Differential Diagnosis in Neurology

Topic 10. Differential Diagnosis of Peripheral Neuropathy

10.14. Diabetic Neuropathy

  • General features:
    • Hyperglycemia, hyperlipidemia, disordered insulin metabolism
    • Affects greater than 5% of USA population
    • 10% have Type I diabetes (autoimmune attack against islets of Langerhans; no endogenous insulin production)
    • Type II-diabetes is characterized by insulin resistance
    • Late complications: neuropathy, retinopathy, nephropathy, accelerated atherosclerosis occur with both forms; in general complications increase with duration and severity of the hyperglycemic state
    • Chronic and symmetric patterns of neuropathy possibly metabolic in origin; acute and focal neuropathy is secondary to microvascular disease

Diabetic Peripheral Neuropathy (Chronic)

  • General features:
    • Approximately 50% of patients will develop clinically significant disease during the course of their illness
    • Distal sensory loss predisposes to poor wound healing; tissue necrosis and gangrene
  • Clinical presentation:
    • Neuropathy develops after 5–10 years of disease
    • Sensory loss occurs distally in the toe and feet; in general when sensory loss crosses the knee, finger tips are involved.
    • Small fiber modalities are involved earlier than large fiber deficits (burning; lancinating pain; deep muscle ache); later loss of vibration and proprioception in the legs-if severe may present as diabetic pseudo-tabes.
    • Autonomic dysfunction:
      • Decreased sweating
      • Erectile dysfunction
      • Gastroparesis (nocturnal diarrhea, pseudoileus)
      • Postural hypotension
  • EMG:
    • Early active denervation
    • Axonal features
  • Laboratory:
    • Fasting blood glucose of 110–125 mg/dl is suspicious for DM
    • Random venous plasma glucose of 200 mg/dl is positive for DM
    • Hgb A1C:
      • 4–6% of normal hemoglobulin
      • Rises with prolonged hyperglycemia
      • Reflects glucose levels of the preceding 5–8 weeks

Acute Diabetic Polyneuropathy

  • General features:
    • Occurs often worsening or improving glycemic control
    • Intense neuropathic pain
    • Occurs in men with Type II diabetes that is poorly controlled
    • Anorexia and weight loss is common
  • Clinical presentation:
    • Severe hyperalgesia, dynamic and static mechano allodynia, feet > arms
    • Mild distal weakness
    • Reduced or absent ankle jerks
    • Weight gain precedes recovery which occurs over months

Insulin Neuropathy

  • General features:
    • Occurs at the initiation of insulin or oral hypoglycemic therapy
    • Intense burning pain
  • Clinical presentation:
    • Normal distal muscle strength in extremities
    • Normal reflexes except for decreased AJ
    • Loss of small caliber axons; axonal regeneration

Proximal Diabetic Neuropathy

  • General features:
    • Diabetic amyotrophy (Bruns–Borland Syndrome)
    • Inflammatory vasculitis causing ischemic nerve damage; nerve infarction (vasovasorum is site of infarction)
    • Associated with weight loss (metabolic factors)
    • Vasculitis possibly due to immune complex deposition
    • Nerve fiber loss is multifocal
    • Site of pathology in PDN (proximal diabetic neuropathy) is proximal branches of the lumbosacral plexus and the spinal nerves
  • Clinical presentation:
    • Affects older patients with Type II much greater than Type I DM (age 50–60 years)
    • Usually during a long period of poor diabetic control
    • Anorexia and weight loss occur prior to or during the process
    • Acute thigh pain that evolves into the hip and thigh muscle weakness
    • Pain in the anterolateral thigh, buttock and perineum (plexus distribution)
    • Atrophy of affected numbness of the upper lumbosacral plexus; iliopsoas, quadriceps and thigh adductors > extensors and hamstrings; peroneal innervated muscles may be affected
    • No sensory loss; concomitant diabetic polyneuropathy
    • Loss of dartos scroti reflex; rare hyperesthesias of the thigh
    • Contralateral leg affected concomitantly or during a second episode in six weeks
    • Weakness is progressive over weeks to months; spontaneous recovery in some patients; some patients symmetrical slowly progressive weakness
    • Rarely upper extremities may be affected (C5–C6 roots)
  • EMG:
    • Associated axonal neuropathy in approximately 50% of patients
    • Decreased femoral nerve innervated muscles; CMAP amplitude loss of largest diameter motor fibers
    • Fibrillation potentials early in the illness; polyphasic MUAP; large amplitude and long duration MUAP (chronic denervation)
  • Laboratory evaluation:
    • Slightly elevated CPK
    • Elevated CSF protein (mean protein 90 mg/dl) due to root involvement
  • Differential Diagnosis:
    • CIDP
    • Polymyositis
    • MND (motor neuron disease)

Diabetic Mononeuropathies and Radiculopathies

  • General features:
    • Acute or subacute onset; middle to late life
    • Painful
    • Setting of weight loss or poor glycemic control
    • Remits in 6–12 months
  • Clinical presentation:
    • Setting of long standing DM
    • Frequent involvement of the external carotid circulation that supplies the cranial nerves
    • III, IV, VI – most commonly involved; onset is acute and painful
    • Partial involvement of the IIIrd nerve; central fascicular ischemia; pupil is spared; painful ophthalmoplegia; lamp shade ptosis greater than that seen with a P-com aneurysm that compresses the nerve (pupil affected)
    • Bell's palsy common in diabetic patients; more commonly in older patients
    • Involvement of the intermediate lateral trunk of the external carotid artery causes V and VII deficits; infarction of the ascending pharyngeal artery IX, X, XI are involved (rare); superior and inferior division infarction causes infarction of III, IV, VI; V and VII are most common combination of nerve deficits from infarction of the external carotid system in a diabetic patient (lateral trunk of ECA)
    • Improves within 3–6 months, no unusual synkinesia on reinnervation as is seen with aneurysm or other mechanical lesions
    • Bell's palsy in diabetic patients affects taste less than non-diabetics

Intercostal Neuropathy

  • General features:
    • Older patients; males > females; in both Type I or II diabetes
    • Occurs during a fluctuation of diabetic control or during weight loss
  • Clinical presentation:
    • May occur concomitantly will diabetic peripheral neuropathy
    • Pain and hyperalgesia; burning (C fiber) or a deep ache (A-delta fiber)
    • Usually the thoracic and abdominal intercostal nerves are involved
      • Affected roots often are contiguous
      • Sensory loss may be incomplete and not follow classic dermatomal distributions
      • Unilateral much greater than bilateral
      • Dorsal or ventral root involvement can occur
      • Focal motor deficits of the abdominal wall occur
      • May resolve in 4–12 months
    • Differential Diagnosis
      • Herpes Zoster (sine Herpete; no concomitant rash)
      • Carcinomatous involvement of the nerve root (lung ca most common)
        • Anhidrosis or hyperhidrosis of the affected dermatome
      • Central cord syndrome
      • Shield and abdominal sensory loss of a length dependent type polyneuropathy
  • EMG:
    • Site of the lesion may be the proximal root of the intercostal and abdominal nervi the posterior primary rami of the affected root
    • Fibrillation potentials noted in the paraspinal muscles in some patients

Diabetic Sensory Neuropathy

  • General features: Large 10–20 μ to small unmyelinated fibers ("C" fibers). Thinly myelinated A-delta fibers (lancinating pain) involved
  • Clinical presentation:
    • Distal numbness; anesthesia with acropathy (ulceration of fingers and toes) in severe sensory loss; destruction of distal small bone with severe neuropathy (diabetic foot)
    • Stocking glove sensory loss
    • Shield midthorax sensory loss (dying back of intercostal nerves)
    • Pseudotabetic form with severe loss of 10–20 u vibration and proprioceptive fibers; imbalance and sensory ataxia is severe
    • Predominant small fiber involvement; 1 u (C fibers; unmyelinated sympathic fibers):
      • Pain and temperature loss greater than vibration and proprioceptive loss
      • Dramatic decrease of cutaneous blood flow (laser Doppler)
      • Reflexes slightly depressed
      • Spontaneous lancinating pain, dysesthesia, paresthesia (1–4 u thinly myelinated fibers); burning pain in the feet (C-fiber)
      • Orthostatic hypotension and sexual dysfunction
      • Mechano dynamic and static allodynia; hyperalgesia are common
      • Cramps of the feet and thigh (neurogenic cramps)

Differential diagnosis of burning feet

  • DM
  • HIV (Distal neuropathy)
  • INH
  • Pyridoxine excess or deficiency
  • Uremia
  • Alcohol
  • Pantothenic acid and B1 deficiency
  • SGPG (epitope)
  • TTR-met 30 (amyloidosis)
  • Anti-Hu antibody (cancer)
  • Fabry's disease
  • Ergotism
  • Drugs (AIDS, chemo therapy, idiosyncratic)
  • Collagen vascular disease (vasculitis)
  • Cigueteras poisoning (paradoxical thermal sensation; nerve receptor)
  • CRPS I/II (chronic regional pain syndrome)

Diabetic Pseudotabes

  • Clinical presentation:
    • Severe symmetric loss of cutaneous and deep pain and joint position and vibration sensibility
    • Tabetic gait; positive Romberg sign
    • Absent reflexes
    • Frequent foot ulcers and arthropathy

Mononeuritis or Mononeuritis Multiplex

  • General features:
    • Affects less than 1% of diabetic patients
    • Disputed; many favor plexopathy or asymmetric neuropathy
  • Clinical presentation:
    • Cranial nerve involvement
      • Lateral trunk of the external carotid artery may involve V and VII concomitantly
    • Intercostal nerve infarction
    • May improve after 12 months; often residual deficits

Alternative Diabetic Neuropathy Classifications

  • Distal Symmetric Polyneuropathy:
    • Mixed sensorimotor neuropathy with some autonomic features (approximately 70% of all diabetic neuropathy)
    • Predominantly sensory neuropathy by modality:
      • Large fiber (50% diabetic neuropathy); pseudotabes
      • Mixed large and small fiber (C-fiber, sympathic fibers, low threshold mechanoreceptors (LTM) approximately 15% of diabetic neuropathy
      • Small fiber predominant (10%); C-fibers, thinly myelinated A-delta fibers and sympathetic fibers
    • Predominantly motor neuropathy less than 1%
    • Autonomic neuropathy (less than 1%)
  • Focal and multifocal neuropathy:
    • Diabetic amyotrophy
    • Cranial neuropathy
    • Intercostal neuropathy
    • Asymptomatic neuropathy
    • Inflammatory neuropathy

Compression Neuropathy in Diabetics

  • Median nerve at the carpal tunnel:
    • Related to body mass index in diabetic patients
    • 6–12% of CTS patients have diabetes
    • 10% of diabetic patients has asymptomatic CTS
    • Median nerve neuropathy increases with duration of the diabetes
  • Ulnar neuropathy at the cubital tunnel:
    • 1–5% of diabetic patients
    • 17% of patients with ulnar neuropathy at the elbow have diabetes
  • Peroneal neuropathy at the fibular head:
    • Rare; possibly 8% occur in diabetic patients
  • Lateral femoral cutaneous nerve (meralgia paresthetica):
    • Occurs in 1% of diabetic patients
  • Rare compression neuropathies in diabetic patients:
    • Radial neuropathy at the spiral groove of the humerus
    • Tarsal tunnel syndrome
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