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A. Overview

  1. Classification of Syndromes
    1. Focal Neuropathies: mononeuropathy and mononeuritis multiplex
    2. Sensorimotor Polyneuropathy
    3. Motor (predominantly) Polyneuropathy
    4. Sensory (predominantly) Polyneuropathy
    5. Autonomic Neuropathy
  2. Etiologies [11]
    1. Metabolic
    2. Toxins and Medications
    3. Immune Mediated: autoimmune and vasculitis-associated
    4. Vascular: atheroscelerotic and vasculitis-associated
    5. Infectious: such as syphilis, leprosy
    6. Paraneoplastic Syndromes: anti-Hu antibody related
    7. Entrapment (compression)
    8. Amyloidosis
    9. Paraproteinemia: CIDP, myeloma, POEMS, monoclonal gammopathy
    10. Renal failure
    11. Heritable / Familial
    12. Idiopathic (small fiber neuropathy)
  3. Epidemiology [2]
    1. Overall prevalence ~2.4%
    2. Prevalence in age >55 years ~8%
    3. Most common cause in developed nations is diabetic neuropathy
    4. Immune mediated neuropathies are second most common cause
    5. Leprosy is an important cause in underdeveloped nations

B. Classification and Pathophysiology

  1. Nerve Fibers Transmitting Pain
    1. Type C nerve fibers appear to be major carriers of nociceptive signals
    2. Type A delta2 nerve fibers detect heat/cold and other noxious stimuli
    3. These fibers carry nociceptive information from visceral and somatic sites
    4. Under conditions of C fiber damage, A delta2 fibers can transmit pain information [19]
    5. Larger nerve fibers (Aß and A-alpha) responsible for proprioception, vibratory sensation, muscle-stretch reflexes and muscle strength may also be affected in pain
  2. Types of Peripheral Nerve Damage
    1. Axonal Degeneration: usually toxic, vascular, metabolic
    2. Demyelination: usually immune/inflammatory
  3. Types of Peripheral Neuropathy
    1. Mononeuropathy
    2. Mononeuropathy (mononeuritis) Multiplex
    3. Polyneuropathy
  4. Mononeuropathy
    1. Focal lesion of single peripheral nerve
    2. usually caused by trauma, focal compression, nerve entrapment
    3. Carpal tunnel syndrome is most common mononeuropathy
    4. Ulnar neuropathy due to compression at or near elbow is second most common
    5. Electrodiagonistic studies required for accurate diagnosis
    6. Main concern is missing diagnosis of mononeuropathy multiplex
  5. Mononeuropathy Multiplex [2,18]
    1. Previously called mononeuritis multiplex (see below)
    2. Involvement of multiple separate noncontiguous peripheral nerves
    3. Multiple nerves may be involved serially or concurrently
    4. Over time, multiple nerve invovement may lead to confluent apparent polyneuropathy
    5. History of lesions over time is critical to distinguish from polyneuropathy
    6. Biopsy of sural or superficial peroneal sensory nerve (with muscle) should be performed
    7. Up to 30% of patients have findings of multifocal demyelination usually due to chronic inflammatory demyelinating polyneuropathy (CIDP)
    8. Hereditary neuropathy with liability to pressure palsies associated with deletion of PMP22 gene well described
  6. Polyneuropathy
    1. Most commonly distal symmetrical polyneuropathy
    2. Nerve fibers are affected in length-dependent fashion
    3. May be primarily sensory, motor, or mixed sensorimotor neuorpathy
    4. Usually due to toxins

C. Evaluation

  1. Overview
    1. History and careful physical examination - compatible with neuropathy ?
    2. Small fiber neuropathy has pain out of proportion to neurologic findings
    3. As larger fibers are involved, neurologic exam findings increase
    4. Laboratory studies are critical unless cause of neuropathy is clearly known
  2. Clinical Classification of Type of Neuropathy
    1. Mononeuropathy, Mononeuropathy (mononeuritis) Multiplex, Polyneuropathy
    2. Electrodiagnostic studies are required to confirm classification of neuropathy
    3. Distinguishing axonal from demyelinating neuropathies also requires electrodiagnostics
  3. Laboratory Evaluations
    1. Screening with serum or urine as needed
    2. Focused on nerve conduction studies (NCS) and electromyography (EMG)
    3. Nerve biopsy (such as sural nerve) may be required
    4. EMG and NCS are normal in small fiber neuropathies
    5. Abnormal EMG/NCS can distinguish demyelinating versus axonal neuropathy
    6. Can also distinguish multiple mononeuropathy versus polyneuropathy
    7. Focus laboratory evaluations based on EMG/NCS results and differential (see below)
  4. Grading Peripheral Neuropathy
    1. Grade 1
    2. Grade 2
    3. Grade 3
    4. Grade 4
  5. Radicular (Nerve Root) Disease usually considered separately (see below)

D. Chronological Categorization of Diseases

  1. Acute Onset Monophasic (days)
    1. Guillain-Barre Syndrome
    2. Porphyric Neuropathy
    3. Diphtheria associated polyneuropathy
    4. Tick paralysis, vasculitis, paraneopastic neuropathy less common
  2. Subacute Onset (weeks)
    1. Many toxins
    2. Nutritional neuropathies
    3. Carcinomatous neuropathy
    4. Uremic neuropathy
  3. Relapsing
    1. Chronic inflammatory demyelinating polyneuropathy (CIDP)
    2. Refsum's Disease
  4. Chronic (months-years)
    1. Diabetic
    2. Chronic inflammatory
    3. Charcot-Marie-Tooth (hereditary sensorimotor neuorpathies)

E. Focal Neuropathies

  1. Nerve Entrapment Syndromes
    1. Carpal Tunnel Syndrome
    2. Ulnar Nerve Palsy (Cubital Tunnel Syndrome)
    3. Brachial Plexus Lesions
    4. Radial Nerve Syndrome
    5. Tarsal Tunnel Syndrome
    6. Meralgia Paresthetica - lateral femoral cutaneous neuropathy
    7. Morton's Neuroma
  2. Mononeuritis Multiplex [18]
    1. Vascular, infectious, paraproteinemia most common etiologies
    2. Vasculitis very common cause and requires prompt treatment to prevent damage
    3. Polyarteritis nodosa (PAN), Churg-Strauss Syndrome commonly cause neuropathy
    4. Vasculitis associated with rheumatoid arthritis or Sjogren Syndrome also associated with peripheral neuropathy
    5. Less commonly sarcoidosis, lymphoma, cryglobulinemia, amyloidosis, leprosy, Lyme Disease
    6. HIV mononeuropathy multiplex well described
    7. Cholesterol Emboli Syndrome
  3. Central Nervous System Disease causing focal deficits
    1. Multiple Sclerosis
    2. Sarcoidosis
    3. Central nervous system vasculitis
    4. Syringomyelia
  4. Radiculopathy (usually compression syndromes)
    1. Cervical
    2. Lumbar
    3. Usually due to bone abnormalities in spine or vertebral disc disease

F. Sensorimotor Polyneuropathies (Generalized)

  1. Alcoholic Neuropathy
  2. Diabetic Neuropathy (see below)
  3. Nutritional Deficiency: Vitamin B12 Deficiency [10]
  4. Toxin Neuropathy (see below)
  5. Metabolic Disorder
  6. Inflammatory Neuropathies (see below)
  7. Critical Illness Polyneuropathy - likely nutritional/metabolic/toxin components

G. Inflammatory Neuropathies

  1. Demyelinating
    1. Acute - Guillain Barre Syndrome (GBS)
    2. CIDP - often associated with monoclonal gammopathies
    3. Paraproteinemia - usually IgM
    4. Hereditary - mainly variants of Charcot-Marie-Tooth disease (PMP22 gene duplication)
    5. Evaluation of cerebrospinal fluid (CSF) is critically important in all of these
  2. Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)
    1. Most common type of acquired demyelinating polyneuropathy
    2. Rate ~2/100,000 persons
    3. Either relapsing or gradually progressive
    4. CSF examination can be helpful; shows raise protein level
    5. Responds to plasma exchange, IVIg, glucocorticoids
  3. Multifocal Motor Neuropathy
    1. Weakness and muscular atrophy
    2. Conduction block in lower motor neurons may be subtle or only present in distal neurons
    3. Demyelinating neuropathy
    4. Responds to IVIg usually given monthly until response is seen
    5. If response is suboptimal, add oral cyclophosphamide (~1.5mg/kg once daily)
    6. improvements may take years
    7. Worsens with glucocorticoids
  4. Infection
    1. Varicella Zoster
    2. Poliomyelitis
    3. Leprosy
    4. Syphilis
    5. Lyme Disease
    6. Herpes Simplex Virus 1 (HSV1) - particularly associated with Bell's palsy (see below)
  5. Autoimmune Etiology
    1. Polyarteritis Nodosa
    2. Rheumatoid Arthritis
    3. Other Vasculitis
  6. Gammopathy and Neuropathy [11]
    1. Paraproteinemias are frequently associated with chronic progressive neuropathies
    2. Direct toxicity of immunoglobulin deposition on neurons may occur
    3. Amyloid deposition may also contribute
    4. Focal and Diffuse Myeloma
    5. Waldenstrom's Macroglobulinemia
    6. Amyloidosis
    7. Cryoglobulinemias
    8. Lymphoma
    9. Chronic Lymphocytic Leukemia
    10. Giant Lymph Node Hyperplasia

H. Predominantly Motor Neuropathies

  1. Guillain-Barre Sydnrome and CIPD (see above)
  2. Acute intermittant porphyria
  3. Lead neuropathy
  4. Heritable motor-sensory neuropathies
  5. Motor Neuron Disease (neuronopathy)
    1. ALS
    2. Infantile Motor Neuron Diseases
    3. Poliomyelitis and Postpolio Syndrome
    4. Autoimmune Syndromes
  6. Bell's Palsy (see below)

I. Bell's Palsy [4,22]

  1. Acute, idiopathic unilateral paralysis of Cranial Nerve (CN) VII (Facial Nerve)
  2. Affects ~25 persons per 100,000 per year, usually ages 30-45
  3. Associations
    1. Herpes zoster or herpes simplex virus (HSV) infections
    2. HSV-1 DNA is found in ~80% of facial nerve endoneural fluid in Bell's Palsy [22]
    3. Less commonly associated with various tumors, sarcoidosis, HIV, vasculitis
    4. Guillian-Barre Syndrome usually with bilateral and symmetrical CNVII palsy
  4. Symptoms
    1. Face pulled to one side due to weakness (loss of CN VII control of facial muscles)
    2. Most other causes of Bell's palsy are associated with unilateral facial weakness
    3. Hyperacusis may also occur due to paralysis of stapedius muscle
    4. Most patients recover well, but ~30% have poor recovery
    5. ~82% of persons have near normal function at 9 months without any therapy [5]
    6. Facial disfigurement, facial pain, psychological difficulties found with incomplete recovery
  5. MRI can show inflammatory changes surrouding CN VII
  6. Treatment [4,5]
    1. Initiate within 3 days of symptoms, as soon as possible
    2. Glucocorticoids and/or antiviral (anti-HSV) agents are used
    3. Prednisone 1mg/kg/day or prednisolone 25mg bid (both oral) x 10 days
    4. Prednisolone had 83% with complete function versus 64% with placebo at 3 months
    5. Prednisolone had ~94% complete recovery at 9 months (82% for placebo)
    6. Acyclovir 400mg given five times (5X) daily x 10 days of no benefit versus placebo
    7. Acyclovir added to prednisolone was no better than prednisolone alone
    8. In more severe disease, valacyclovir was more effective than placebo [6]
    9. Either valacyclovir (1gm bid) or famciclovir (750mg tid) for 7-10 days recommended in addition to glucocorticoids for sevre disease
    10. Surgical decompression is used in some cases, within 14 days of onset

J. Predominantly Sensory Polyneuropathies [1]

  1. Symptoms of Neuropathic Pain (smaller fibers)
    1. Burning - area "on fire"
    2. Sharp pain - knife-like, jabbing, and/or pins and needles
    3. Shooting pain
    4. Aching in distal extremities
    5. EMG/NCS typically normal
  2. Symptoms of Peripheral Nerve Pain (larger fibers)
    1. Tingling
    2. Numbness
    3. Feeling wooden or dead
    4. Often exacerbated at night
    5. EMG/NCS are abnormal
  3. Global Loss of Sensory Inputs
    1. Diabetic polyneuropathy (see below)
    2. Dysproteinemias: Monoclonal gammopathies, paraproteinemias, cryoglobulinemia
    3. Tabes dorsalis
  4. Primary Loss of Pain and Thermal Sensibility
    1. Small fiber losses
    2. Diabetic polyneuropathy (see below)
    3. Amyloid Deposition
    4. Hereditary sensory neuropathies
    5. Lepromatous leprosy
  5. Ataxic Neuropathies
    1. Primary loss of joint position and vibration sensation
    2. Carcinomatous sensory neuroapthy
    3. Sjogren Syndrome
    4. Chemotherapeutic Agents: cisplatin
    5. Metronidazole
    6. Vitamin B6 overdose
    7. Friedreich's Ataxia
  6. Sensory abnormalities may predominate in neuropathy with paraproteinemias
  7. Normal EMG/NCS
    1. Idiopathic small fiber painful sensory neuropathy [21]
    2. Fabry's Disease
    3. Celiac Disease (may show abnormal EMG/NCS)
  8. Abnormal EMG/NCS
    1. Diabetic peripheral neuropathy
    2. Inherited neuropathies
    3. Connective tissue disease
    4. Peripheral neurve vasculitis
    5. Dysproteinemia
    6. Paraneoplastic sensory neuropathy
    7. Familial and acquired amyloid polyneuropathy
    8. Neuropathy with renal disease
    9. Hereditary sensory autonomic neuropathy
    10. Sarcoid polyneuropathy
    11. Arsenic neuropathy
    12. HIV related neuropathy
  9. Treatment Overview
    1. Tricyclic Antidepressants (TCA): nortriptyline, amitriptyline, imipramine
    2. Other antidepressants have some activity, not as effective as TCA
    3. Anticonvulsants: carbamazepine, phenytoin, gabapentin
    4. Gabapentin (Neurontin®) is about as effective as TCA and better tolerated
    5. Mexilitine for painful diabetic neuropathy has been variably effective
    6. Topical capsaicin has had some benefit

K. Diabetic Neuropathy

  1. Complex interplay of multiple etiologic mechanisms
    1. Metabolic and vascular abnormalities
    2. Hypertension increases progression of neuropathy
    3. Improved glycemic control associated with reduction in progression of neuropathy
    4. Improvement in other vascular risk factors also reduces diabetic neuropathy [8]
    5. Proliferative microvascular disease is likely a major contributor
    6. Increased capillary leakage and arteriovenous shunting also play a role
    7. Basement membrane thickening (glycated biomolecules) also found
  2. Types
    1. Rapidly reversible hyperglycemic neuropathy
    2. Distal Symmetric Sensory Neuropathy
    3. Mononeuropathy (multiplex)
    4. Autonomic neuropathy (common)
    5. Subacute Proximal Neuropathy (uncommon)
  3. Distal Symmetric Sensory Neuropathy
    1. Predominantly affects sensory and autonomic function
    2. Most common type of diabetic neuropathy
    3. Distal axonopathy of dying-back type is most likely pathology
  4. Mononeuropathy
    1. Cranial, thoraco-abdominal, and limb neuropathies
    2. Proximal lower limb motor neuropathy (diabetic amyotrophy) can occur
    3. Local vascular insufficiency with nerve ischemia is most likely underlying problem
    4. Focal inflammatory and vasculitic pathologies may occur
  5. Diabetic Amyotrophy
    1. Acute, monophasic, painful lower limb weakness and areflexia
    2. Minimal sensory loss
    3. Axonal destruction
  6. Subacute Diabetic Proximal Neuropathy
    1. Proximal muscle weakness associated with reduced or absent lower extremity reflexes
    2. Axonal degeneration and some demyelination on NCS and biopsy
    3. Autonomic failure is commonly found
    4. Sural nerve biopsy shows demyelination; less commonly inflammation
    5. CSF protein is typically increased
    6. Active treatments were sometimes used (similar to CIDP)
    7. Disease frequently self-limiting
    8. This entity may be severe variant of bilateral lumbosacral radiculoplexopathy
  7. Pathology [20]
    1. Small caliber sensory neurons (type C and A delta) are primarily affected
    2. Damage to skin sensory neurons occurs very early with insulin resistance
    3. Abnormal oral glucose tolerance test may be most sensitive to detect early disease
    4. Skin biopsy with special neuronal stains show early and marked loss of small caliber neurons
    5. Cardiovascular risk factors (in addition to diabetes) contribute to neuropathy [8]
  8. Screening for Peripheral Neuropathy [7]
    1. Semmes-Weinstein monofilament (SWM) test for protective sensation on dorsum of foot
    2. SWM 5.07 consists of plastic handle supporting nylon filament
    3. Filament is placed perpendicular to skin and pressure applied until filament buckles
    4. Hold filament in place for ~1 second, then release
    5. Inability to perceive this ~1gm force indicates clinically significant large fiber neuropathy
    6. Testing 10 sites with SWM on the foot may improve sensitivity and specificity
  9. Treatment
    1. Tight glucose control prevents progression of neuropathy
    2. ACE inhibitor trandolapril showed improvement in NCS/EMG studies in type 1 DM [16]
    3. Intensive therapy with various ACE-I + Vitamin E + Vitamin C in Type II DM with microalbuminuria reduced progression of neuropathy >60% over three years [17]
    4. Axonal regeneration of sensory fibers has not yet been demonstrated in progressive DM
    5. Urinary Retention - often responds to cholinergic agents such as bethanechol
    6. Fecal Incontinence
  10. Types of Agents for Painful Diabetic Neuropathy [13]
    1. Duloxetine (Cymbalta®)
    2. Pregabalin (Lyrica®)
    3. Gabapentin (Neurontin®) - approved for post-herpetic neuralgia; often effective
    4. Tricyclic antidepressants (TCA) - amitryptilline and others; sedating, arrhythmogenic
    5. Carbamazepine (Tegretol®) - antiseizure agent, effective in some patients
    6. Capsaicin cream (0.075%, Zostrix®) for 8 weeks sometimes relieves painful neuropathy
    7. Liodcaine Patch (Lidoderm®)
    8. Opioids
    9. Mexilitine is effective but not often used
    10. Number needed to treat (NNT) 3-5 for at least moderate (>50%) pain reduction [13]
  11. Duloxetine (Cymbalta®) [23]
    1. Approved (60mg qd po; up to 60mg po bid) for diabetic neuropathic pain
    2. Selective serotonin and norepinephrine reuptake inhibitor (SNRI)
    3. Also approved for depression
    4. ~50% of patients had >50% reduction in pain in 24 hours and reduction in other pain drugs
    5. Open label extension showed efficacy out to 52 weeks
    6. Nausea (22%), dizziness (14%), somnolence (15%), consiptation (11%) main side effects
    7. Erectile dysfunction occurs in some patients
    8. Abrupt withdrawal leads to irritability, headache, vomiting, insomnia
  12. Pregabalin (Lyrica®) [24]
    1. Structural analog of GABA and gabapentin
    2. Approved for postherpetic neuralgia and diabetic peripheral neuropathic pain
    3. Also approved for epilepsy
    4. Initial dose is 150mg per day divided 2-3 times (bid or tid)
    5. May increase to maximum of 300mg per day for neuropathic pain, 600mg/d for epilepsy
    6. Adverse effects are dose related: dizziness, somnolence, blurred vision
    7. Associated with euphoria and Schedule V controlled substance by FDA
  13. Gabapentin (Neurontin®) [14,15]
    1. FDA approved for post-herpetic neuralgia and for seizure treatment
    2. Various effects on brain neurotransmitters
    3. Dose: 900-3600 mg qd divided (2-3 times)
    4. Combination with morphine more effective than either alone in severe painful neuropathy [3]
    5. Generally well tolerated with very good efficacy in diabetic pain reduction
    6. Side effects: diziness, somnolence, confusion (all <8%)
  14. Mexilitine
    1. Anti-arrhythmic agent (Type 1B) fairly effective for painful diabetic neuropathy
    2. Dose: 75-150mg po tid
    3. Contraindicated in long QTc, cardiac arrhythmias
    4. Side effects include confusion, fatigue, nausea
  15. Gastroparesis
    1. Consider tegaseride (Zelnorm®) which has some promotility activity (marketing restricted)
    2. Also responds to erythromycin 750mg po qd (inexpensive but poorly tolerated)
    3. Propulsid (Cisapride®) has been withdrawn from marketing but may be available for specific patients
  16. Failed Therapies
    1. Gangliosides
    2. Gamma-linolenic acid
    3. Acetyl-L-carnitine (levocarnitine)
    4. Antioxidants
    5. Tolrestat (Alredase®) has been withdrawn from the market

L. Toxin (Drug) Associated Neuropathies

  1. Amiodarone
  2. Thalidomide
  3. Didanosine, Stavudine (d4T), DDC
  4. Chemotherapeutic Agents (see below)
  5. Dapsone
  6. Disulfiram
  7. Gold Salts
  8. Isoniazid
  9. Metronidazole
  10. Phenytoin (Dilantin)
  11. Suramin

M. Chemotherapy Associated Peripheral Neuropathy

  1. Vinca Alkyloids - vincristine (less so with vinblastine)
  2. Paclitaxel (Taxol®)
  3. Topoisomerase Inhibitors
    1. Etoposide
    2. Etanidazole
  4. Carboplatin
  5. High Dose Cytosine Arabinoside (HiDAC)
  6. Thalidomide (Thalomid®)
  7. Bortezomib (Velcade®)
  8. Bone Marrow Transplantation - may be severe; multiple causes

N. HIV Peripheral Polyneuropathy

  1. Mononeuritis Multiplex (CD4>500/µL or <50/µL)
  2. Distal Symmetrical Polyneuropathy
    1. Similar to diabetic sensory neuropathy
    2. EMG shows distal axonopathy
    3. Analgesics, tricyclic agents, anticonvulsants and capsaicin may be effective
  3. Inflammatory Demyelinating Polyneuropathy (CIDP related)
    1. CD4<50 or >500/µL
    2. Often associated with cerebrospinal fluid (CSF) abnormalities
    3. Responses to glucocorticoids, plasmapheresis, intravenous Ig reported
  4. Non-inflammatory Neuropathy, Sensorimotor (early and late) Disease
  5. Autonomic Nervous System
  6. CMV Polyradiculopathy (Cauda equina syndrome)
    1. Patients with CMV infection in cauda equina region
    2. All symptoms of cauda equina destruction may occur
    3. Includes pain, lower extremity weakness, and incontinence
    4. Treatment: Foscarnet or Ganciclovir or both
  7. Neither amitriptyline nor acupuncture were effective against pain for this syndrome [12]

O. Other Systemic Diseases

  1. Peripheral Arterial Disease (PAD)
  2. Uremic Neuropathy
  3. Thyroid Disease
    1. Mainly hypothyroidism causing carpal tunnel syndrome
    2. Hypothyroidism also increases peripheral nerve symptoms from other causes
  4. Acromegaly
    1. Usually due to pituitary adenoma
    2. Nerve entrapment syndromes, particularly carpal tunnel syndrome

P. Radicular (Nerve Root) Disease

  1. Nerve roots pass through thecal sac to neural foramina
  2. Narrowing of the neural foramina can lead to root dysfunction
  3. Bone spurs, disk prolapse or herniation are the most common causes of radiculopathy
  4. Weakness and pain are the most common presenting symptoms
  5. Commonly Affected Regions and Weakness
    1. Cervical C5, C6, and C7
    2. Lumbar L4 and L5
    3. Sacral S1
  6. Sites of Weakness
    1. C5: shoulder abduction
    2. C6: elbow flexion
    3. C7: elbow extension, wrist flexion and extension, and hand grip
    4. C8: hand grip, hand intrinsic muscles
    5. L2-3: hip flexion
    6. L5-S1: hip extension and ankle plantar flexion
    7. L3-4: knee extension
    8. L4-5: knee flexion and ankle dorsiflexion

References

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  6. Hato N, Yamada H, Kohno H, et al. 2007. Otol Neurotolaryngology. 28:408 abstract
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  13. Wong MC, Chung JW, Wong TK. 2007. Brit Med J. 335(7610):87 abstract
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  16. Malik RA, Williamson S, Abbott C, et al. 1998. Lancet. 352(9145):1978 abstract
  17. Gaede P, Vedel P, Parving HH, Pedersen O. 1999. Lancet. 353(9153):617 abstract
  18. Gorson KC, Hedley-Whyte ET, Skinner MM. 2001. NEJM. 344(12):917 (Case Record)
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  20. Polydefkis M, Griffin JW, McArthur J. 2003. JAMA. 290(10):1371 abstract
  21. Amato AA and Oaklander AL. 2004. NEJM. 350(21):2181 (Case Record) abstract
  22. Gilden DH. 2004. NEJM. 351(13):1323 abstract
  23. Duloxtine for Diabetic Neuropathic Pain. 2005. Med Let. 47(1215):67
  24. Pregabalin for Diabetic Neuropathic Pain. 2005. Med Let. 47(1217):75 abstract