Chapter 31 Neuropathological examination of peripheral nerves in painful neuropathies (neuralgias)

Handbook of Clinical Neurology, Vol. 81 (3rd series) Pain F. Cervero, T.S. Jensen, Editors © 2006 Elsevier B.V. All rights reserved

Neurophysiological examinations in neuropathic pain Chapter 31

Neuropathological examination of peripheral nerves in painful neuropathies (neuralgias) ANNE LOUISE OAKLANDER*

Nerve Injury Unit, Departments of Anesthesiology, Neurology, and Neuropathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

31.1. Rationale and methods for pathological examination of tissues from patients with neuralgia Pathology is the bedrock upon which our understanding of disease rests. It is integral to neurology and neurosurgery, both for understanding processes that occur in many diseases, and for diagnosing specific diseases by their pathological characteristics. Early neuropathology was as often undertaken by neurologists and neurosurgeons as by pathologists. Harvey Cushing was the first to describe systematically brain tumor pathology and to correlate cellular features with survival estimates. Weekly “brain cutting” sessions are still routine in academic neurology departments; most neurology residents still rotate on the neuropathology service (and answer neuropathology questions during their board examinations), and neuropathologists typically participate in neurology grand rounds. In short, neurologists and neurosurgeons work closely with pathologists, as do many medical and surgical specialties. Unfortunately, the pain field does not. Only a handful of investigators study the pathology of human pain, but there is a pressing need to identify the cells that generate it. Fundamental questions remain unanswered, such as the cellular changes that cause mechanical allodynia and lancinating pain. Most advances in understanding pain mechanisms have come from studying animal models, but although these have revealed preliminary information of likely relevance to human patients, there has been almost no confirmation of animal data in humans. Acute inflammatory/injury pain is primarily generated by excess activity of primary (peripheral)

nociceptive neurons, but the situation is far more complex in the neuralgias. Here, the relative contributions of directly injured primary nociceptive afferents, nearby uninjured nociceptive neurons, non-nociceptive neurons that change their properties, autonomic neurons, and the direct and indirect central targets of these neurons, remains unclear (Campbell, 2001). The contributions of non-neuronal cells also deserve further elucidation. The pathological study of pain patients can go a long way towards answering these questions, as it has for many other illnesses. Sophisticated imaging technology now allows us to “see” anatomical or functional abnormalities within the nervous systems of living people, but unless tissue pathology is studied in parallel, radiological changes can only be tentatively interpreted. Pathological studies of the effects of pain therapies are also needed. There are few data about the long-term effects of newer pain medications, to which patients may be exposed to for decades, and about therapeutic devices such as implanted bipolar neural stimulators. In some patients, these appear to have disease-modifying effects, causing dramatic improvements in pain that persist even when the stimulators are off (Labar and Ponticello, 2003). These effects suggest anatomical changes, but pathological confirmation is needed. Pathological examination is particularly important when pain treatments go awry (Kelly et al., 1975; Myers et al., 1986; Kalichman et al., 1988). We must understand iatrogenic complications in order to prevent them. Better understanding of the pathological causes of neuropathic pain may have additional implications.

*Correspondence to: Anne Louise Oaklander, M.D., Ph.D., Massachusetts General Hospital, 55 Fruit Street, Clinics 3, Boston, MA 02114-2696, USA. E-mail: [email protected], Tel: +1-617-724-2177, Fax: +1-617-724-4488.

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Some patients (e.g. those with small-fiber neuropathies, or complex regional pain syndrome type I) have little objective evidence of disease, leading to suspicion that these conditions reflect psychopathology rather than neurological disease. Pain patients without an identified pathological basis for their symptoms can have difficulty getting treatment, disability payments, or compensation for injuries. So identification of biomarkers of pain can have economic as well as medical implications. Pathological study cannot provide all the answers. Not all mechanisms that contribute to neuropathic pain are reflected in anatomical changes. Injuries cause profound changes in neural gene expression with resultant changes in signal transduction, conduction, and synaptic transmission, as well as in general processes such as cell growth, which may not create anatomical changes. However, most chronic neuropathic pain syndromes originate in the more-exposed peripheral nervous system (PNS), and reflect injury to some portion of the smalldiameter, thinly myelinated (A-δ) or unmyelinated (C-fiber) axons that subserve pain and autonomic function. Damage to nociceptive afferents does not cause overt signs (e.g. weakness, muscle atrophy or loss of reflexes) and is not captured by electromyography and nerve conduction studies, the standard tests for diagnosing neuropathy. Hence the importance of pathological research. There is pathological evidence that nonspecific trauma may disproportionately affect small-fiber axons to leave chronic pain. P.K. Thomas hypothesized that myelin might shield axons from calcium influx and other imbalances that lead to Wallerian degeneration (Thomas, 1973). Injuries also have long-term, pro-algesic, pathologically identifiable effects. Peripheral axonopathies can cause preferential long-term loss of central terminals of unmyelinated axons (Coggeshall et al., 1997), and delayed death of some nociceptive neuronal cell bodies (Tandrup et al., 2000). These changes disconnect injured nociceptive afferents, and set the stage for transsynaptic damage in central pain pathways. Inhibitory GABAergic interneurons in the dorsal horn down-regulate their activity (Moore et al., 2002), and may even undergo trans-synaptic degeneration (Sugimoto et al., 1990). These events trigger pathological axonal sprouting and “rewiring” of synaptic contacts that has been demonstrated to occur at every level of the neuraxis, up to and including the sensory cortex (Maïhofner et al., 2003). Pathological study is needed to determine the relevance of these changes for pain development.

directly fatal, and thus autopsy may not be considered, but chronic pain patients can be educated about the importance of eventual anatomical donation for diagnostic and research purposes. The clinician needs to request permission to perform a complete autopsy in order to study the spine and the brain, and should speak with the pathologist, or leave written instructions to ensure that the appropriate tissues (e.g. specific ganglia or nerves) are sampled. Brain banks have been established to obtain, process, preserve and disburse neural tissues to neurological investigators, but they are of limited utility to pain investigators, because information about donors’ pain histories is not usually collected. Another limitation is postmortem delay, which averages about 24 h, and causes some cellular degradation. This can make electron microscopy or some types of immunohistochemistry difficult, although autopsy tissues are fine for many uses. Autopsy findings from a few or even one patient can be enough to spark new hypotheses (Watson et al., 1991). Surgical pathology involves the study of tissues removed from living patients. Only rarely are tissues surgically removed from pain patients to treat pain or the underlying cause of pain. In the 19th and early 20th centuries, there were no or few medications effective for neuralgias, so ablative neurosurgery was common, based on the naïve hope that cutting the nerves carrying pain sensations would relieve pain. A lively pathological literature was generated from those exploits, and insights can be gained even today by reading these works. Today, pain-related surgeries that generate tissues for examination include peripheral nerve grafts and repairs, and neuroma resections. Rare patients undergo spinal ganglionectomy for diagnosis or treatment of a recalcitrant thoracic or upper cervical radiculopathy (Wilkinson and Chan, 2001). If a clinician knows that a patient will have surgery that might provide tissues useful for study, every attempt should be made before the surgery to ensure that these tissues are preserved for study (Poletti, 1996). Surgically removed tissues are immediately fixed and are thus of higher quality than autopsy specimens. Special techniques may need to be arranged ahead of time (e.g. aldehyde fixation and epoxy embedding for ultrastructural study, or cryoprotection and freezing for immunohistochemistry). A potential bias of data gathered from patients undergoing surgery is that these represent the most severely affected patients, and thus findings may not accurately represent those present in the entire population of patients with that condition.

31.1.1. Anatomical and surgical pathology Anatomical pathology, the examination of tissues obtained at autopsy, can provide definitive diagnostic information about individual patients. Pain is not

31.1.2. Sural nerve biopsy The third method of obtaining neural tissue samples for pathological study is by biopsy. This can be performed

NEUROPATHOLOGICAL EXAMINATION OF PERIPHERAL NERVES IN NEURALGIAS

both in the central nervous system (CNS); more often the brain than the spinal cord and the PNS, but since both procedures risk neural damage as well as routine operative complications, they are only performed if the clinical knowledge to be gained justifies the risk. Since neuropathic pain is not usually progressive or fatal, and specific pathological findings do not influence clinical decisions, CNS biopsies are virtually never performed for pain syndromes. Samples of peripheral nerve are easier to obtain, and specific pathological findings (e.g. vasculitis, infection, demyelination, or neoplastic cells) can influence treatment. Because of this, removal of all or part of the sural nerve from the lower lateral leg for pathological study is performed at some medical centers to help diagnose the cause and severity of motor and/or sensory symptoms of polyneuropathy. The sural is the only human nerve routinely biopsied, because it is a pure sensory nerve and thus can be damaged without causing weakness. In recent years, there has been increasing appreciation of the potentially disabling sensory loss and even chronic pain that sural biopsy can cause (Dahlin et al., 1997; Theriault et al., 1998), and now surgeons try to remove only a few fascicles. Most centers can evaluate sural nerve biopsies by light microscopy, but the electron microscopic examination and morphometric densitometry needed to study nociceptive axons are so poorly reimbursed that few departments can offer it for clinical diagnosis. Analysis of individual fibers teased from fascicles is not performed for pain indications because it only evaluates large myelinated fibers. Light microscopic analyses focus on evaluation of semi-thin 1–2 µm epoxy-embedded nerve cross sections. The pathologist must assess the integrity and appearance of the nerve parenchyma, or endoneurium, which contains interstitial fluid, various cells, and collagen. The endoneurium surrounds the axon–Schwann cell units and blood vessels. The perineurium surrounds individual fascicles and their endoneurial blood vessels to form the blood nerve barrier. The epineurium is a tough fibrovascular sheath that encloses bundles of fascicles to form a nerve that is distinct from surrounding connective tissue. In neuropathy associated with Sjögren’s or sicca syndrome, inflammation of the epineurium may be the most common pathological change (Grant et al., 1997). In nerve edema, the endoneurial volume normally increases by 20–30%. The appearance and density of inflammatory cells must also be assessed, they are present but rare in normal nerves, and can be increased by injury, inflammation or degeneration (Cornblath et al., 1990). Bleeding, vasculitis, neoplastic cells, and storage of metabolic products such as amyloid can also be diagnosed. The density, thickness, and appearance of blood vessels must be evaluated.

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Proliferation and hypertrophy of endoneurial vessels is common in neuralgias and can contribute to neural ischemia (Yasuda and Dyck, 1987). Although unmyelinated fibers can be faintly seen using oil immersion, light microscopic evaluation of nerve biopsies yields information mostly about myelinated fibers. Schwann cells and myelin can be assessed, and demyelination, intramyelinic edema, or myelin phagocytosis are readily evident. “Onion bulbs” represent repeated cycles of demyelination and Schwann cell mitosis characteristic of primary demyelinating neuropathies. Visible axonal changes include edema, dissolution or clumping of the organelles or cytoskeleton, or axon dilations implying blockage of axonal transport. Recent axonal degeneration leaves behind empty myelin sheaths or Schwann cells; later this myelin undergoes secondary degeneration. The presence of axonal sprouts with absent or thin myelin sheaths also implies earlier degeneration. These sprouts can grow outside the epineurium, and sometimes even grow proximally. Tangles of sprouts unable to innervate their target can form mechanically sensitive neuromas. Very severe damage can leave nerves containing mostly collagen. Evaluation by transmission electron microscopy of thin nerve sections that have been fixed in isoosmolar glutaraldehyde and osmium tetroxide can be used for morphometric analysis of the density, shape, diameter distribution, and spatial distribution of fibers. Details obtainable from myelinated fibers include myelin sheath areas, perimeters, and the ratio of axon diameter to myelin thickness, which is relatively constant in health. For pain patients, the major cells of interest are the unmyelinated nociceptive axons that are ensheathed in Schwann cell plasmalemmal infoldings. Subtle signs of damage can include axonal swelling, but the most common finding in painful neuropathies is reduced numbers of unmyelinated axons, leaving redundant stacks of empty Schwann cell processes (see Fig. 31.1). A caveat in interpreting fiber diameter spectra is that any injury producing Wallerian degeneration will trigger axonal sprouting, and all axon sprouts, regardless of the size of the parent axon, are small-diameter unmyelinated neural processes morphologically indistinguishable from normal nociceptive fibers. Regenerating sprouts sometimes have a different relationship with Schwann cells than C-fibers. Human cutaneous nerves in areas remote from Schwann cell somas often contain only one or two C-fibers, as opposed to clusters of unmyelinated axon sprouts within individual Schwann cell bands of Büngner during regeneration. Labeling for growthassociated proteins, enriched during regeneration, can also help distinguish between these situations.

A. L. OAKLANDER

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Fig. 31.1. For full colour figure, see plate section. Hematoxylin and eosin ×10 specimen from a sural-nerve biopsy from a patient with idiopathic painful small-fiber neuropathy. The endoneurial fascicular contents appear normal at lightmicroscopy resolution; large myelinated fibers are mostly unaffected. There is a small perineurial infiltrate around a vessel in the center of the image; it does not extend through the vessel wall nor meet other criteria for vasculitis.

31.1.3. Neurodiagnostic skin biopsy Because sural nerve biopsies are only useful for diseases that affect the sural nerve and cannot be repeated to monitor disease progress or the effects of therapy, they are being supplanted by neurodiagnostic skin biopsies for the evaluation of painful neuropathies. In this method, vertical sections of small skin biopsies (or epidermal sheets removed by suction) are immunolabeled

A

to reveal the axons and nerve endings within. Skin biopsies do not sample motor or large myelinated sensory fibers, and provide no information about myelin or abnormalities of nerve cytoarchitecture, and so they are not useful for the diagnosis of demyelinating or inflammatory neuropathies. However, they are exceptionally useful for evaluating painful neuropathies (see Fig. 31.2), because more than 90% of epidermal neurites are TRPV1+ nociceptive axons (Nolano et al., 1999). Methodological advantages of neurodiagnostic skin biopsies include its minimally invasive nature: the standard is to remove 3 mm diameter punch biopsies from anesthetized skin. The sites heal well without suturing, and no serious complications have been reported. After performing well over 1000 of these, we have seen two or three minor skin infections that resolved with oral antibiotics, and one that required intravenous antibiotics, in an AIDS patient with a very low lymphocyte count. Because they are so minimally invasive, skin biopsies can be performed on many different body areas, and can be repeated to monitor disease progress or the effects of therapy. The standard site for the diagnosis of painful neuropathies is 10 cm above the lateral malleolus. The skin biopsy punches are fixed and immunolabeled against PGP9.5, a pan-neuronal lysosomal enzyme, to enable quantification of axonal density (Dalsgaard et al., 1989). Localization has been ultrastructurally verified and methods standardized (Hilliges et al., 1995). Presently, quantitative data can only be obtained from the epidermis, where axons divide into individual nerve terminals that can be seen and counted. Skin biopsies have revealed reduced innervation in every neuralgic condition studied

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Fig. 31.2. For full colour figure, see plate section. PGP9.5-immunolabeled axonal endings in biopsies from normal human skin (A) and skin from a patient with painful small-fiber neuropathy (B). Skin biopsies from the distal leg were vertically sectioned and immunolabeled. Individual neurites and neurite bundles are visible within the epidermis and superficial dermis, respectively. The epidermis from normal skin (A) is thicker and more densely innervated than that from the subject with neuropathic pain (B), whose neurites are fewer and fragmented.

NEUROPATHOLOGICAL EXAMINATION OF PERIPHERAL NERVES IN NEURALGIAS

(Griffin et al., 2001). For clinical diagnosis, it is important that a laboratory has a bank of normative data, preferably from subjects of various ages, against which neurite densities from clinical specimens can be compared to offer diagnosis (McArthur et al., 1998). The current standard is not to diagnose polyneuropathy unless densities are below 5% of normal. Clearly, this cut-off has high specificity but low sensitivity for the earlier stages when neurite counts have not yet sunk so low. In the early stages of painful neuropathies, neurite counts appear maintained, and densities within skin biopsy can even appear elevated artifactually, due to axonal fragmentation (Amato and Oaklander, 2004). Limitations of the use of skin biopsies for the diagnosis of polyneuropathies include the fact that, like sural nerve biopsy, it is only available at specialized centers, and is laborious to perform and interpret. In the USA, insurance reimbursement often does not cover costs. 31.2. Pathological features of painful lesions affecting spinal primary afferent neurons; their peripheral axons, the dorsal root ganglia, or their central axons (spinal nerves and roots) Lesions of primary afferent neurons are the most common cause of neuropathic pain, and encompass many syndromes and etiologies. The etiology of the lesion is less important than its location, the normal functions of the neurons injured and the percentage of neurons that are injured. The symptoms of nerve injury vary because most of the PNS contains mixed populations of neurons with different properties. Chronic pain does not develop unless nociceptive neurons are damaged. Some forms of neuropathy (e.g. toxic, autoimmune or genetic) disable only very specific subsets of neurons. These are particularly important to investigate pathologically because they can reveal the functions of the missing neurons. 31.2.1. Painful polyneuropathies (axonopathies) Polyneuropathies are the diseases that affect many or most of the peripheral nerves. Distal parts of the nerves are usually the first affected, because most (but not all) of the synthesis of macromolecules in peripheral neurons takes place in the centrally located cell bodies, and require long-distance NADH and ATP-dependent transport along axons. If transport should fail at any point, for any reason, the distal axon can no longer maintain viability, and undergoes Wallerian degeneration (Oaklander and Spencer, 1988). The distal axon is also most vulnerable to the accumulated effects of randomly distributed nerve disturbances. In practice, this means that the earliest clinical symptoms and

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pathological signs of polyneuropathy usually occur in the feet. Pain is a common symptom, but surprisingly little neuropathy research has focused on it. Almost all somatic peripheral nerves contain mixed populations of fibers, including motor axons carrying messages to muscles, several varieties of sensory axons and postganglionic sympathetic axons. Axonal function is reflected in the diameter of axons, and this determines whether they are myelinated. Axons with a diameter of greater than about 1 µm are myelinated to accelerate axonal conduction. The so-called “small-fibers” are the small-diameter, slowly conducting, thinly myelinated A-δ fibers and unmyelinated C-fibers that mediate various painful sensations, and have efferent autonomic and trophic functions as well. Generalized polyneuropathies can be caused by many different problems, but regardless of cause, many preferentially affect specific subtypes of axon. Neuropathies that preferentially or completely affect only the small-caliber sensory axons are known as “small-fiber neuropathies” (Wolfe et al., 1999; Mendell and Sahenk, 2003). They are notoriously cryptic because they do not produce traditional signs of nerve injury such as weakness, reflex loss or muscle atrophy. Small-fiber neuropathy patients typically present with bilateral burning foot pain. Autonomic dysfunction is often present as well, producing symptoms such as abnormalities of sweating, blood flow and temperature regulation, or skin and hair growth (Parkhouse and Le Quesne, 1988; Novak et al., 2001). Confusingly, small-fiber neuropathies with the most prominent autonomic features are also termed “erythromelalgia” (Jeffcoate et al., 2004) or “erythermalgia” (Cummins et al., 2004) by some authors. Purely demyelinating polyneuropathies are not usually painful, although small-fibers can undergo bystander damage even if they are not the primary targets of attack. Even pure motor nerves have small-fibers innervating their blood vessels, and bystander damage to these may account for pain in primarily motor neuropathies such as acute inflammatory demyelinating polyneuropathy (Guillain–Barré syndrome). 31.2.1.1. Diabetic distal symmetric polyneuropathy Diabetes is the most common identifiable cause of painful neuropathy in western societies. The clinical syndrome is described in detail in Chapter 40. Diabetic vasculitis is discussed in the sections below on plexopathies and radiculopathies. Nonpainful diabetic nerve damage (e.g. oculomotor neuropathy) will not be covered. Here I describe the pathology of diabetic distal symmetric polyneuropathy (DSPN), the most common cause of chronic pain in diabetics. This is primarily a small-fiber sensory polyneuropathy, commonly accompanied by autonomic polyneuropathy. When severe,

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large sensory and motor fibers also become affected to give a pan-neuropathy. As in other neuropathies, the actual cause of pain in DSPN remains elusive. However, since DSPN is the best-studied neuralgia, it is worth reviewing current knowledge. Early efforts focused on identifying whether a particular pathological process (e.g. demyelination, degeneration, regeneration), or damage to specific types of axons, was associated with pain. Classical light microscopic studies revealed loss of myelinated fibers accompanied by Schwann cell proliferation and endoneurial microvascular inflammation and remodeling (Woltman and Wilder, 1929). Segmental demyelination was identified in teased fibers from diabetic patients and causes the slowing of conduction velocities, but is not likely to be related to the presence of pain. Llewelyn et al. (1991) found no correlation between the presence of pain and degeneration of myelinated fibers. Later ultrastructural studies demonstrated a distal dying-back degeneration of unmyelinated axons as well, and identified a relationship between the presence of pain and the severity of degeneration of unmyelinated but not of myelinated fibers (Britland et al., 1990). However, quantification of C-fiber numbers is difficult, because C-fiber losses can be artifactually masked by axonal sprouting. Dyck et al. found a correlation between the severity of pain and degree of smallfiber axonal degeneration, and hypothesized that ongoing degeneration of nerve fibers itself triggered pain by causing affected axons to fire inappropriately (Dyck et al., 1976). A problem with this theory is that diabetic neuropathy is a central–peripheral distal peripheral axonopathy (CDPA), and thus the degenerating primary afferents are likely to be disconnected from their central targets by degeneration of their central as well as peripheral axons (Sima and Yagihashi, 1985). Asbury and Fields (1984) postulated that regenerating sprouts were a major cause of DSPN pain. Given the contribution of axon sprouts to pain after nerve injuries (e.g. in neuromas), this seems likely. Furthermore, exogenous nerve growth factor administration induces C-fiber sprouting, and is painful (Dyck et al., 1997). Since impaired support by nerve growth factor and other neurotrophins is clearly involved in diabetesrelated neural dysfunction, the situation is complex. Because severe or chronic diabetes devastates the entire PNS, it became apparent that to investigate the cause of pain in DSPN it would be more useful to study mild or early cases in which pain was the only or predominant complaint. By doing so, selective loss of small-diameter (A-δ nociceptive) over large diameter fibers was identified (Brown et al., 1976). Britland and co-workers (1990) performed detailed morphometric

sural nerve biopsies from six diabetic patients, four with active acute painful neuropathy and two with recent remission from the same condition, and found no clear morphological differences. Teased-fiber analysis showed that similar myelinated axon and Schwann cell abnormalities were present in both groups of diabetic patients. Electron microscopic studies revealed evidence of both myelinated and unmyelinated fiber degeneration and regeneration in the nerves of all DSPN patients, regardless of whether or not they had pain. There was a hint that pain might be associated with a less abnormal axon/Schwann cell caliber ratio, more successful myelinated fiber regeneration and less active unmyelinated fiber regeneration, but their major finding was the similarity in the nerve pathology in diabetic patients with active and remitting painful neuropathy. However, this study was very small, and it cannot be assumed that the mechanisms of remission from DSPN pain are the same as those that prevent pain. One hypothesis that has not yet been carefully examined is that partial small-fiber degeneration and/or axonal regeneration trigger pain, but that when diabetes worsens to the point where no axons remain and regeneration ceases, pain may remit. Although the clinical effects of DSPN are felt peripherally, it is increasingly clear that central changes are involved in pain pathogenesis. Pathological studies have demonstrated that DSPN appears to affect the central axons of primary afferents as well as the peripheral axons. Pathological study of the gracile tract of spontaneously diabetic BB rats demonstrated both early (neurofilament malorientation and axonal organelle sequestration) and late findings of progressive axonal atrophy followed by Wallerian degeneration of both myelinated and unmyelinated fibers (Sima and Yagihashi, 1985). Quantification revealed a proximal to distal gradient in severity. All findings were analogous to those in diabetic nerves and confirm that DSPN is a central– peripheral distal axonopathy. Autopsy has revealed the same in human DSPN patients (Dolman, 1963). Non-neuronal cells are also severely affected in DSPN, although whether or not they directly or indirectly contribute to pain pathogenesis is unclear. One of the most characteristic findings in DSPN is endoneurial blood vessel damage and remodeling (Woltman and Wilder, 1929). The most characteristic changes are hyperplasia of endothelial cells and thickening of basement membranes. This reduplication is likely to represent repeated cycles of loss and replacement of pericytes (Vracko, 1974). Other changes such as the density of microvessels, or their total luminal area, are inconsistent. The severity of endoneurial vascular changes correlates with pathological and electrophysiological measurements of the severity of DSPN, although these have

NEUROPATHOLOGICAL EXAMINATION OF PERIPHERAL NERVES IN NEURALGIAS

not been correlated specifically with the presence or absence of pain. Undoubtedly, endoneurial vascular changes contribute to the unfavorable and ischemic milieu within diabetic nerves (which worsens axonal degeneration), as well as to symptoms such as leg edema and poor healing. These endoneurial vascular changes are usually assumed to be primary consequences of diabetic angiopathy, but they have also been described in patients with other causes of neuropathic pain than diabetes (van der Laan et al., 1998), which suggests that a more general association with neuropathic pain is present. A recent finding from animal research is that the treatment of type 1 diabetic BB/Wor rats with insulinomimetic C-peptide significantly prevents thermal hyperalgesia and C-fiber atrophy, degeneration and loss (Kamiya et al., 2004). C-peptide administration prevented decreased levels of dorsal root ganglia nociceptive peptides such as substance P and calcitonin gene-related peptide, and maintained normal expression of insulin, insulin growth factor-1, nerve growth factor and neurotrophin 3 receptors in dorsal root ganglion cells. The authors concluded that perturbed C-peptide action plays an important pathogenetic role in nociceptive sensory neuropathy and that C-peptide replacement might help treat painful diabetic neuropathy in type-1 or insulindeficient diabetics (Kamiya et al., 2004). 31.2.1.2. Other painful small-fiber polyneuropathies Even in Western countries, diabetes is far from the only cause of painful polyneuropathy. As discussed in Chapter 41, any number of toxic, inflammatory, genetic, vasculitic, or autoimmune processes affect small-fiber axons and make pain the most common presenting symptom of polyneuropathy. Even with the best of investigation, many if not most patients with painful small fiber neuropathies are left with the nondiagnosis of “idiopathic painful neuropathy”, meaning the cause of their neuropathy is unknown at present. Because of the enormous length of peripheral axons and volume of cytoplasm to be maintained predominantly from the cell body, any process that interferes with the body’s energy metabolism can produce widespread distal axonopathy. With few exceptions, the pathology of nondiabetic painful peripheral neuropathies is not different from that of diabetic neuropathies. If only or predominantly small-fibers are affected, the nerve can appear normal, or only minimally abnormal at the light microscopic level. Ultrastructural examination can reveal axonal edema, perineurial sheath hypertrophy, infiltration of fibroblasts and collagen into the endoneurial compartment, increased interaxonal space, and decreased order and density of axonal packing.

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A number of patients from families with genetic polyneuropathies have been examined at autopsy. Depending on the mutation (and presumably on environmental influences as well), various neuropathologic features have been described. But the neuromuscular specialists who study such families have not often collected information about the presence and characteristics of neuropathic pain. Such cases are termed “congenital insensitivity to pain” and it is not often mentioned that many such patients also experience chronic neuropathic pain in their limbs. 31.2.2. Painful mononeuropathies (axonopathies) Pathologically, nerve injuries can be classified into those that are transient (neurapraxia) and produce temporary failure of signal transmission due to nerve ischemia or acute edema or demyelination. These are common in clinical practice, but since patients recover without intervention, they are of limited clinical significance. However, nerves that are swollen, for instance from diabetic neuropathy, have an increased risk of entrapment, which can cause additive injury and require surgical decompression (e.g. at the tarsal tunnel of the ankle) for best pain relief (Aszmann et al., 2000). Longerlasting symptoms develop if axons are physically disrupted but the connective tissue around them remains intact (axonotmesis). This occurs in compression, entrapments or crush injuries, as well as in vasculitic injuries, for instance those associated with diabetes. The prognosis for axonal regeneration permitting functional recovery is reasonable. If there is destruction of the epineurial and/or perineurial connective tissue, as after nerve transection or root avulsion, axons will have difficulty regenerating across the gap, and recovery is unlikely unless the proximal and distal stumps are surgically anastomosed. Infections are a rare cause of painful focal neuropathies, but because they are potentially curable, they must be considered in the differential diagnosis. Nerve biopsy may be necessary to identify the organism causing local infections. The bacillus Mycobacterium leprae has a predilection for superficial nerves of the limbs and extremities, which are at its preferred temperature, below 37ºC. These are most often cutaneous sensory nerves, and thus can be painful. Isolated highly inflamed lesions are characteristic of lepromatous leprosy. Microscopic pathology shows large pale “foamy” macrophages, as well as other inflammatory cells of hematogenous origin. The acid-fast bacilli are sparse, and most often inside macrophage vacuoles. Treatment of lepromatous leprosy occasionally provokes secondary vasculitis that can affect peripheral nerves.

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31.2.3. Complex regional pain syndrome Pathological evidence has now established that CRPS-I as well as CRPS-II is caused by nerve injury, usually initiated by trauma. Focal persistent nerve injuries, which often to go unrecognized, account for the chronicity of symptoms despite healing of non-neuronal injuries. These pathological studies have eliminated any meaningful distinctions between the CRPS-I and CRPSII classifications. The core lesion appears to be damage to the small-fibers that subserve pain and autonomic function, as shown by the best nerve pathology study of CRPS-I. Direct support comes from the best nerve pathology study of CRPS. A Dutch team studied legs amputated from eight chronic CRPS-I patients with severe disease (van der Laan et al., 1998). The large nerves of the lower leg were normal by light microscopic examination in most but not all of the patients studied. However, electron microscopic (ultrastructural) examination is required to reveal the small-diameter unmyelinated C-fibers as well as to detect subtle large-fiber loss. The investigators could only gather quantitative ultrastructural data from the sural, the only nerve for which normative standards are available. Overall, there was no statistically significant reduction in density of sural myelinated fibers, although four patients had mild reductions. Degeneration of unmyelinated fibers was present, but could not be quantified for technical reasons. The authors concluded that even severely affected CRPS-I patients do not have overt nerve degeneration, but at least some have degeneration of unmyelinated fibers, and loss of some myelinated axons as well. Considering that the sural is but one of the four major nerves in the leg, detection of sural damage in 50% of the CRPS-I subjects studied is biologically significant and supports the hypothesis that CRPS-I is associated with underlying nerve injuries that affect nociceptive axons. Skin biopsy study has now confirmed this hypothesis. An early study of biopsies from nine CRPS-I patients’ painful areas used visual inspection only and failed to detect neurite losses (Drummond et al., 1996). A more recent morphometric evaluation of neurite densities, within skin biopsies taken from painful and control nonpainful sites of 18 CRPS-I patients’ limbs, identified a significant focal 29% decrease in neurite densities in CRPS-I affected painful skin (Oaklander et al., 2006). These results are congruent with the study of amputated limbs in that both show that CRPS-I arises in the setting of minimal rather than severe nerve damage. CRPS symptoms very rarely develop from lesions entirely restricted to the CNS. Central CRPS is mentioned here because pathological study suggests that at least some central cases originate from PNS lesions.

Seven middle cerebral artery stroke patients who developed CRPS in their paretic arm or hand (shoulder– hand syndrome) have been studied at autopsy (Braus et al., 1994). A blinded study of the periarticular soft tissues from both shoulders (CRPS-affected and unaffected) revealed pre-mortem microhemorrhages, inflammation, and scarring around the CRPS-affected shoulder joints only, suggesting that the CRPS was only indirectly related to stroke, but was directly caused by shoulder trauma (due to post-stroke hemineglect, sensory loss, and shoulder joint subluxation) that damaged nearby neural structures. The authors tested these conclusions by instituting measures to protect the paretic shoulders and arms of such patients, and significantly reduced the frequency of CRPS. Because the brachial plexi themselves were not studied, these data are indirect and require further confirmation. 31.2.4. Painful lesions of the brachial or lumbosacral plexi A number of miscellaneous processes can cause isolated painful plexus disorders, including inherited disorders, compression or trauma, tumors, and effects of radiation therapy. Some cases follow immunizations containing animal antisera (e.g. horse tetanus antitoxin) or heroin injection. Perhaps idiopathic autoimmune attack is the most common. These are best described in the brachial plexus, originally as Parsonage–Turner syndrome, but they also affect the lumbosacral plexus. Some cases are associated with diabetes (diabetic amyotrophy) or autoimmune diseases including Sjögren’s, sicca, periarteritis nodosa and other rheumatological diseases (Dyck et al., 2000), but often the cause and molecular targets of attack remain unidentified. A significant number of autoimmune cases are bilateral, and restricted forms affecting only one nerve can occur. Proximal limb pain is usually the first symptom, and in some patients, pain remains long after the attack. In most described cases, weakness, muscle atrophy, and reflex loss have been present, although since these are required for diagnosis (Evans et al., 1981) the possibility of pure small-fiber autoimmune plexidites that produce only pain and autonomic dysfunction seems probable. Pathological study of autoimmune cases has revealed regional microvasculitis causing inflammation, ischemia, infarction, and axonal degeneration (Suarez et al., 1996; Dyck et al., 2000). Although autoimmune plexitis is usually monophasic, recovery can take years, and sometimes residual symptoms persist indefinitely (Evans et al., 1981). If the initial illness is not diagnosed, these patients can later present with vague limb weakness and chronic pain that permits only presumptive diagnosis of earlier idiopathic plexitis.

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31.2.5. Painful lesions of the dorsal root ganglia (sensory neuropathies) In neuropathies, the primary target of disease is the cell body (soma) of peripheral neurons. Only diseases that affect somatosensory neurons with nociceptive potential can produce pain. For instance, diseases that affect the cell bodies of lower motor neurons (e.g. amyotrophic lateral sclerosis) are not usually painful. The nociceptive somas are located in the 30 paired paraspinal sensory ganglia (dorsal root ganglia or DRG) and in the four cranial nerve ganglia that have somatosensory function (vide infra). Although ganglia are not uncommonly damaged by processes affecting nearby neural structures, such as the spinal cord or nerve roots (Poletti, 1996), they are only rarely an independent target, with the important exception of varicella zoster, which is discussed separately in Chapter 43. It is likely that the vulnerability of sensory ganglia to these diseases is enhanced by their lack of a perineurial blood–neural barrier, which allows penetration of both hematogenous infections and immunocytes. Other painful ganglionopathies are far less common than herpes zoster. If many ganglia are affected, the patients present with widespread pain and sensory loss, whereas focal ganglionopathies present with segmental sensory complaints as in zoster. Ganglionopathies can be acute, subacute or chronic, and are classified by the type of inflammatory cell that invades the ganglia: namely, polyclonal, monoclonal (as from lymphoma) or antibody mediated, as in the paraneoplastic syndromes associated with small-cell carcinoma of the lung. When damage is severe, the cell body degenerates, leaving behind a characteristic rosette of remaining satellite cells known as a nodule of Nageotte. The central and peripheral axonal processes will degenerate, mimicking central–peripheral distal axonopathy. Among the autoimmune diseases, Sjögren’s and scleroderma have been most associated with ganglionitis (see Fig. 31.3). These diseases affect more women than men. In Sjögren’s, the ganglionopathy can be the presenting symptom of disease. Pathological study of three ganglia revealed lymphocytic (T-cell) infiltrates in the dorsal roots and ganglia, with focal clusters around neurons. In the more mildly affected ganglia, individual sensory neurons were undergoing degeneration. In the most advanced case, very few neurons remained (Griffin et al., 1990). 31.2.6. Painful lesions of the spinal nerves and dorsal roots 31.2.6.1. Compressive lesions Compression by degenerative spinal osteoarthritis is the most common cause of radicular pain. Several structures form the walls of the lateral spinal foramen,

Fig. 31.3. For full colour figure, see plate section. CD45-immunolabeled section from trigeminal ganglion obtained at autopsy from patient with Sjögren’s disease and facial pain. This marker of lymphocyte common antigen highlights increased lymphocytes. Photograph by Tim-Rasmus Kiehl M.D.

including the facet joints, the intervertebral disk, the interosseous ligaments, and the pedicles. Expansion or displacement of any of these structures can produce a “pinched” nerve, as these are commonly called. Although sciatica, from compression of the L4, L5 or S1 nerve roots is most common, followed by occipital neuralgia from C2 or C3 root compression (Poletti, 1996), any nerve root can be compressed and cause neuralgia. Unexplained segmental neuralgia (including in the abdomen) should provoke spinal imaging to look for compressive lesions. Other causes of compressive radiculopathies include trauma, vertebral fractures from osteoporosis, spine infections or abcesses (e.g. Pott’s disease from M. tuberculosis, primary or metastatic tumors affecting the spine, meninges or nerve roots). Arteriovenous malformations (e.g. cavernous hemangiomas) are possible, and may require sophisticated imaging to be demonstrated. Compressive hemorrhages can be related to intrinsic or iatrogenic coagulopathies, or to medical procedures. Miscellaneous rare lesions include arachnoid cysts and ligamentous ossification. The nerve roots course through the epidural space, and are vulnerable to infection (meningitis) or inflammation there. The microscopic pathology of compression is reviewed here, because compression at the lateral neural foramena is the most common nerve root lesion, but the same pathological findings have been demonstrated after compression of the plexi and peripheral nerves. The two major effects of compression are to produce mechanical disruption and to cause ischemia. Disruption appears to be the most important factor in the genesis of pain from compression. Nerves and roots are well vascularized by extensively interconnecting vessels, and thus resistant to ischemia. Neural tissue can recover

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from several minutes of even total ischemia, but the briefest of compressions, such as to cervical nerve roots by hyperextension during an automobile injury (whiplash), can produce long-lasting mechanical damage. Furthermore, pathological patterns of compression-induced damage do not usually correspond to individual vascular territories. Although herniated nucleus pulposus is the most familiar cause of radicular compression, in most patients, degeneration of other parts of the “window frame” (foramen) contribute, including osteophytes (bone spurs) of the inferior or superior vertebral articular plates, vertebral misalignment (spondylolisthesis), thickened facet joints, and hypertrophy and redundancy of the dorsal longitudinal ligaments. Cadaver study has revealed that the vertebral artery can intrude into the lateral portion of the C2–3 neural foramen and contribute to C3 or lesser occipital neuralgia, which affects the neck, underside of the chin, or the scalp around the ear (Poletti, 1996). The mechanical effects of compressive disruption disproportionally affect the endoneurial fascicular contents, leaving the mechanically strong collagenous perineurium and epineurium intact. Intraneural blood vessels are also protected and usually remain intact, but chronic inflammation can lead to vascular proliferation and thickened vessel walls. The hallmark of compressive damage is that fascicles or nerve fibers closest to the outside of the compressed neural structure are more severely affected than nerve fibers at the nerve center. Although myelin disruption is easily visible using light microscopy, the effects on unmyelinated C-fibers are harder to characterize. Electron microscopy is required to quantify the density of nociceptive fibers, and to determine if these values are reduced. In severe longstanding cases, secondary pathological lesions can be noted including Wallerian degeneration of the ascending and descending long tracts. The nerve roots may be abnormally flattened and atrophied, adherent to thickened meninges, and there is overall axonal loss. Microscopically, signs of axonal degeneration and regeneration may be evident. Intrafascicular edema is common after compression, and causes endoneurial compression that persists after external compression is relieved. 31.2.6.2. Vasculitic lesions Diabetic and other vasculitides can produce painful truncal radiculopathy as well as involvement of nerves and plexi, as discussed earlier. This typically presents as a unilateral band of pain affecting the thorax or abdomen in the territory of one or a few sensory segments. If enough motor axons are damaged, muscle denervation can produce a focal abdominal bulge; this is rarely clinically significant but provides a helpful diagnostic clue. Evaluation of nerve biopsies shows

identical findings to those in the diabetic and idiopathic plexidites (vide supra). Vasculitic radiculopathies improve if the damaged axons can regenerate (Lauria et al., 1998), justifying immunosuppression with corticosteroids and cyclophosphamide, or intravenous immunoglobulin. 31.2.6.3. Chronic inflammation (Arachnoiditis) Any type of injury, infection or inflammation that affects the cerebrospinal fluid or arachnoid or pial membranes can damage nerve roots. Medical procedures, including spine surgery or intrathecal injections for diagnostic, anesthetic or therapeutic purposes, can contribute. Arachnoiditis, which can produce chronic pain (sometimes accompanied by motor or autonomic disturbances) of the pelvis and legs, usually does not develop until several months after the causative insult. Pathological study (and MRI) reveals thickening of the leptomeninges with adhesions that tether adjacent nerve roots. Within the roots, blood vessels with thickened walls, and occasional arachnoid cysts may be evident within this scarred tissue. Arachnoiditis damages the endoneurial fascicular contents by combinations of stretch, compression, and ischemic injury and chronic inflammation that produce axonal degeneration. 31.3. Pathological features of painful lesions affecting cranial primary afferent neurons; their peripheral axons, their ganglia or their central axons (cranial nerves and roots) Classical trigeminal neuralgia has been documented since the 19th century. Less known is the fact that damage to any of the other cranial nerves that contain somatosensory nociceptive axons (VII, IX, X) can also cause neuralgia. Other cranial neuralgias are sometimes misdiagnosed as trigeminal neuralgia, which can complicate treatment. Any cranial neuralgia can be caused by any type of lesion that damages peripheral cranial axons, or their nuclei, roots or central projections. Pathological study has revealed vascular lesions, multiple sclerosis, and neoplastic, infectious or degenerative diseases. Diagnostic imaging is indicated for new onset cranial neuralgias to identify potential structural causes (e.g. tumors). Lumbar puncture may be indicated to identify infectious or autoimmune causes. In many patients, no lesion will be identified. Because the central and peripheral processes of the cranial nerves are so spatially proximate, the same disease process can often affect more than one cranial nerve to give mixed or atypical presentations. Like spinal nerves, cranial nerves are vulnerable to acute compression by nerve root edema, or chronic compression by processes that narrow their bony foramina (e.g. meningiomas). Diseases of nearby

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major blood vessels are the best-known pathological cause of cranial neuralgias. 31.3.1. Anatomy and pathology of trigeminal (V) neuralgias The trigeminal (V) provides the major somatosensory innervation of the face, its paranasal sinuses, oral and nasal mucosal cavities, and the meninges of the anterior and middle cerebral fossae, as well as of the tentorium cerebelli. It is involved in migraine pathogenesis, which is not discussed in this chapter. Its ganglion, the Gasserian is located medially in a depression in the petrous temporal bone near the internal carotid artery and the cavernous sinus, and is therefore occasionally involved in cavernous sinus thrombosis or carotid–cavernous fistulae. The ganglion is somatotopically organized, and emits distally from its upper pole the ophthalmic or V1 division through the superior orbital fissure to innervate the front half of the scalp, the forehead and brow, and the middle part of the nose. From the middle portion, the maxillary or V2 division emerges from the foramen rotundum, and the mandibular or V3 division emerges from the foramen ovale to innervate the lower jaw. The ganglion is well protected and only rarely injured by trauma, most commonly fractures involving the base of the middle fossa, or the backward and medial rotation of the petrous tip of the temporal bone. Each division branches extensively. Because the ganglia of the different trigeminal divisions are physically conjoined, more than one division can be simultaneously involved by a single lesion. Different disease processes preferentially affect different divisional dermatomes; classical trigeminal neuralgia is most common in V2, and least common in V1 (Sindou et al., 2002), whereas herpes zoster, which has a predilection for the cranial part of sensory ganglia (Head and Campbell, 1900) most often affects the ophthalmic division (Watson et al., 1988). 31.3.1.1. Classical trigeminal neuralgia (tic douloureux) Anatomical observations by neurosurgeons have suggested that most patients with tic have mechanical compression, visible as indentation or flattening of the trigeminal roots. In a series of nearly 600 patients undergoing microvascular decompression for tic douloureux, such compression by blood vessels affected the trigeminal root entry zone in half the patients, the mid-third of the cranial nerve in half, and the distal end, or entry into Meckel’s cave, in 10% (Sindou et al., 2002). The superior cerebellar artery was the most common offender, implicated in 88% of patients, with the anterior–inferior cerebellar artery affecting 25%. In nearly 40% of patients, multiple vessels appeared to be involved. Other anatomical observations included arachnoiditis with

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local adhesions in 20% of patients, prominent petrous ridge that angulated the trigeminal root in about 10%, and a small posterior fossa in less than 5% (Sindou et al., 2002). One of the important findings of this study was the correlation between the circumferential site of the trigeminal root impingement and the location of the patient’s symptoms, providing a clinicopathological relationship. It must be remembered that surgical series contain patients with the most severe and typical symptoms, and thus findings may not be as marked in the population at large of all patients with trigeminal neuralgia (TN). See Chapter 38 for further details. Microscopic examination of anatomical features has been performed in trigeminal ganglion or root specimens from two dozen or more patients with TN, and attempts made to correlate the pathological, clinical and physiological features of the disease. Devor and colleagues (2002) examined biopsies of the trigeminal root from 12 patients with TN undergoing microvascular decompression, and demonstrated that the severity of microscopic pathology correlated with the severity of intra-operatively observed gross pathology (see Fig. 31.4). The most consistent finding was areas of demyelination that allow close apposition of “naked” axons. Several arguments suggest that demyelination may contribute to pain pathogenesis, and indeed the prototypic demyelinating disease, multiple sclerosis, is a well recognized cause of a minority of cases of TN (Gass et al., 1997). Symptoms caused by demyelination are far more reversible than those caused by axonal or neuronal death, and they are consistent with several features of tic, including a relapsing, remitting course, which leaves many patients with long symptom-free intervals, particularly early in the disease. Furthermore, the ability to initiate pain by lightly touching the facial trigger zone must involve low-threshold mechanical afferents, which are usually large-diameter myelinated axons. It has been proposed that demyelination contributes to ephaptic transmission, by allowing action potentials to jump laterally between adjacent demyelinated axons. However, some aspects of TN are hard to explain by demyelination alone. Demyelination usually begins in the paranodal regions, and the retraction of juxtanodal myelin exposes potassium channels and inhibits electrical transmission. Demyelination increases the capacitance and decreases the radial resistance of axons, thus slowing and reducing action potential propagation. Demyelination of more than three consecutive internodes usually produces conduction block. Furthermore, pain sensations are usually transmitted by unmyelinated, not myelinated, axons, at least in the periphery. Additionally, if pain sensations were transmitted

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Fig. 31.4. Electron micrograph demonstrating pathological changes in trigeminal root biopsies removed during microvascular decompression treatment of trigeminal neuralgia. A: central zone of demyelination, surrounded by detritus of degeneration (myelin debris, swollen axons on left). B: residual myelin sheath containing clusters of regenerating axon sprouts. C: a cluster of demyelinated axons in contact. Arrows show membrane-to-membrane contacts. Bars: A, 5 µm; B and C, 2 µm. Reproduced with permission from Devor et al., 2002 with permission from the Amercian Association of Neurological Surgeons.

between axons in close contact, the somatotopic organization of the trigeminal ganglion would result in pain being felt adjacent to the trigger area, yet this is often not the case. However, in a ganglion that has undergone repeated bouts of axonal injury and regeneration,

somatotopy may no longer be absolute. Other pathological findings described in tissue samples from patients with TN include patchy areas containing lesser degrees of myelin abnormalities, including clumps of myelin debris, and excessive collagen. Some areas had reduced

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axonal densities, or no axons at all, consistent with degeneration. No study has found active inflammation. It is possible that the good pain relief obtained from a number of surgical procedures reflects acute or chronic separation of nearby axons. The effects of even microvascular decompression are often evident immediately postoperatively, far too soon for a return to normal anatomy. One can speculate that they may reflect immediate postoperative intrafascicular edema, and that delayed effects of destructive procedures such as injection of alcohol or glycerol may be correlated with the development of intrafascicular fibrosis that reduces the abnormal spread of action potentials. Careful pathological study of well-characterized patients who have or have not had relief of pain from these procedures would be needed to test this hypothesis. The worst outcome of surgical procedures for the treatment of TN is anesthesia dolorosa, or pain that arises in a desensate part of the face. The pathological correlate of this is complete destruction of the axons or cell bodies. This complication was seen more in the past when destructive procedures, including complete rhizotomy or ganglionectomy, were common. 31.3.1.2. Atypical trigeminal neuralgia The next most common important cause of TN (called by some trigeminal neuropathy) is shingles, a lesion readily diagnosed in patients with a history of lesions in the same division as the pain (usually V1). Rare patients have zoster without any apparent cutaneous lesions (sine herpete) (Easton, 1970). Herpes simplex I or II is a far more common cause of facial vesicles (usually in or around the mouth in V2 or V3) than zoster, and can usually be distinguished from zoster by its recurrences, and fewer vesicles. In contrast to zoster, herpes simplex causes far less necrosis, and so rarely leaves scars, and very rarely causes neuralgia (Gonzales, 1992). 31.3.2. Anatomy and pathology of geniculate, or facial nerve (VII), neuralgias The facial nerve’s main function is motor, but it also provides somatosensory innervation to the external surface of the tympanic membrane, the outer ear canal, a piece of skin behind the ear, and an area of the cheek anterior to the ear including the tragus via the nervus intermedius. This area is variably sized, and in some patients, facial neuralgias affect half of the cheek and can be mistaken for V3 neuralgias. To differentiate between these, the clinician must look for evidence of involvement of other branches of V3 or of VII. Because VII and VIII run so closely together, patients with lesions of VII often have bystander damage to VIII, and vice versa. The cell bodies of nervus intermedius axons

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are located in the geniculate ganglion within the petrous bone; their central axons enter the brainstem and descend in the spinal tract of the trigeminal to synapse in the spinal portion of the trigeminal nucleus in the upper medulla. From there, second order neurons project to the contralateral ventral posterior nucleus of the thalamus. Third order neurons terminate in the postcentral somatosensory cortex and other areas. Lesions of any of these structures can produce geniculate neuralgias. Most geniculate, or nervus intermedius, neuralgias are caused by viruses, most commonly shingles (herpes zoster). In this uncommon presentation known as Ramsay Hunt syndrome, vesicles appear in the ear canal or outer ear, and acute facial weakness is common. Pathological changes include inflammatory CNS changes (DennyBrown et al., 1944). Impingement by ectatic vessels is another surgically treatable cause of geniculate neuralgia. 31.3.3. Anatomy and pathology of glossopharyngeal nerve (IX) neuralgias The glossopharyngeal nerve carries pain and temperature sensation (and probably touch) from the posterior third of the tongue, the internal surface of the tympanic membrane, and the pinna. It also has visceral sensory (carotid body) and special sensory (taste from the back third of the tongue) functions, as well as parasympathetic and motor functions. The cell bodies of these somatosensory axons are located in either the superior or inferior glossopharyngeal ganglia, and send their central axons to descend in the spinal trigeminal tract to terminate in the caudal portion of the nucleus. From there, second order neurons decussate in the medulla to project to the contralateral ventral posterior nucleus of the thalamus. Third order neurons terminate in the postcentral somatosensory cortex and other areas. IX, X and XI are closely associated, and so lesions of one often affect the other. Lesions that affect any of these structures can produce glossopharyngeal neuralgia. Many patients appear to have an artery compressing the nerve root as it exits the medulla and traverses the subarachnoid space to the jugular foramen. Tumors arising from the eighth nerve or jugular foramen can impinge on the ninth nerve. Neurinomas can arise within the glossopharyngeal nerve itself, or metastases or chordomas can compress it. Basal skull fractures, multiple sclerosis, or syringobulbia are other rare causes. Imaging can identify structural lesions including intramedullary or cerebellopontine-angle tumors, vascular malformations, or aneurysms. Lumbar puncture may be indicated if there is evidence of infection (tuberculosis, syphilis) or inflammation (Guillain–Barré syndrome). A history of vesicles on the anterior pillar of the fauces suggests

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shingles followed by postherpetic neuralgia (PHN), although vesicles of the posterior pharynx can go unperceived. Pain arising from glossopharyngeal neuralgia is usually perceived in the side of the throat, within the ear, or behind the angle of the jaw, and has similar clinical features to TN. Patients may have a trigger zone in the posterior oral cavity or throat, with pain triggered by touch, cough, swallowing, or tongue protrusion. Damage to the motor, visceral sensory, or autonomic fibers can impair palatal elevation, salivation, or taste, and produce cough. Dysphagia, disturbances of balance or hearing, and autonomic symptoms (including asystole), can accompany glossopharyngeal pain and influence treatment decisions. Glossopharyngeal damage often produces loss or reduction of the gag reflex on the affected side. Parts of the IX and X nerve surgically removed for therapeutic reasons have been carefully examined (Devor et al., 2002). This procedure only provided partial pain relief, and produced new pain that was treated by further ablative neurosurgical procedures. The nerves had only minimal damage, affecting less than 20% of axons. A few superficial areas of complete demyelination were present, where many demyelinated and unmyelinated axons were closely apposed without intervening glial processes. Scattered axons exhibited less severe abnormalities including intramyelinic edema. 31.3.4. Anatomy and pathology of vagus nerve (X) neuralgias The vagus is a primarily motor, parasympathetic and visceral sensory nerve but it also transmits pain, touch, and temperature from the larynx, pharynx, part of the external ear (pinna), and the external tympanic membrane and ear canal, and the meninges of the posterior fossa. Peripheral axons travel via the recurrent laryngeal nerve (from the vocal folds and lower larynx), the internal laryngeal nerve (upper larynx), and the auricular branch (from the ear). Cell bodies from the laryngeal nerves are located in the inferior vagal ganglion, while those from the ear are located in the superior vagal ganglion. Central axons descend in the spinal trigeminal tract to synapse in its nucleus, second order axons project to the contralateral ventral posterior thalamus, and third order neurons project through the internal capsule to the somatosensory cortex and other targets. Lesions of these structures are a rare cause of cranial neuralgias that usually present as lancinating pains perceived in the angle of the jaw, or less commonly the ear. The trigger zone is most commonly in the larynx, so pain can be triggered by talking, swallowing, yawning or coughing. A characteristic symptom is chronic hiccups (singultus).

31.4. Conclusions Pathological understanding of painful nerve injuries is primitive compared to the knowledge of other neurological conditions. Understanding the normal and pathological anatomy of pain will be necessary for the pain field to move beyond palliative treatments to devise preventions and cures. Pain specialists need to begin to routinely seek autopsy study of their patients, and existing or new tissue repositories should be organized to gather clinical information and pathological tissues pertinent to neuropathic pain. A particular push should be made to confirm or refute the presence in patients of changes described in animal models. The following summarizes what is known to date. 31.4.1. Proven anatomical markers of neuralgia For an injury or disease to produce neuralgic pain, it is now certain that it must specifically damage the subset of peripheral and/or central neurons responsible for nociception and pain perception. Neuropathic pain is clearly associated with reduced nociceptive innervation of painful skin. Skin biopsies have demonstrated losses of cutaneous nociceptive innervation in every neuropathic pain syndrome studied. Neuropathic pain has proved far more often associated with partial than total nerve injuries such as major nerve transection or limb amputation. This is most evident in complex regional pain syndrome type I, where nerve injuries can be so minor [e.g. to superficial sensory branches of the forearm after needle puncture at the antecubital fossa (Horowitz, 2000)] as to go clinically undetected. An important question that follows is whether conversion of partial to total nerve injuries can relieve neuralgic pain. This has been posited to explain cases of spontaneous resolution of diabetic neuropathy pain as the condition progresses. 31.4.2. Possible anatomical markers of neuralgia Several anatomical abnormalities have been strongly associated with the presence of pain after nerve injury, rather than being a nonspecific sequel of the underlying injury itself. The most convincing human data come from comparing patients with and without pain (postherpetic neuralgia or PHN) after shingles. To summarize information presented in more detail in Chapter 44, three anatomical abnormalities have been specifically associated with the presence of PHN pain after zoster: greater severity of loss of nociceptive axons (Oaklander et al., 1998; Oaklander, 2001), atrophy of the dorsal horn of the spinal cord (Watson et al., 1991), and the presence of partial loss of axonal markers at the

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“mirror-image” contralesional site (Oaklander et al., 1998). It is unclear whether these changes are specific for PHN, or are more-widespread biomarkers of neuralgia. Pain in diabetic neuropathy is also associated with worse nociceptive neurite loss (Dyck et al., 1976; Holland et al., 1997). 31.4.3. Potential anatomical markers of neuralgia Since only rare neural injury patients are left with chronic pain, injury to nociceptive neurons alone is not sufficient. Perhaps only those peripheral nociceptive injuries that also cause CNS changes cause chronic pain. This is likely for stimulus-independent pain in PHN, which can be considered a “phantom skin pain” because it ensues only in patients left with less than 25% of normal innervation (Oaklander, 2001). The ability of loss of primary afferent neurons to increase electrical activity of their postsynaptic CNS targets is wellestablished. In the auditory system, hearing loss due to death of hair cells or VIII nerve damage up-regulates activity of the 2nd order sensory neurons in the dorsal cochlear nucleus (e.g. denervation supersensitivity). This “turning up the gain” maintains function in the face of injury, but if too many afferents degenerate, spontaneous electrical activity of the dorsal cochlear nucleus leads to the perception of sound (tinnitus) even when there are no incoming signals (Jastreboff, 1990). This phenomenon also occurs in the visual system (visual hallucinations after retinal or optic nerve damage), as the Charles Bonnet syndrome (Schultz and Melzack, 1991). Corresponding dorsal horn hyperexcitability has been documented in patients with painful peripheral lesions (Loeser et al., 1968). There are several ways that loss of nociceptive afferent input can increase electrical activity postsynaptically, one is down-regulation of GABAergic inhibitory interneurons (Moore et al., 2002). Mechanical allodynia (pain triggered by innocuous touch) requires functional synapses between low threshold mechanoreceptors and central nociceptive neurons. These are not normally in evidence. The spinal cord terminals of primary afferents are topographically ordered with different sensory functions segregated into different dorsal horn laminae: low-threshold mechanoreceptors synapse in laminae III and IV and highthreshold mechanical nociceptors in laminae I, II and V. Woolf and co-workers (1992) reported that after sural nerve axotomy in rats, regenerating central axons of myelinated afferents, including large A-β fibers that transmit touch, sprout into superficial lamina II, a primary origin of projection pain neurons. A follow-up rat experiment that used common-sciatic transection (which does not usually cause mechanical allodynia)

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failed to find such sprouting (Hughes et al., 2003). The conclusions of both studies are limited by failure to document the presence or absence of mechanical allodynia in studied rats, and lack of information about which somatotopic area of the dorsal horn was studied. For instance, totally axotomy of sciatic branches usually produces allodynia in the territory of the plantar hindpaw innervated by adjacent uninjured nerve branches, but not in the part of the plantar hindpaw innervated by the cut nerve, which is desensate (Decosterd and Woolf, 2000). Further experiments that compare dorsal-horn axonal plasticity between rats with or without mechanical allodynia after identical nerve injuries might be helpful. The contralesional effects of unilateral neuralgic peripheral injuries offer additional evidence that peripheral injuries must affect the CNS to cause pain. Since there is no direct connection between primary afferents that innervate the right and left halves of the body, the existence of these effects (Koltzenburg et al., 1999) requires CNS involvement. Contralesional anatomical changes, though incompletely understood, appear specifically associated with those nerve injuries that cause chronic pain (Oaklander et al., 1998). I close by reiterating several tasks including more anatomical study of animal models of pain. To identify pain-specific changes, animals without neuralgia need to be studied as well. Pathological examination of tissues from pain patients needs to be performed more often. The development of less-invasive surrogate markers of anatomical changes, such as functional imaging (see Chapter 32) or measurements of axonal reflex flares, will help. References Amato AA, Oaklander AL (2004). Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 16-2004. A 76-year-old woman with pain and numbness in the legs and feet. N Engl J Med 350: 2181–2189. Asbury AK, Fields HL (1984). Pain due to peripheral nerve damage: an hypothesis. Neurology 34: 1587–1590. Aszmann OC, Kress KM, Dellon AL (2000). Results of decompression of peripheral nerves in diabetics: a prospective, blinded study. Plast Reconstr Surg 106: 816–822. Braus DF, Krauss JK, Strobel J (1994). The shoulder– hand syndrome after stroke: a prospective clinical trial. Ann Neurol 36: 728–733. Britland ST, Young RJ, Sharma AK, Clarke BF (1990). Association of painful and painless diabetic polyneuropathy with different patterns of nerve fiber degeneration and regeneration. Diabetes 39: 898–908. Brown MJ, Martin JR, Asbury AK (1976). Painful diabetic neuropathy. A morphometric study. Arch Neurol 33: 164–171.

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A

B

Figure 31.2. PGP9.5-immunolabeled axonal endings in biopsies from normal human skin (A) and skin from a patient with painful small-fiber neuropathy (B). Skin biopsies from the distal leg were vertically sectioned and immunolabeled. Individual neurites and neurite bundles are visible within the epidermis and superficial dermis, respectively. The epidermis from normal skin (A) is thicker and more densely innervated than that from the subject with neuropathic pain (B), whose neurites are fewer and fragmented. (See page 466.)

Figure 31.3. CD45-immunolabeled section from trigeminal ganglion obtained at autopsy from patient with Sjögren’s disease and facial pain. This marker of lymphocyte common antigen highlights increased lymphocytes. Photograph by TimRasmus Kiehl M.D. (See page 471.)