetic hypo gastric nerve innervates • The same nerve closes bladder neck • Ejaculation effected by bulbo cavernosus muscle and perineal muscles – by pudendal branch

34. Diabetes Autonomic Neuropathy: 15 • Abnormalities of functions: Males: • Impotence – diabetic neuropathy the single most important cause • Erectile dysfunction 30 – 59% • Can be the presenting sign of diabetes • Poor glucose control associated • Β blockers, psychotropics, alcohol contribute • Nocturnal penile tumescence serves as the simplest, most direct clue

35. Diabetes Autonomic Neuropathy: 16 • Diabetic cystopathy – 1 • Progressive fall in sensations of bladder, detrusor areflexia and progressively increasing residual volume • Seen more in Type I • Autonomic neuropathy late • Detrusor afferent abnormality early - common

36. Diabetes Autonomic Neuropathy: 17 • Cystopathy: • Detrusor afferents do not carry sensation of fullness to CNS • Detrusor motor component from S3 – S4 through pelvic nerve not activated • Bladder trigone and neck innervated by sympathetic via hypogastric nerve [T11 – 12] • S3 – S4 degeneration will cause emptying difficulty • Hypo gastric nerve damage - incontinence

37. Diabetes Autonomic Neuropathy: 18 • Female cystopathy – • Additional complicating factors vesical prolapse • Hypoestrogenised urogenital tract • Will need surgical correction • Will need hormone therapy • Hormones help a great deal in urogenital syndromes of PMS

38. Treatment of Autonomic Neuropathies - 1 General • Good diabetes control • Use of insulin when required earliest • Smoking x x x • Blocker drugs? • Alcohol, overweight, inactivity, over exertion, mental stresses, preoccupation • Needs correction, review of one’s own life

39. Neuropathic (n) / Ischemic ulcer (i) Site Pressure points (n) Sides / tips of toes (i) Pain --- ( n ) +++ ( i ) Callus ++ ( n ) --- ( i ) Pulse ++ ( n ) --- ( i ) ABI > 1( n ) < .6 ( i ) Healing ++ ( n ) --- ( i )

40. Autonomic neuropathy - 1 * Damages sympathetic innervation of lower limb * This results in Decreased sweating Results in dry skin fissures / cracks Super added infection

41. Autonomic neuropathy - 2 Opening of arteriovenous channels Warm skin ( misleadingly healthy ) Shunting of nutrients and oxygen from the tissues Impaired vascular response to infection

44. Autonomic neuropathyclassical signs Dry skin Fissuring Distended veins over the dorsum of foot and the ankle

45. Neuropathic joint or Charcot’s arthropathy - 1 1868 French neurologist I.M. Charcot First described in tabes Can also be seen in leprosy, syringomyelia, hereditary sensory neuropathy, Charcot Marie Tooth disease etc

46. Neuropathic joint or Charcot’s arthropathy - 2 Relatively rare Potentially devastating disorder Long standing diabetes Dense peripheral neuropathy Peripheral vascular disease is typically absent

47. Neuropathic joint or Charcot’s arthropathy - 1 Sympathetic failure-- increased blood flow due to arteriovenous anastomosis Bone demineralisation (diabetic osteopenia) Susceptibility to minor, recurrent fractures

48. Fig Charcot’s Foot with Acute Stage of Destruction

49. Neuropathic joint or Charcot’s arthropathy - 4 Painless disintegration of bone in response to trivial trauma Common joints involved are • Tarso metatarsal • Metatarso phalangeal • Ankle joint • Knee joint

50. Fig Bilateral Charcot’s Foot in Acute Stage of Destruction