diabetic cranial and autonomic neuropathies clinical spectrum and treatment sanjeev kelkar medical...

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


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 +


Pathogenesis:

Focal ischemia

Segmental demyelination

Aberrant remyelination as in any nerve regrowth


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


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


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


Pupillary abnormalities: • Clinically - small sized pupils• Reduced light reflex - sympathetic dysfunction• Severe reduction both PNS / SNS involved


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


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)


• 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


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,


• 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


• 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


• 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


• Gastrointestinal tract – 4• Diabetic constipation• Vagal denervation critical• SNS overtone due to ↓ PNS tone, sphincteric

tightening• Very common• Laxative unresponsive• Erythromycin, cisapride


• 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


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


• 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


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


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


• 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%


• 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


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


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


• 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


• 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


• 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


• 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


Relatively rare

Potentially devastating disorder

Long standing diabetes

Dense peripheral neuropathy

Peripheral vascular disease is typically

absent


Sympathetic failure-- increased blood

flow due to arteriovenous anastomosis

Bone demineralisation (diabetic

osteopenia)

Susceptibility to minor, recurrent fractures

Fig

Charcot’s Foot with Acute Stage of Destruction


Painless disintegration of bone in response to trivial trauma

Common joints involved are – Tarso metatarsal– Metatarso phalangeal– Ankle joint– Knee joint

Fig Bilateral Charcot’s Foot in Acute Stage of Destruction


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)


Differentiation from osteomyelitis is difficult

* TC 99 Scan

* Indium labeled white cell scan

* MRI


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

diabetic cranial and autonomic neuropathies clinical spectrum and treatment sanjeev kelkar medical...

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