Patients with disorders of the peripheral nervous system (mononeuropathy, polyneuropathy, plexopathy or radiculopathy) often present with the chief complaint of pain in one or both legs. Of course, leg pain of vascular and orthopedic etiology is ultimately perceived via the peripheral nervous system and may share many attributes of pain derived from primary disease of the nerves. The goal for the clinician is to be able to recognize primary neuropathic pain and separate it from the many secondary causes. The differential diagnosis, subsequent evaluation, and potential treatments are markedly different from disorders affecting blood vessels, bone, joints, and soft tissues.
The situation is confounded by some disorders having a propensity to affect not only nerve but blood vessels and occasionally joints as well. Diabetes mellitis, with its frequent complication of peripheral neuropathy and association with peripheral vascular disease, is the most common condition in which differentiating the source of leg pain is difficult. However, with close attention to history, physical examination, and judicious use of laboratory testing, often the separation can be made, or at a minimum, an appreciation can be reached of how much each is contributing to the leg pain.
Anatomy of neuropathic pain
To understand neuropathic pain first requires some knowledge of the gross and microscopic anatomy of peripheral nerve. Peripheral nerve contains somatic and autonomic, motor and sensory fibers. All somatic motor fibers are ultimately derived from motor neurons that reside in the anterior gray matter of the spinal cord. Motor neurons receive direct information from the frontal lobe of the brain via the cortical spinal track (the upper motor neuron), as well as from numerous other indirect pathways connecting to adjacent spinal cord segments, the brain stem, the basal ganglia and the cerebral cortex. Autonomic motor fibers to the leg originate from cells in the intermediolateral gray matter of the spinal cord. They exit ventrally with the somatic motor fibers and run in the ventral (motor) roots.
On the sensory side, the primary sensory neuron is the dorsal root ganglion that, in contrast to the motor neuron, does not lie within the substance of the spinal cord, but resides outside in the intervertebral foramen of the spinal column. This cell is a bipolar cell giving rise to both a central and a peripheral process. The central processes of the dorsal root ganglia form the dorsal root entering the dorsal horn of the spinal cord, where some fibers ascend in the posterior columns of the spinal cord (supplying vibration and position sense), where others synapse, cross and then ascend in the contralateral anterior lateral spinothalamic track conveying pain and temperature. It is dysfunction or disease of this latter tract and its peripheral connections that are responsible for the perception of pain in the leg. The peripheral processes of the dorsal ganglion cell unite with the motor roots from the motor neurons of each spinal segment to form the spinal nerve. The spinal nerve exits through the intervertebral foramen (where it is susceptible to compression from disk herniation, spondylosis, etc.) and quickly bifurcates into a dorsal and ventral ramus. The dorsal and ventral rami both contain motor and sensory fibers. The dorsal rami supply the paraspinal muscles for motor function and the area over the skin of the back for sensation. The ventral rami in the lumbosacral region come together to form the lumbosacral plexus. From the lumbosacral plexus, individual peripheral nerves of the leg are derived. The major peripheral nerves of the leg are the femoral, sciatic (terminates into the tibial and common peroneal), superior gluteal, inferior gluteal, lateral cutaneous nerve of the thigh, and the posterior cutaneous nerve of the thigh.
Each peripheral nerve contains motor and sensory innervation from several spinal segments (myotomes and dermatomes, respectively). Nerve fibers ultimately supply all muscles for locomotion as well as sensory fibers to all skin areas for cutaneous sensation. In addition, there are sensory fibers to deep tissues including muscles, bones and joints, and autonomic fibers supplying blood vessels and sweat glands.
Microscopically, peripheral nerve contains both myelinated and unmyelinated nerve fibers. Myelin is derived from concentric rolls of Schwann cell cytoplasm (the Schwann cell being the major supporting cell of the peripheral nerve). Myelin is an effective insulator of peripheral nerve that greatly allows for dramatically increased speed of conduction compared with unmyelinated fibers (50 m/s compared with 1 m/s). Larger fibers have more myelin than smaller fibers and many small axons are not myelinated at all. The large myelinated fibers convey all motor function as well as sensory function for touch, vibration and joint position sense. The smaller axons, both myelinated and unmyelinated, supply pain and temperature sensation as well as autonomic function. It is disease or dysfunction of these small fibers that account for much of the pain and unpleasant dysesthesias associated with neuropathy and other disorders of the peripheral nervous system.
Internal anatomy of peripheral nerve is comparable to the internal anatomy of muscle. There are several layers of connective tissue. Around a nerve trunk is the thick epineurium, which at the nerve root level is a direct continuation of the dura mater. Beyond the epineurium, nerve fibers are grouped together in clusters known as fascicles. Each fascicle has a connective tissue barrier, the perineurium. Within each fascicle is additional connective tissue running between the individual nerve fibers known as the endoneurium. The epineurium has a rich anastomotic network of arteries and veins known as the vasa nervosum. From this anastomotic network, individual venules and arterioles penetrate the peri- and endoneurium to supply the nerve.
Pathophysiology of neuropathic pain
When a nerve is injured, it can only react in a limited number of ways. Nerve dysfunction can cause either lack of function (negative symptoms and signs) or extra or disturbed function (positive symptoms and signs). When sensory fibers are diseased, extra or disturbed function is often more troubling than lack of function. Most can relate to leaning on an elbow, having the arm ‘fall asleep’ (lack of function—negative symptom) followed by return of blood flow leading to ‘pins and needle’ paresthesias (extra function—positive symptom). If motor nerve loses function, weakness, fatigue and atrophy develop. Extra or disturbed motor function may result in fasciculations or cramps. As for the sensory system, often the type of positive and negative symptoms denotes which type of nerve fiber has been affected. The large sensory nerve fibers convey touch, vibration and joint position sense. Lack of function of these fibers will lead to loss of these modalities on examination. Extra or disturbed function of this type of nerve will lead to ‘pins and needle’ paresthesias. This is in contrast to small fibers that convey pain and temperature which, when disordered, result in loss of temperature and pain sensation but, when disturbed or over-functioning, may cause burning, stinging, and other unpleasant paresthesias.
Most neuropathic pain occurs because of disturbed function or hyper-activity of the small pain fibers. Patients typically use the words ‘burning’, ‘jabbing’, or ‘shooting’ to describe these abnormal sensations. When these sensations are due to primary dysfunction of peripheral nerve, they are usu-ally perceived as superficial, affecting the skin. Lightly touching the skin, even with non-painful stimuli, may lead to the generation of painful paresthesias. Such would not be expected in primary orthopedic or vascular diseases.
Mechanisms of nerve injury
Nerve can be injured by a variety of mechanisms. First, transient compression will result in ischemia to nerve that can quickly be reversed when the compression is lessened. No structural abnormality occurs. If the compression is more severe or lasts a greater length of time, subsequent mechanical deformation of the myelin sheath will occur, followed by frank demyelination. Although there is a structural abnormality of the myelin sheath, the underlying axon remains intact. If the compression is relieved, repair can occur by the process of remyelination that usually occurs over several weeks.
If the compression lasts long enough or is more severe, not only will there be mechanical deformation of myelin, but also of the underlying axon as well. Subsequently, the distal axon undergoes the process of wallerian degeneration which results in complete degeneration of the axon and its myelin sheath distal to the compression. This type of injury is much more serious than simple demyelination. If the compression is relieved, the nerve can recover, but must do so by regrowing from the terminal stump. If there has not been disruption of the connective tissue surrounding the nerve, the nerve will commonly be successful in regrowing. However, this regrowth is quite slow (typically the rate of slow axonal transport does not occur faster than a millimeter a day).
Finally, the most severe type of compressive or traumatic injury is one where there is not only disruption of the axon with its myelin sheath, but also of the surrounding connective tissue. In this type of injury, the nerve has been severely disrupted and any attempt at regrowth is usually futile. The nerve often grows into a tangled painful scar known as a neuroma.
Beyond compression and trauma, there are additional mechanisms which may damage nerve. The most common are various metabolic and toxic factors that may adversely poison the metabolic machinery of nerve. There are many endogenous (e.g. liver and renal disease) and exogenous toxins (e.g. alcohol, prescription drugs, chemotherapy, occupational toxins) that may damage peripheral nerve. Most of these toxic metabolic conditions tend to cause the most severe dysfunction to the nerves which are the longest. These nerves have the greatest metabolic demand and therefore are much more susceptible. Clinically, this results in the most distal and longest nerve being affected first (the longest nerve in the body is the sciatic nerve running from the back to the tip of the toes, approximately three feet in length).
Besides toxic and metabolic factors, there are several other mechanisms of nerve injury. Many inherited and genetic abnormalities may adversely affect either the motor neuron, its axon or the myelin sheath. Inherited neuropathies are often quite mild or advance slowly, over years or decades. Rarely, peripheral nerve may be damaged by frank infiltration of tumor of granulomatous tissue. Finally, there are many inflammatory (infectious, but more often, autoimmune) conditions which depending on the site of inflammation may damage the peripheral nerve. Lyme, leprosy, cytomegalovirus (CMV), herpes simplex virus (HSV), herpes zoster virus (HZV), and human immuno-deficiency virus (HIV) are among the various infectious agents that commonly affect peripheral nerve. Autoimmune attack on the myelin nerve sheath results in Guillain–Barré syndrome acutely and when chronic, chronic inflammatory demyelinating polyneuropathy (CIDP). Vasculitis, an inflammatory attack directed at blood vessels, may have profound secondary effects on nerve via ischemia and subsequent nerve infarction.
Recognition of peripheral nerve dysfunction involves a directed neurological history and examination with special emphasis on the motor and sensory system and reflexes. During the motor examination all major muscle groups in the lower extremity should be inspected for the presence of normal muscle bulk and fasciculations (involuntary brief muscle twitches). Decreased muscle bulk (atrophy) and fasciculations are signs of peripheral nerve disease. In addition, testing muscle tone (resistance to passive motion) of both legs is important. Increased muscle tone may be seen in disorders of the central nervous system (spinal cord or brain), but may sometimes be a manifestation of guarding due to pain. Muscle strength should be tested for dorsiflexion, plantarflexion, inversion and eversion around the ankle; flexion and extension around the knee; and flexion, extension, adduction and abduction around the hip. It is important to recognize that subtle weakness is often missed on the examining table. To demonstrate subtle weakness, it is often very useful to put patients through functional tests or put their muscles at mechanical dis-advantage (toe and heel walking, walking up and down stairs, getting out of a low chair without using their hands, doing a deep knee bend, etc.).
The sensory examination should include assessment of vibration sense at the great toe, ankle and knee, both in comparison with the examiner and the contralateral asymptomatic leg if possible. In addition, joint position sense of the great toe and ankle should be assessed. Both vibration and joint position sense test large sensory fibers. To test small fiber function, ‘pin-prick’ and temperature should be assessed in both legs. It is important to check the distribution of all major nerves. Therefore as a rule it is important to check sensation in the webspace of the great toe (deep peroneal), dorsum of the foot (superficial peroneal), sole (tibial nerve), lateral calf (superficial peroneal), medial calf (saphenous), anterior thigh (femoral), lateral thigh (lateral femoral cutaneous nerve), and the posterior thigh (posterior cutaneous nerve of the thigh).
The reflex examination should be a routine part of any examination of a patient with a painful leg. Each reflex is mediated via a sensory afferent pathway, a synapse in the spinal cord, and a subsequent motor efferent. Both knee and ankle reflexes need to be compared and contrasted with each other. The knee reflex travels through the femoral nerve, lumbar plexus and L2–4 nerve roots. The ankle reflex travels through the tibial nerve, sciatic nerve, lumbosacral plexus and the S1–2 nerve roots. Reduced or absent reflexes are a sign of peripheral nerve disease. Bilaterally reduced ankle reflexes are com-mon in polyneuropathy. Any significant reflex asymmetry suggests a focal nerve lesion somewhere along the reflex arc. The Babinski response should be elicited by stroking the lateral sole and looking for a normal flexion move-ment of the great toe. An extensor response suggests the presence of a central nervous system lesion.
Finally, the extremities should be inspected for trophic changes. Many of these changes may be seen in vascular disease as well, including change in the color of the skin, loss of hair and shininess of the skin. Ultimately, all autonomic function is mediated via the peripheral nerves. As autonomic fibers innervate blood vessels, dysfunction of these fibers can result in vascular changes, usually most marked distally at the small artery or arteriole level. Autonomic fibers are mediated by small myelinated and unmyelinated nerve fibers, the same as fibers that mediate pain and temperature sensation. Some neuropathies will preferentially affect small fibers (e.g. amyloid, alcohol, diabetes) leading both to distal autonomic and pain/temperature dysfunction.
In a patient with a painful leg or legs, any definite abnormality of the motor, sensory or reflex examination suggests, at a minimum, that there may be a possible neurological component to the patient’s pain. As the differential diagnosis of peripheral nerve disorders is quite large, the possibilities must first be limited by the neuroanatomic localization. Only certain disorders affect certain parts of the peripheral nervous system. Some symptoms of polyneuropathy, sciatic neuropathy and lumbar radiculopathy may be very similar, but the differential diagnosis of disorders affecting those three sites is very different. The pattern of weakness, atrophy, reflex loss and sensory disturbance usually allows a correct neuroanatomic localization. Often, the localization is confirmed or defined by nerve conduction studies and electromyography. With the anatomy localized, in conjunction with the history, the differential diagnosis quickly narrows and allows a more directed and appropriate evaluation.