V
Vagal Input and Descending Modulation
C
INDYL. T
HURSTON-S
TANFIELD1, A
LANR
ANDICH21
University of South Alabama, Mobile, AL, USA
2
University of Alabama, Birmingham, AL, USA cthursto@usouthal.edu, arandich@uab.edu
Synonyms
Vagal Stimulation Produced Antinociception; Vagally- Mediated Analgesia; Vagally-Mediated Hyperalgesia Definition
Input from vagal afferents to neurons in the brain that control spinal nociceptive transmission. The vagus nerve (cranial nerve X) contains both afferent and efferent fibers that innervate viscera throughout the body. Activation of certain vagal afferents produces
antinociception, whereas activation of others pro- duces
hyperalgesia. Both the antinociception and hyperalgesia result from altering neural activity in cer- tain areas of the brain. These brain regions, through a descending pathway, then alter communication be- tween
primary afferent neurons and
spinothalamic neurons.
Characteristics
Activation of a number of regions in the brainstem pro- duces antinociception, as evidenced by either the atten- uation/absence of behavioral responses to noxious stim- uli, or decreases in the responses of spinal/trigeminal dorsal horn neurons to noxious stimuli. Studies that are more recent indicate that some of these same regions can also produce hyperalgesia, when activated by either dif- ferent types of stimuli or different intensities of electri- cal stimulation. These descending inhibitory and facili- tatory pain-modulating systems are affected by a variety of input, including signals generated by visceral stim- uli and transmitted to the central nervous system by va- gal afferents. Vagal afferents transmit signals from the esophagus, lower airways, heart, gastrointestinal tract, liver, gallbladder, and pancreas to the
nucleus tractus solitarius in the medulla oblongata.
Electrical, pharmacological, and physiological activa- tion of either cervical or subdiaphragmatic vagal affer-
ents alters nociception, by activating these central de- scending pain modulatory systems. Analogous to cen- tral stimulation, activation of vagal afferents can either facilitate or inhibit nociception. For example, electrical stimulation of vagal afferents has been shown to both facilitate and attenuate nociception, depending on the intensity of stimulation.
In rats, low intensity electrical stimulation of cervical vagal afferents facilitates the nociceptive tail flick reflex, and enhances noxious heat-evoked responses in spinal cord dorsal horn neurons (Randich and Gebhart 1992).
High intensity electrical stimulation of cervical or sub- diaphragmatic vagal afferents has the opposite effect, inhibiting the tail flick reflex, decreasing formalin- induced nociceptive behavior, attenuating heat-evoked responses in spinal cord dorsal horn neurons, and de- creasing formalin-induced Fos expression in trigeminal nuclei (Bohotin et al. 2003; Randich and Gebhart 1992;
Ren et al. 1993; Tanimoto et al. 2002, Thurston and Randich 1992). In humans, electrical stimulation of the cervical vagus has been shown to either decrease the thermal pain threshold (Ness et al. 2000), or have no effect on thermal pain and decrease the intensity of tonic pressure pain perception (Kirchner et al. 2000).
Pharmacological activation of vagal afferents, with intravenous administration of serotonin or low dose opioids, also inhibits spinal nociceptive reflexes and the response of spinothalamic neurons to noxious stimuli (Meller et al. 1992; Randich et al. 1993). The opioids that support a vagally-induced antinociception include morphine, (D-Ala
2)-methionine enkephalinamide, and DAGO, all mu agonists (Randich et al. 1993).
Certain stimuli that reproduce normal physiological
activation of vagal afferents produce either antinoci-
ception or hyperalgesia. Volume expansion produces
a vagally-mediated attenuation of nociceptive reflexes
and inhibition of trigeminal neuronal responses to a
noxious stimulus (Takeda et al. 2002). In a model of in-
flammation, bradykinin-induced plasma extravasation
and hyperalgesia are enhanced by subdiaphragmatic
vagotomy, indicating that subdiaphragmatic vagal
afferent activity normally suppresses these inflamma-
tory responses (Miao et al. 2001). In these same studies,
subdiaphragmatic vagotomy decreased paw withdrawal
thresholds in untreated rats, also indicating an attenua-
tion of nociception by tonic vagal activity. In terms of
2600 Vagal Input and Descending Modulation
Vagal Input and Descending Modulation, Figure 1 Vagal input to descending pain inhibitory systems in the nucleus raphe magnus and locus coeruleus.
Ascending pathways are shown on the left. Vagal afferents terminate in the nucleus tractus solitarius (NTS).
Pathways from the NTS to the nucleus raphe magnus (NRM) and locus coeruleus (LC) are unknown, but both regions are necessary for vagally-mediated antinociception.
Descending pathways are shown on the right. Activation of vagal afferents results in the spinal release of serotonin (5-HT), norepinephrine (NE), and opioids, which inhibits transmission between the primary afferent and spinothalamic neurons (not shown).
hyperalgesia, both lipopolysaccharide-induced illness and fasting produce a hyperalgesia that is reversed by subdiaphragmatic vagotomy (Khasar et al. 2003;
Watkins et al. 1995). The illness-induced hyperalgesia can also be attenuated by the more selective resection of the hepatic branch of the vagus (Watkins et al. 1995).
Much of the circuitry, whereby activation of vagal affer-
ents attenuates nociception, has been established (see
Fig. 1). Attenuation of nociception requires activation
of vagal
C Fiber, possibly associated with
Visceral
Nociception and Pain (Ren et al. 1993). Some of the
neural substrates mediating vagally-induced attenua-
V
Vaginismus and Dyspareunia 2601
tion of nociception include the nucleus tractus solitarius (NTS), the
nucleus raphe magnus (NRM), the
locus coeruleus (LC), and a descending spinal pathway in the
dorsolateral funiculus (Miao et al. 2001; Randich and Gebhart 1992; Thurston and Randich 1992; Thurston- Stanfield et al. 1999). Neurons descending from the nucleus raphe magnus and locus coeruleus are hypoth- esized to release serotonin (5-HT) and norepinephrine (NE), respectively, and cause the local release of opi- oids (Randich and Gebhart 1992). These actions block the transmission of a nociceptive signal between the primary afferent neuron and the spinothalamic neuron.
The neural substrates that mediate vagal afferent- induced facilitation of nociception are not as well established, and tend to vary according to the stim- ulus that activates the vagus. For example, electrical stimulation-induced hyperalgesia likely requires thinly- myelinated A fibers, forebrain structures, and the spinal
ventrolateral funiculus, but not the nucleus raphe magnus, or locus coeruleus (Randich and Gebhart 1992; Ren et al. 1993). Studies suggest that vagal stim- ulation facilitates nociception through spinal actions of opioids and serotonin, acting at kappa opioid and 5-HT
1receptor types, respectively (Ren et al. 1991). In con- trast, illness-induced hyperalgesia requires the nucleus raphe magnus and dorsolateral funiculus (Watkins et al. 1995).
Clearly, vagal input has complex influences on descend- ing pain modulation. The complexity is partly related to the numerous visceral terminal fields innervated by the vagus, the diversity of functions served by those viscera, and the need to understand both visceral pain and mod- ulation of visceral pain in general. The importance of these findings is a better understanding of natural stim- uli that can activate the endogenous analgesia systems, and how these systems work under normal and patho- logical conditions.
References
1. Bohotin C, Scholsem M, Multon S et al. (2003) Vagus Nerve Stimulation in Awake Rats Reduces Formalin-Induced Nocicep- tive Behavior and Fos-Immunoreactivity in Trigeminal Nucleus Caudalis. Pain 101:3–12
2. Khasar SG, Reichling DB, Green PG et al. (2003) Fasting is a Physiological Stimulus of Vagus-Mediated Enhancement of Nociception in the Female Rat. Neurosci 119:215–221 3. Kirchner A, Birklein F, Stefan H et al. (2000) Left Vagus Nerve
Stimulation Suppresses Experimentally Induced Pain. Neurol 55:1167–1171
4. Meller ST, Lewis SJ, Brody MJ et al. (1992) Vagal Afferent- Mediated Inhibition of a Nociceptive Reflex by I.V. Serotonin in the Rat. II. Role of 5-HT receptor subtypes. Brain Res 585:71–86 5. Miao, FJ-P, Janig W, Jasmin L et al. (2001) Spino-Bulbo- Spinal Pathway Mediating Vagal Modulation of Nociceptive- Neuroendocrine Control of Inflammation in the Rat. J Physiol 532:811–822
6. Ness TJ, Fillingim RB, Randich A, Backensto EM, Faught E (2000) Low Intensity Vagal Nerve Stimulation Lowers Human Thermal Pain Thresholds. Pain 86:81–85
7. Randich A, Gebhart GF (1992) Vagal Afferent Modulation of Nociception. Brain Res Rev 17:77–99
8. Randich A, Robertson JD, Willingham T (1993) The Use of Spe- cific Opioid Agonists and Antagonists to Delineate the Vagally Mediated Antinociceptive and Cardiovascular Effects of Intra- venous Morphine. Brain Res 603:186–200
9. Ren K, Randich A, Gebhart GF (1991) Spinal Serotonergic and Kappa Opioid Receptors Mediate Facilitation of the Tail Flick Reflex Produced by Vagal Afferent Stimulation. Pain 45:321–329 10. Ren K, Zhuo M, Randich A, Gebhart GF (1993) Vagal Affer- ent Stimulation-Produced Effects on Nociception in Capsaicin- Treated Rats. J. Neurophysiol 69:1530–1540
11. Takeda M, Tanimoto T, Nashikawa T et al. (2002) Volume Ex- pansion Suppresses the Tooth-Pulp Evoked Jaw-Opening Reflex Related Activity of Trigeminal Neurons in Rats. Brain Res Bull 58:83–89
12. Tanimoto T, Takeda M, Matsumoto S (2002) Suppressive Effect of Vagal Afferents on Cervical Dorsal Horn Neurons Responding to Tooth Pulp Electrical Stimulation in the Rat. Exp. Brain Res 145:468–479
13. Thurston CL, Randich A (1992) Electrical Stimulation of the Subdiaphragmatic Vagus in Rats: Inhibition of Heat-Evoked Re- sponses of Spinal Dorsal Horn Neurons and Central Substrates Mediating Inhibition of the Nociceptive Tail Flick Reflex. Pain 51:349–365
14. Thurston-Stanfield CL, Ranieri JT, Vallabhapurapu R et al.
(1999) Role of Vagal Afferents and the Rostral Ventral Medulla in Intravenous Serotonin-Induced Changes in Nociception and Arterial Blood Pressure. Physiol Behav 67:753–767
15. Watkins LR, Maier SF, Goehler LE (1995) Immune Activation:
The Role of Pro-Inflammatory Cytokines in Inflammation, Illness Responses and Pathological Pain States. Pain 63:289–302
Vagal Stimulation Produced Antinociception
Vagal Input and Descending Modulation
Vagally-Mediated Analgesia
Vagal Input and Descending Modulation
Vagally-Mediated Hyperalgesia
Vagal Input and Descending Modulation
Vaginal Hyperalgesia Model
Visceral Pain Models, Female Reproductive Organ Pain
Vaginismus and Dyspareunia
Dyspareunia and Vaginismus
2602 Vague, Strange Feeling
Vague, Strange Feeling
Definition
Responses in the bowel without pain, these include dis- comfort, weak feelings.
Morphology, Intraspinal Organization of Visceral Af- ferents
Valdecoxib
Definition
(trade name: Bextra). Valdecoxib is a COX–2 inhibitor that is more selective for COX–2 than celecoxib. In ad- dition to the risk of myocardial infarction, it carries the risk of serious skin reactions and its sales have been sus- pended.
Cyclooxygenases in Biology and Disease
Validity
D
AVIDV
IVIANMetro Spinal Clinic, Caulfield, VIC, Australia dvivian@metrospinal.com.au
Definition
Validity is the measure of the extent to which a diag- nostic test actually does what it is supposed to do, i.e.
how well it actually detects the condition it is supposed to detect. The term is derived from the Latin – validus, meaning strong or robust.
Characteristics
Validity is determined by correlating the results of a test with those of a reference standard, known as the crite- rion standard, or formerly known as the “gold standard”.
The criterion standard differs according to the test whose validity is being sought. The essential feature of a cri- terion standard is that, by consensus, it provides a more direct observation of the abnormality in question than the test in question and is, therefore, less susceptible to error. Moreover, the criterion standard must use meth- ods independent of those used by the test in question.
For clinical tests, such as those that rely on palpation, the criterion standard may be a radiographic finding, a post-mortem finding, or an observation at surgery, for these standards are less susceptible to error than palpa- tion through skin and muscle, and rely on vision rather than touch.
Sometimes, when a criterion standard is not available, investigators have used a consensus view of a panel of experts, who determine whether or not the index con- dition is present, as the criterion standard. However, if
Validity, Table 1 The structure of a 2× 2 contingency table comparing the results of a diagnostic test with those of a criterion standard.
Criterion Standard
Result of Test Positive Negative
Positive a b
Negative c d
those experts establish their diagnosis using the same or similar tests as the one in question, they are not assessing validity. Rather, theirs is a test of
reliability, for they are measuring the extent to which two observers using the same test agree on the results.
Validity is determined by subjecting the same sample of patients to the test in question and to the criterion stan- dard. The results of this exercise can be summarised in a 2 × 2 contingency table, from which numerical indices of validity can be calculated (Table 1). Four cells are gen- erated, in which ’a’ is the number of cases in which the test and the criterion standard are both positive (i.e. both tests agree that the condition was present); ’b’ is the num- ber of cases in which the test was positive but the criterion standard was negative (i.e. the condition was not present despite the test being positive); ’c’ is the number of cases in which the test was negative but the criterion standard was positive (i.e. the condition was present but the test missed it); and ’d’ is the number of cases in which the test and the criterion standard were both negative (i.e.
both tests agreed that the condition was absent).
Clearly, the ’a’ and ’d’ cases are correct results of the test, but the ’b’ and ’c’ cases are mistakes. In the ’b’ cases, the test was positive but should not have been. Those results are false-positive. In the ’c’ cases the test was negative, but should not have been (false-negative). A good test is one that carries few, if any, false-positive and false-negative results. From the contingency table, two fundamental values can be derived. These stem from the columns under criterion standard.
The
sensitivity of the test measures how well it detects the condition when the condition is present (Sackett et al. 1991). It is derived down the first column. Numeri- cally it is the ratio: a / (a+c). Idiomatically, it is the ratio between the number of true-positive results and all pos- itive cases. This ratio constitutes the true-positive rate.
The
specificity of the test measures how well it ex- cludes the condition when the condition is absent (Sack- ett et al. 1991). It is derived up the second column. Nu- merically it is the ratio: d / (b+d). Idiomatically it is the ratio between the number of true negative results and all negative cases, and constitutes the true-negative rate. Its complement, b / (b+d), i.e. [1 – specificity], is the false- negative rate.
A valid test is one with high sensitivity and high speci-
ficity. The validity of the test is compromised if either
of these indices are low.
V
Vanilloid Receptor, Regulation by Protons 2603
From the sensitivity and the specificity, a single measure of the validity of a test can be derived. It is the positive likelihood ratio, which indicates how often positive re- sults of the test are truly positive. Idiomatically, the pos- itive likelihood ratio is the true-positive rate discounted by the false-positive rate, and is defined as (true-positive rate) / (false-positive rate). Numerically it is (sensitiv- ity) / (1 – specificity) (Sackett et al. 1991).
The virtue of the positive likelihood ratio is that it reveals the extent to which confidence in diagnosis is increased by a positive result of the diagnostic test. This can be quantified from the relationship:
(prevalence odds) × (positive likelihood ratio) = (diag- nostic confidence odds)
where prevalence odds are the pre-test likelihood that the condition is present, expressed as odds; and diagnostic confidence odds is the post-test likelihood that the con- dition is present, expressed as odds (Sackett et al. 1991).
Odds, instead of percentages, are used in order for the equation to work mathematically (Bogduk 1999). If the prevalence of a condition is 40%, the odds that it is present are 40:60, i.e. 40:(100-40). If the diagnos- tic confidence odds are 8:2, the diagnostic confidence is 80%, i.e. 8 / (8+2).
If a diagnostic test has a positive likelihood ratio of 1.0, the test has no validity. From the equation it can be seen that applying the test does not improve diagnostic con- fidence. The odds after the test are the same as before the test.
For a test to be valid, the positive likelihood ratio must be substantially greater than 1.0. Exactly by how much greater it has to be depends on the prevalence of the con- dition and the diagnostic confidence required. As a rule, if the condition is common, the positive likelihood ratio needs only to be modestly large. If the condition is rare, the positive likelihood ratio must be extremely large. If greater diagnostic confidence is required or desired, the test must have a proportionately larger positive likeli- hood ratio.
If the natural prevalence of a condition is, say, 40%, and one wants to be 80% confident in the diagnosis, the value required of the positive likelihood ratio (PLR) can be derived:
40:60 × PLR = 80:20 PLR = 6
Thus, for a condition with a prevalence of 40%, if the de- sired diagnostic confidence is 80%, a test is sufficiently valid if its positive likelihood ratio is 6 or more. A test whose positive likelihood ratio is less than 6 lacks suf- ficient validity to serve the purpose required.
If the natural prevalence of a condition is, say 10%, and one wants to be 80% confident in the diagnosis, the value required of the positive likelihood ratio is different:
10:90 × PLR = 80:20 PLR = 36
Thus, in this example, a much larger positive likelihood ratio is required. This arises because of the lower preva- lence of the condition being sought.
When the condition in question is uncommon, patients who do not have the condition, but who might neverthe- less generate a positive result, outnumber those patients who do have the condition. This increases the chances of a false-positive result. To overcome this false-positive rate, a large positive likelihood ratio is required.
As a general rule, tests that have a positive likelihood ratio with a magnitude of the order of 1.0 or 2.0 have little or no useful validity. Few clinical tests in pain medicine exceed these values. Consequently, few tests are valid.
Disability Assessment, Psychological / Psychiatric Evaluation
Multiaxial Assessment of Pain
Oswestry Disability Index
Pain Assessment in Children
Pain Assessment in Neonates
Pain Inventories
Whiplash
References
1. Bogduk N (1999) Truth in Musculoskeletal Medicine. Truth in Diagnosis – Validity. Australasian Musculoskeletal Medicine 4:32–39
2. Sackett DL, Haynes RB, Guyatt GH, Tugwell P (1991) Clinical Epidemiology. A Basic Science for Clinical Medicine, 2ndedn.
Little, Brown & Co, Boston, pp 119–139
Valsalva Maneuver
Definition
The Valsalva Maneuver consists of a forced expiration against a closed glottis and nasal airway. This obstructs venous return to the heart and increases intrathoracic and intra-cranial pressure.
Primary Cough Headache
Primary Exertional Headache
Valsalva Manoeuvre Headache
Primary Cough Headache
Vanilloid Receptor, Regulation by NGF
TRPV1, Regulation by Nerve Growth Factor
Vanilloid Receptor, Regulation by Protons
TRPV1, Regulation by Protons
2604 Vanilloid Receptor Subtype 1
Vanilloid Receptor Subtype 1
Capsaicin Receptor
TRPV1
TRPV1 Receptor, Species Variability
Vanilloids
Definition
Vanilloids are a group of compounds containing a vanillyl residue. Most data exists about capsaicin, the pungent substance in hot pepper varieties. Vanilloids act by stimulating certain transient receptor potentials (TRPV1) on nociceptive afferent neurons, cation chan- nels that are also opened by noxious heat or acidic pH.
Neuropeptide Release in the Skin
VAP
Ventral Amygdaloid Pathway
Varicosities
Definition
The terminals of unmyelinated axons bear a number of swellings called varicosities that contain accumulations of mitochondria, small and large synaptic vesicles and other organelles. The small vesicles contain neurotrans- mitter agents, while the large vesicles also contain neu- ropeptides. The varicosities are the sites of transmitter release, although the probability of release of the con- tents of one vesicle from a single varicosity is normally very low (<0.001).
Sympathetic and Sensory Neurons after Nerve Le- sions, Structural Basis for Interactions
VAS
Visual Analog Scale
Vasa Nervorum
Definition
Blood vessels supplying, and located within, a nerve trunk.
Neuropathic Pain Model, Diabetic Neuropathy Model
Vascular Compression Syndromes
Definition
Vascular compression of the cranial nerves leading to syndromes characterized by increased neuronal activity such as spontaneous pain (this entry) or muscle spasm, i.e. hemifacial spasm or twisting neck movements known as torticollis.
Trigeminal, Glossopharyngeal, and Geniculate Neu- ralgias
Vascular Hypertrophy
Sympathetic and Sensory Neurons after Nerve Le- sions, Structural Basis for Interactions
Vascular Neuropathies
C
LAUDIAS
OMMERDepartment of Neurology, University of Würzburg, Würzburg, Germany
sommer@mail.uni-wuerzburg.de
Synonyms
Ischemic Neuropathies; vasculitic neuropathies Definition
Neuropathies caused by malfunction of nerve blood ves- sels.
Characteristics
Neuropathies in Peripheral Arterial Occlusive Disease (PAOD)
Peripheral nerve function depends on an adequate
blood supply. Since peripheral nerves have a dual blood
supply (an intrinsic system consisting of longitudinal
microvessels within the endoneurium and an extrinsic
system of regional arteries, arterioles, venules, and
epineurial vessels, in addition, extensive anastomos-
ing), peripheral nerves are relatively protected from
ischemic injury (Nukada et al. 1993). However, acute
ischemia leads to axonal nerve damage (Wilbourn et
al. 1983). In chronic endoneurial ischemia, histological
studies of nerves show signs of axonal pathology, and
signs of
demyelination have been reported (Chalk
and Dyck 1993). Furthermore, there is a correlation
between the severity of nerve damage and the stage of
the vascular insufficiency (Laghi Pasini et al. 1996). By
definition, activity-induced or resting pain is a prevalent
symptom in patients with PAOD. Few studies have tried
to distinguish between ischemic and neuropathic pain
in these patients. In one study, paresthesias, indicating
neuropathic pain, were present in about 50% of patients
with
Peripheral Arterial Occlusive Disease (PAOD).
V
Vascular Neuropathies 2605
Since the patients’ symptoms are usually dominated by activity-dependent pain, and restrictions in activity are associated with vascular
claudication, the neu- ropathic component receives less attention and often does not require separate treatment (Weber and Ziegler 2002). In a study of 19 patients with PAOD, equally non- neuropathic and local causes of pain (superficial skin ulceration, osteomyelitis, and claudication) dominated the patient’s concern and attention. Pain symptoms attributed to the neuropathy were rest pain in the toes or foot (58%), numbness (58%), burning (42%), and paresthesias (37%) (Weinberg et al. 2001). Trophic skin changes may be caused by both the arterial disease itself and by the neuropathy. Treatment is aimed at improvement of blood flow.
Diabetes being the most common cause of small ves- sel disease in industrialized societies, PAOD is often caused by or associated with diabetic complications.
Diabetes leads to a multifactorial neuropathy by itself (see
diabetic neuropathies), which may be enhanced by ischemia due to small vessel occlusion.
Vasculitic Neuropathies
Vasculitic neuropathies are immune mediated diseases of the peripheral nervous system, in which inflamma- tion of the blood vessels causes damage to the nerves.
Vasculitismay be part of a systemic disease in primary systemic vasculitis or in
connective tissue diseases, or may be an isolated phenomenon in peripheral nerves, called non-systemic vasculitic neuropathy (NSVN). The typical clinical picture consists of an asymmetric or mul- tifocal, painful sensorimotor neuropathy with an acute, subacute or chronic course and acute relapses. However, vasculitis can also cause a rather unspecific syndrome of distal symmetric, sensorimotor neuropathy.
Systemic vasculitis has an incidence of 4/100,000 per year and, untreated, has a poor prognosis, which is greatly improved by the use of immunosuppres- sive treatment. The prognosis of NSVN is gener- ally better, although many patients need long-term
immunosuppression.
Primary systemic vasculitis and secondary vasculi- tis in connective tissue diseases has been classified in different ways, the latest generally accepted clas- sification being the one of the Chapel Hill Consen- sus Conference in 1994 (Jennette et al. 1994), which groups diseases according to the size of the affected arteries. Neuropathies are a frequent manifestation in polyarteritis nodosa, in Wegener’s granulomatosis and Churg-Strauss-syndrome, in Sjögren’s syndrome, and in rheumatoid arthritis. Stage II and III borreliosis may also lead to vasculitic neuropathy. Hepatitis B and C may be associated with cryoglobulinemic vasculitic neuropathy. Malignant tumors may rarely cause vas- culitic neuropathy as a paraneoplastic syndrome. One third of the patients coming to attention with vasculitic neuropathy have isolated peripheral nerve vasculitis.
Vascular Neuropathies, Figure 1 (a) Frozen section from a sural nerve biopsy specimen from a patient with isolated peripheral nerve vasculi- tis, immunostained for T-cells. Note dense infiltration of the vessel wall.
(b) Paraffin section from a sural nerve biopsy specimen from a patient with isolated peripheral nerve vasculitis, elastica-van-Gieson stain. Note narrowing of vessel lumen and perivascular infiltrates. Bar = 10μm.
A diagnosis of definite vasculitis can be made with evidence of vasculitis in a biopsy specimen (Fig. 1);
histologic criteria for this diagnosis have been defined (Collins et al. 2000).
The neuropathy in vasculitis is partially caused by is- chemia, partially due to direct inflammatory damage of the nerves. Endothelial cells have antigen presenting capacities, they express adhesion molecules which then recruit inflammatory cells. Immunoglobulin complex deposits in the vessel walls may trigger the activation of the complement system, and generate chemotactic factors attracting granulocytes. These further produce
cytokines, prostaglandins,
metalloproteases and
perforin, leading to tissue damage and sensitization
of nerve fibers (Kissel 2001; Satoi et al. 1998). The
expression of proinflammatory cytokines in peripheral
nerves is increased in most vasculitic neuropathies,
and in particular in specimens from patients in whom
pain is a prominent symptom (Lindenlaub and Sommer
2606 Vascular Orofacial Pain
2003). Nerve growth factor (NGF) has also been im- plied as a pain-inducing factor in vasculitic neuropathies (Yamamoto et al. 2003).
Thus, in the vasculitic neuropathies, pain is thought to be induced by a combination of axonal injury and in- flammatory changes. Changes induced directly through axonal injury are, for example, the altered distribution of sodium channels. In addition, the release of inflam- matory mediators in the vicinity of the nerve fibers is increased. Inflammatory mediators, in particular in combination (‘inflammatory soup’), are known to in- crease the excitability of nociceptors, and even more so of those that have suffered an injury (Michaelis et al. 1998; Schäfers et al. 2003). This may be a reason why pain and paresthesias are usually the first symp- toms to respond to treatment with corticosteroids in patients with vasculitic neuropathies. However, many patients still need symptomatic treatment for pain, at least temporarily.
Treatment of the underlying disorders consists of im- munosuppression, to which most patients respond. De- pending on the severity of the disorder and on general organ involvement, treatment may consist of a combi- nation of corticosteroids with
cyclophosphamide or methotrexate. After achievement of remission, in gen- eral after 6–12 months, cyclophosphamide is substituted by
azathioprine or methotrexate (Jayne 2001). NSVN can sometimes be treated with corticosteroids alone.
If the neuropathy progresses, when these are tapered, azathioprine may be necessary, or even temporarily cy- clophosphamide (Dyck et al. 1987; Kissel 2001; Kissel and Mendell 1992). Pain in isolated peripheral nerve vasculitis is treated according to the general rules of treatment of neuropathic pain.
References
1. Chalk CH, Dyck PJ (1993) Ischemic Neuropathy. In: Dyck PJ, Thomas PK, Griffin JW et al. (eds) Peripheral Neuropathy. WB Saunders, Philadelphia, pp 980–989
2. Collins MP, Mendell JR, Periquet MI et al. (2000) Superficial Per- oneal Nerve/Peroneus Brevis Muscle Biopsy in Vasculitic Neu- ropathy. Neurology 55:636–643
3. Dyck PJ, Benstead TJ, Conn DL et al. (1987) Nonsystemic Vas- culitic Neuropathy. Brain 110:843–854
4. Jayne D (2001) Update on the European Vasculitis Study Group trials. Curr Opin Rheumatol 13:48–55
5. Jennette JC, Falk RJ, Andrassy K et al. (1994) Nomenclature of Systemic Vasculitides. Proposal of an International Consensus Conference. Arthritis Rheum 37:187–192
6. Kissel J (2001) Vasculitic Neuropathies. In: Gilman S (ed) MedLink Neurology. MedLink Corporation, San Diego 7. Kissel JT, Mendell JR (1992) Vasculitic Neuropathy. Neurol Clin
10:761–781
8. Laghi Pasini F, Pastorelli M, Beermann U et al. (1996) Peripheral Neuropathy Associated with Ischemic Vascular Disease of the Lower Limbs. Angiology 47:569–577
9. Lindenlaub T, Sommer C (2003) Cytokines in Sural Nerve Biop- sies from Inflammatory and Non-Inflammatory Neuropathies.
Acta Neuropathol 105:593–602
10. Michaelis M, Vogel C, Blenk KH et al. (1998) Inflammatory Mediators Sensitize Acutely Axotomized Nerve Fibers to Me- chanical Stimulation in the Rat. J Neurosci 18:7581–7587
11. Nukada H, Powell HC, Myers RR (1993) Spatial Distribution of Nerve Injury after Occlusion of Individual Major Vessels in Rat Sciatic Nerves. J Neuropathol Exp Neurol 52:452–459 12. Satoi H, Oka N, Kawasaki T et al. (1998) Mechanisms of Tissue
Injury in Vasculitic Neuropathies. Neurology 50:492–496 13. Schäfers M, Lee DH, Brors D et al. (2003) Increased Sensitivity
of Injured and Adjacent Uninjured Rat Primary Sensory Neurons to Exogenous Tumor Necrosis Factor-Alpha after Spinal Nerve Ligation. J Neurosci 23:3028–3038
14. Weber F, Ziegler A (2002) Axonal Neuropathy in Chronic Pe- ripheral Arterial Occlusive Disease. Muscle Nerve 26:471–476 15. Weinberg DH, Simovic D, Isner J et al. (2001) Chronic Ischemic Monomelic Neuropathy from Critical Limb Ischemia. Neurology 57:1008–1012
16. Wilbourn AJ, Furlan AJ, Hulley W et al. (1983) Ischemic Monomelic Neuropathy. Neurology 33:447–451
17. Yamamoto M, Ito Y, Mitsuma N et al. (2003) Pain-Related Dif- ferential Expression of NGF, GDNF, IL–6, and their Receptors in Human Vasculitic Neuropathies. Intern Med 42:1100–1103
Vascular Orofacial Pain
Synonyms VOP Definition
Vascular orofacial pain (VOP) shares many of the signs and symptoms of other vascular-type craniofacial pains.
It is confined to the oral cavity, the perioral region and lower part of the face. When affecting a tooth it may mimic pulpitis.
Atypical Facial Pain, Etiology, Pathogenesis and Management
Atypical Odontalgia
Vascularization
Definition
Vascularization is a physiological process to form new blood vessels. The tissue becomes vascular and develops capillaries.
NSAIDs and Cancer
Vascular-Type Craniofacial Pain
Definition
This is a unilateral, periodic, pulsatile, severe pain in the craniofacial region that may wake from sleep, accompa- nied by autonomic phenomena. This includes pain syn- dromes such as migraine, cluster headache and parox- ysmal hemicrania.
Atypical Facial Pain, Etiology, Pathogenesis and Management
Atypical Odontalgia
V
VDCCs 2607
Vasculitic
Definition
Pertaining to vasculitis.
Hansen’s Disease
Vasculitic Neuropathy
Definition
Neuropathy caused by vasculitis of the nerve.
Diabetic Neuropathies
Vascular Neuropathies
Vasculitis
Definition
Inflammation within and around the walls of blood ves- sels that can deprive nearby tissues of normal blood flow and lead to secondary damage or cell death. Axons are vulnerable to damage from vasculitis.
Diabetic Neuropathies
Headache Due to Arteritis
Vascular Neuropathies
Viral Neuropathies
Vasoactive Intestinal Polypeptide
Synonyms VIP
Definition
Vasoactive intestinal polypeptide (VIP), a 28–amino acid peptide, was isolated as a vasodilator peptide from lung and intestine, and was later also localized to ner- vous tissue. VIP acts as an anti-inflammatory peptide, but is itself also produced by immune cells. In the nervous system, it modulates pain sensation as well as other neuronal processes. Apart from its involvement in brain metabolism, it relaxes smooth muscle and stimulates secretory glands. In postganglionic fibers of the autonomic nervous system it is a co-transmitter of acetylcholine.
Neuropeptide Release in the Skin
Peptides in Neuropathic Pain States
Postsynaptic Dorsal Column Projection, Anatomical Organization
Vasodilator
Definition
An agent that causes dilation of the blood vessels.
Headache Attributed to a Substance or its Withdrawal
Vasomotor
Definition
One of the important functions of the sympathetic ner- vous system is control of blood flow to tissues. This is achieved by narrowing or widening of the blood vessels depending on the need for oxygen and other nutrients for optimal tissue function. This function of the sympa- thetic nervous system is known as vasomotor function.
Vasomotor dysfunction may occur in CRPS resulting in abnormally warm or cold limbs.
Sympathetically maintained pain in CRPS II, human experimentation
Vasomotor Dysfunction
Definition
Affecting blood perfusion.
Causalgia, Assessment
Vasovagal Response
Definition
Vasovagal response refers to an exaggerated response by the autonomic nervous system. During the vasovagal re- sponse, heart rate and blood pressure decrease rapidly, which reduces blood flow to the brain. This reduction of blood flow leads to feelings of warmth, lightheaded- ness, and dimming of vision and hearing. If the vasovagal response progresses, further reducing blood flow to the brain, the individual may faint (vasovagal syncope). Fre- quent triggers of fainting include pain, trauma, fatigue, blood loss or prolonged, motionless standing.
Experimental Pain in Children
VDCCs
Calcium Channels in the Spinal Processing of Noci-
ceptive Input
2608 Vector
Vector
Definition
Gene delivery is accomplished through the use of “vec- tors”. These may be derived from viruses (viral vectors) or constructed using non-viral elements (nonviral vec- tors). In ex vivo applications, cells removed from the body are cultured in a dish, transduced with the vector of choice, and after determining that the transgene is expressed appropriately are transplanted back into the body to achieve the desired therapeutic effect. In vivo applications of gene therapy rely on the use of vectors to deliver the therapeutic transgene to an intact organism by injection into a blood vessel or directly into a target tissue.
Opioids and Gene Therapy
Vein Thrombosis
Postoperative Pain, Venous Thromboembolism
Venereal Arthritis
Reiter’s Syndrome
Ventral Amygdaloid Pathway
Synonyms VAP
Definition
A collection of fibers that reciprocally connect the amyg- dala with the lateral hypothalamus and brainstem areas such as the parabrachial area.
Nociceptive Processing in the Amygdala, Neurophys- iology and Neuropharmacology
Ventral Basal Complex of the Lateral Thalamus
Definition
Human nomenclature (VC), VP or VB in monkeys or cats, includes VPL & VPM.
Thalamus, Dynamics of Nociception
Ventral Basal Nucleus (VB)
Definition
VPL and VPM nuclei in the cat thalamus.
Thalamic Plasticity and Chronic Pain
Ventral Caudal Nucleus (Vc)
Definition
Human nomenclature for VP or VB in monkeys or cats, includes VPL and VPM.
Burst Activity in Thalamus and Pain
Human Thalamic Nociceptive Neurons
Thalamic Bursting Activity, Chronic Pain
Thalamus, Receptive Fields, Projected Fields, Human
Ventral Lateral Nucleus
Definition
It is the ventral nucleus anterior to VP. The region is heav- ily connected with the motor cortex.
Spinothalamic Terminations, Core and Matrix
Ventral Medial Nucleus
Synonyms Vmpo Definition
The posterior part (Vmpo) of the ventral medial nucleus of the thalamus. The region is claimed to be the main spinothalamic termination site for lamina I neurons in humans and in the monkey.
Human Thalamic Nociceptive Neurons
Ventral Posterior Complex (VP)
Definition
A group of nuclei in the ventral tier of the thalamus, receiving the different somatosensory inputs from the whole body. The complex is organized in a topological way, the head being placed medially (ventral poste- rior medial nucleus), and the foot laterally close to the internal capsule (ventral posterior lateral nucleus).
Nociceptive cells have been found in the different parts
of the complex, but more specifically in the ventral
posterior inferior nucleus, where a pain homunculus
V
Ventral Tegmental Area 2609
was described. The complex projects mainly to cortical areas SI, SII and the insula.
Thalamotomy for Human Pain Relief
Ventral Posterior Inferior Nucleus
Synonyms VPI
Definition
The VPI nucleus is part of the somatosensory thalamus.
It is located just ventral to the ventral posterior lateral and medial nuclei. Many of the neurons in the VPI nucleus are nociceptive. One source of input to the VPI nucleus is the spinothalamic tract. The thalamocortical output probably includes SII.
Spinothalamic Input, Cells of Origin (Monkey)
Spinothalamic Terminations, Core and Matrix
Thalamic Nuclei Involved in Pain, Human and Mon- key
Thalamus, Nociceptive Cells in VPI, Cat and Rat
Ventral Posterior Lateral Nucleus
Synonyms VPL
Definition
The VPL nucleus is a part of the somatosensory tha- lamus. As the name implies, this nucleus is located in the ventral part of the posterior thalamus. It is lateral to another part of the somatosensory thalamus, the ventral posterior medial (VPM) nucleus. The VPL nucleus is concerned with somatosensory input from the body, whereas the VPM nucleus receives information con- cerning the head. In primates, the VPL nucleus receives synaptic input from both the dorsal column-medial lem- niscus pathway, spino-cervicothalamic pathway and the spinothalamic tract. Some VPL neurons are noci- ceptive, although most are mechanoreceptive. The VPL nucleus projects to, and thus conveys somatosensory information to, the SI and SII regions of the cerebral cortex.
Burst activity in Thalamus and Pain
Lateral Thalamic Lesions, Pain Behavior in Animals
Spinothalamic Input, Cells of Origin (Monkey)
Spinothalamic Terminations, Core and Matrix
Thalamic Nuclei Involved in Pain, Human and Mon- key
Thalamic Plasticity and Chronic Pain
Thalamus, Visceral Representation
Ventral Posterior Medial
Synonyms VPM Definition
Medial portion of VP. Neurons in this nucleus respond mainly to touch and proprioception applied to the head.
Burst activity in Thalamus and Pain
Human Thalamic Response to Experimental Pain (Neuroimaging)
Spinothalamic Terminations, Core and Matrix
Thalamic Nuclei Involved in Pain, Human and Mon- key
Thalamus, Visceral Representation
Ventral Posterior Nuclear Group of the Thalamus
Definition
Ventral Posterior Nuclear Group of the Thalamus is a summary term for the specific somatosensory nuclei of the thalamus. Most commonly used taxonomy is for monkey thalamus: VPL (ventro-postero-lateral), VPM (ventro-postero-medial), VPI (ventro-postero-inferior).
In humans: Vc (ventro-caudal).
Nociceptive Processing in the Secondary Somatosen- sory Cortex
Ventral Posterior Nucleus (Human Ventral Caudal)
Definition
The principle somatic sensory nucleus of thalamus, which receives projections from the spinothalamic tract. Other nuclei receiving such input are posterior and inferior to VP including the posterior nucleus, the ventral posterior inferior nucleus, and the ventral medial nucleus - posterior part (VMpo).
Angina Pectoris, Neurophysiology and Psychophysics
Lateral Thalamic Pain-Related Cells in Humans.
Ventral Tegmental Area
Definition
Region of the midbrain containing dopaminergic neu- rons that project to cortical and limbic structures.
Nociceptive Processing in the Nucleus Accumbens,
Neurophysiology and Behavioral Studies
2610 Ventricular Collapse
Ventricular Collapse
Headache Due to Low Cerebrospinal Fluid Pressure
Ventrolateral Funiculus
Definition
White matter of the ventral and lateral aspects of the spinal cord.
Vagal Input and Descending Modulation
Ventrolateral Orbital Cortex
Synonyms VLO
Definition
The VLO is a region of the frontal cortex that envelops the rhinal fissure at its medial limits, and is respectively bounded by the lateral and medial orbital regions. Its lo- cation in the so-called limbic (emotional) areas of the cortex, and its interconnections with the SM and PAG, suggest that VLO neurons may process motivational- affective aspects of nociception.
Spinothalamocortical Projections from SM
Ventromedial Nucleus
Definition
The most medial portion of the ventrobasal or ventral posterior nucleus.
Brainstem Subnucleus Reticularis Dorsalis Neuron
Spinothalamocortical Projections to Ventromedial and Parafascicular Nuclei
Ventroposterior Lateral Nucleus
Synonyms VPL
Definition
Lateral portion of VP. Neurons in this nucleus respond mainly to touch and proprioception applied to the lower body and lower limbs.
Human Thalamic Response to Experimental Pain (Neuroimaging)
Verapamil
Definition
Calcium channel blocker.
Migraine, Preventive Therapy
Vertebro-Basilar Arterial Disease
Definition
This causes obstruction of flow in the vertebral arteries or the basilar artery that they join to form. This system supplies the hindbrain and brainstem with blood.
Primary Cough Headache
Vertigo
Definition
An illusory sensation of motion (rotational, transla- tional, or tilting of the visual environment) of either the self or the surrounding.
Coordination Exercises in the Treatment of Cervical Dizziness
Vesical
Definition Of the bladder.
Nocifensive Behaviors of the Urinary Bladder
Visceral Pain Model, Urinary Bladder Pain (Irritants or Distension)
Vesical Pain Models
Visceral Pain Model, Urinary Bladder Pain (Irritants or Distension)
Vesicular Inhibitory Amino Acid Transporter
Synonyms VIAAT Definition
A transporter protein that transports GABA and glycine into presynaptic vesicles.
GABA and Glycine in Spinal Nociceptive Processing
V
Viral Neuropathies 2611
Vestibulectomy
Definition
A vestibulectomy is a minor surgical procedure involv- ing the excision of a portion of the vestibular area in women with vulvar vestibulitis to treat vulvar pain.
Dyspareunia and Vaginismus
Vulvodynia
Vestibulodynia
Definition
A localized form of vulvodynia (pain is localized to the vulvar vestibule); this definition has been introduced to replace the term vulvar vestibulitis, since it was felt that the suffix „-itis„ in vestibulitis might incorrectly suggest an inflammatory etiology.
Vulvodynia
VIAAT
Vesicular Inhibitory Amino Acid Transporter
Viagra
Sildenafil
Vibration
Definition
Oscillating movements of body parts or of the whole body relative to a midposition. These movements are generated by constantly alternating forces or moments.
In most cases these forces are produced outside the body by a motor. Mainly whole-body and hand-arm vibrations are distinguished, during which the whole body or only the hand-arm unit, respectively, are exposed to vibra- tions. The measure for the magnitude of a mechanical vibration is the mean effective acceleration, expressed in m/s
2.
Ergonomic Counseling
Massage and Pain Relief Prospects
Vicarious Experience
Definition
Observing another individual enacting a particular be- havior or responding to particular environmental condi- tions.
Psychology of Pain, Self-Efficacy
Vicarious Instigation
Definition
Vicarious instigation describes the phenomenon that, possibly mediated by empathy, mere observation of another person’s response to a stimulus or a situation (e.g. a pain response) can induce a similar response in the observer, in the absence of any direct experience with the eliciting stimulus or situation. In the context of pain, it is still a matter of debate whether observing another person in pain can induce a pain-like vicarious response in the observer, or whether it elicits a more generalized emotional response in the observer.
Modeling, Social Learning in Pain
Vicarious Learning
Modeling, Social Learning in Pain
VIP
Vasoactive Intestinal Polypeptide
Viral Meningitis
Headache in Aseptic Meningitis
Viral Neuropathies
C
ATHERINEC
HO, L
YDIAE
STANISLAO, D
AVIDS
IMPSONClinical Neurophysiology Laboratories, Mount Sinai Medical Center, New York, NY, USA
david.simpson@mssm.edu
Synonyms
Virus-Induced Nerve Dysfunction; Nerve Viral Infec-
tion
2612 Viral Neuropathies
Definition
Viruses may directly infect neurons or nerve fibers (nerve viral infection) or trigger
neuroinflammation and
neuroimmune activation. These mechanisms result in virus-induced nerve dysfunction or viral neu- ropathy.
Characteristics
Herpes zoster or Varicella zoster virus causes a condi- tion called shingles (Kost and Straus 1996). After pri- mary infection, the virus becomes latent in the dorsal root ganglia and sensory ganglia of the cranial nerves.
As
cell-mediated immunity wanes, the virus is reac- tivated, causing hemorrhagic inflammation. The infec- tion subsequently spreads to the skin, which is also in- flamed and partially denervated. Ipsilateral segmental
myelitis and
leptomeningitis with involvement of the adjacent spinal levels may occur and have been doc- umented in post-mortem studies. Pathologically, there is hemorrhagic necrosis in the peripheral nerve and dorsal root ganglion, which is accompanied by neuronal loss.
In the central nervous system, the dorsal horn also un- dergoes
neurodegeneration. Inflammation in both the peripheral nerve and central nervous system can persist for months. Peripherally, there is scarring of the skin, de- myelination of the nerve,
wallerian degeneration, and fibrosis of both the nerve and the dorsal root ganglion.
In some cases, there is atrophy of the dorsal horn.
Human immunodeficiency virus (HIV) may cause neu- ropathy in over 30% of infected patients in the form of distal symmetric polyneuropathy (DSP). While the mechanism of HIV DSP is uncertain, there is in vitro evidence that the gp120 subunit of HIV may act as a cofactor in the pathogenesis of DSP (Herzberg and Sagen 2001); (Keswani et al. 2003). Tumor necrosis factor alpha (TNF-α), interleukin-1 (IL-1), and other cytokines have been identified in peripheral nerve and dorsal root ganglia, after exposure of the peripheral nerve to gp120. In one study using a rat model, tran- sient axonal swelling developed after the sciatic nerve was exposed to gp120 (Herzberg et al. 2001). A second phase of astrocytic and microglial activation in the spinal cord persisted after exposure. The latter finding correlated with rat neuropathic pain behavior.
In a study using cell culture, Schwann cells secreted proinflammatory cytokines after ligation of gp120 to the CXCR4 chemokine receptors (Keswani et al. 2003).
These cofactors might mediate gp120 neurotoxicity via a cascade of interactions with cytokines. Pathology reveals degeneration of myelinated and unmyelinated axons in nerve biopsies of nearly all patients with AIDS.
Mild epineurial and endoneurial perivascular mononu- clear inflammation is present in two-thirds of patients.
Suppressor/cytotoxic cells (CD8) are more prevalent in the endoneurial infiltrate, while the ratio between CD8 and helper/inducer (CD4) cells is about equal in
the epineurial infiltrate. Activated macrophages are also detected among the inflammatory cells. In autopsy studies, dorsal root ganglion cells and the gracilis tract show inflammatory and neurodegenerative changes, but these are mild in comparison to those found in distal peripheral nerves.
Of all the human herpes viruses, cytomegalovirus (CMV) is the most consistently reactivated, and causes the most severe clinical consequences, particularly in immunocompromised patients such as those with AIDS.
CMV infection in AIDS patients causes progressive
polyradiculopathy by both direct infection of the dor- sal root ganglia (ganglionitis) and immune-mediated neuronal damage. Pathologic changes include necrosis and inflammation of ventral and dorsal roots, with giant cells and inclusion bodies in Schwann cells, endothelial cells, and within the nerve. Features consistent with vasculitis are also present. Focal myelitis adjacent to the involved nerve roots is common.
Among the several forms of viral hepatitis, hepatitis C virus (HCV) has emerged as the most clinically impor- tant virus (Lange and Tolunsky 2002). The pathogenesis of HCV-associated neuropathies is unclear. A necro- tizing vasculitis associated with HCV infection is one mechanism of neuropathy. Although neuropathies asso- ciated with HCV are presumed to be immune-mediated, evidence for direct infection causing neuropathy was demonstrated, with localization of HCV RNA in nerve and muscle biopsies (Authier et al. 2003). However, replicative RNA was not detected, raising doubt of the role of direct infection in neuropathy.
All of the viral neuropathies discussed have pain as a prominent clinical manifestation. Acute Herpes zoster is manifested by pain, which may precede the rash by days to weeks (Geraci et al. 2002). The eruption starts as patches of erythema that progress to form grouped vesi- cles. Usually one or two dermatomes are involved. The lesions pustulate and crust over the next 7–10 days. This is followed by a period of pain, anesthesia, and changes in pigmentation that lasts 4–6 weeks after the crusting of the lesions. The thoracic levels are most commonly involved, followed by the ophthalmic division of the trigeminal nerve. Reactivation of zoster in the genicu- late ganglion leads to Ramsay-Hunt syndrome. Zoster infection may occur without a characteristic cutaneous rash, a condition called zoster sine herpete. In some cases, the pain may last more than 4–6 weeks, and even years, after the rash has resolved, termed postherpetic neuralgia (PHN). The risk of PHN is increased in the elderly.
Pain in the feet is the most common symptom of
HIV-DSP. Patients often have an antalgic gait due
to
dysesthesia in the distal lower extremities. The
pain can be so intense that light contact can be perceived
as excruciating. A significant proportion of AIDS pa-
tients with neuropathy may be asymptomatic (Keswani
et al. 2003). The distal upper extremities may be af-
V
Viral Neuropathies 2613
fected later in the course of DSP. Numbness may also be present, but muscle weakness is usually absent. Absent or depressed muscle stretch reflexes in the ankles and
hypesthesia to all sensory modalities are the most common signs of DSP. Weakness, if present, is usually confined to the intrinsic foot muscles.
Asymptomatic CMV is common in the general popula- tion, but symptomatic and severe disease may develop in patients who are immunocompromised, particularly in AIDS. Progressive polyradiculopathy (PP) presents as severe radiating pain and paresthesias, hyporeflexia, progressive flaccid paraparesis, and sphincter dysfunc- tion (Anders and Goebel 1998). Early recognition is crit- ical, as the majority of untreated patients have severe neurological sequela or die. In the presence of neuro- logic CMV infection, cerebrospinal fluid studies show a polymorphonuclear pleocytosis, elevated protein, and low glucose. CMV is difficult to culture from CSF, and polymerase chain reaction (PCR) analysis is a far more sensitive assay (Anders et al. 1998). Electrodiagnostic studies reflect axonal loss in a radicular pattern. Imaging studies may show nodular thickenings of multiple roots with leptomeningeal enhancement.
Mixed
cryoglobulinemia, present in 56% of patients with HCV, is the most common extrahepatic immuno- logic manifestation of chronic HCV infection (Cacoub et al. 2000). Approximately 9% of HCV-infected patients have peripheral neuropathy. The most common type of neuropathy is painful distal sensory polyneuropathy in the presence of vasculitis and mixed cryoglobulinemia (Authier et al. 2003).
Despite similarities in the pathogenesis and clinical manifestations of pain among the different viral neu- ropathies, therapy has to be individualized because success varies between patients. In the treatment of acute zoster, acyclovir, famciclovir, and valacyclovir significantly reduce the duration and intensity of pain if initiated within 72 hours of rash (Kost et al. 1996). If there is no contraindication to corticosteroid treatment, combination with prednisone therapy may improve the quality of life and reduce pain. Topical analgesics or narcotics may provide additional pain relief. Some studies suggest that nerve blocks provide some acute benefit. Non-narcotic analgesics are usually ineffec- tive. The management of PHN presents a challenge, and many patients continue to suffer despite the avail- able treatments. Of the topical therapies, aspirin with ether, indomethacin with ether, lidocaine, and lidocaine with prilocaine may be useful. Lidocaine and capsaicin have both been studied in controlled trials for PHN and were proven effective for short-term analgesia. How- ever, the burning experienced when using currently available formulations of low concentration capsaicin is poorly tolerated, limiting its use. An experimental high concentration capsaicin patch has shown efficacy in preliminary trials of PHN (Backonja, Neurology, 2003; AAN abstract). Narcotics can be helpful in the
treatment of PHN but are limited by the side effects experienced at effective doses (Kost et al. 1996). Neu- roleptics, lorazepam, and dopamine agonists have been used with varying success (Mendell and Sahenk 2003).
Some norepinephine-selective tricyclics (maprotiline and desipramine) have also been shown to reduce pain as compared with placebo, maprotiline less so than amitriptyline. Serotonin reuptake inhibitors have not been useful in the treatment of PHN. Gabapentin has been compared with amitriptyline and has been shown to be equally efficacious in the treatment of zoster neuropathic pain.
Other nonpharmacological therapies can be used alone or as adjuncts (Mendell et al. 2003). Skin excision and neurosurgical interventions, including electros- timulation of the thalamus, anterolateral cordotomy, cingulotomy, and dorsal root entry zone lesions, have shown some benefit. These are treatments of last resort for intractable pain and only anecdotal evidence sup- ports these modalities. Sympathetic nerve blocks are helpful for the pain in acute zoster, but do not seem to have benefit in PHN. Transcutaneous electrical nerve stimulation and ethyl chloride spray have shown partial benefit in PHN. There is no evidence supporting the efficacy of acupuncture.
Treatment of HIV DSP is directed towards lowering HIV viral load and alleviating symptoms. Plasma HIV viral load may serve as a predictor of the occurrence of HIV neuropathy, and correlates with the severity of pain (Simpson et al. 2002). HIV RNA levels that are greater than 10,000 copies/ml predispose an individual to a 2.3-fold greater risk of sensory neuropathy (Childs et al. 1999). It is not clear if the HIV viral load will continue to be predictive of HIV DSP in the current post-HAART era (Highly Active Anti-Retroviral Ther- apy). Effective virologic suppression with HAART improves quantitative sensory function of HIV DSP (Martin et al. 2000), although its effect on symptoms is unknown.
Guidelines established by the World Health Organiza- tion for the management of cancer pain can be applied to DSP treatment. Nonopioid analgesics are first line therapy for mild to moderate pain. Adjuvant agents, such as tricyclic antidepressants, may help in more disabling pain, although amitriptyline and mexiletine did not demonstrate superior pain relief as compared to placebo in a study of painful HIV DSP (Mendell et al.
2003). Of the anticonvulsants used in managing pain,
lamotrigine has shown significant pain reduction in HIV-
associated DSP in a placebo-controlled study, although
this benefit was limited to the subgroup treated with
neurotoxic antiretroviral agents. Gabapentin has not
been sufficiently studied in randomized controlled trials
in HIV neuropathy, but has proven to have some ben-
efit in controlled studies of other painful neuropathies
(Rosner et al. 1996; Mendell et al. 2003). A new related
compound, pregabalin, is being developed for the treat-
2614 Viral Vectors
ment of several painful neuropathies, including diabetic, PHN and HIV. Topical agents, including lidocaine and capsaicin, are emerging as potential treatments in HIV neuropathy. An open label study of a high concen- tration capsaicin patch demonstrated substantial pain relief, lasting three months, after a single application (Simpson et al. 2004). Larger placebo-controlled trials of this agent are underway. When pain is refractory to these treatments, narcotics may be required. Long- acting agents, such as sustained-release morphine or oxycodone, may be preferable in these patients.
CMV-induced PP is fatal if untreated. When CMV is clinically suspected, antiviral therapy should be imme- diately initiated. While no controlled studies in AIDS- associated PP have been undertaken, agents may include ganciclovir, foscarnet, or cidofovir, alone or in combina- tion. Neurologic stabilization and improvement may fol- low effective therapy. HAART is essential for immune recovery.
Treatment in HCV neuropathy is directed towards HCV infection and cryoglobulinemia. Corticosteroids, cyclophosphamide, plasma exchange and cryophere- sis have been used with varying success. Interferon-α has been helpful, presumably by resolution of HCV- associated cryoglobulinemia. There are no studies of analgesics in the treatment of HCV neuropathy. In clinical practice, it is reasonable to use agents with demonstrated efficacy in other forms of painful neu- ropathy for the treatment of HCV neuropathy.
Research is continuing to develop treatment based on the molecular mechanisms of the various types of pain.
For now, the approach to the treatment of pain in viral neuropathies largely relies on treatment of the under- lying viral disease, together with symptomatic relief through trials of different pharmacologic agents and non-pharmacologic modalities.
References
1. Anders H, Goebel F (1998) Cytomegalovirus Polyradiculopathy in Patients with AIDS. Clin Infect Dis 27:345–352
2. Authier F, Bassez G, Payan C et al. (2003) Detection of Ge- nomic Viral RNA in Nerve and Muscle of Patients with HCV Neuropathy. Neurology 60:808–812
3. Backonja et al. (2003) Pilot study of High-Dose Capsaicin Patches to Treat Postherpetic Neuralgia Pain. AAN 55thAnnual Meeting Abstract SLB 003
4. Cacoub P, Renou C, Rosenthal E et al. (2000) Extrahepatic Manifestations Associated with Hepatitis C Virus Infection:
A Prospective Multicenter Study of 321 Patients. Medicine 79:47–56
5. Childs EA, Lyles RH, Selnes OA et al. (1999) Plasma Viral Load and CD4 Lymphocytes Predict HIV-Associated Dementia and Sensory Neuropathy. Neurology 52:607–613
6. Geraci A, Wulff E, Simpson D (2002) Infectious and Granulo- matous Neuropathies. In: Katirji B, Kaminski H, Preston D et al.
(eds) Neuromuscular Disorders in Clinical Practice. Butterworth- Heinemann, Woburn
7. Herzberg U, Sagen J (2001) Peripheral Nerve Exposure to HIV Viral Envelope Protein gp120 Induces Neuropathic Pain and Spinal Gliosis. J Neuroimmunol 116:29–39
8. Keswani S, Polley M, Pardo C et al. (2003) Schwann Cell Chemokine Receptors Mediate HIV–1 gp120 Toxicity to Sensory Neurons. Ann Neurol 54:287–296
9. Kost R, Straus S (1996) Postherpetic Neuralgia – Pathogenesis, Treatment, and Prevention. N Engl J Med 335:32–42 10. Lange D, Tolunsky E (2002) Infections and Peripheral Neuropa-
thy. In: Brown W, Bolton C, Aminoff M (eds) Neuromuscular Function and Disease: Basic, Clinical, and Electrodiagnostic As- pects. WB Saunders Company, Philadelphia, pp 1251–1262 11. Martin C, Solders G, Sonnerborg A et al. (2000) Antiretrovi-
ral Therapy may Improve Sensory Function in HIV-Infected Pa- tients: A Pilot Study. Neurology 54:2120–2127
12. Mendell J, Sahenk Z (2003) Painful Sensory Neuropathy. N Engl J Med 348:1243–1255
13. Newshan G (1998) HIV Neuropathy Treated with Gabapentin.
AIDS 12:219–221
14. Rosner H, Rubin L, Kestenbaum A (1996) Gabapentin Adjunc- tive Therapy in Neuropathic Pain States. Clin J Pain 12: 56–58 15. Simpson D, Brown S, Sampson J et al. (2004) A Single Applica- tion of High Concentration Trans-Capsaicin Leads to 12 Weeks of Pain Relief in HIV DSP: Results of an Open Label Trial.
Platform Presentation. 56thAmerican Academy of Neurology Annual Meeting, San Diego
16. Simpson D, Olney R, McArthur J et al. (2000) A Placebo- Controlled Trial of Lamotrigine for Painful HIV-Associated Neuropathy. Neurology 54:2115–2119
17. Simpson DM, Haidich AB, Schifitto G et al. (2002) Severity of HIV-Associated Neuropathy is Associated with Plasma HIV–1 RNA Levels. AIDS 16:407–412
Viral Vectors
Opioids and Gene Therapy
Virus-Induced Nerve Dysfunction
Viral Neuropathies
Visceral
Definition
Pertaining to any organ within the great cavities of the body, mainly describing the soft internal abdominal or- gans, particularly the intestines.
Recurrent Abdominal Pain in Children
Visceral Afferent
Definition
Afferent fibers from the viscera to the central nervous system. These fibers originate from dorsal root ganglion cells and vagal (nodose) ganglion cells.
Morphology, Intraspinal Organization of Visceral Af-
ferents
V
Visceral Nociception and Pain 2615
Visceral Hyperalgesia
Descending Modulation of Visceral Pain
Visceral Pain Model, Esophageal Pain
Visceral Hypersensitivity
Definition
Heightened perception of visceral events both physio- logical and experimental.
Descending Modulation of Visceral Pain
Thalamus and Visceral Pain Processing (Human Imaging)
Visceral Pain Model, Irritable Bowel Syndrome Model
Visceral Inflammation
Visceral Pain Model, Pancreatic pain
Visceral Modulation
Thalamus, Visceral Representation
Visceral Nociceptive Tracts
Postsynaptic Dorsal Column Projection, Functional Characteristics
Spinal Dorsal Horn Pathways, Dorsal Column (Vis- ceral)
Visceral Nociception and Pain
P
AULM. M
URPHYDepartment of Anaesthesia and Pain Management, Royal North Shore Hospital, St Leonard’s, NSW, Australia
drpmurphy@hotmail.com
Definition
Visceral Nociception and Pain originates from body organs. Visceral
nociceptors are located within body organs and internal cavities. The relative scarcity of no- ciceptors in these areas results in a pain that is often of a vague cramping/aching quality, diffuse, poorly localised and of a longer duration than somatic pain.
Visceral Nociception and Pain, Table 1 Comparison of Somatic Versus Visceral Pain
Somatic Visceral
Stimuli Mechanical
Thermal Inflammatory
Ischaemia Distension Inflammatory
Localisation Precise Poor,
Referred to somatic structures Autonomic
Symptoms
Yes No
