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bulbia
Handbook of Clinical Neurology, Vol. 81 (3rd series) Pain F. Cervero, T.S. Jensen, Editors © 2006 Elsevier B.V. All rights reserved
Chapter 47
Pain in syringomyelia/bulbia NADINE ATTAL* AND DIDIER BOUHASSIRA Hôpital Ambroise Paré, Boulogne-Billancourt and Université Versailles Saint-Quentin, France
47.1. Introduction Syringomyelia is a chronic progressive lesion of the spinal cord. It consists of a cystic cavitation of the central spinal cord, commonly in cervical or cervicodorsal region, which sometimes extends upwards into the medulla oblongata and pons (syringobulbia). In rare cases, the syrinx is confined to the dorsolumbar segments. More than 90% of cases are associated with developmental disorders, particularly Chiari I malformation. Acquired cases are most commonly due to traumatic spinal cord injury. In these cases, the syrinx is situated above the original injury (0.2 to 4.5% of spinal cord trauma) (Rossier et al., 1985; Schurch et al., 1996; Caroll and Brackenridge, 2005). Other acquired cases are more rarely due to spinal arachnoiditis and spinal cord tumors. Syringomyelia is clinically characterized by segmental sensory loss, generally of a dissociated type (loss of thermal and pain sensations whilst retaining tactile and proprioceptive sensation) and is associated with segmental amyotrophy (generally of the hands) in severe cases. It is frequently associated with pain, particularly neuropathic central pain (Merskey and Bogduk, 1994), which is often extremely difficult to treat (Milhorat et al., 1996; Attal and Bouhassira, 2004; Attal et al., 2006). The main clinical characteristics of such pain are not specific to syringomyelia, but rather similar to those observed in most other neuropathic pain disorders (Attal and Bouhassira, 2004; Bouhassira and Attal, 2004). This suggests that there may be common mechanisms involved in these various conditions. However, as in other painful conditions, syringomyelic patients do not represent a homogeneous group (Bouhassira et al., 2000). Thus these patients may have different combinations of symptoms and signs, which may depend on distinct mechanisms and possibly respond differentially to treatments.
This chapter is devoted to pain associated with syringomyelia/bulbia with a particular emphasis on neuropathic pain. The clinical characteristics and theoretical mechanisms of the condition itself are beyond the scope of this review (Heiss et al., 1999; Victor and Ropper, 2001; Levine, 2004). 47.2. Clinical symptomatology Pain is the most common symptom associated with syringomyelia/bulbia. It is mainly neuropathic and is considered a direct consequence of spinal cord lesion (central pain) (Merskey and Bogduk, 1994). Generally the pain is strictly or predominantly unilateral and most commonly located in the hand, shoulder, thorax or neck in cervicodorsal cavities, and sometimes in the lower limbs in dorso-lumbar syringomyelia (Williams, 1990; Attal et al., 1999; Boivie, 1999, 2003). Typically, there is a long delay (from months to years) between injury and the onset of pain, particularly in cases of posttraumatic syringomyelia (Shannon et al., 1981; Vernon et al., 1982; Rossier et al., 1985; Williams, 1990), although the pain may also be the initial symptom of the condition (Boivie, 1999). 47.2.1. Central (neuropathic) pain The neuropathic pain associated with syringomyelia includes a variety of symptoms: spontaneous ongoing/ paroxysmal pain, and allodynia/hyperalgesia, often associated with paresthesia and dysesthesia (Jensen et al., 2001; Jensen and Baron, 2003; Attal and Bouhassira, 2004; Boivie, 2006). Spontaneous pain refers to pain in the absence of any stimulus and it may be ongoing (superficial or deep) or paroxysmal. Its exact prevalence is unknown in the
*Correspondence to: Nadine Attal, INSERM E-332, Centre d’Evaluation et de Traitement de la Douleur, Hôpital Ambroise Paré, AP-HP, Boulogne-Billancourt and Université Versailles Saint-Quentin, France. E-mail: [email protected], Tel: +33-1-49-09-44-34.
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absence of epidemiological data but it has been estimated between 37% (Milhorat et al., 1996) and 67% (Ducreux et al., 2006). Superficial burning pain is the most common symptom, but the pain has also been described as nonburning (i.e. squeezing, pressing, aching, cold) (Milhorat et al., 1996; Attal and Bouhassira, 2004; Boivie, 2006). There may also be paroxysmal pain, which has been described as shooting, electric shock-like or stabbing. In many cases, different types of pain may coexist in the same patient, occurring in the same region or in different parts of the body. The pain is often related to, or enhanced by, coughing, straining or Valsalva’s maneuver, probably because of the dynamic characteristics of the syrinx fluid and flow (Rossier et al., 1985; Attal et al., 2004). Psychological factors, such as emotion, anxiety and stress, may worsen the pain, as seen for other pain conditions. Evoked pain, such as allodynia, which is “pain due to a stimulus which does not normally provoke pain” or hyperalgesia, which is “an increased response to a stimulus which is normally painful” (Merskey and Bogduk, 1994) is common (64% of painful patients in a psychophysical study of 46 consecutive patients with or without pain) (Attal et al., 2005; Ducreux et al., 2006). It can be assessed by standard neurological examination, quantitative sensory testing (Boivie et al., 1994; Boivie, 2003; Cruccu et al., 2004) or more simply by specific neuropathic pain questionnaires, (Bouhassira et al., 2004). The pain is most frequently evoked by brushing (dynamic mechanical allodynia), punctate stimuli using a pinprick or Von Frey filaments (punctate mechanical allodynia/hyperalgesia) or cold stimuli (cold allodynia/ hyperalgesia) (Attal et al., 1999; Ducreux et al., 2006). Less commonly, it can be evoked by static pressure (static mechanical allodynia/hyperalgesia) or heat stimuli (heat allodynia/hyperalgesia). In most cases, allodynia coexists with spontaneous pain, but mechanical allodynia alone has also been described after spinal lesion (Attal et al., 1998). Evoked pain may also persist after stimulation (aftersensation), appear some time after stimulation (delayed sensation), spread beyond the site of stimulation (radiation) or be increased or provoked by repetitive stimuli (temporal summation). Many patients suffer from hyperpathia, which is “a painful syndrome characterised by an abnormally painful reaction to a stimulus, especially a repetitive stimulus, as well as an increased threshold” (Merskey and Bogduk, 1994). Hyperpathia can therefore be considered as a combination of hyperalgesia, temporal summation and post-sensation. Abnormal spontaneous or evoked positive symptoms are frequent (paresthesia or dysesthesia) and are often described as “tingling”, “pins and needles”, and sometimes “numbness”.
Patients may also have signs of autonomic impairment on the painful side. The painful area may be cooler and vasoconstricted or warmer and occasional changes in sweating have been reported (Bowsher, 1996). 47.2.1.1. Is the neuropathic pain of syringomyelia distinct from or similar to that of other neuropathic pain conditions? Using a specific neuropathic pain questionnaire, the Neuropathic Pain Symptom Inventory (NPSI) (Bouhassira et al., 2004), we recently compared the frequency of descriptors in syringomyelic patients and other major etiologies of neuropathic pain. Our results, based on a sample of 411 consecutive patients, show that there are more similarities than differences between the characteristics of neuropathic pain associated with syringomyelia and those of other neuropathic disorders (Bouhassira et al., 2005). In particular, a similar proportion of syringomyelic patients to those with other central pain disorders (post-stroke pain, spinal cord trauma with below level pain, multiple sclerosis) had the five distinct dimensions of neuropathic pain identified with the NPSI (burning pain, deep squeezing/ pressing pain, paroxysmal pain, evoked pain and paresthesia/dysesthesia) syringomyelic patients in comparison with other central pain disorders (Fig. 47.1). More generally, aside from cold evoked pain, which is significantly more common in central pain, the clinical characteristics of our sample of central pain patients (n = 106) are similar to those of patients with peripheral neuropathic pain (n = 305). These data are further confirmed by a multiple correspondence analysis which showed no association between the painful symptoms (or paresthesia/dysesthesia) and the etiology or location of the lesion. Thus the principal differences between the neuropathic pain of syringomyelia and other peripheral or central lesions are the location of the pain and the associated neurological symptoms and signs. 47.2.1.2. Correlation with morphological findings No correlations have been detected between cyst dimensions by magnetic resonance imaging (MRI) and clinical symptoms of the syrinx (Vaquero et al., 1990; Arias et al., 1991) including the intensity of neuropathic pain (Attal et al., 1999). In addition, there is no correlation between the effects of surgery on the syrinx (foramen stenosis, syrinx diameter, syrinx/canal index) and the outcome of neuropathic pain (Attal et al., 2004). However, the position of the syrinx cavity (i.e. central, paracentral or eccentric cavities), rather than its size, may be better correlated with the clinical findings (Milhorat et al., 1995). It was found that neuropathic pain is generally homolateral to the cavitation in cases of paracentral or eccentric cavities (Milhorat et al., 1995, 1996; Attal et al., 1999; Boivie, 1999).
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PAIN IN SYRINGOMYELIA/BULBIA Fig. 47.1 Comparison of the frequency of neuropathic dimensions (%) between patients with syringomyelia (n = 36), central post-stroke pain (n = 24), multiple sclerosis (n = 23) and traumatic spinal cord injury (n = 15) (Bouhassira et al., 2005).
% 100 90 80 70 60 50 40 30 20 10 0
Burning
Deep pain Paroxysmal pain Allodynia
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47.2.2. Other types of pain Coexisting painful symptoms are frequent in syringomyelia/bulbia depending on the etiology of the syrinx (50 to 90% of cases) (Milhorat et al., 1996, 1999). Thus headache (generally a benign exertional headache, i.e. a headache that is intensified by coughing or sneezing), migraine, or cervico-occipital pain are frequent in patients with Chiari type I malformation (Milhorat et al., 1999; Taylor and Larkins, 2002; Buzzi et al., 2003). Benign exertional headache is thought to be related to the increased intrathecal pressure caused by the free flow of CSF being obstructed in the subarachnoid space and may respond to surgical treatment of the Chiari (Taylor and Larkins, 2002; Sansur et al., 2003). However, migraine and benign exertional headache may coexist in the same patient and respond similarly to anti-migraine pharmacologic treatment (Buzzi et al., 2003). Trigeminal neuralgia and cluster-like facial pain have also been described and may also respond to surgical treatment of the syrinx (Rosetti et al., 1999). Visceral pain (due to renal calculus, bowel, or sphincter dysfunction, for example) and musculoskeletal pain (due to bone, joint, muscle trauma or inflammation, mechanical instability, muscle spasms and secondary overuse syndrome) may be observed in syringomyelia related to spinal cord trauma (Siddall et al., 1997; Siddall and Loeser, 2001). Finally, peripheral neuropathic pain due to nerve root entrapment or arachnoiditis is common in syringomyelia caused by meningitis. 47.2.3. Sensory deficits All patients with syringomyelia have some degree of thermoalgesic deficit in their painful area. Such a deficit may be unilateral or bilateral and have a segmental distribution, generally over the neck, shoulder, trunk and arms, but may also affect the face. It is located or predominates
Post-stroke Pain
Spinal Cord Trauma
Paresthesia
Multiple Sclerosis
ipsilaterally to the paracentral extension of the syrinx in cases of eccentric or paracentral cavities (Milhorat et al., 1996; Attal et al., 1999; Ducreux et al., 2006). It may range from mild hypoesthesia or hypoalgesia (diminished pain in response to a normally painful stimulus) to complete anesthesia or analgesia. Sensory deficit can be detected and quantified best by quantitative sensory testing (QST), which indicates an impairment of thermal sensation in nearly 100% of cases. There are almost always increased warm and cold detection thresholds and to a lesser extent increased pain thresholds (Boivie et al., 1994; Attal et al., 1999; Boivie, 2003, 2006; Bouhassira et al., 2000; Ducreux et al., 2006). This is similar to that observed in other central pain conditions (Vestergaard et al., 1995; Bowsher, 1996, 1998; Eide et al., 1996; Boivie, 2003, 2006; Defrin et al., 2001; Finnerup et al., 2003). QST is also useful to follow the outcome of syringomyelic patients (Attal et al., 2004). Thus we have recently shown that the thermoalgesic deficit generally does not improve after surgical decompression of the syrinx, except in patients operated on early (i.e. less than 2 years) after the onset of their symptoms (Attal et al., 2004). Proprioceptive/tactile sensation is usually considered to be not affected. However, in up to 50% of patients, loss of proprioceptive/tactile sensation has been observed (Honan and Williams, 1993). Increased vibration and/or mechanical thresholds may be observed by quantitative sensory testing (Attal et al., 1999, 2004; Ducreux et al., 2006). Other signs of dorsal column dysfunction, such as an impairment of graphesthesia and movement direction, may also be observed (Attal et al., 1999; Ducreux et al., 2006). Proprioceptive deficits, assessed using quantitative sensory tests respond better than the thermal deficits to surgical treatment of the syrinx (Attal et al., 2004). Loss of vibration and position sense may also be present in the lower limbs, particularly in cases of Chiari malformation.
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47.2.4. Associated symptoms and signs Generally there is no motor impairment in the early stages of the disease. By contrast, as the cavity enlarges, there may be corticospinal tracts and/or segmental impairment of the anterior horn, leading to pyramidal syndrome and muscular amyotrophy, respectively. Tendon reflexes are generally absent, except in some patients with Chiari malformation. In these patients the tendon reflexes may be normal or increased. Depending on the etiology of the syrinx, patients may also have variable clinical features, including nystagmus, cerebellar ataxia and lower cranial nerve impairment such as palatal and vocal cord paresis, particularly in Chiari malformation (with or without syringobulbia). Kyphoscoliosis is present in many cases and overt cervico-occipital malformation is present in nearly a quarter of patients (Victor and Ropper, 2001). 47.3. Mechanisms of central pain in syringomyelia Syringomyelia is a typical model of a “pure” intraspinal lesion predominantly affecting the spinothalamic tract. It is therefore of particular interest for studying the mechanisms underlying central pain, particularly with regards to the disputed role of spinothalamic lesion in neuropathic pain. In animal models developed over the last few years to study the mechanisms of central pain, lesions are usually induced by excitotoxic or ischemic injury, leading to damage of the spinal gray matter. These models present pathological characteristics, including neuronal loss, glial response and syrinx formation, resembling those observed in syringomyelia, particularly post-traumatic cavities (Christensen and Hulsenbosch, 1997; Yezierski et al., 1998; Vierck et al., 2000; Yezierski, 2001). Therefore they are of particular interest for studying the cellular, molecular, anatomical and physiological consequences of an intraspinal injury. Here, we will review the main theories of the mechanisms of central pain and their possible relevance for syringomyelia, the role of spinal versus supraspinal structures in the pain of syringomyelia, and then present evidence suggesting that the clinical symptoms of syringomyelia may be sustained by distinct mechanisms. 47.3.1. The main hypotheses of central pain mechanisms and their relevance to syringomyelia The mechanisms of central pain have been studied for over 100 years but still remain largely unknown. The principal hypotheses fall into two major categories: central imbalance and/or disinhibition and central sensitization.
Both phenomena can trigger abnormal neuronal hyperexcitability of spinal and/or supraspinal structures (references in Finnerup et al., 2003; Attal and Bouhassira, 2004; Finnerup and Jensen, 2004). Such hyperexcitability has been observed in animal models of spinal cord injury (Vierck et al., 2000; Yezierski, 2000) and also in some patients with central pain, in the dorsal horn (Loeser et al., 1968; Edgar et al., 1993; Falci et al., 2002) and in the lateral and medial thalamus (Lenz et al., 1989, 1994, 2000; Jeanmonod et al., 1993). 47.3.1.1. Central imbalance Patients with central pain nearly always have abnormal temperature and pain sensibility, but may have normal touch and vibration sensation (Boivie, 2006). This suggests that the presence of a spinothalamic dysfunction is a necessary condition for the occurrence of central pain, whereas the dorsal columns/medial lemniscus system are less commonly affected. This is further supported by studies showing abnormalities in laserevoked potentials (reflecting the function of A–δ nociceptive fibers) on the painful side of patients with post-stroke pain (references in Attal and Bouhassira, 2004) and syringomyelia (Kakigi et al., 1991; Treede et al., 1991), whereas sensory evoked potentials served by large-diameter fibers, correlated to the decrease in touch and vibration sensibility, may be preserved (Beric et al., 1988). It has been proposed that below-level pain associated with spinal cord injury is induced by an imbalance of integration between the unaffected dorsal column/medial lemniscus activity and the affected spinothalamic tract (Beric et al., 1988; Beric, 1993). However, recent psychophysical studies of patients with spinal cord injury with or without below-level pain have shown that there is a similar degree of thermoalgesic deficits in patients with pain and those without pain (Defrin et al., 2001; Finnerup et al., 2003). Similarly, the extent and magnitude of thermal deficits, assessed in 46 consecutive patients with syringomyelia, are similar in patients with pain and those without pain (Attal et al., 1999; Bouhassira et al., 2000; Ducreux et al., 2006). These data suggest that the spinothalamic lesion is necessary but not sufficient to account for the development of central pain. 47.3.1.2. Disinhibition theories Since the original hypothesis of Head and Holmes (1911), the notion of a central disinhibition, particularly in the thalamus, has been one of the most favored pathophysiological theories of central pain (Cassinari and Pagni, 1969; Pagni, 1989; Casey, 1991; Jeanmonod et al., 1996). One hypothesis, the “thermosensory disinhibition” theory by Craig (1998, 2000, 2003 for references),
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which is based on the observation that thermosensory loss is the basic feature of nearly all central pain patients, proposes that central pain (particularly burning pain and cold allodynia) may be due to a reduction of the physiological inhibition of thermal (cold) systems on nociceptive neurons. In contrast with traditional conceptions, this theory views pain not only as a sensation but also as a “homeostatic emotion” and an aspect of interoception, defined as the physiological condition of the body. We recently tested this hypothesis in a psychophysical study of 46 patients with syringomyelia, of whom 31 suffered from neuropathic pain (Attal et al., 2005; Ducreux et al., 2006). We did not observe any correlation between the magnitude of thermal deficits and the amount of pain in the entire group of painful patients. However, patients with spontaneous pain only (without evoked pains) had more severe thermal deficits than those with allodynia, and the intensity of burning pain was correlated to the extent of warm and cold deficits. These patients also had more asymetrical thermal deficits compared to those with allodynia and painless patients. This might reflect an imbalance in thermoregulation which involves bilateral brain integration (Craig, 1998). Thus these data are compatible with the disinhibition theory of central pain in a subgroup of syringomyelic patients (ie, patients with spontaneous pain only) Another form of central disinhibition has been proposed to account more specifically for the pain of syringomyelia. In a study of 137 patients with syringomyelia, Milhorat et al. (1996) observed that the syrinx extended onto the dorsolateral quadrant of the spinal cord on the same side of the pain in 84% of patients. It was suggested that pain was due to a disturbance of pain-modulating centers in the dorsolateral quadrant of the spinal cord. However, it was not stated whether this pattern was less common in pain-free patients. 47.3.1.3. Central sensitization The hyperactivity of nociceptive neurons in central pain may also result from direct modifications of their electrophysiological properties, i.e. central sensitization. This may be due to damage to central neurons caused by excitatory amino acids related to NMDA receptor activation (Eide, 1998; Vierk et al., 2000) and possibly also from sodium channels (Max and Hagen, 2000; Hains et al., 2003). Indirect evidence for the role of central sensitization in spinal cord injury pains is provided by the beneficial effects of NMDA antagonists and sodium channel blockers seen in animal models (Wiesenfeld-Hallin et al., 1997; Eide, 1998)
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and patients with spinal cord injury pain (Eide et al., 1995; Attal et al., 2000, 2002; Finnerup et al., 2005) including syringomyelia (Attal et al., 2000, 2002). 47.3.2. Role of spinal versus supraspinal structures in the pain of syringomyelia Several recent studies on animals and humans have suggested, that the primary pain generator in at-level and below-level neuropathic pain associated with spinal cord injury pain may be the injury region itself (references in Finnerup et al., 2003; Finnerup and Jensen, 2004). The observation that pain and sensory deficits associated with syringomyelia predominate ipsilaterally to the extension of the cavity in cases of paracentral or eccentric cavities (Attal et al., 1999) is consistent with this hypothesis. More specifically, the ipsilateral dorsal horn or spinothalamic fibers before they cross the midline may be important sites for pain generation (Boivie, 2006). Animal models of intraspinal excitotoxic lesion have also shown spontaneous nociceptive behavior and enhancement of nociceptive reponses in dermatomes ipsilateral to the lesion (references in Vierk et al., 2000; Yezierski, 2001). Electrophysiological recordings in these models have demonstrated abnormal neuronal excitation in the dorsal horn adjacent to the injury (Yezierski and Park, 1993; Christensen and Hulsebosch, 1997; Vierck et al., 2000; Yezierski, 2001). The possible mechanisms of such segmental hyperexcitability are probably not specific and may involve sensitization or disinhibition. 47.3.3. Are the pain symptoms of syringomyelia sustained by distinct or similar mechanisms? Recent studies have suggested that the various painful symptoms of syringomyelia, particularly with regard to the subtypes of allodynia (mechanical or thermal), may be sustained by distinct mechanisms. Pharmacological studies have shown preferential effects of intravenous administration of the sodium channel blocker lidocaine on mechanical (dynamic and static) but not cold allodynia in patients with central pain, including several syringomyelic patients (Attal et al., 2000). Along the same lines, a recent functional imaging study of patients with syringomyelia presenting with cold or brush induced allodynia has revealed distinct activations patterns depending on the submodality of allodynia (Attal et al., 2005; Ducreux et al., 2006). Thus cold allodynia activates a “cold pain network” including activation of insular and cingular areas, which is similar to the pattern induced by noxious cold in heatlhy controls (Craig, 2000). In contrast, brushevoked allodynia did not induce significant activation
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of several structures of the “pain matrix”, particularly the insula and the ACC. The different patterns of activation between the two subtypes of allodynia might reflect distinct pathophysiological mechanims. 47.4. Treatment of central pain associated with syringomyelia As with other chronic pain syndromes, pain associated with syringomyelia has a major impact on quality of life and affective state (Widenström-Noga, 2002). Therefore, the treatment of such pain should include management of disability and the affective comorbid conditions through the cognitive behavioral therapies and rehabilitation programmes (Sjölund, 2002). 47.4.1. Pharmacological treatment There are no trials specifically devoted to the neuropathic pain of syringomyelia (Attal et al., 2006). Therefore recommended treatments must rely on studies carried out for other neuropathic pain conditions. On the basis of randomized controlled trials in spinal cord injury pain, pharmacological classes shown to have some efficacy include antiepileptics (particularly gabapentin and to a lesser extent lamotrigine), strong opioids, local anesthetics (i.v. lidocaine) and NMDA receptor antagonists (i.v. ketamine) and will not be detailed here (for reviews see Attal and Bouhassira, 2004; Attal et al., 2006; Finnerup and Jensen, 2004). Tricyclic antidepressants are considered the mainstay of therapy. However, the only placebo-controlled trial of amitriptyline in traumatic spinal cord injury pain proved negative, although this may be due to insufficient dosages and/or to inadequate assessment of neuropathic pain (Cardenas et al., 2002). Importantly, the response of these treatments may not play a major role in the etiology or topography of central pain. In controlled trials of intravenous morphine and lidocaine carried out in patients with central pain, the response to these drugs appeared similar in patients with syringomyelia, spinal cord trauma and post-stroke pain (Attal et al., 2000, 2002). Treatments may also have similar efficacy on at-level and belowlevel neuropathic pain due to spinal cord injury, as recently shown in a placebo-controlled trial of i.v. lidocaine (Finnerup et al., 2005). The response to treatments may rather be influenced by the clinical symptoms or their combination, suggesting distinct pain mechanisms (Bouhassira and Attal, 2004; Attal et al., 2006). However, these findings are based on small samples of patients. Therefore pharmacological studies in larger cohorts of patients using a detailed assessment of their various neuropathic pain symptoms and signs
are needed to confirm these data and define possible predictors of the response to treatments. 47.4.2. Is the surgical treatment of the syrinx effective on neuropathic pain? Although surgery (generally foramen magnum decompression in patients with Chiari malformation) is commonly proposed to syringomyelic patients with progressive neurological deterioration, very few prospective studies have evaluated its effects on neuropathic pain (references in Attal et al., 2004). These studies generally reported disappointing results, in contrast to the positive effects seen for the pain associated with Chiari malformation, such as headache and cervical pain. We recently carried out a prospective 2-year study of 15 patients with syringomyelia, of whom eight presented with neuropathic pain. We found that surgery of the syrinx produced no overall significant effect on ongoing pain intensity at 2 years, whereas pain induced by straining, as well as coexisting dynamic symptoms (i.e. pains induced by coughing, Valsalva’s maneuver) were relieved (Attal et al., 2004). The latter pains are probably more dependent on the dynamic characteristics of the syrinx fluid and flow, and may be particularly affected by surgical decompression which reduces the subarachnoid pressure. 47.4.3. Other surgical techniques Surgical neuromodulative or neuroablative techniques may be proposed in patients suffering refractory pain, although these techniques have seldom been studied in patients with syringomyelia. Spinal cord stimulation, although generally no longer recommended in the treatment of central pain, may still be an option in patients suffering from steady at level neuropathic pain, who have incomplete spinal lesions and preservation of dorsal column function (Sindou and Mertens, 2000). Thus syringomyelic patients may be possible candidates for such techniques. Data concerning extradural stimulation of the motor cortex are very limited in spinal cord injury pain. Studies have so far only concerned patients with traumatic lesions (references in N’Guyen et al., 2003). Among neuroablative surgical procedures, dorsal root entry zone (DREZ) may be beneficial in at level neuropathic pain after incomplete spinal cord injury, particularly paroxysmal and evoked pain (Sindou et al., 2001). However, there are very few data concerning the effects of this technique in syringomyelic patients (Prestor, 2001). Moreover, DREZ may occasionally aggravate the sensory deficits which are generally incomplete in patients with syringomyelia. Therefore this technique has a marginal
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place in the treatment of pain associated with syringomyelia. 47.5. Conclusion Pain is frequently associated with syringomyelia and generally consists of neuropathic (central) pain. Its main characteristics (burning, deep pain, paroxysmal pain and allodynia/hyperalgesia) are similar to those of other central pain conditions, which suggests that common mechanisms (either central sensitization or disinhibition) may be involved in these various pain disorders. However, the nature of these mechanisms may differ, depending on the clinical presentation, as suggested from psychophysical and functional MRI studies of syringomyelic patients. These data may have important implications with regard to pharmacological treatment. References Arias A, Millan I, Vaquero J (1991). Clinico-morphological correlation in syringomyelia: a statistical study assisted by computer measurement of magnetic resonance images. Acta Neurochir (Wien) 111: 33–39. Attal N, Bouhassira D (2004). Central pain states. In: The Neurobiology of Pain. Pappagallo M (Ed.). McGraw Hill, New York, pp. 301–320. Attal N, Brasseur L, Chauvin M, Bouhassira D (1998). A case of “pure” dynamic mechano-allodynia due to a lesion of the spinal cord: pathophysiological considerations. Pain 75: 399–404. Attal N, Cruccu G, Hanpaa M, Hansson N P, Jensen TS, Nurmikko T, Sampaio C, Sindrup S, Wiffen P (2006). EFNS guidelines on pharmacological treatment of neuropathic pain. E. J Neurol. in press. Attal N, Ducreux D, Parker F, Bouhassira D (2005). Central representation of allodynia in patients with syringomyelia. Abstract 50.5, Soc for Neurosciences, Washington. Attal N, Gaude V, Brasseur L, Dupuy M, Guirimand F, Parker F, Bouhassira D (2000). Intravenous lidocaine in central pain. A double-blind placebo-controlled psycho-physical study. Neurology 544: 564–574. Attal N, Guirimand F, Brasseur L, Gaude V, Chauvin M, Bouhassira D (2002). Effects of IV morphine in central pain: A randomized placebo-controlled study. Neurology 58: 554–563. Attal N, Parker F, Brasseur L, Tadié M, Bouhassira D (1999). Characterization of sensation disorders and neuropathic pain related to syringomyelia. A prospective study. Neurochirurgie 1,45(suppl.): 84–94. Attal N, Parker F, Tadié M, Aghakani N, Bouhassira D (2004). Effects of surgery on the sensory deficits of syringomyelia and predictors of outcome: a long term prospective study. J Neurol Neurosurg Psychiatry 75: 1025–1030. Baumgartner U, Magerl W, Klein T, et al. (2002). Neurogenic hyperalgesia versus painful hypoalgesia: two distinct mechanisms of neuropathic pain. Pain 96: 141–151. Beric A (1993). Central pain: “new” syndromes and their evaluation. Muscle Nerve 16: 1017–1024. Beric A, Dimitrijevic MR, Lindblom U (1988). Central dysesthesia syndrome in spinal cord injury patients. Pain 34: 109–116.
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Boivie J (2006). Central pain. In : Wall and Melzack’s Textbook of Pain, Fifth edition, S.B. McMahon and M. Koltzenburg (Eds), Churchill Livingstone, Elsevier, pp. 1057–1074. Boivie J (2003). Central pain and the role of quantitative sensory testing (QST) in research and diagnosis. Eur J Pain 7: 339–343. Boivie J, Hansson P, Lindblom U (Eds.) (1994). Touch, Temperature and Pain in Health and Disease: Mechanisms and Assessment. IASP Press, Seattle. Bouhassira D, Attal N (2004). Novel strategies for neuropathic pain. In: Physiopharmacology of Pain. Proceedings of a symposium in the honor of J-M Besson. Villanueva L, Dickenson AE (Eds.), Seattle, IASP Press, pp. 299–310. Bouhassira D, Attal N, Parker F, Brasseur L (2000). Quantitative sensory evaluation of painful and painless patients with syringomyelia. Proceedings of the IXth World Congress on Pain. Devor M, Rowbotham MC, WiesenfeldHallin (Eds.), Seattle, IASP Press, pp. 401–411. Bouhassira D, Attal N, Fermanian J, Al-Chaar M, Gautron M, Boureau F, Grisart J, Masquelier E, Rostaing S, Collin E, Lanteri-Minet M (2004). Development and validation of the Neuropathic Pain Symptom Inventory. Pain. 108: 248–257. Bouhassira D, Attal N, Alchaar M, Lanteri-Minet M (2005). Neuropathic pain symptom inventory: complementary validation study and classification of neuropathic pain. Abstract, XIth World Congress on Pain, Sydney, August 2005. Bowsher D (1996). Central pain: clinical and physiological characteristics. J Neurol Neurosurg Psychiatry 61: 62–69. Bowsher D, Leijon G, Thomas KA (1998). Central poststroke pain: correlation of MRI with clinical pain characteristics and sensory abnormalities. Neurology 51: 1352–1358. Buzzi MG, Formisano R, Colonnese C, Pierelli F (2003). Chiari-associated exertional, cough, and sneeze headache responsive to medical therapy. Headache 43: 404–406. Cardenas DD, Warms CA, Turner JA, Marshall H, Brooke MM, Loeser JD (2002). Efficacy of amitriptyline for relief of pain in spinal cord injury: results of a randomized controlled trial. Pain 96: 365–373. Carroll AM, Brackenridge P (2005). Post-traumatic syringomyelia: a review of the cases presenting in a regional spinal injuries unit in the North East of England over a 5-year period. Spine 30: 1206–1210. Casey KL (Ed.) (1991). Pain and Central Nervous Disease: The Central Pain Syndromes. Raven Press, New York. Cassinari V, Pagni CA (1969). Central Pain: A Neurological Survey. Harvard University Press, Cambridge, MA. Christensen MD, Hulsebosch CE (1997). Chronic central pain after spinal cord injury. J Neurotrauma 14: 517–537. Craig AD (1998). A new version of the thalamic disinhibition hypothesis of central pain. Pain Forum 7: 1–14. Craig AD (2000). The functional anatomy of lamina I and its role in post-stroke central pain. Prog Brain Res 129: 137–151. Craig AD (2003). A new view of pain as a homeostatic emotion. Trends Neurosci 26: 303–307. Cruccu G, Anand P, Attal N, Haanpaa M, Jorum E, GarciaLarrea L, Serra J, Jensen TS (2004). EFNS guidelines on assessment of neuropathic pain and treatment. Eur J Neurology 11: 153–162. Defrin R, Ohry A, Blumen N, Urca G (2001). Characterization of chronic pain and somatosensory function in spinal cord injury subjects. Pain 89: 253–263.
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Ducreux D, Attal N, Parker F, Bouhassira D (2006). Mechanisms of central neuropathic pain : a combined psychophysical and fMRI study in syringomyelia. Brain, in press. Edgar RE, Best LG, Quail PA, Obert AD (1993). Computerassisted DREZ microcoagulation: posttraumatic spinal deafferentation pain. J Spinal Disord 6: 48–56. Eide PK (1998). Pathophysiological mechanisms of central neuropathic pain after spinal cord injury. Spinal Cord 36: 601–612. Eide PK, Stubhaug A, Stenehjem AE (1995). Central dysesthesia pain after traumatic spinal cord injury is dependent on N-methyl-D-aspartate receptor activation. Neurosurgery 37: 1080–1087. Eide PK, Jorum E, Stenehjem AE (1996). Somatosensory findings in patients with spinal cord injury and central dysesthesia pain. J Neurol Neurosurg Psychiatry 60: 411–415. Falci S, Best L, Bayles R, Lammertse D, Starnes C (2002). Dorsal root entry zone microcoagulation for spinal cord injury-related central pain: operative intramedullary electrophysiological guidance and clinical outcome. J Neurosurg 97: 193–200. Finnerup NB, Jensen TS (2004). Spinal cord injury pain – mechanisms and treatment. Eur J Neurol 11: 73–82. Finnerup NB, Johannesen IL, Fuglsang-Frederiksen A, Bach FW, Jensen TS (2003). Sensory function in spinal cord injury patients with and without central pain. Brain 126: 57–70. Finnerup NB, Biering-Sorensen F, Johannesen IL, Terkelsen AJ, Juhl GI, Kristensen AD, Sindrup SH, Bach FW, Jensen TS (2005). Intravenous lidocaine relieves spinal cord injury pain: A randomized controlled trial. Anesthesiology 102: 1023–1030. Hains BC, Klein JP, Saab CY, Craner MJ, Black JA, Waxman SG (2003). Upregulation of sodium channel Nav1.3 and functional involvement in neuronal hyperexcitability associated with central neuropathic pain after spinal cord injury. J Neurosci 23: 8881–8892. Head H, Holmes G (1911). Sensory disturbances from cerebral lesions. Brain 34: 102–154. Heiss JD, Patronas N, DeVroom HL, Shawker T, Ennis R, Kammerer W, Eidsath A, Talbot T, Morris J, Eskioglu E, Oldfield EH (1999). Elucidating the pathophysiology of syringomyelia. J Neurosurg 91: 553–562. Honan WP, Williams B (1993). Sensory loss in syringomyelia: not necessarily dissociated. J R Soc Med 86: 519–520. Jeanmonod D, Magnin M, Morel A (1996). Low-threshold calcium spike bursts in the human thalamus. Common physiopathology for sensory, motor and limbic positive symptoms. Brain 119: 363–375. Jensen TS, Baron R (2003). Translation of symptoms and signs into mechanisms in neuropathic pain. Pain 102: 1–8. Jensen TS, Gottrup H, Sindrup SH, Bach FW (2001). The clinical picture of neuropathic pain. Eur J Pharmacol 429: 1–11. Kakigi R, Shibasaki H, Kuroda Y, Neshige R, Endo C, Tabuchi K, Kishikawa T (1991). Pain-related somatosensory evoked potentials in syringomyelia. Brain 114: 1871–1889. Lenz F, Kwan HC, Dostrovsky JO, Tasker RR (1989). Characteristics of the bursting pattern of action potentials that occurs in the thalamus of patients with central pain. Brain Res 496: 357–360. Lenz FA, Kwan HC, Martin R, Tasker R, Richardson RT, Dostrovsky JO (1994). Characteristics of somatotopic organization and spontaneous neuronal activity in the region of the thalamic principal sensory nucleus in patients with spinal cord transection. J Neurophysiol 72: 1570–1587.
Lenz FA, Lee JI, Garonzik IM, Rowland LH, Dougherty PM, Hua SE (2000). Plasticity of pain-related neuronal activity in the human thalamus. Prog Brain Res 129: 259–273. Levine DN (2004). The pathogenesis of syringomyelia associated with lesions at the foramen magnum: a critical review of existing theories and proposal of a new hypothesis. J Neurol Sci 220: 3–21. Loeser JD, Ward AA JR, White Jr LE (1968). Chronic deafferentation of human spinal cord neurons. J Neurosurg. 29: 48–50. Max MB, Hagen NA (2000). Do changes in brain sodium channels cause central pain? Neurology 54: 544–545. Merskey H, Bogduk N (Eds.) (1994). Classification of Chronic Pain. IASP Press, Seattle. Milhorat TH, Chou MW, Trinidad EM, Kula RW, Mandell M, Wolpert C, Speer MC (1999). Chiari I malformation redefined: clinical and radiographic findings for 364 symptomatic patients. Neurosurgery. 44: 1005–1017. Milhorat TH, Johnson RW, Milhorat RH, Capocelli AL, Pevsner PH (1995). Clinicopathological correlations in syringomyelia using axial magnetic resonance imaging. Neurosurgery 37: 206–213. Milhorat TH, Kotzen RM, MU HTM, Capocelli AL, Milhorat RH (1996). Dysesthetic pain in patients with syringomyelia. Neurosurgery 38: 940–947. N’Guyen JP, Lefaucheur JP, Keravel Y (2003). Motor cortex stimulation. In: Electrical Stimulation and the Relief of Pain. Pain Research and Clinical Management, Vol. 15. Simpson B (Ed.) Elsevier, Amsterdam, pp. 197–209. Pagni CA (1989). Central pain due to spinal cord and brainstem damage. In: Textbook of Pain. Wall PD, Melzack R (Eds.) Churchill Livingstone, Edinburgh, pp. 634–655. Prestor B (2001). Microsurgical junctional DREZ coagulation for treatment of deafferentation pain syndromes. Surg Neurol 56: 259–265. Rosetti P, Ben Taib NO, Brotchi J, De Witte O (1999). Arnold Chiari Type I malformation presenting as a trigeminal neuralgia: case report. Neurosurgery 44: 1122–1123. Rossier AB, Foo D, Shillito J, Dyro FM (1985). Posttraumatic cervical syringomyelia. Incidence, clinical presentation, electrophysiological studies, syrinx protein and results of conservative and operative treatment. Brain 108: 439–461. Sansur CA, Heiss JD, DeVroom HL, Eskioglu E, Ennis R, Oldfield EH (2003). Pathophysiology of headache associated with cough in patients with Chiari I malformation. J Neurosurg 98: 453–458. Schurch B, Wichmann W, Rossier AB (1996). Post-traumatic syringomyelia (cystic myelopathy): a prospective study of 449 patients with spinal cord injury. J Neurol Neurosurg Psychiatry 60: 61–67. Shannon N, Symon L, Logue V, Cull D, Kang J, Kendall B (1981). Clinical features, investigation and treatment of posttraumatic syringomyelia. J Neurol Neurosurg Psychiatry 44: 35–42. Siddall PJ, Loeser JD (2001). Pain following spinal cord injury. Spinal Cord 39: 63–73. Siddall PJ, Taylor DA, Cousins MJ (1997). Classification of pain following spinal cord injury. Spinal Cord 35: 69–75. Sindou M, Mertens P (2000). Neurosurgical management of neuropathic pain. Stereotact Funct Neurosurg 75: 76–80. Sindou M, Mertens P, Wael M (2001). Microsurgical DREZotomy for pain due to spinal cord and/or cauda equina injuries: long-term results in a series of 44 patients. Pain 92: 159–171.
PAIN IN SYRINGOMYELIA/BULBIA Sjolund BH (2002). Pain and rehabilitation after spinal cord injury: the case of sensory spasticity? Brain Res Rev 40: 250–256. Taylor FR, Larkins MV (2002). Headache and Chiari I malformation: clinical presentation, diagnosis, and controversies in management. Curr Pain Headache Rep. 6: 331–337. Treede RD, Lankers J, Frieling A, Zangemeister WH, Kunze K, Bromm B (1991). Cerebral potentials evoked by painful, laser stimuli in patients with syringomyelia. Brain 114: 1595–1607. Vaquero J, Martinez R, Arias A (1990). Syringomyelia-Chiari complex: magnetic resonance imaging and clinical evaluation of surgical treatment. J Neurosurg 73: 64–68. Vernon JD, Silver JR, Ohry A (1982). Post-traumatic syringomyelia. Paraplegia. 20: 339–364. Victor M, Ropper AH (2001). Diseases of the spinal cord. In: Adam’s and Victor’s Principles of Neurology, seventh edition. Adams RD, Victor M (Eds.) McGraw Hill, New York. pp. 1293–1345. Vierck Jr CJ, Siddall P, Yezierski RP (2000). Pain following spinal cord injury: animal models and mechanistic studies. Pain 89: 1–5.
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Widerström-Noga EG (2002). Evaluation of clinical characteristics of pain and psychosocial factors after spinal cord injury. In: Spinal Cord Injury Pain: Assessment, Mechanisms, Management. Progress in Pain Research and Management. Yezierski RP, Burchiel KJ (Eds.) 23. IASP Press, Seattle, pp. 53–82. Wiesenfeld-Hallin Z, Aldskogius H, Grant G, Hao JX, Hokfelt T, Xu XJ (1997). Central inhibitory dysfunctions: mechanisms and clinical implications. Behav Brain Sci 20: 420–425. Williams B (1990). Post-traumatic syringomyelia, an update. Paraplegia 28: 296–313. Yezierski RP (2001). Pain following spinal cord injury: pathophysiology and central mechanisms. In: Progress in Brain Research. Yezierski RP, Burchiel KJ (Eds.) 129, Elsevier, New York, pp. 429–448. Yezierski RP, Park SH (1993). The mechanosensitivity of spinal sensory neurons following intraspinal injections of quisqualic acid in the rat. Neurosci Lett. 157: 115–119. Yezierski RP, Liu S, Ruenes GL, Kajander KJ, Brewer KL (1998). Excitotoxic spinal cord injury: behavioral and morphological characteristics of a central pain model. Pain 75: 141–155.
Chapter 47
Pain in syringomyelia/bulbia NADINE ATTAL* AND DIDIER BOUHASSIRA Hôpital Ambroise Paré, Boulogne-Billancourt and Université Versailles Saint-Quentin, France
47.1. Introduction Syringomyelia is a chronic progressive lesion of the spinal cord. It consists of a cystic cavitation of the central spinal cord, commonly in cervical or cervicodorsal region, which sometimes extends upwards into the medulla oblongata and pons (syringobulbia). In rare cases, the syrinx is confined to the dorsolumbar segments. More than 90% of cases are associated with developmental disorders, particularly Chiari I malformation. Acquired cases are most commonly due to traumatic spinal cord injury. In these cases, the syrinx is situated above the original injury (0.2 to 4.5% of spinal cord trauma) (Rossier et al., 1985; Schurch et al., 1996; Caroll and Brackenridge, 2005). Other acquired cases are more rarely due to spinal arachnoiditis and spinal cord tumors. Syringomyelia is clinically characterized by segmental sensory loss, generally of a dissociated type (loss of thermal and pain sensations whilst retaining tactile and proprioceptive sensation) and is associated with segmental amyotrophy (generally of the hands) in severe cases. It is frequently associated with pain, particularly neuropathic central pain (Merskey and Bogduk, 1994), which is often extremely difficult to treat (Milhorat et al., 1996; Attal and Bouhassira, 2004; Attal et al., 2006). The main clinical characteristics of such pain are not specific to syringomyelia, but rather similar to those observed in most other neuropathic pain disorders (Attal and Bouhassira, 2004; Bouhassira and Attal, 2004). This suggests that there may be common mechanisms involved in these various conditions. However, as in other painful conditions, syringomyelic patients do not represent a homogeneous group (Bouhassira et al., 2000). Thus these patients may have different combinations of symptoms and signs, which may depend on distinct mechanisms and possibly respond differentially to treatments.
This chapter is devoted to pain associated with syringomyelia/bulbia with a particular emphasis on neuropathic pain. The clinical characteristics and theoretical mechanisms of the condition itself are beyond the scope of this review (Heiss et al., 1999; Victor and Ropper, 2001; Levine, 2004). 47.2. Clinical symptomatology Pain is the most common symptom associated with syringomyelia/bulbia. It is mainly neuropathic and is considered a direct consequence of spinal cord lesion (central pain) (Merskey and Bogduk, 1994). Generally the pain is strictly or predominantly unilateral and most commonly located in the hand, shoulder, thorax or neck in cervicodorsal cavities, and sometimes in the lower limbs in dorso-lumbar syringomyelia (Williams, 1990; Attal et al., 1999; Boivie, 1999, 2003). Typically, there is a long delay (from months to years) between injury and the onset of pain, particularly in cases of posttraumatic syringomyelia (Shannon et al., 1981; Vernon et al., 1982; Rossier et al., 1985; Williams, 1990), although the pain may also be the initial symptom of the condition (Boivie, 1999). 47.2.1. Central (neuropathic) pain The neuropathic pain associated with syringomyelia includes a variety of symptoms: spontaneous ongoing/ paroxysmal pain, and allodynia/hyperalgesia, often associated with paresthesia and dysesthesia (Jensen et al., 2001; Jensen and Baron, 2003; Attal and Bouhassira, 2004; Boivie, 2006). Spontaneous pain refers to pain in the absence of any stimulus and it may be ongoing (superficial or deep) or paroxysmal. Its exact prevalence is unknown in the
*Correspondence to: Nadine Attal, INSERM E-332, Centre d’Evaluation et de Traitement de la Douleur, Hôpital Ambroise Paré, AP-HP, Boulogne-Billancourt and Université Versailles Saint-Quentin, France. E-mail: [email protected], Tel: +33-1-49-09-44-34.
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absence of epidemiological data but it has been estimated between 37% (Milhorat et al., 1996) and 67% (Ducreux et al., 2006). Superficial burning pain is the most common symptom, but the pain has also been described as nonburning (i.e. squeezing, pressing, aching, cold) (Milhorat et al., 1996; Attal and Bouhassira, 2004; Boivie, 2006). There may also be paroxysmal pain, which has been described as shooting, electric shock-like or stabbing. In many cases, different types of pain may coexist in the same patient, occurring in the same region or in different parts of the body. The pain is often related to, or enhanced by, coughing, straining or Valsalva’s maneuver, probably because of the dynamic characteristics of the syrinx fluid and flow (Rossier et al., 1985; Attal et al., 2004). Psychological factors, such as emotion, anxiety and stress, may worsen the pain, as seen for other pain conditions. Evoked pain, such as allodynia, which is “pain due to a stimulus which does not normally provoke pain” or hyperalgesia, which is “an increased response to a stimulus which is normally painful” (Merskey and Bogduk, 1994) is common (64% of painful patients in a psychophysical study of 46 consecutive patients with or without pain) (Attal et al., 2005; Ducreux et al., 2006). It can be assessed by standard neurological examination, quantitative sensory testing (Boivie et al., 1994; Boivie, 2003; Cruccu et al., 2004) or more simply by specific neuropathic pain questionnaires, (Bouhassira et al., 2004). The pain is most frequently evoked by brushing (dynamic mechanical allodynia), punctate stimuli using a pinprick or Von Frey filaments (punctate mechanical allodynia/hyperalgesia) or cold stimuli (cold allodynia/ hyperalgesia) (Attal et al., 1999; Ducreux et al., 2006). Less commonly, it can be evoked by static pressure (static mechanical allodynia/hyperalgesia) or heat stimuli (heat allodynia/hyperalgesia). In most cases, allodynia coexists with spontaneous pain, but mechanical allodynia alone has also been described after spinal lesion (Attal et al., 1998). Evoked pain may also persist after stimulation (aftersensation), appear some time after stimulation (delayed sensation), spread beyond the site of stimulation (radiation) or be increased or provoked by repetitive stimuli (temporal summation). Many patients suffer from hyperpathia, which is “a painful syndrome characterised by an abnormally painful reaction to a stimulus, especially a repetitive stimulus, as well as an increased threshold” (Merskey and Bogduk, 1994). Hyperpathia can therefore be considered as a combination of hyperalgesia, temporal summation and post-sensation. Abnormal spontaneous or evoked positive symptoms are frequent (paresthesia or dysesthesia) and are often described as “tingling”, “pins and needles”, and sometimes “numbness”.
Patients may also have signs of autonomic impairment on the painful side. The painful area may be cooler and vasoconstricted or warmer and occasional changes in sweating have been reported (Bowsher, 1996). 47.2.1.1. Is the neuropathic pain of syringomyelia distinct from or similar to that of other neuropathic pain conditions? Using a specific neuropathic pain questionnaire, the Neuropathic Pain Symptom Inventory (NPSI) (Bouhassira et al., 2004), we recently compared the frequency of descriptors in syringomyelic patients and other major etiologies of neuropathic pain. Our results, based on a sample of 411 consecutive patients, show that there are more similarities than differences between the characteristics of neuropathic pain associated with syringomyelia and those of other neuropathic disorders (Bouhassira et al., 2005). In particular, a similar proportion of syringomyelic patients to those with other central pain disorders (post-stroke pain, spinal cord trauma with below level pain, multiple sclerosis) had the five distinct dimensions of neuropathic pain identified with the NPSI (burning pain, deep squeezing/ pressing pain, paroxysmal pain, evoked pain and paresthesia/dysesthesia) syringomyelic patients in comparison with other central pain disorders (Fig. 47.1). More generally, aside from cold evoked pain, which is significantly more common in central pain, the clinical characteristics of our sample of central pain patients (n = 106) are similar to those of patients with peripheral neuropathic pain (n = 305). These data are further confirmed by a multiple correspondence analysis which showed no association between the painful symptoms (or paresthesia/dysesthesia) and the etiology or location of the lesion. Thus the principal differences between the neuropathic pain of syringomyelia and other peripheral or central lesions are the location of the pain and the associated neurological symptoms and signs. 47.2.1.2. Correlation with morphological findings No correlations have been detected between cyst dimensions by magnetic resonance imaging (MRI) and clinical symptoms of the syrinx (Vaquero et al., 1990; Arias et al., 1991) including the intensity of neuropathic pain (Attal et al., 1999). In addition, there is no correlation between the effects of surgery on the syrinx (foramen stenosis, syrinx diameter, syrinx/canal index) and the outcome of neuropathic pain (Attal et al., 2004). However, the position of the syrinx cavity (i.e. central, paracentral or eccentric cavities), rather than its size, may be better correlated with the clinical findings (Milhorat et al., 1995). It was found that neuropathic pain is generally homolateral to the cavitation in cases of paracentral or eccentric cavities (Milhorat et al., 1995, 1996; Attal et al., 1999; Boivie, 1999).
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PAIN IN SYRINGOMYELIA/BULBIA Fig. 47.1 Comparison of the frequency of neuropathic dimensions (%) between patients with syringomyelia (n = 36), central post-stroke pain (n = 24), multiple sclerosis (n = 23) and traumatic spinal cord injury (n = 15) (Bouhassira et al., 2005).
% 100 90 80 70 60 50 40 30 20 10 0
Burning
Deep pain Paroxysmal pain Allodynia
Syringomyelia
47.2.2. Other types of pain Coexisting painful symptoms are frequent in syringomyelia/bulbia depending on the etiology of the syrinx (50 to 90% of cases) (Milhorat et al., 1996, 1999). Thus headache (generally a benign exertional headache, i.e. a headache that is intensified by coughing or sneezing), migraine, or cervico-occipital pain are frequent in patients with Chiari type I malformation (Milhorat et al., 1999; Taylor and Larkins, 2002; Buzzi et al., 2003). Benign exertional headache is thought to be related to the increased intrathecal pressure caused by the free flow of CSF being obstructed in the subarachnoid space and may respond to surgical treatment of the Chiari (Taylor and Larkins, 2002; Sansur et al., 2003). However, migraine and benign exertional headache may coexist in the same patient and respond similarly to anti-migraine pharmacologic treatment (Buzzi et al., 2003). Trigeminal neuralgia and cluster-like facial pain have also been described and may also respond to surgical treatment of the syrinx (Rosetti et al., 1999). Visceral pain (due to renal calculus, bowel, or sphincter dysfunction, for example) and musculoskeletal pain (due to bone, joint, muscle trauma or inflammation, mechanical instability, muscle spasms and secondary overuse syndrome) may be observed in syringomyelia related to spinal cord trauma (Siddall et al., 1997; Siddall and Loeser, 2001). Finally, peripheral neuropathic pain due to nerve root entrapment or arachnoiditis is common in syringomyelia caused by meningitis. 47.2.3. Sensory deficits All patients with syringomyelia have some degree of thermoalgesic deficit in their painful area. Such a deficit may be unilateral or bilateral and have a segmental distribution, generally over the neck, shoulder, trunk and arms, but may also affect the face. It is located or predominates
Post-stroke Pain
Spinal Cord Trauma
Paresthesia
Multiple Sclerosis
ipsilaterally to the paracentral extension of the syrinx in cases of eccentric or paracentral cavities (Milhorat et al., 1996; Attal et al., 1999; Ducreux et al., 2006). It may range from mild hypoesthesia or hypoalgesia (diminished pain in response to a normally painful stimulus) to complete anesthesia or analgesia. Sensory deficit can be detected and quantified best by quantitative sensory testing (QST), which indicates an impairment of thermal sensation in nearly 100% of cases. There are almost always increased warm and cold detection thresholds and to a lesser extent increased pain thresholds (Boivie et al., 1994; Attal et al., 1999; Boivie, 2003, 2006; Bouhassira et al., 2000; Ducreux et al., 2006). This is similar to that observed in other central pain conditions (Vestergaard et al., 1995; Bowsher, 1996, 1998; Eide et al., 1996; Boivie, 2003, 2006; Defrin et al., 2001; Finnerup et al., 2003). QST is also useful to follow the outcome of syringomyelic patients (Attal et al., 2004). Thus we have recently shown that the thermoalgesic deficit generally does not improve after surgical decompression of the syrinx, except in patients operated on early (i.e. less than 2 years) after the onset of their symptoms (Attal et al., 2004). Proprioceptive/tactile sensation is usually considered to be not affected. However, in up to 50% of patients, loss of proprioceptive/tactile sensation has been observed (Honan and Williams, 1993). Increased vibration and/or mechanical thresholds may be observed by quantitative sensory testing (Attal et al., 1999, 2004; Ducreux et al., 2006). Other signs of dorsal column dysfunction, such as an impairment of graphesthesia and movement direction, may also be observed (Attal et al., 1999; Ducreux et al., 2006). Proprioceptive deficits, assessed using quantitative sensory tests respond better than the thermal deficits to surgical treatment of the syrinx (Attal et al., 2004). Loss of vibration and position sense may also be present in the lower limbs, particularly in cases of Chiari malformation.
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47.2.4. Associated symptoms and signs Generally there is no motor impairment in the early stages of the disease. By contrast, as the cavity enlarges, there may be corticospinal tracts and/or segmental impairment of the anterior horn, leading to pyramidal syndrome and muscular amyotrophy, respectively. Tendon reflexes are generally absent, except in some patients with Chiari malformation. In these patients the tendon reflexes may be normal or increased. Depending on the etiology of the syrinx, patients may also have variable clinical features, including nystagmus, cerebellar ataxia and lower cranial nerve impairment such as palatal and vocal cord paresis, particularly in Chiari malformation (with or without syringobulbia). Kyphoscoliosis is present in many cases and overt cervico-occipital malformation is present in nearly a quarter of patients (Victor and Ropper, 2001). 47.3. Mechanisms of central pain in syringomyelia Syringomyelia is a typical model of a “pure” intraspinal lesion predominantly affecting the spinothalamic tract. It is therefore of particular interest for studying the mechanisms underlying central pain, particularly with regards to the disputed role of spinothalamic lesion in neuropathic pain. In animal models developed over the last few years to study the mechanisms of central pain, lesions are usually induced by excitotoxic or ischemic injury, leading to damage of the spinal gray matter. These models present pathological characteristics, including neuronal loss, glial response and syrinx formation, resembling those observed in syringomyelia, particularly post-traumatic cavities (Christensen and Hulsenbosch, 1997; Yezierski et al., 1998; Vierck et al., 2000; Yezierski, 2001). Therefore they are of particular interest for studying the cellular, molecular, anatomical and physiological consequences of an intraspinal injury. Here, we will review the main theories of the mechanisms of central pain and their possible relevance for syringomyelia, the role of spinal versus supraspinal structures in the pain of syringomyelia, and then present evidence suggesting that the clinical symptoms of syringomyelia may be sustained by distinct mechanisms. 47.3.1. The main hypotheses of central pain mechanisms and their relevance to syringomyelia The mechanisms of central pain have been studied for over 100 years but still remain largely unknown. The principal hypotheses fall into two major categories: central imbalance and/or disinhibition and central sensitization.
Both phenomena can trigger abnormal neuronal hyperexcitability of spinal and/or supraspinal structures (references in Finnerup et al., 2003; Attal and Bouhassira, 2004; Finnerup and Jensen, 2004). Such hyperexcitability has been observed in animal models of spinal cord injury (Vierck et al., 2000; Yezierski, 2000) and also in some patients with central pain, in the dorsal horn (Loeser et al., 1968; Edgar et al., 1993; Falci et al., 2002) and in the lateral and medial thalamus (Lenz et al., 1989, 1994, 2000; Jeanmonod et al., 1993). 47.3.1.1. Central imbalance Patients with central pain nearly always have abnormal temperature and pain sensibility, but may have normal touch and vibration sensation (Boivie, 2006). This suggests that the presence of a spinothalamic dysfunction is a necessary condition for the occurrence of central pain, whereas the dorsal columns/medial lemniscus system are less commonly affected. This is further supported by studies showing abnormalities in laserevoked potentials (reflecting the function of A–δ nociceptive fibers) on the painful side of patients with post-stroke pain (references in Attal and Bouhassira, 2004) and syringomyelia (Kakigi et al., 1991; Treede et al., 1991), whereas sensory evoked potentials served by large-diameter fibers, correlated to the decrease in touch and vibration sensibility, may be preserved (Beric et al., 1988). It has been proposed that below-level pain associated with spinal cord injury is induced by an imbalance of integration between the unaffected dorsal column/medial lemniscus activity and the affected spinothalamic tract (Beric et al., 1988; Beric, 1993). However, recent psychophysical studies of patients with spinal cord injury with or without below-level pain have shown that there is a similar degree of thermoalgesic deficits in patients with pain and those without pain (Defrin et al., 2001; Finnerup et al., 2003). Similarly, the extent and magnitude of thermal deficits, assessed in 46 consecutive patients with syringomyelia, are similar in patients with pain and those without pain (Attal et al., 1999; Bouhassira et al., 2000; Ducreux et al., 2006). These data suggest that the spinothalamic lesion is necessary but not sufficient to account for the development of central pain. 47.3.1.2. Disinhibition theories Since the original hypothesis of Head and Holmes (1911), the notion of a central disinhibition, particularly in the thalamus, has been one of the most favored pathophysiological theories of central pain (Cassinari and Pagni, 1969; Pagni, 1989; Casey, 1991; Jeanmonod et al., 1996). One hypothesis, the “thermosensory disinhibition” theory by Craig (1998, 2000, 2003 for references),
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which is based on the observation that thermosensory loss is the basic feature of nearly all central pain patients, proposes that central pain (particularly burning pain and cold allodynia) may be due to a reduction of the physiological inhibition of thermal (cold) systems on nociceptive neurons. In contrast with traditional conceptions, this theory views pain not only as a sensation but also as a “homeostatic emotion” and an aspect of interoception, defined as the physiological condition of the body. We recently tested this hypothesis in a psychophysical study of 46 patients with syringomyelia, of whom 31 suffered from neuropathic pain (Attal et al., 2005; Ducreux et al., 2006). We did not observe any correlation between the magnitude of thermal deficits and the amount of pain in the entire group of painful patients. However, patients with spontaneous pain only (without evoked pains) had more severe thermal deficits than those with allodynia, and the intensity of burning pain was correlated to the extent of warm and cold deficits. These patients also had more asymetrical thermal deficits compared to those with allodynia and painless patients. This might reflect an imbalance in thermoregulation which involves bilateral brain integration (Craig, 1998). Thus these data are compatible with the disinhibition theory of central pain in a subgroup of syringomyelic patients (ie, patients with spontaneous pain only) Another form of central disinhibition has been proposed to account more specifically for the pain of syringomyelia. In a study of 137 patients with syringomyelia, Milhorat et al. (1996) observed that the syrinx extended onto the dorsolateral quadrant of the spinal cord on the same side of the pain in 84% of patients. It was suggested that pain was due to a disturbance of pain-modulating centers in the dorsolateral quadrant of the spinal cord. However, it was not stated whether this pattern was less common in pain-free patients. 47.3.1.3. Central sensitization The hyperactivity of nociceptive neurons in central pain may also result from direct modifications of their electrophysiological properties, i.e. central sensitization. This may be due to damage to central neurons caused by excitatory amino acids related to NMDA receptor activation (Eide, 1998; Vierk et al., 2000) and possibly also from sodium channels (Max and Hagen, 2000; Hains et al., 2003). Indirect evidence for the role of central sensitization in spinal cord injury pains is provided by the beneficial effects of NMDA antagonists and sodium channel blockers seen in animal models (Wiesenfeld-Hallin et al., 1997; Eide, 1998)
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and patients with spinal cord injury pain (Eide et al., 1995; Attal et al., 2000, 2002; Finnerup et al., 2005) including syringomyelia (Attal et al., 2000, 2002). 47.3.2. Role of spinal versus supraspinal structures in the pain of syringomyelia Several recent studies on animals and humans have suggested, that the primary pain generator in at-level and below-level neuropathic pain associated with spinal cord injury pain may be the injury region itself (references in Finnerup et al., 2003; Finnerup and Jensen, 2004). The observation that pain and sensory deficits associated with syringomyelia predominate ipsilaterally to the extension of the cavity in cases of paracentral or eccentric cavities (Attal et al., 1999) is consistent with this hypothesis. More specifically, the ipsilateral dorsal horn or spinothalamic fibers before they cross the midline may be important sites for pain generation (Boivie, 2006). Animal models of intraspinal excitotoxic lesion have also shown spontaneous nociceptive behavior and enhancement of nociceptive reponses in dermatomes ipsilateral to the lesion (references in Vierk et al., 2000; Yezierski, 2001). Electrophysiological recordings in these models have demonstrated abnormal neuronal excitation in the dorsal horn adjacent to the injury (Yezierski and Park, 1993; Christensen and Hulsebosch, 1997; Vierck et al., 2000; Yezierski, 2001). The possible mechanisms of such segmental hyperexcitability are probably not specific and may involve sensitization or disinhibition. 47.3.3. Are the pain symptoms of syringomyelia sustained by distinct or similar mechanisms? Recent studies have suggested that the various painful symptoms of syringomyelia, particularly with regard to the subtypes of allodynia (mechanical or thermal), may be sustained by distinct mechanisms. Pharmacological studies have shown preferential effects of intravenous administration of the sodium channel blocker lidocaine on mechanical (dynamic and static) but not cold allodynia in patients with central pain, including several syringomyelic patients (Attal et al., 2000). Along the same lines, a recent functional imaging study of patients with syringomyelia presenting with cold or brush induced allodynia has revealed distinct activations patterns depending on the submodality of allodynia (Attal et al., 2005; Ducreux et al., 2006). Thus cold allodynia activates a “cold pain network” including activation of insular and cingular areas, which is similar to the pattern induced by noxious cold in heatlhy controls (Craig, 2000). In contrast, brushevoked allodynia did not induce significant activation
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of several structures of the “pain matrix”, particularly the insula and the ACC. The different patterns of activation between the two subtypes of allodynia might reflect distinct pathophysiological mechanims. 47.4. Treatment of central pain associated with syringomyelia As with other chronic pain syndromes, pain associated with syringomyelia has a major impact on quality of life and affective state (Widenström-Noga, 2002). Therefore, the treatment of such pain should include management of disability and the affective comorbid conditions through the cognitive behavioral therapies and rehabilitation programmes (Sjölund, 2002). 47.4.1. Pharmacological treatment There are no trials specifically devoted to the neuropathic pain of syringomyelia (Attal et al., 2006). Therefore recommended treatments must rely on studies carried out for other neuropathic pain conditions. On the basis of randomized controlled trials in spinal cord injury pain, pharmacological classes shown to have some efficacy include antiepileptics (particularly gabapentin and to a lesser extent lamotrigine), strong opioids, local anesthetics (i.v. lidocaine) and NMDA receptor antagonists (i.v. ketamine) and will not be detailed here (for reviews see Attal and Bouhassira, 2004; Attal et al., 2006; Finnerup and Jensen, 2004). Tricyclic antidepressants are considered the mainstay of therapy. However, the only placebo-controlled trial of amitriptyline in traumatic spinal cord injury pain proved negative, although this may be due to insufficient dosages and/or to inadequate assessment of neuropathic pain (Cardenas et al., 2002). Importantly, the response of these treatments may not play a major role in the etiology or topography of central pain. In controlled trials of intravenous morphine and lidocaine carried out in patients with central pain, the response to these drugs appeared similar in patients with syringomyelia, spinal cord trauma and post-stroke pain (Attal et al., 2000, 2002). Treatments may also have similar efficacy on at-level and belowlevel neuropathic pain due to spinal cord injury, as recently shown in a placebo-controlled trial of i.v. lidocaine (Finnerup et al., 2005). The response to treatments may rather be influenced by the clinical symptoms or their combination, suggesting distinct pain mechanisms (Bouhassira and Attal, 2004; Attal et al., 2006). However, these findings are based on small samples of patients. Therefore pharmacological studies in larger cohorts of patients using a detailed assessment of their various neuropathic pain symptoms and signs
are needed to confirm these data and define possible predictors of the response to treatments. 47.4.2. Is the surgical treatment of the syrinx effective on neuropathic pain? Although surgery (generally foramen magnum decompression in patients with Chiari malformation) is commonly proposed to syringomyelic patients with progressive neurological deterioration, very few prospective studies have evaluated its effects on neuropathic pain (references in Attal et al., 2004). These studies generally reported disappointing results, in contrast to the positive effects seen for the pain associated with Chiari malformation, such as headache and cervical pain. We recently carried out a prospective 2-year study of 15 patients with syringomyelia, of whom eight presented with neuropathic pain. We found that surgery of the syrinx produced no overall significant effect on ongoing pain intensity at 2 years, whereas pain induced by straining, as well as coexisting dynamic symptoms (i.e. pains induced by coughing, Valsalva’s maneuver) were relieved (Attal et al., 2004). The latter pains are probably more dependent on the dynamic characteristics of the syrinx fluid and flow, and may be particularly affected by surgical decompression which reduces the subarachnoid pressure. 47.4.3. Other surgical techniques Surgical neuromodulative or neuroablative techniques may be proposed in patients suffering refractory pain, although these techniques have seldom been studied in patients with syringomyelia. Spinal cord stimulation, although generally no longer recommended in the treatment of central pain, may still be an option in patients suffering from steady at level neuropathic pain, who have incomplete spinal lesions and preservation of dorsal column function (Sindou and Mertens, 2000). Thus syringomyelic patients may be possible candidates for such techniques. Data concerning extradural stimulation of the motor cortex are very limited in spinal cord injury pain. Studies have so far only concerned patients with traumatic lesions (references in N’Guyen et al., 2003). Among neuroablative surgical procedures, dorsal root entry zone (DREZ) may be beneficial in at level neuropathic pain after incomplete spinal cord injury, particularly paroxysmal and evoked pain (Sindou et al., 2001). However, there are very few data concerning the effects of this technique in syringomyelic patients (Prestor, 2001). Moreover, DREZ may occasionally aggravate the sensory deficits which are generally incomplete in patients with syringomyelia. Therefore this technique has a marginal
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place in the treatment of pain associated with syringomyelia. 47.5. Conclusion Pain is frequently associated with syringomyelia and generally consists of neuropathic (central) pain. Its main characteristics (burning, deep pain, paroxysmal pain and allodynia/hyperalgesia) are similar to those of other central pain conditions, which suggests that common mechanisms (either central sensitization or disinhibition) may be involved in these various pain disorders. However, the nature of these mechanisms may differ, depending on the clinical presentation, as suggested from psychophysical and functional MRI studies of syringomyelic patients. These data may have important implications with regard to pharmacological treatment. References Arias A, Millan I, Vaquero J (1991). Clinico-morphological correlation in syringomyelia: a statistical study assisted by computer measurement of magnetic resonance images. Acta Neurochir (Wien) 111: 33–39. Attal N, Bouhassira D (2004). Central pain states. In: The Neurobiology of Pain. Pappagallo M (Ed.). McGraw Hill, New York, pp. 301–320. Attal N, Brasseur L, Chauvin M, Bouhassira D (1998). A case of “pure” dynamic mechano-allodynia due to a lesion of the spinal cord: pathophysiological considerations. Pain 75: 399–404. Attal N, Cruccu G, Hanpaa M, Hansson N P, Jensen TS, Nurmikko T, Sampaio C, Sindrup S, Wiffen P (2006). EFNS guidelines on pharmacological treatment of neuropathic pain. E. J Neurol. in press. Attal N, Ducreux D, Parker F, Bouhassira D (2005). Central representation of allodynia in patients with syringomyelia. Abstract 50.5, Soc for Neurosciences, Washington. Attal N, Gaude V, Brasseur L, Dupuy M, Guirimand F, Parker F, Bouhassira D (2000). Intravenous lidocaine in central pain. A double-blind placebo-controlled psycho-physical study. Neurology 544: 564–574. Attal N, Guirimand F, Brasseur L, Gaude V, Chauvin M, Bouhassira D (2002). Effects of IV morphine in central pain: A randomized placebo-controlled study. Neurology 58: 554–563. Attal N, Parker F, Brasseur L, Tadié M, Bouhassira D (1999). Characterization of sensation disorders and neuropathic pain related to syringomyelia. A prospective study. Neurochirurgie 1,45(suppl.): 84–94. Attal N, Parker F, Tadié M, Aghakani N, Bouhassira D (2004). Effects of surgery on the sensory deficits of syringomyelia and predictors of outcome: a long term prospective study. J Neurol Neurosurg Psychiatry 75: 1025–1030. Baumgartner U, Magerl W, Klein T, et al. (2002). Neurogenic hyperalgesia versus painful hypoalgesia: two distinct mechanisms of neuropathic pain. Pain 96: 141–151. Beric A (1993). Central pain: “new” syndromes and their evaluation. Muscle Nerve 16: 1017–1024. Beric A, Dimitrijevic MR, Lindblom U (1988). Central dysesthesia syndrome in spinal cord injury patients. Pain 34: 109–116.
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Boivie J (2006). Central pain. In : Wall and Melzack’s Textbook of Pain, Fifth edition, S.B. McMahon and M. Koltzenburg (Eds), Churchill Livingstone, Elsevier, pp. 1057–1074. Boivie J (2003). Central pain and the role of quantitative sensory testing (QST) in research and diagnosis. Eur J Pain 7: 339–343. Boivie J, Hansson P, Lindblom U (Eds.) (1994). Touch, Temperature and Pain in Health and Disease: Mechanisms and Assessment. IASP Press, Seattle. Bouhassira D, Attal N (2004). Novel strategies for neuropathic pain. In: Physiopharmacology of Pain. Proceedings of a symposium in the honor of J-M Besson. Villanueva L, Dickenson AE (Eds.), Seattle, IASP Press, pp. 299–310. Bouhassira D, Attal N, Parker F, Brasseur L (2000). Quantitative sensory evaluation of painful and painless patients with syringomyelia. Proceedings of the IXth World Congress on Pain. Devor M, Rowbotham MC, WiesenfeldHallin (Eds.), Seattle, IASP Press, pp. 401–411. Bouhassira D, Attal N, Fermanian J, Al-Chaar M, Gautron M, Boureau F, Grisart J, Masquelier E, Rostaing S, Collin E, Lanteri-Minet M (2004). Development and validation of the Neuropathic Pain Symptom Inventory. Pain. 108: 248–257. Bouhassira D, Attal N, Alchaar M, Lanteri-Minet M (2005). Neuropathic pain symptom inventory: complementary validation study and classification of neuropathic pain. Abstract, XIth World Congress on Pain, Sydney, August 2005. Bowsher D (1996). Central pain: clinical and physiological characteristics. J Neurol Neurosurg Psychiatry 61: 62–69. Bowsher D, Leijon G, Thomas KA (1998). Central poststroke pain: correlation of MRI with clinical pain characteristics and sensory abnormalities. Neurology 51: 1352–1358. Buzzi MG, Formisano R, Colonnese C, Pierelli F (2003). Chiari-associated exertional, cough, and sneeze headache responsive to medical therapy. Headache 43: 404–406. Cardenas DD, Warms CA, Turner JA, Marshall H, Brooke MM, Loeser JD (2002). Efficacy of amitriptyline for relief of pain in spinal cord injury: results of a randomized controlled trial. Pain 96: 365–373. Carroll AM, Brackenridge P (2005). Post-traumatic syringomyelia: a review of the cases presenting in a regional spinal injuries unit in the North East of England over a 5-year period. Spine 30: 1206–1210. Casey KL (Ed.) (1991). Pain and Central Nervous Disease: The Central Pain Syndromes. Raven Press, New York. Cassinari V, Pagni CA (1969). Central Pain: A Neurological Survey. Harvard University Press, Cambridge, MA. Christensen MD, Hulsebosch CE (1997). Chronic central pain after spinal cord injury. J Neurotrauma 14: 517–537. Craig AD (1998). A new version of the thalamic disinhibition hypothesis of central pain. Pain Forum 7: 1–14. Craig AD (2000). The functional anatomy of lamina I and its role in post-stroke central pain. Prog Brain Res 129: 137–151. Craig AD (2003). A new view of pain as a homeostatic emotion. Trends Neurosci 26: 303–307. Cruccu G, Anand P, Attal N, Haanpaa M, Jorum E, GarciaLarrea L, Serra J, Jensen TS (2004). EFNS guidelines on assessment of neuropathic pain and treatment. Eur J Neurology 11: 153–162. Defrin R, Ohry A, Blumen N, Urca G (2001). Characterization of chronic pain and somatosensory function in spinal cord injury subjects. Pain 89: 253–263.
712
N. ATTAL AND D. BOUHASSIRA
Ducreux D, Attal N, Parker F, Bouhassira D (2006). Mechanisms of central neuropathic pain : a combined psychophysical and fMRI study in syringomyelia. Brain, in press. Edgar RE, Best LG, Quail PA, Obert AD (1993). Computerassisted DREZ microcoagulation: posttraumatic spinal deafferentation pain. J Spinal Disord 6: 48–56. Eide PK (1998). Pathophysiological mechanisms of central neuropathic pain after spinal cord injury. Spinal Cord 36: 601–612. Eide PK, Stubhaug A, Stenehjem AE (1995). Central dysesthesia pain after traumatic spinal cord injury is dependent on N-methyl-D-aspartate receptor activation. Neurosurgery 37: 1080–1087. Eide PK, Jorum E, Stenehjem AE (1996). Somatosensory findings in patients with spinal cord injury and central dysesthesia pain. J Neurol Neurosurg Psychiatry 60: 411–415. Falci S, Best L, Bayles R, Lammertse D, Starnes C (2002). Dorsal root entry zone microcoagulation for spinal cord injury-related central pain: operative intramedullary electrophysiological guidance and clinical outcome. J Neurosurg 97: 193–200. Finnerup NB, Jensen TS (2004). Spinal cord injury pain – mechanisms and treatment. Eur J Neurol 11: 73–82. Finnerup NB, Johannesen IL, Fuglsang-Frederiksen A, Bach FW, Jensen TS (2003). Sensory function in spinal cord injury patients with and without central pain. Brain 126: 57–70. Finnerup NB, Biering-Sorensen F, Johannesen IL, Terkelsen AJ, Juhl GI, Kristensen AD, Sindrup SH, Bach FW, Jensen TS (2005). Intravenous lidocaine relieves spinal cord injury pain: A randomized controlled trial. Anesthesiology 102: 1023–1030. Hains BC, Klein JP, Saab CY, Craner MJ, Black JA, Waxman SG (2003). Upregulation of sodium channel Nav1.3 and functional involvement in neuronal hyperexcitability associated with central neuropathic pain after spinal cord injury. J Neurosci 23: 8881–8892. Head H, Holmes G (1911). Sensory disturbances from cerebral lesions. Brain 34: 102–154. Heiss JD, Patronas N, DeVroom HL, Shawker T, Ennis R, Kammerer W, Eidsath A, Talbot T, Morris J, Eskioglu E, Oldfield EH (1999). Elucidating the pathophysiology of syringomyelia. J Neurosurg 91: 553–562. Honan WP, Williams B (1993). Sensory loss in syringomyelia: not necessarily dissociated. J R Soc Med 86: 519–520. Jeanmonod D, Magnin M, Morel A (1996). Low-threshold calcium spike bursts in the human thalamus. Common physiopathology for sensory, motor and limbic positive symptoms. Brain 119: 363–375. Jensen TS, Baron R (2003). Translation of symptoms and signs into mechanisms in neuropathic pain. Pain 102: 1–8. Jensen TS, Gottrup H, Sindrup SH, Bach FW (2001). The clinical picture of neuropathic pain. Eur J Pharmacol 429: 1–11. Kakigi R, Shibasaki H, Kuroda Y, Neshige R, Endo C, Tabuchi K, Kishikawa T (1991). Pain-related somatosensory evoked potentials in syringomyelia. Brain 114: 1871–1889. Lenz F, Kwan HC, Dostrovsky JO, Tasker RR (1989). Characteristics of the bursting pattern of action potentials that occurs in the thalamus of patients with central pain. Brain Res 496: 357–360. Lenz FA, Kwan HC, Martin R, Tasker R, Richardson RT, Dostrovsky JO (1994). Characteristics of somatotopic organization and spontaneous neuronal activity in the region of the thalamic principal sensory nucleus in patients with spinal cord transection. J Neurophysiol 72: 1570–1587.
Lenz FA, Lee JI, Garonzik IM, Rowland LH, Dougherty PM, Hua SE (2000). Plasticity of pain-related neuronal activity in the human thalamus. Prog Brain Res 129: 259–273. Levine DN (2004). The pathogenesis of syringomyelia associated with lesions at the foramen magnum: a critical review of existing theories and proposal of a new hypothesis. J Neurol Sci 220: 3–21. Loeser JD, Ward AA JR, White Jr LE (1968). Chronic deafferentation of human spinal cord neurons. J Neurosurg. 29: 48–50. Max MB, Hagen NA (2000). Do changes in brain sodium channels cause central pain? Neurology 54: 544–545. Merskey H, Bogduk N (Eds.) (1994). Classification of Chronic Pain. IASP Press, Seattle. Milhorat TH, Chou MW, Trinidad EM, Kula RW, Mandell M, Wolpert C, Speer MC (1999). Chiari I malformation redefined: clinical and radiographic findings for 364 symptomatic patients. Neurosurgery. 44: 1005–1017. Milhorat TH, Johnson RW, Milhorat RH, Capocelli AL, Pevsner PH (1995). Clinicopathological correlations in syringomyelia using axial magnetic resonance imaging. Neurosurgery 37: 206–213. Milhorat TH, Kotzen RM, MU HTM, Capocelli AL, Milhorat RH (1996). Dysesthetic pain in patients with syringomyelia. Neurosurgery 38: 940–947. N’Guyen JP, Lefaucheur JP, Keravel Y (2003). Motor cortex stimulation. In: Electrical Stimulation and the Relief of Pain. Pain Research and Clinical Management, Vol. 15. Simpson B (Ed.) Elsevier, Amsterdam, pp. 197–209. Pagni CA (1989). Central pain due to spinal cord and brainstem damage. In: Textbook of Pain. Wall PD, Melzack R (Eds.) Churchill Livingstone, Edinburgh, pp. 634–655. Prestor B (2001). Microsurgical junctional DREZ coagulation for treatment of deafferentation pain syndromes. Surg Neurol 56: 259–265. Rosetti P, Ben Taib NO, Brotchi J, De Witte O (1999). Arnold Chiari Type I malformation presenting as a trigeminal neuralgia: case report. Neurosurgery 44: 1122–1123. Rossier AB, Foo D, Shillito J, Dyro FM (1985). Posttraumatic cervical syringomyelia. Incidence, clinical presentation, electrophysiological studies, syrinx protein and results of conservative and operative treatment. Brain 108: 439–461. Sansur CA, Heiss JD, DeVroom HL, Eskioglu E, Ennis R, Oldfield EH (2003). Pathophysiology of headache associated with cough in patients with Chiari I malformation. J Neurosurg 98: 453–458. Schurch B, Wichmann W, Rossier AB (1996). Post-traumatic syringomyelia (cystic myelopathy): a prospective study of 449 patients with spinal cord injury. J Neurol Neurosurg Psychiatry 60: 61–67. Shannon N, Symon L, Logue V, Cull D, Kang J, Kendall B (1981). Clinical features, investigation and treatment of posttraumatic syringomyelia. J Neurol Neurosurg Psychiatry 44: 35–42. Siddall PJ, Loeser JD (2001). Pain following spinal cord injury. Spinal Cord 39: 63–73. Siddall PJ, Taylor DA, Cousins MJ (1997). Classification of pain following spinal cord injury. Spinal Cord 35: 69–75. Sindou M, Mertens P (2000). Neurosurgical management of neuropathic pain. Stereotact Funct Neurosurg 75: 76–80. Sindou M, Mertens P, Wael M (2001). Microsurgical DREZotomy for pain due to spinal cord and/or cauda equina injuries: long-term results in a series of 44 patients. Pain 92: 159–171.
PAIN IN SYRINGOMYELIA/BULBIA Sjolund BH (2002). Pain and rehabilitation after spinal cord injury: the case of sensory spasticity? Brain Res Rev 40: 250–256. Taylor FR, Larkins MV (2002). Headache and Chiari I malformation: clinical presentation, diagnosis, and controversies in management. Curr Pain Headache Rep. 6: 331–337. Treede RD, Lankers J, Frieling A, Zangemeister WH, Kunze K, Bromm B (1991). Cerebral potentials evoked by painful, laser stimuli in patients with syringomyelia. Brain 114: 1595–1607. Vaquero J, Martinez R, Arias A (1990). Syringomyelia-Chiari complex: magnetic resonance imaging and clinical evaluation of surgical treatment. J Neurosurg 73: 64–68. Vernon JD, Silver JR, Ohry A (1982). Post-traumatic syringomyelia. Paraplegia. 20: 339–364. Victor M, Ropper AH (2001). Diseases of the spinal cord. In: Adam’s and Victor’s Principles of Neurology, seventh edition. Adams RD, Victor M (Eds.) McGraw Hill, New York. pp. 1293–1345. Vierck Jr CJ, Siddall P, Yezierski RP (2000). Pain following spinal cord injury: animal models and mechanistic studies. Pain 89: 1–5.
713
Widerström-Noga EG (2002). Evaluation of clinical characteristics of pain and psychosocial factors after spinal cord injury. In: Spinal Cord Injury Pain: Assessment, Mechanisms, Management. Progress in Pain Research and Management. Yezierski RP, Burchiel KJ (Eds.) 23. IASP Press, Seattle, pp. 53–82. Wiesenfeld-Hallin Z, Aldskogius H, Grant G, Hao JX, Hokfelt T, Xu XJ (1997). Central inhibitory dysfunctions: mechanisms and clinical implications. Behav Brain Sci 20: 420–425. Williams B (1990). Post-traumatic syringomyelia, an update. Paraplegia 28: 296–313. Yezierski RP (2001). Pain following spinal cord injury: pathophysiology and central mechanisms. In: Progress in Brain Research. Yezierski RP, Burchiel KJ (Eds.) 129, Elsevier, New York, pp. 429–448. Yezierski RP, Park SH (1993). The mechanosensitivity of spinal sensory neurons following intraspinal injections of quisqualic acid in the rat. Neurosci Lett. 157: 115–119. Yezierski RP, Liu S, Ruenes GL, Kajander KJ, Brewer KL (1998). Excitotoxic spinal cord injury: behavioral and morphological characteristics of a central pain model. Pain 75: 141–155.