diab cranial auto neuropathy

1. Diabetic Cranial and Autonomic
Neuropathies
Clinical 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 neuropathy
classical 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

51. Neuropathic joint or
Charcot’s arthropathy - 5
Acute Charcot’s arthropathy may mimic infection
Chronic Charcot’s foot is classically described as
‘bag of bones’
(Gross destruction of joint surfaces and bone with
effusion which is typically painless)

52. Neuropathic joint or
Charcot’s arthropathy - 6
Differentiation from osteomyelitis is difficult
* TC 99 Scan
* Indium labeled white cell scan
* MRI

53. Neuropathic joint or
Charcot’s arthropathy - 7
Early diagnosis and intervention are important to
prevent deformity and loss of function
Treatment includes
*Long term immobilization in plaster of Paris cast, (up to
even 1 year)
*Charcot’s Restraint Orthotic Walker (CROW) which
allows pressure to be off loaded
*Pamidronate - tried as a new treatment of Charcot’s
arthropathy