Introduction
Peripheral neuropathy is common, with a preva-lence of about 2.5% in adults, rising in the elderly to almost 8%. The myriad causes include meta-bolic disturbances (diabetes mellitus and uremia), toxins (alcohol, cisplatin, and arsenic), vitamin deficiencies (B12 and B2), genetic (hereditary sen-sorimotor neuropathy and porphyria), immune-mediated illness (Guillain-Barré syndrome and chronic inflammatory demyelinating polyneu-ropathy), vasculitis (rheumatoid arthritis, Sjö-gren’s syndrome, and polyarteritis nodosa), and neoplastic disorders (lymphoma, multiple myeloma, and paraneoplastic neuropathy). Dia-betic neuropathy accounts for over 1/2of all causes.
Diabetes mellitus affects more than 100 million people worldwide. Diabetic neuropathy, present in about 10% of patients at the time of diagnosis, rises to over 50% when the diabetes has been pres-ent for years. While diabetes causes several types of peripheral nerve disease, distal peripheral poly-neuropathy accounts for over 90% of cases.
Pathophysiology
The pathogenesis of diabetic neuropathy, while multifactorial, likely stems from persistent hyper-glycemia. At the nerve cell body located in the dor-58 FUNDAMENTALS OF NEUROLOGIC DISEASE
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sal root ganglion there is cellular injury, leading to impaired protein and lipid synthesis and impaired axonal transport. At the distal end of the nerve, due to the impaired transport, there is nerve degeneration. The degeneration is exacerbated by the loss of skin trophic support. So the nerve ini-tially (over a period of many years) becomes dys-functional in a distal-to-proximal fashion but in severe cases there is total nerve loss. Other proposed pathogenic mechanisms include (1) hyperglycemia-induced increases in polyol pathway activity, with accumulation of sorbitol and fructose in nerves and secondary axonal damage, (2) microvascular disease of peripheral nerves, leading to nerve ischemia and hypoxia, (3) increased glycosylation of proteins crit-ical to neuronal function, (4) reduction in expres-sion or binding of neurotrophic factors, and (5)
impaired detoxification of reactive oxygen species that then mediate nerve damage.
Diabetic nerves examined from biopsies or autopsies demonstrate damage to both myelinated and unmyelinated axons that is more pronounced distally than proximally. In addition, local vascular disease within the perineurium includes basement membrane thickening, endothelial cell prolifera-tion, and vessel occlusions.
Major Clinical Features
This insidious syndrome initially affects the toes bilaterally and symmetrically. Here the loss of small unmyelinated axons diminishes appreciation of pain and temperature. As axon loss progresses to involve the foot and then the lower leg, the
CHAPTER 6—Disorders of Peripheral Nerves 59
Table 6-1 Clinical Features that Suggest Peripheral Nerve Diseases
Specific Peripheral Nerve Damage
• Both sensory loss and muscle weakness are present.
• Sensory loss and muscle weakness occur in the territory of the peripheral nerve.
• Involved muscles atrophy after a month down to 1/3 of their former size.
• Sensory changes cause loss of pain, touch, temperature, vibration, and position sense if the lesion is destruc-tive or produce pain or paresthesias if the lesion is irritadestruc-tive.
• Diminished or loss of tendon reflex corresponds to the involved nerve.
• Secondary trophic skin changes may slowly develop from the lack of autonomic nerve innervation.
• Onset may be acute or gradual depending on etiology.
• Involvement is unilateral and seldom bilaterally symmetrical, although multiple nerves may be involved (mononeuritis multiplex).
Distal Symmetrical Polyneuropathy or “Dying-Back” Neuropathy
• Maximum loss of sensation should be in toes and feet.
• Sensory and motor loss should be symmetrical.
• Onset is gradual and not acute.
• Loss of sensation is usually greater than loss of strength.
• Painful dysesthesias may occur mainly in the feet.
• Fingers lose sensation when the leg neuropathy advances to about the knee.
• Muscle loss in the feet usually begins as “hammer toes” or pulling back of toes dorsally due to weakness of flexor intrinsic foot muscles without corresponding weakness of extensor muscles located in the leg.
• Trophic changes in the foot and nails are common from loss of autonomic nerves.
Demyelination of Peripheral Nerves
• Major finding is weakness, with minimal loss of myelinated sensory fibers for vibration and position sense.
• Weakness is usually bilateral and symmetrical.
• Pain, touch, and temperature sensations are preserved.
• Onset may be abrupt (Guillain-Barré syndrome), subacute (lead), or gradual (hereditary sensorimotor neuropathy).
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numbness ascends with it. Because of the inability to appreciate pain, injuries of the foot and ankle can lead to secondary foot ulcers and traumatic arthritis of joints (Charcot joints). Often the patient remains unaware of the loss of sensation in the feet until secondary foot or ankle problems develop. When the neuropathy has marched to the knees, the patient usually notes loss of sensation in the fingertips (Figure 6-1).
In 10% of patients with diabetic polyneuropa-thy, damage to small axons leads to persistent foot pain. The pain, typically described as burning, constant, prickling, and painful to light touch (allodynia), may be so uncomfortable that the patient seeks medical attention.
Large, sensory, myelinated axon damage with subsequent loss of vibration and position sense in toes and feet produces gait and balance problems.
Motor nerve axons may be involved with weakness of intrinsic foot muscles.
Autonomic nerve axons are also impaired, lead-ing to loss of sweatlead-ing, thinnlead-ing of involved skin,
asymmetrical pupils that poorly accommodate to darkness, erectile dysfunction, loss of ejaculation, constipation and/or diarrhea, and orthostatic hypotension.
Major Laboratory Findings
Since the neuropathy begins distally in the feet and involves unmyelinated axons, nerve conduction studies of sensory and motor nerves of the leg may initially show mild changes, as electrophysiologic studies seldom detect abnormalities in unmyeli-nated axons. As the neuropathy progresses, the findings of axonal degeneration predominate, with diminished amplitude of compound muscle action potentials and sensory nerve action potentials.
Needle electromyography of intrinsic foot muscles shows denervation potentials. There is relative preservation of proximal conduction velocities.
A nerve biopsy, while seldom performed, shows nonspecific axonal damage to both myelinated and unmyelinated axons. A nerve biopsy should come 60 FUNDAMENTALS OF NEUROLOGIC DISEASE
Hand involvement is usually not apparent until disease is quite advanced and numb-ness is up to knees.
Knee jerks are lost as deficits progress.
Ankle jerk reflexes are diminished and lost early.
Variable distal motor deficit usually lags behind sensory loss.
Figure 6-1 Peripheral polyneuropathy distribution.
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from a sensory nerve (like the sural nerve) that has a small area of sensory innervation. Biopsy of a mixed nerve will lead to paralysis of innervated muscles and thus is performed only on an intercostal nerve.
Skin-punch biopsy (3–4 mm full-thickness biopsy) with immunohistochemical staining for peripheral nerve axons is becoming more popular.
The histologic sections demonstrate marked reduction in the density of epidermal nerve fibers that is helpful, but not diagnostic, for diabetic neu-ropathy. Thus the diagnosis relies mainly on the clinical history and neurologic examination of the feet and lower legs.
Principles of Management and Prognosis The management of diabetic neuropathy can be divided into preventing progression of the neu-ropathy, minimizing problems from anesthesia of feet and hands, and reducing burning foot pain.
Numerous studies demonstrate that good con-trol of blood glucose can slow, halt, or reverse pro-gression of the neuropathy. Glucose control involves weight loss, exercise, and use of hypo-glycemic agents.
Foot anesthesia predisposes this limb to ulcera-tion and infeculcera-tion. Proper footwear minimizes foot and ankle trauma. The individual should be instructed to inspect their feet regularly for signs of infection or ulceration and to place their hand in shoes to detect objects in the soles. If loss of position sense in the feet declines, the patient should use night-lights and caution when walking on uneven surfaces or in the dark.
Treating the patient with a painful peripheral neuropathy is a challenge. For many patients, the pain is reduced with tricyclic antidepressants (amitriptyline and nortriptyline) in low doses.
Anticonvulsants, such as gabapentin or carba-mazepine, may be slowly added if the pain relief is insufficient. In some patients, foot pain sponta-neously subsides when the sensory neuropathy progresses to anesthesia.