diabetic cranial and autonomic neuropathies clinical spectrum and treatment sanjeev kelkar medical...
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Diabetic Cranial and Autonomic Neuropathies
Clinical spectrum and Treatment
Sanjeev Kelkar
Medical Director
Novo Nordisk Education Foundation
Bangalore
India
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
Diabetic Neuropathy: Schema
Cranial NeuropathiesPeripheral Neuropathies
Sensory, motor, mixedAutonomic Neuropathies
Parasympathetic / SympatheticSudomotorOrgan system related
Radiculo-myelopathies with or without muscle involvement
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
Diabetic Cranial Neuropathies - 2
Oculomotor Nerves III, IV and VIWide variations on incidence reported. No hard data.Gender ratio not reported.Oculomotor Nerves:
Acute ipsilateral head acheRefractory to analgesicsDiplopia, ptosisPupilary abnormalities +
Diabetic Cranial Neuropathies - 3
Pathogenesis:
Focal ischemia
Segmental demyelination
Aberrant remyelination as in any nerve regrowth
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
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
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
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
Diabetes Autonomic Neuropathy: 2
Pupillary abnormalities: • Clinically - small sized pupils• Reduced light reflex - sympathetic dysfunction• Severe reduction both PNS / SNS involved
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
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)
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
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,
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
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
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
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
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
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
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
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
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
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.
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
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
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.
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
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%
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
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
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
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
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
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
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
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
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 )
Autonomic neuropathy - 1
* Damages sympathetic innervation of lower limb
* This results in
Decreased sweating
Results in dry skin fissures / cracks
Super added infection
Autonomic neuropathy - 2
Opening of arteriovenous channels
Warm skin ( misleadingly healthy )
Shunting of nutrients and oxygen from
the tissues
Impaired vascular response to infection
Autonomic neuropathyclassical signs
Dry skin
Fissuring
Distended veins over the dorsum of foot
and the ankle
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
Neuropathic joint or Charcot’s arthropathy - 2
Relatively rare
Potentially devastating disorder
Long standing diabetes
Dense peripheral neuropathy
Peripheral vascular disease is typically
absent
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
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
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)
Neuropathic joint or Charcot’s arthropathy - 6
Differentiation from osteomyelitis is difficult
* TC 99 Scan
* Indium labeled white cell scan
* MRI
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