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1. Peripheral neuropathic pain syndromes (i) Painful polyneuropathies

The majority of neuropathic pain syndromes affect the peripheral nerves, at least at their onset. Because peripheral nerves contain motor and autonomic fibers, pain is often accompanied by changes in the functions subserved by these components during the course of the syndrome. Motor symptoms typically include weakness and affect the distal muscles, often the extensor groups. Sensory disturbance is confirmed on examination by loss of pinprick, temperature, and vibratory perception. Painful peripheral neuropathies may be classified by etiology, distribution, and pathology. The diagnostic workup includes a thorough history to ascertain the cause, including questions regarding systemic illnesses, nutritional deficiencies, family history, and potential injury.

Painful sensory neuropathies can be associated with systemic disorders such as diabetes mellitus, alcohol abuse, amyloidosis, rheumatoid arthritis, malignant cancers such as oat cell carcinoma, and benign monoclonal gammopathies (IgG, IgA, and IgM). The chronicity of the specific disease process is an important factor. Most inherited neuropathies, such as the hereditary motor and sensory neuropathies, and neurofibromatosis are less commonly associated with neuropathic pain because of their predilection for non-nociceptive neurons. Fabry's disease is a painful inherited sensory neuropathy associated with loss of almost all nociceptive nerve endings in the skin. Some painful small-fiber neuropathies of unknown cause (idiopathic) are present in multiple family members and undoubtedly have genetic causes that await investigation. Other acquired neuropathies are those related to toxin and drug exposure, some of which produce painful neuropathies.

The distribution of neuropathies can be generalized and symmetrical, asymmetrical, multifocal, or focal. The symmetrical generalized polyneuropathies commonly affect sensory and motor modalities in a distal-to-proximal gradient. Neuronal dysfunction is first reported in the extremities, the distal portions of the longest axons. So the earliest symptoms of axonal neuropathy are those of the autonomic and small-fiber sensory modalities. Loss or alteration of pain and temperature perception due to injury to the unmyelinated or thinly myelinated axons can herald more global deficits.

Diabetic neuropathy affects up to 15% of the 5 million patients with diabetes mellitus. It may be the most common peripheral polyneuropathy in the United States. Pain can be due to damage at many levels of the nervous system, but the small nerve fibers are disproportionately affected. The symmetrical, small-fiber neuropathy

associated with diabetes mellitus presents with “burning feet” and autonomic features of impaired thermoregulation and sweat production. Neuropathy and vascular insufficiency are the main risk factors for diabetic foot ulcers and amputation.

In patients with painful diabetic polyneuropathy, pathologic studies demonstrate loss of both myelinated and unmyelinated fibers. Demyelination can be present as well. Endoneurial vascular damage, insufficient neurotrophic support, and autoimmune inflammation may all contribute. Diabetes mellitus is associated with other types of peripheral neuropathies, including proximal motor neuropathies (diabetic amyotrophy), autonomic neuropathies, vulnerability to compressive lesions, acute painful neuropathies from nerve ischemia, hypoglycemic neuropathy, treatment-induced neuropathy, and distal motor neuropathies.

Patients with multifocal neuropathies (mononeuropathy multiplex) usually develop focal loss of function in several peripheral nerves. The pathologic basis of these syndromes is usually ischemic with infarction of the vasa nervorum. Prognosis for recovery is favorable if the underlying cause of the infarction can be addressed. Systemic lupus erythematosus, rheumatoid arthritis, cholesterol emboli, and polyarteritis nodosa as well as diabetes mellitus can cause this pattern.

(ii) Painful mononeuropathies

Isolated focal peripheral nerve lesions are most commonly caused by trauma. Although accidents are the most common cause, iatrogenic injuries due to surgery or needlestick are a close second. Since a proportion of accidents occur on the job, or from participation in sports, these patients are likely to be young, in their most productive years, and they are often male. Nerve injuries may not be diagnosed at the time of the initial accident, since they are not visible on radiographs, and medical attention usually focuses on more obvious injuries. Nerve lesions affecting predominantly sensory neurons and producing pain as the major symptom are less likely to be diagnosed than those that produce frank motor deficit as well. Such delays in diagnosis are unfortunate, as some peripheral nerve injuries benefit from early surgical nerve repair. Furthermore, failure to diagnose a nerve injury can result in repeated surgeries if the pain is erroneously attributed to other causes.

Patients without a history of trauma or surgery usually have internal entrapment, compression, or nerve ischemia. Chronic nerve entrapment injury can be associated with rheumatic disease, diabetes mellitus, uremia, repetitive use, or malnutrition, or can occur in otherwise healthy individuals.

The hallmark of nerve injuries is that the pain is primarily in the distribution of a particular peripheral nerve or branch. The most useful aid to diagnosis is to ask the patient to outline on their body the area of worst pain. Often, this corresponds to the innervation territory of a specific nerve or branch. However, the clinical picture can be confusing since the pain can spread widely, outside traditional nerve territories. Most often, this is because C fibers trifurcate within the substantia gelatinosa on entry to the spinal cord. They send collateral axons approximately two segments up and down the cord, so that lesions of single nerves can be expected to produce more-widespread effects. Additionally, loss of afferent input into the spinal cord causes ectopic axonal sprouting that serves to enlarge the receptive fields of spinal pain-processing neurons. Interestingly, a few of these patients develop bilateral pain with contralateral pain in the area immediately opposite the nerve injury.

A common focal neuropathy is carpal tunnel syndrome. This causes pain, and in severe cases weakness, of the medianinnervated thumb and forefinger. Another common entrapment lesion is meralgia paresthetica. This presents as intermittent pain along the anterior thigh. It is caused by entrapment of branches of the lateral femoral cutaneous nerve as they pass beneath the inguinal ligament. It can be worsened by obesity or pregnancy. Saphenous nerve injury may produce pain in the knee joint and/or medial surface of the lower leg in the setting of prior knee surgery or arthroscopy. Virtually any nerve, branch, or twig containing sensory neurons can be entrapped with resultant neuropathic pain.

Clinicians should evaluate these patients with the aid of a handbook that demonstrates the individual nerve territories. Stewart's textbook Focal Peripheral

Neuropathies is an invaluable resource for diagnosing these syndromes. Occasionally, it is helpful to refer patients with difficult-to-diagnose syndromes for evaluation by a neurologist or neurosurgeon with subspecialty training in peripheral nerve injury.

(iii) Painful neuronopathies

Painful neuronopathies are injuries that are centered on the neuronal cell body. For somatosensory neurons, these are in the dorsal root ganglia, and in the trigeminal (Gasserian) ganglion for axons innervating the face. Sensory neuronopathies can occur from shingles, as paraneoplastic syndromes, and as part of Sjögren's

syndrome. In two thirds of patients with paraneoplastic syndromes, the sensory neuronopathy precedes the discovery of the malignancy. An important clue that points to a neuronal rather than an axonal process is that the first manifestations may not involve the neurons with the longest axons (in the feet) as is usual with

axonopathies. The onset is usually rapid and associated with burning dysesthesias or paresthesias. Areflexia may ultimately result from this syndrome because of loss of the afferent limb of the monosynaptic reflex.

With over 850,000 cases in the United States annually, acute herpes zoster is by far the most common sensory neuronopathy. Both herpes zoster and PHN

disproportionately affect the elderly. Fifty percent of patients over age 60 with zoster will experience PHN. Suppression of cell-mediated immunity often associated with advancing age or concurrent medical illness permits latent varicella-zoster virus (VZV) to erupt into shingles. The dermatomal distribution and vesicular rash are the clinical signatures of VZV reactivation in the dorsal root ganglia. The thoracic segments are the most commonly affected. The next most common site is the ophthalmic division of the trigeminal nerve. The pain is described as burning, often associated with itching and volleys of lancinating pain. The diagnosis of PHN requires the persistence of pain 3 months after the initial rash. Over time, the distribution of pain symptoms can widen to involve adjacent dermatomes.

Shingles causes neuropathic pain syndromes affecting every area of the body including the limbs and genitals. These areas are vulnerable to motor and autonomic abnormalities as well, and adjunctive therapies may be needed. PHN is rarely present after shingles with an absent or inapparent rash (zoster sin herpete ).

Acute zoster produces a mixed inflammatory/nociceptive and neuropathic pain syndrome that is present in the peripheral nerves, dorsal root ganglia, and spinal cord. Early treatment with antiviral medications (acyclovir, famciclovir, or valacyclovir) shortens and lessens the symptoms of zoster and decreases by about one half the likelihood of progressing to PHN. Antiviral therapy should be used in virtually all shingles patients, and it should be instituted as soon as possible. Early and aggressive pain control with tricyclics and opiates is also helpful in decreasing the likelihood of long-term PHN.

Clearance of myelin debris can take more than 1 year within the CNS, but the inflammation of acute zoster eventually subsides in most patients. Those left with PHN experience neuropathic pain. PHN is an excellent model of neuropathic pain and has been the subject of many research studies. Evidence from psychophysical studies and examination of nerve endings within skin biopsies suggests that in many cases there is severe loss of cutaneous innervation, especially nociceptive innervation, in PHN-affected skin.

(iv) Amputation

Pain often remains a major problem following amputation. Although best described after limb amputation, these syndromes can occur after a wide variety of

amputations, including mastectomy and removal of visceral organs such as the rectum. Several different mechanisms can cause pain in these patients. Stump pain is pain perceived proximal to the site of amputation. It can have several causes, including skin breakdown or infection, vascular insufficiency, excess pressure by a prosthesis, or mechanical causes. Sectioned nerves can form painful neuromas.

Phantom pain, in contrast, is perceived distal to the site of the amputation. The most important initial question to ask amputees complaining of pain is whether the pain is proximal or distal to the amputation. Pain is only one of many phantom sensations that can be experienced by amputees. Patients in pain before their amputation (e.g., from infection or injury) may experience precise “memories” of their earlier pain. Although incompletely understood, these phantom sensations are thought to result from spontaneous electrical activity in central sensory neurons that are deprived of their normal afferent input.

2. Central pain syndromes

Neuropathic pain of central origin was originally described after thalamic injury, but these syndromes may occur from lesions in various locations throughout the CNS. Virtually any type of lesion including demyelinating, vascular, infectious, inflammatory, and trauma can produce pain. With central lesions, the onset of pain can be delayed by weeks, months, and occasionally years after a temporally well-defined insult such as a stroke. This may reflect the slower rate of degeneration within the CNS than the peripheral nervous system.

The painful somatic territory typically localizes to the corresponding central pain pathway, as in the thalamic pain syndrome characterized by Dejerine and Roussey. In those cases, the entire contralateral hemibody may be involved in the pain syndrome, or merely a portion of it. In virtually every case of central pain, the spinothalamic pathways are implicated. Out of the absence or disruption of sensory input to the CNS, pain attributable to “deafferentation” emerges. The challenging aspect of central pain syndromes is not usually diagnosis, since these patients often have a constellation of neurologic symptoms associated with their primary disorder. Management seems to be even more difficult than for patients with peripheral neuropathic pain syndromes. Phantom sensations in numb regions are described.

(i) Post-stroke pain

Up to 6% of all strokes are associated with chronic pain that limits rehabilitation and contributes to the development of poststroke depression. The most common description is that of “burning,” which is remarkably similar to accounts by patients with multiple sclerosis, post-cordotomy dysesthesia, and syringomyelia. The neuropathic features of pain in post-stroke syndromes have several characteristic features:

The region of most intense pain encompasses only a portion of the total territory of sensory deficits. Functional recovery is poorest in the regions of most severe pain.

The modalities of thermal perception and sensation to pinprick are more commonly affected than light touch. (ii) Trigeminal neuralgia

Most commonly, neuralgias arise from lesions of the peripheral nerve; however, clinically similar syndromes develop with lesions of the cranial nerve nuclei and outflow tracts as a result of ischemic lesions. The peak onset of trigeminal neuralgia is in patients over 50 years old. The syndrome is marked by brief paroxysms of lancinating pain, usually in the territory of the second and third divisions of the trigeminal nerve. Light mechanical stimuli often trigger the pain. New onset of this syndrome in a younger adult (under 30 years) suggests multiple sclerosis. Older adults should be imaged to screen for compression by tumors or aneurysms. Glossopharyngeal neuralgia, which is caused by lesions affecting the somatosensory component of the IXth cranial nerve, shares similar jolts of pain but in the region of the throat or behind the angle of the jaw. These syndromes are also described in Chapter 29.

(iii) Spinal cord syndromes

Spinal cord syndromes are most often associated with trauma and demyelinating diseases such as multiple sclerosis. Chronic pain due to dysesthetic phantom limb, and visceral sensations occur in more than one third of patients with spinal cord injury, and 10% of these patients characterize their pain as severely disabling. The pain is classified as (a) peripheral segmental, (b) central cord, (c) visceral, and (d) mechanical. Spinal fractures can also produce pain by compressing the remaining neural structures.

In more than half of the patients, the onset is within 6 months of the initial injury. It is variously described as “burning,” “shooting,” and “crushing.” The most common level of injury associated with pain is the cauda equina, followed by central cord injuries. Syringomyelia and syringobulbia as a delayed consequence of trauma or congenital malformation can interrupt central nociceptive afferents and produce neuropathic symptoms that affect a segment of the body. Since the spinothalamic pathways cross in the midline of the spinal cord near the site of entry to the cord, pain is the most common and earliest symptom of these syndromes.

(iv) Multiple sclerosis

Neuropathic pain is frequently associated with multiple sclerosis and is a significant cause of disability. The locations of plaques most commonly implicated are in the cervical spinal cord involving nociceptive afferents. Demyelination of the cervical and thoracic cords is common in multiple sclerosis and can produce lancinating pain in radicular distribution, or episodes of burning pain. Other sites where plaques produce neuropathic symptoms are in the radicular region at the dorsal root entry zone and the cranial nerves (see section IV, 2, ii).