​Kembara Xta - Medicine - Diabetic Polyneuropathy

​Kembara Xta - Medicine - Diabetic Polyneuropathy 
Introduction 
Diabetes causes peripheral nerve impairment, with several patterns described: 
Radiculoplexus neuropathy (diabetic amyotrophy) - Symmetric polyneuropathy - Distal sensory or sensorimotor - Mononeuropathy, radiculopathy, and polyradiculopathy - Cranial neuropathy - Focal limb or truncal neuropathy
Chronic inflammatory demyelinating polyneuropathy (CIDP), autonomic neuropathies, and acute painful small fiber neuropathy

Incidence and prevalence in Epidemiology 

Cross-sectional prevalence: 15% by symptoms; 50% by nerve conduction. Generalized polyneuropathy: 10% at diabetes diagnosis; 50% at 10 years.
16.7% of people with autonomic neuropathy in a UK research

Pathophysiology and Etiology 
Metabolic disturbance brought on by hyperglycemia - Aldose reductase turns too much glucose into sorbitol, which harms the nerves.
- Neural proteins and lipids are glycated nonenzymatically, creating harmful advanced glycosylation end products.
- Vascular endothelial alterations are brought on by protein kinase C activation.
- Oxidative stress caused by an excessive amount of reactive oxygen species generation - Activation of cycloxygenase-2 and poly (ADPribose) polymerase Vasculopathy leading to nerve ischemia is a major contributing factor to mononeuropathies.

Risk factors include poor glycemic management, long-term diabetes, hypertension, hyperlipidemia, and use of tobacco and alcohol.

Prevention, regular blood sugar maintenance, exercise, and a healthy diet

Presenting History - Symmetric distal sensory or sensorimotor polyneuropathy is the most common form (typical) - Distressing numbness, tingling, and pain in the legs and feet; allodynia; hyperalgesia - Often silent sensory loss, patient unaware - Ataxia and falls due to proprioceptive loss - Neuropathic foot ulcers caused by analgesia and repetitive injury - Neuropathic degeneration of foot joints
Femoral, sciatic, or peroneal neuropathy: weakening or discomfort in the nerve distribution. Focal cranial or limb mononeuropathy: may affect the third, fourth, sixth, or seventh cranial nerve. - Any significant peripheral nerve may be affected.

Lumbar radiculoplexus neuropathy (diabetic amyotrophy) - Unilateral hip and thigh pain - Pelvic girdle and thigh weakness with atrophy - Recovery over months - Truncal neuropathies: painful radiculopathy over dermatomes - Diabetic autonomic neuropathy - GI: nocturnal diarrhea, occasionally alternating with constipation; gastroparesis with postprandial fullness; - Urogenital: erectile dysfunction, overflow incontinence, dry vagina, and sexual dysfunction CIDP: gradual, severe motor loss; Sudomotor: anhidrosis or hyperhidrosis; gustatory sweating of the head and upper body; Diabetic cachexia: painful small fiber neuropathy with obvious weight loss and sadness

clinical assessment 
"Stocking-and-glove" distal sensory loss due to symmetric distal polyneuropathy
- Large fiber neuropathy (10-g monofilament): loss of sensation to light touch and vibration - Pinpricking and temperature loss due to small fiber involvement - Lack of ankle reflexes - Wasting, weakened small foot muscles, altered foot arch, or clawing of the toes - Even though there may be discomfort, minor fiber involvement may prevent an objective sensory impairment.
Symmetric proximal polyneuropathy: Proximal wasting and weakening in the legs, arms, and hands
3rd cranial nerve palsy: painful ophthalmoplegia and ptosis; retained pupillary reflexes (in contrast to compressive palsies) - Loss of patellar reflexes - Focal cranial or limb mononeuropathy - Lateral gaze palsy, 6th cranial nerve
- Femoral neuropathy: sensory loss in the anterior thigh, hip flexion, quadriceps atrophy, weakness in lower leg extension Pain or sensory loss at the back of the thigh and leg; hamstring and lower leg muscle weakening are symptoms of sciatic neuropathy. Foot drop is a symptom of peroneal neuropathy.
Lumbar radiculoplexopathy (amyotrophy) - Weakness and wasting in the pelvic girdle and thigh - Sensory loss in L2-L3 - Absence of the patellar reflex - Truncal neuropathies: sensory loss along the dermatome - Autonomic neuropathy - Cardiovascular: resting tachycardia; orthostatic hypotension - Gastroparesis: postprandial distension; gastric splash

Differential diagnoses include uremic polyneuropathy, drug-induced antineoplastic drugs such as cisplatin, vincristine, isoniazid, and amiodarone, toxic chronic arsenic poisoning caused by n-Hexane or methyl-n-butyl ketone, nutritional deficiency, which is typically linked to alcoholism, paraneoplastic polyneuropathy, and hypothyroidism.

Initial test results from the laboratory and imaging
Fasting plasma glucose, a 2-hour glucose tolerance test, or hemoglobin A1c are used to diagnose and evaluate glycemic management; "prediabetes" may result in one of these tests.
Test for vasculitis, paraproteinemia, and sarcoid in mononeuropathy/mononeuritis multiplex. Creatinine and BUN levels. Thyroid function. Serum vitamin B12 levels. Syphilis testing. Serum protein electrophoresis. 25-OH vitamin D.
Imaging tests for radiculopathy or mononeuropathy to rule out compressive lesions 

Other/Diagnostic Procedures
Bedside testing of vibration perception with a 128-Hz tuning fork, monofilament perception with a 10-g filament, pinprick testing, and temperature testing Quantitative sensory testing for vibratory and thermal thresholds - Standardized measures for determining the severity and risk of foot ulceration Electromyogram nerve conduction velocity - Useful to confirm mononeuropathy and entrapment syndromes –
Diabetic polyneuropathy presence and severity sensitive yet nonspecific index Test results may be normal in painful small unmyelinated fiber neuropathy.
Skin biopsy with epidermal nerve fiber density - Enables direct examination of tiny nerve fibers that are challenging to assess electrophysiologically. Corneal confocal microscopy - Noninvasive method. Lumbar puncture - In CIDP, elevation of spinal fluid protein. Neuropathy and corneal innervation loss are related. 

Test interpretation: Wallerian degeneration, localized axonal swellings containing neurofilaments, axonal atrophy, and demyelination are all visible in peripheral nerve biopsy samples.
Obliterative microvascular lesions and perivascular inflammation Thick neural capillary basement membrane and endothelial proliferation 

Provide proper footwear to prevent pressure harm to sensitive feet. Manage blood sugar levels.


Other than better glucose management, there is no medication available to reverse nerve damage. Pain reduction is the focus of current therapy.
Initial Line
Management of sensory neuropathy and discomfort
Calcium channel modulators include gabapentin, which is used off-label. Gabapentin binds to the Ca2+ channel-associated protein 2- and suppresses the release of neurotransmitters.
- Negative effects: edema, tiredness, and dizziness

Calcium channel modulators include pregabalin, which binds to the same calcium channel as gabapentin and has a quicker onset of action. Usual doses range from 150 to 600 mg per day, with NNTs between 4 and 10. Adverse effects include edema and vertigo.
Duloxetine (1), (2), (4) is a selective serotonin and norepinephrine reuptake inhibitor. The usual dose is 30 to 60 mg per day; the NNT ranges from 4 to 9.
● Tricyclic antidepressants (TCA) (off-label) (1),(2),(4) - Analgesia may be related to effects on sodium channels; NNT ~2 to 5, NNH ~3 to 16 - Amitriptyline 25 to 150 mg at bedtime - Nortriptyline (25 to 150 mg); desipramine (25 to 200 mg) less sedating than amitriptyline but limited trial data ○ Anticholinergic effects and cardiac arrhythmias may occur.
Orthostatic hypotension - Autonomic neuropathy management
(Off-label) Fludrocortisone (1) Midodrine (1) (off-label) Erythromycin (off-label) - Gastroparesis - Metoclopramide (1) or domperidone
- Loperamide, Clonidine (off-label), Octreotide (off-label), and Diabetic Diarrhea
 Topical glycopyrrolate Antibiotics for bacterial overgrowth in hyperhidrosis Propantheline (off-label)

 Aspects of Geriatrics
TCAs' anticholinergic actions can result in cardiac arrhythmias and urine retention.


Venlafaxine (75 to 225 mg daily) (off-label): second-line antidepressants, NNT 2 to 5.
Topical treatments with capsaicin (2),(4),(5) 0.075% cream applied TID are serotonin-norepinephrine reuptake inhibitors.
Depletes substance P from skin's C fibers.
Limited information on the efficacy of daily Lidocaine 5% (700 mg) foot patches used off-label  Leads to blockage of sodium channels
Opiate analgesia: 100 to 400 mg of tramadol per day, NNT 3 to 9.
Tapentadol (1), (2), (4) binds to opiate receptors and prevents the reuptake of norepinephrine and serotonin, reducing the likelihood of adverse opiate effects.


Factors that Influence Referrals 

Refer to a neurologist for an evaluation and treatment if CIDP is suspected.

Additional therapies include Actovegin, dextromethorphan with quinidine, transcutaneous electrical nerve stimulation, percutaneous nerve stimulation, electrical spinal cord stimulation, and others. 

Surgical Techniques 
electrical stimulation of the spinal cord


Suppportive Therapy 
No conclusive trial data exist for electromagnetic field therapy, Reiki, or acupuncture.
Generalized symmetric polyneuropathies typically proceed slowly and chronically.
Focal neuropathies - Recovery over months to years - Insensitive but painless foot as pain decreases

Complications 
Neurotropic ulceration - Painless ulcers in the weight-bearing area - Callus production is a prelude to ulceration. Claw foot deformity.
Neuropathic arthropathy causes the Charcot joint in the foot and total disruption of the joint structure.