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Diabetic Polyneuropathy
Samir Malkani, MD, MRCP—UK
image BASICS
DESCRIPTION
Peripheral nerve dysfunction seen in diabetes; several patterns described (1):
  • Symmetric polyneuropathy
    • Distal sensory or sensorimotor
    • Proximal lower extremity polyneuropathy
  • Focal and multifocal neuropathy
    • Cranial neuropathy
    • Focal limb or truncal neuropathy
    • Radiculoplexus neuropathy (diabetic amyotrophy)
  • Acute painful small fiber neuropathy
  • Autonomic neuropathies
  • Chronic inflammatory demyelinating polyneuropathy (CIDP)
EPIDEMIOLOGY
Prevalence
  • Generalized polyneuropathy
    • 10% at diabetes diagnosis
    • 50% at 25 years
    • Cross-sectional prevalence: 15% by symptoms; 50% by nerve conduction
  • Autonomic neuropathy: 16.7% in a United Kingdom study
ETIOLOGY AND PATHOPHYSIOLOGY
  • Metabolic derangement due to hyperglycemia
    • Aldose reductase converts excess glucose to sorbitol, which causes nerve damage.
    • Nonenzymatic glycation of neural proteins and lipids forms damaging advanced glycosylation end products.
    • Protein kinase C activation causes vascular endothelial changes.
    • Oxidative stress from excessive production of reactive oxygen species
    • Cyclo-oxygenase 2 and poly (ADP ribose) polymerase activation
  • Vasculopathy causing nerve ischemia: predominant factor in mononeuropathies
RISK FACTORS
  • Poor glycemic control
  • Duration of diabetes
  • Hypertension
  • Hyperlipidemia
  • Alcohol consumption
GENERAL PREVENTION
Maintenance of normal blood sugar
image DIAGNOSIS
PHYSICAL EXAM
  • Symmetric distal polyneuropathy
    • “Stocking-and-glove” distal sensory loss
    • Large-fiber neuropathy: loss of perception of vibration and light touch (10-G monofilament)
    • Small-fiber involvement: loss of temperature and pinprick
    • Absent ankle reflexes
    • Wasting, weakness of small muscles in foot; changes to arch of foot or clawing of toes
    • With small-fiber involvement, there may be lack of objective sensory deficit despite pain.
  • Symmetric proximal polyneuropathy
    • Proximal leg, arm wasting, and weakness
    • Loss of patellar reflexes
  • Focal cranial or limb mononeuropathy
    • 3rd cranial nerve palsy: painful ophthalmoplegia and ptosis; preserved pupillary reflexes (in contrast to compressive palsies)
    • 6th cranial nerve: lateral gaze palsy
    • Femoral neuropathy: weakness of lower leg extension, hip flexion, quadriceps wasting, absent patellar reflex, sensory loss in anterior thigh
    • Sciatic neuropathy: pain or sensory loss in back of thigh and leg; weakness of hamstrings, lower leg muscles
    • Peroneal neuropathy: foot drop
  • Truncal neuropathies: sensory loss along dermatome
  • Lumbar radiculoplexopathy (amyotrophy)
    • Weakness and wasting pelvic girdle and thigh
    • Sensory loss in L2-L3
    • Absent patellar reflex
  • Autonomic neuropathy
    • Cardiovascular: resting tachycardia; orthostatic hypotension
    • Gastroparesis: postprandial distension; gastric splash
  • CIDP: motor weakness
DIFFERENTIAL DIAGNOSIS
  • Uremic polyneuropathy
  • Drug induced
    • Antineoplastic drugs: cisplatin, vincristine
    • Isoniazid
    • Amiodarone
  • Toxic
    • Chronic arsenic poisoning
    • n-Hexane, methyl-n-butyl ketone
  • Nutritional deficiency
    • Usually associated with alcoholism
  • Paraneoplastic polyneuropathy
  • Hypothyroidism
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • Fasting plasma glucose, 2-hour glucose tolerance test or hemoglobin A1c for diagnosis and to assess glycemic control
  • Serum B12
  • Thyroid function
  • Creatinine and BUN
  • Syphilis testing
  • Serum protein electrophoresis
  • Vitamin D
  • In mononeuropathy/mononeuritis multiplex, test for vasculitis, paraproteinemia, and sarcoid.
  • In radiculopathy or mononeuropathy, imaging studies to exclude compressive lesions
Diagnostic Procedures/Other
  • Bedside testing of vibration perception with 128-Hz tuning fork, monofilament perception of 10G filament
  • Quantitative sensory testing for vibratory and thermal thresholds
    • Standardized measures for assessing severity and risk of foot ulceration
  • Electromyogram nerve conduction velocity
    • Useful to confirm mononeuropathy and entrapment syndromes
    • Sensitive but nonspecific index of presence and severity of diabetic polyneuropathy
    • In small unmyelinated fiber painful neuropathy, test may be normal.
  • Lumbar puncture
    • In CIDP, elevation of spinal fluid protein
  • Skin biopsy with epidermal nerve fiber density
    • Enables direct study of small nerve fibers that are difficult to assess electrophysiologically
  • Corneal confocal microscopy
    • Noninvasive approach based on examination of corneal innervation
Test Interpretation
  • In nerve biopsy of peripheral nerve, Wallerian degeneration, focal axonal swellings containing neurofilaments, axonal atrophy, and demyelination are seen.
  • Thick neural capillary basement membrane and endothelial proliferation
  • Obliterative microvascular lesions and perivascular inflammation
P.299

image TREATMENT
GENERAL MEASURES
  • Maintain blood glucose close to normal.
  • Provide appropriate footwear to prevent pressure damage to insensate feet.
MEDICATION
First Line
  • Management of pain and sensory neuropathy
    • Tricyclic antidepressants (TCA) (2),(3)[A] (off-label)
  • Analgesia may be related to effects on sodium channels. NNT ˜ 1.5 to 5.5, NNH ˜ 3 to 16
  • Amitriptyline 25 to 150 mg at bedtime
  • Nortriptyline (25 to 150 mg); desipramine (25 to 200 mg) is less sedating than amitriptyline but limited trial data.
  • Anticholinergic side effects may occur.
    • Calcium channel modulators: gabapentin (2),(3)[A] (off-label)
  • Binds Ca2+ channel-associated protein &agr;2-&dgr;, inhibits neurotransmitter release
  • Dose range from 300 to 1,200 mg TID, NNT ˜ 4 to 12
  • Reduce dose in renal insufficiency.
  • Adverse effects: dizziness, fatigue, edema
  • Fewer side effects than TCA
    • Calcium channel modulators: pregabalin (2),(3)[A]
  • Binds same calcium channel as gabapentin
  • Linear pharmacokinetics, unlike gabapentin
  • Usual dose: 150 to 300 mg/day, NNT ˜3 to 6
  • Adverse effects are dizziness and edema.
    • Duloxetine (2),(3)[A]
  • Selective serotonin and norepinephrine reuptake inhibitor
  • Usual dose is 60 mg/day. NNT ˜ 3 to 6
  • Adverse effects are nausea and dizziness.
  • Management of autonomic neuropathy
    • Orthostatic hypotension
      • Fludrocortisone (off-label)
      • Midodrine (off-label)
    • Gastroparesis
      • Metoclopramide or domperidone
      • Erythromycin (off-label)
    • Diabetic diarrhea
      • Loperamide
      • Clonidine (off-label)
      • Octreotide (off-label)
      • Antibiotics for bacterial overgrowth
    • Hyperhidrosis
      • Propantheline (off-label)
Geriatric Considerations
Anticholinergic effects of TCAs may cause urinary retention and arrhythmias.
Second Line
  • Antidepressants
    • Venlafaxine (2),(3)[B] (75 to 225 mg daily) (off-label)
      • Serotonin-norepinephrine reuptake inhibitor
  • Anticonvulsants
    • Carbamazepine (3)[C] (off-label)
      • Blocks sodium channels
      • Dose 100 to 800 mg/day
  • Topical therapies
    • Capsaicin 0.075% cream applied TID
      • Depletes C fibers in skin of substance P
    • Lidocaine 5% (700 mg) patches applied daily to feet (off-label):
      • Causes sodium channel blockade
  • Opiate analgesia
    • Tramadol (3)[B] (off-label): 100 to 400 mg/day, NNT 3 to 8
      • Binds opiate receptors; also inhibits reuptake of norepinephrine and serotonin; fewer opiate side effects
    • Tapentadol (3)[B]
      • Binds to &mgr;-opiate receptor and inhibits norepinephrine uptake
  • &agr;-lipoic acid (3)[C]
    • Antioxidant properties may limit free radical-mediated damage.
    • 600 mg/day PO dose showed benefit in small studies; intravenous more effective.
ISSUES FOR REFERRAL
If CIDP is suspected, refer to neurologist for investigation and treatment.
ADDITIONAL THERAPIES
  • Transcutaneous electrical nerve stimulation
  • Percutaneous nerve stimulation
  • Electrical spinal cord stimulation
  • Actovegin, dextromethorphan with quinidine
  • C-peptide
COMPLEMENTARY & ALTERNATIVE MEDICINE
Acupuncture, Reiki, electromagnetic field treatment: no convincing trial data
SURGERY/OTHER PROCEDURES
Electrical spinal cord stimulation
image ONGOING CARE
PROGNOSIS
  • Generalized symmetric polyneuropathies
    • Usually slow, chronic progression
    • Insensitive but painless foot as pain lessens
  • Focal neuropathies
    • Recovery over months to years
REFERENCES
1. Albers JW, Pop-Busui R. Diabetic neuropathy: mechanisms, emerging treatments, and subtypes. Curr Neurol Neurosci Rep. 2014;14(8):473.
2. Griebeler ML, Morey-Vargas OL, Brito JP, et al. Pharmacologic interventions for painful diabetic neuropathy: an umbrella systematic review and comparative effectiveness network meta-analysis. Ann Intern Med. 2014;161(9):639-649.
3. Kaku M, Vinik A, Simpson DM. Pathways in the diagnosis and management of diabetic polyneuropathy. Curr Diab Rep. 2015;15(6):609.
Additional Reading
&NA;
  • Bril V, England J, Franklin GM, et al. Evidence-based guideline: treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology. 2011;76(20):1758-1765.
  • Javed S, Petropoulos IN, Alam U, et al. Treatment of painful diabetic neuropathy. Ther Adv Chronic Dis. 2015;6(1):15-28.
  • Saarto T, Wiffen PJ. Antidepressants for neuropathic pain: a Cochrane review. J Neurol Neurosurg Psychiatry. 2010;81(12):1372-1373.
  • Tesfaye S, Boulton AJ, Dickenson AH. Mechanisms and management of diabetic painful distal symmetrical polyneuropathy. Diabetes Care. 2013;36(9):2456-2465.
See Also
&NA;
Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2
Codes
&NA;
ICD10
  • E10.42 Type 1 diabetes mellitus with diabetic polyneuropathy
  • E11.42 Type 2 diabetes mellitus with diabetic polyneuropathy
  • E13.42 Oth diabetes mellitus with diabetic polyneuropathy
Clinical Pearls
&NA;
  • Occasionally, when glycemic control improves dramatically, as can occur when treatment for diabetes is initiated, there may be a worsening of neuropathy symptoms. Symptoms usually stabilize and gradually improve as glycemic control is maintained.
  • It is common to combine agents with different mechanisms of action in the management of neuropathic pain. Topical therapies can be combined with systemic therapies. There is limited evidence-based data to support combination therapy.