Central post-stroke pain: Current evidence

Journal of the Neurological Sciences 284 (2009) 10–17

Contents lists available at ScienceDirect

Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s

Review

Central post-stroke pain: Current evidence Gyanendra Kumar ⁎, Chetan Rasiklal Soni Department of Neurology, University of Missouri-Healthcare Columbia, Columbia, Missouri, USA

a r t i c l e

i n f o

Article history: Received 18 December 2008 Received in revised form 18 March 2009 Accepted 21 April 2009 Available online 6 May 2009

a b s t r a c t This article reviews the definition, epidemiology, and current evidence on pathophysiology, neuroanatomy, clinical features, and treatment of central post-stroke pain. © 2009 Elsevier B.V. All rights reserved.

Keywords: Central post-stroke pain Post-stroke pain CPSP

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . Epidemiology. . . . . . . . . . . . . . . 2.1. Incidence and prevalence . . . . . . 2.2. Age of onset of CPSP . . . . . . . . 2.3. Sex distribution . . . . . . . . . . 2.4. Time to onset of CPSP from stroke . 3. Pathophysiology . . . . . . . . . . . . . 4. Site of lesions that may result in CPSP . . . 4.1. Thalamus . . . . . . . . . . . . . 4.2. Lenticulocapsular hemorrhage (LCH) 4.3. Brainstem . . . . . . . . . . . . . 4.4. Cortical lesions . . . . . . . . . . 5. Size of lesions . . . . . . . . . . . . . . 6. Clinical features . . . . . . . . . . . . . 6.1. Laterality of lesions . . . . . . . . 6.2. Distribution of pain . . . . . . . . 6.3. Character of pain. . . . . . . . . . 7. Somatosensory evaluation . . . . . . . . . 8. Treatment . . . . . . . . . . . . . . . . 8.1. Pharmacologic treatment . . . . . . 8.2. Non-pharmacological approaches . . 9. Conclusion . . . . . . . . . . . . . . . . 10. Glossary . . . . . . . . . . . . . . . . . 10.1. Interoceptive cortex . . . . . . . . References . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

10 11 11 11 11 11 11 12 12 13 13 13 13 13 13 13 13 13 13 13 14 15 15 15 15

1. Introduction

⁎ Corresponding author. CE507, 5 Hospital Dr, Columbia, Missouri 65212, USA. Tel.: +1 573 882 4141; fax: +1 573 884 4249. E-mail address: [email protected] (G. Kumar). 0022-510X/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2009.04.030

International association for the study of pain (IASP) defines Central Pain (CP) as “pain initiated or caused by a primary lesion or dysfunction of the central nervous system (CNS)” [1], i.e., of the spinal cord, brainstem or cerebral hemispheres. This definition is broad

G. Kumar, C.R. Soni / Journal of the Neurological Sciences 284 (2009) 10–17

enough to encompass pain associated with movement disorders (e.g., Parkinson's disease and dystonias) and epileptic fits which are not associated with spinothalamocortical dysfunction, a cardinal feature in CP. Thus, CP may be accurately identified in the presence of “spontaneous and/or evoked, persistent and/or paroxysmal pain or dysasthesia/parasthesia that is caused by dysfunction of spinothalamocortical pathway resulting from a lesion of the CNS.” Any disease process affecting the spino- and quintothalamic pathways, anywhere from dorsal horn/sensory nucleus of trigeminal nerve to the parietal cortex, can cause CP. CP that results from stroke is referred to as central post-stroke pain (CPSP). CPSP has been confused with a number of other conditions, most prominently peripheral neuropathic pain (PNP), and thalamic pain. CPSP and PNP have been typically lumped together under the rubric of “deafferentation pain” on the premise that they are associated with sensitization resulting from decreased sensory input into CNS and also share clinical features [2]. In 1990 a consensus group [3] concluded that: “The term ‘deafferentation pain’ as presently used is misleading and should perhaps be abandoned altogether for purposes of clinical diagnosis.” Thalamic pain, although a less common but best known form of CPSP, has been indiscriminately and interchangeably used to mean CPSP ever since Dejerine and Roussy described it in thalamic stroke in 1906 [109]. Most CPSP is due to extrathalamic lesions but the term pseudothalamic pain (i.e., CP caused by extrathalamic lesions) can be misleading and should be avoided. CPSP continues to be an underrecognized complication of stroke despite its potential to impair activities of daily living and deteriorate quality of life, consequently undermining rehabilitation efforts [4–6]. Its indescribable and incomprehensible character and nagging and constant nature render the patient functionless by deteriorating motivation, interfering with thought processes, altering mood and intellect, leading to neurotic tendencies and depression, and even conferring suicide risk [7,8]. CPSP, coupled with loss of sleep and appetite, often results in prescription drug dependence, further leading to loss of libido, poor social interactions and inability to work vocationally. The overall burden of CPSP, combined with the financial obligation on society, is immense and devastating [5,9,10]. 2. Epidemiology 2.1. Incidence and prevalence CPSP had been considered rare for years with the assumption based on retrospective surveys [11,12]. The prevalence varies from 8% to 46% [13–16]. Clinical studies in stroke patients, based on observations in general wards, stroke units and recently a population based survey, have evaluated CPSP [5–8]. Wide variation in prevalence rates is attributed to heterogeneity of lesions in the patient populations surveyed, difference in study design, as well as different times from the onset of stroke at the time of study [17]. Incidence and prevalence based on lesion location are discussed in Table 1.

11

2.2. Age of onset of CPSP General impression from most prospective and retrospective studies is that CPSP may affect younger patients (sixth decade versus seventh decade), however this remains unconfirmed [34]. 2.3. Sex distribution Stroke is more common in men than in women. Nasreddine and Saver's review found more men suffering CPSP after thalamic stroke [18]. Wallenburg syndrome is more common in men than in women. One would expect men to be suffering more from CPSP but definitive data delineating sex distribution is lacking. 2.4. Time to onset of CPSP from stroke CPSP can develop immediately or up to 10 years after the cerebrovascular event. CPSP is a presenting symptom in 1/4th patients but usually develops 3–6 months after stroke [34]. After a thalamic stroke CPSP develops immediately in 18%, within the first week in 18%, 1 week to 1 month 20%, 1–3 months 15%, 3–6 months 12%, 6–12 months 6%, more than 1 year after thalamic infarct in 11% [18]. CPSP occurred up to a month after thalamic hemorrhage [25]. In another series it occurred immediately in 40% in posterolateral and 34% in dorsal hemorrhages, and up to 14 days after admission on average [27]. CPSP after LMI (lateral medullary infarcts) developed immediately in 14.3%, after 1 month in 28.6%, between 1 and 3 months in 43%, after 6 months in 7% [32]. Average time span between LMI and CPSP was 4 weeks (range 1–24 weeks) [29]. Lenticulocapsular hemorrhage produced CPSP in 0–24 months after the ictus, more prominently in legs than other areas [72]. CPSP develops 1–7 months after a cortical inciting lesion [35,36]. 3. Pathophysiology Although thalamus is still considered to play a key role recent studies have accorded diverse pathophysiological mechanisms, including cortical processing [17,37], to generation of CPSP. Functional reorganization of somatosensory circuits occurs in CPSP as has been revealed by functional neuroimaging [38] and thalamic microelectrode recordings [39]. Several hypotheses have been proposed to explain central pain. The major ones are: A. Central imbalance, B. Central disinhibition (thermosensory disinhibition), C. Cerebral sensitization leading to hyperactivity or/hyperexcitability of spinal/supraspinal nociceptive neurons, and, D. Grill illusion theory. A. Central imbalance: Dissociated sensory loss [abnormal temperature and pain sensitivity but normal touch and vibration perception] is an important phenomenon in central pain suggesting the possibility of

Table 1 Incidence and prevalence based on lesion location. Site of stroke Thalamus [18]

Incidence

Prevalence

Any thalamic stroke

No data

Thalamic infarcts [19–23]

7.5% [11% with sensory impairment; 17% with inferolateral territory lesions and ventrocaudalis lesions] 9–32%

11% (range 8–16%); rises to 24% (range 13–59%) with geniculothalamic artery stroke. 6–30% [geniculothalamic 24%]

Thalamic hemorrhage [24–27]

Brainstem [28–32] Cortex [33]

Pontine stroke Wallenburg Medial medullary infarction

12% 24% 29% 4–5%

6–32% [Posteromedial hemorrhage 25%; Posterolateral 32%; Dorsolateral 32%; Anterior and global 0%; hemorrhage localized in the thalamus (9.5%); extends to internal capsule (5.7%); extends into midbrain or putamen (3.2%)] No data 25–44% No data No data

12

G. Kumar, C.R. Soni / Journal of the Neurological Sciences 284 (2009) 10–17

an imbalance in CPSP. Laser evoked potential studies which evaluate Aδ nociceptive fibers are abnormal, [40,41] on the other hand somatosensory evoked potentials, which evaluate large diameter fibers, correlate with increased touch and vibration sensitivity [42]. It has been proposed that central pain and dysesthesia could be induced by imbalance of integration between spared dorsal column/medial lemniscus activity and lesioned spinothalamic tract [43,44]. However, central pain may also occur following complete supra-spinal lesions that affect all types of sensations. The changes can range from alteration in threshold for warmth and cold to total absence of sensation. Spinothalamic modulatory deafferentation at different levels of CNS is variable and responsible for minimal to severe sensory loss in the affected region. The intensity of pain does not correlate with the degree of spinothalamic deafferentation; however, central pain may develop in the absence of pain perception in hemibody. Damaged spinothalamic tract results in transmission of nociceptive impulses through alternate pathways — multisynaptic paleo-spinothalamic pathways. Transmission of pain through alternate pathways (e.g. dorsal column) has been supported by persistence of pelvic pain despite spinothalamic deafferentation of the opposite side i.e. relief of cancer related pelvic pain through dorsal myelopathy [45,46]. Imbalance of dorsal and spinothalamic, and submodalities of spinothalamic sensation is the most viable basis. Rarely pain is aggravated by transcutaneous electrical nerve stimulation (TENS) or spinal cord stimulation [47]. Another form of imbalance in between lateral spinothalamic system which projects via lateral thalamic nuclei to insular region and medial system projecting to medial thalamic system to anterior cingulate region has been proposed to account for post stroke allodynia [48]. The mechanisms by which an imbalance of integration between these two systems could induce central pain are however unknown. B. Central disinhibition (thermosensory disinhibition hypothesis): Central disinhibition, particularly at thalamic level, has been one of the most popular pathophysiological theories of central pain [49]. Head and Holmes proposed that stroke in the lateral thalamus could disinhibit the activity of medial thalamus and cause pain [50]. An indirect route of such disinhibition via thalamic reticular nuclei that contain inhibitory interneurons has been suggested [51]. Delay in onset of CPSP frequently coincides with slow return of motor and sensory functions, mainly dorsal column function, after stoke. Both central and dorsolateral thalamus receive afferents from all modalities with close intrinsic network of GABAergic neurons in ventral posterolateral (VPL) thalamic nuclei. Medial thalamus has some modulatory effect on lateral thalamus [52]. It has been speculated that the loss of these GABAergic neurons caused by early nonspecific deafferentation, the return of function in the large afferent system now lacking, results in intrinsic inhibition of VPL. Subsequently, this activates other cortical areas in an unlearned fashion which results in a sensation never experienced before. This may also explain that sometimes focal cortical and subcortical lesions may abolish central pain [53]. Thermo-sensory loss is the central feature of nearly all central pain. It has been suggested that CPSP, particularly burning pain and cold allodynia might be due to reduction of physiological inhibition of thermal (cold) system on nociceptive neurons. This thermosensory disinhibition theory provides a general framework for understanding homeostatic nature of pain [54]. This theory, based on healthy volunteers and animals, posits that central pain results from the loss of descending controls from interoceptive cortex on brainstem homeostatic sites that drive thermoregulatory behaviour by way of the medial thalamus and the anterior cingulate cortex. The disinhibition proposed by this hypothesis is conceptually similar to the unmasking shown by the thermal-grill illusion (discussed below). This proposal views central pain as a thermoregulatory dysfunction, and it emphasizes the concept that pain is not only a feeling, but also a behavioural drive that signals a homeostatic imbalance [55]. A study comparing stroke patients with and without pain provided indirect support for this theory by showing

that painful patients with supratentorial lesions had more cold deficit than pain-free controls [56]. C. Central sensitization: Hyperexcitability of central nociceptive neurons may be responsible for spontaneous pain and allodynia. Microelectrode recordings in patients with central pain have revealed abnormal spontaneous evoked bursting activity within deafferented regions of lateral and medial thalamic nuclei in some patients with CPSP [51,57]. Abnormal qualitative firing of thalamic neurons [58] leads to apparent lack of generalized increase in thalamic excitation. There may not be a large surge in thalamic activity, rather an abnormal haphazard and asynchronous multifocal continuous activity that results in an overall decrease in thalamic activity which is evident as hypometabolism on PET scans and hypoperfusion on SPECT. The metabolic activity increases with pain relieving procedures [59]. Hypoperfusion and hypometabolism of thalamus on SPECT and PET may be epiphenomena of thalamic dysfunction or thalamic deafferentation. Hyperactivity of nociceptive neurons in central pain results from direct modification of their electrophysiological properties— central sensitization. This could involve damage to central neurons from excitatory amino acids related to NMDA receptor activation and possibly also from sodium channels. Indirect evidence for the role of central sensitization in central pain is provided by beneficial effect of NMDA antagonists and sodium channel blockers in animal models [60]. D. Grill illusion theory: Alternate wires on Thunberg's grill (1896) [62] are warmed or cooled to an extent short of producing pain. PET studies have shown that cingulum is activated during illusion and not during warm or cold stimulation, suggesting important role of cingulum in central pain [61]. The thermal-grill illusion can be explained physiologically by an unmasking of the cold evoked activity of polymodal nociceptive lamina I spinothalamic neurons by spatial summation of the simultaneous warm stimuli in the thermoreceptive but not the nociceptive neurons [62]. Functional imaging has confirmed that the thermal grill produces a pattern of activity in the cortex that is identical to the activation produced by noxious cold [61]. This theory explains how the medial thalamic lamina I spinothalamic tract projection to the mediodorsal thalamic nucleus might be the crucial site for the inhibition of thermal pain by cold [55]. 4. Site of lesions that may result in CPSP Despite detailed clinical and radiological evaluation as well as indepth assessment of deficits in a large number of patients it has been difficult to draw outlines that would be able to accurately illustrate the lesion in CPSP [37]. 4.1. Thalamus Most CPSP is supratentorial (roughly 80%) [2]. Contrary to earlier belief, less than one third of CP of brain origin is purely thalamic [2,63–67] and complete thalamic syndromes are exceptional. Ventrposterolateral (VPL) thalamic ischemic lesions [24], specifically ventrocaudalis nucleus, may result in CPSP; right sided (nondominant) thalamic lesions were more commonly associated with CPSP [68]. There may be extension of lesions into posterior limb of internal capsule or corona radiate [69]. The most consistent association is with thalamogeniculate (posterolateral/inferolateral thalamic) infarcts [18–21,23]. It has been a fairly consistent observation that CPSP does not develop after median/centromedian thalamic infarcts [68,70] or complete deafferentation of the ventrolateral nuclei [70] that results in analgesia [71]. Thalamic lesions producing CPSP tend to be very small and involve ventrocaudalis (3/4) and ventrocaudalis, parvocellularis and pulvinar in 1/4 cases [22]. CPSP did not occur in any patient in the anterior and global thalamic hemorrhage (large hematomas occupying the whole thalamus, clinically and radiologically similar to posterolateral group) groups [27]. Authors

G. Kumar, C.R. Soni / Journal of the Neurological Sciences 284 (2009) 10–17

have attributed compressive effects from median and dorsal lesions (thalamic hemorrhage) to development of CPSP [25]. 4.2. Lenticulocapsular hemorrhage (LCH) In Kim's patients, lesions involved the dorsal part of PLIC and leg was more severely involved than the arm. Higher frequency of CPSP in legs following intracerebral hemorrhage (ICH) was attributed to medio-lateral arrangement of fibers to face, arm, trunk and leg in the ventroposterior nucleus of thalamus. Posterolateral thalamus may have been involved in some patients with LCH [72]. 4.3. Brainstem The most common site of brainstem stroke is the medulla oblongata (medial and lateral medullary infarcts), with few cases of pontine and midbrain spontaneous CP having been reported [67,73–75]. CPSP of brainstem origin is generally due to thrombosis of the posteroinferior cerebellar artery (PICA) resulting in Wallenberg's syndrome.

13

burning, pricking, lancinating, tearing, squeezing, throbbing, icy, scalding, cutting, splitting, sore, etc. When asked to describe their pain quality CPSP patients sound like pain imbeciles. They only tell of the components if they pay very close attention, and then only with cues from the examiner (www.painonline.org). ‘Burning’ may connote more than one pain quality, often composed of a burn plus a metallic sensation, an icy cold feeling and usually a wet component [18,29,37,56,67,72,83]. There are three components to pain of CPSP [2]. A spontaneous constant pain is almost always present. A spontaneous intermittent component (15%) that has an intense severity and a shooting, lancinating, quality, the duration of which may vary from a few seconds to a few minutes, may be the predominant complaint. It is usually a daily pain with varying pain-free intervals lasting a few hours at the most. A third evoked component, seen in 65% patients, is hyperalsgesia, hyperpathia, hyperesthesia, and/or allodynia [2]. A given patient may experience one or more of these components. Spontaneous pain tends to be more distal as opposed to evoked pains that are more proximal in location. Incomplete loss of motor strength predisposes to a greater number of pain components [18,29].

4.4. Cortical lesions 7. Somatosensory evaluation All cortical lesions responsible for CP involve, exclusively or in combination, the parietal lobe, and specifically SI (and also SII) [76]. Lesions of deep white matter in the parietal lobe underlying the rostral inferior parietal lobe and SII may be associated with CPSP [77]. SI (postcentral gyrus) was spared in all 4 of Bowsher's patients and involved SII, SII + Insula, both banks of sylvian fissure + dorsal insula, and upper bank of sylvian in the fourth [78]. 5. Size of lesions Data have suggested that complete destruction of thalamus is incompatible with generation of CPSP [79]. It appears that site of lesion is more important than the volume of lesion. 6. Clinical features 6.1. Laterality of lesions Right sided lesions predominate among CPSP patients at both cortical and thalamic levels [34]. The difference is not due to difficulty in communication after left lesions (moreover, right lesions may cause anosognosia and neglect more frequently). The reason for such laterality is not known. 6.2. Distribution of pain Pain of CPSP is diffuse and difficult to characterize but its location is easily described by most patients. It can be easily localized to the site of lesion, for example, left face and hemibody in right thalamic infarct, left face. The area of pain may be the same as the sensorimotor deficit but may also be patchy, involving only a part of the area harboring the neurological deficit [36,80]. Pain may wander from one limb to another and intense pain in one limb may be associated with only paresthesias in the face, or vice versa [81,82]. It may also occur with complete anaesthesia but never localized to an area not involved by the stroke. It may be experienced as deep as if coming from the bones, superficial as if occurring in the skin, or both in varying proportions. 6.3. Character of pain Patients find it difficult to characterize the quality of their pain. Patients may experience one or more types of pain at a given time, in one or more body regions. Variation in pain quality is more of a rule than an exception. Pain may be commonly aching, shooting, stabbing,

Although CPSP is more common in patients with right sided lesions, hypoasthesia, abnormalities of deep sensibility and dysasthesia seem equally frequent in patients with left sided or right sided lesions [68]. SEP in 24 CPSP and 6 pain-free thalamic syndrome patients revealed complete loss of contralateral cortical SEPs but preservation of P9, P14, N18 far-fields in 10 patients. All 10 patients complained of spontaneous burning/crushing pain. Hyperpathic overreaction to touch was seen in 7 of them. Six patients had geniculothalamic artery infarcts, 3 posterior thalamic hemorrhages, and 1 had a capsulothalamic hemorrhage. In 6/24 abnormal contralateral cortical SEPs with prolonged latency and/or decreased voltage were seen. These patients had painful paresthesias and hyperpathic reaction to repeated touch. Four had a geniculothalamic infarct and 2 capsulothalamic hemorrhage. In remaining 8/24 there was no difference in cortical SEPs between affected and unaffected side. These patients complained of painful paresthesia and allodynia/hyperpathia. None of them had spontaneous pain. Lesion was located in anterolateral thalamus in 2 cases, caudal pole of posterior thalamus in 1 case and posterolateral thalamus in 5 cases. In 6 pain-free patients cortical SEPs were absent after median nerve stimulation on the affected side but P9, P14, and N18 were unaffected [42]. In another study on 43 patients with thalamic or thalamocapsular lesions, 12 patients had impaired SEPs, 12 had abolished, and 5 had normal SEPs. Hyperpathia was seen in 18/20 and allodynia in 13/20 patients [70]. 8. Treatment Treatment of CPSP remains a challenge as treatment options are limited in number and efficacy. CPSP affects the quality of life as well as mood of patients, thus intertwining pain management with management of psychological comorbidity. There are pharmacological and surgical approaches to treatment. 8.1. Pharmacologic treatment Pharmacological options include antidepressants, antiepileptics, opioids, NMDA-receptor antagonists, antiarrhythmics, and miscellaneous therapies. Some authors have advocated a stepwise approach to treatment of their patients but these remain untested and lack a strong evidence base [7]. The three-step process begins with the use of tricyclics and other

14

G. Kumar, C.R. Soni / Journal of the Neurological Sciences 284 (2009) 10–17

antidepressants and includes treatment of any adverse side effects caused by these agents. If antidepressant therapy is not effective, anticonvulsants, especially carbamazepine, are added if the pain has a sharp, lancinating component. Opioids or other agents are given if antidepressants and anticonvulsants alone are not helpful. If all standard pharmacologic treatments fail, continuing supportive therapy with a psychiatrist or psychologist experienced in pain management and treatment of ongoing psychological problems, especially depression, is mandatory [7]. Antidepressants: Antidepressants, especially tricyclic antidepressants (TCA), have specific analgesic activity independent of their antidepressant effect. The efficacy of TCA in central pain is supported by only a small randomized trial. In 15 patients with post stroke pain, amitryptiline 75 mg was superior to carbamazepine and placebo [84]. There is great intra-individual variability as to the optimal dosage of TCA for pain relief. Contradictory results have been reported concerning plasma levels of TCA and pain relief. Higher plasma levels of amitryptiline were associated with greater relief in CPSP [84]. Treatment is typically begun with a low dose, 10–20 mg/d, titrating upward weekly to a dose that results in relief or intolerable side effects. Onset of efficacy is apparent 4–7 days after reaching the optimal dose. It is recommended to treat for several months before trying dose reduction. Most patients are unable to reach an optimal dose of TCA for pain relief because of anticholinergic side effects. Elderly patients are particularly sensitive to side effects of TCA, hence caution is recommended after the age of 65 years. Antidepressants with a better side-effect profile (i.e. serotonin-specific re-uptake inhibitor category) appear to be significantly less effective in CPSP, but there are no published clinical studies that confirm this lack of benefit [85]. In an unrandomized, uncontrolled trial on 31 CPSP patients fluvoxamine was shown to be of benefit [86]. Antiepileptic drugs (AED): Antiepileptic drugs are the second most frequently used drugs in the management of central pain. These drugs reduce abnormal neuronal hyperexcitability through modulation of sodium/calcium channels and/or their effect on excitatory amino acids and/or GABA mediated disinhibition. Early studies on AEDs in central pain were not very promising. Carbamazepine (CBZ) 800 mg/d did not produce significant pain relief compared to placebo in 15 patients with CPSP. As with the TCAs, the use of carbamazepine is limited by its sideeffect profile and by the need for very gradual dose escalation, especially in the elderly (Leijon and Boivie [84]). However, a third of the patients responded to CBZ and more may have done so had higher plasma levels been achieved. CBZ may be effective in paroxysmal shooting pain related to CNS but side effects are reported in 25–50% patients, dizziness and somnolence being most common [87]. Carbamazepine caused more dose limiting side effects than amitryptiline. Titration should be gradual, beginning with 100 mg/d and increased to efficacy or intolerable side effects. Average analgesic dose is 800 mg (600–1600)/day. Oxcarbazepine, a ketoanalogue of CBZ, may be a possible substitute in patients intolerant to CBZ or with significant drug interaction but published controlled trails are lacking. A recent RCT reported significant efficacy of lamotrigine (200 mg/ d) in patients with CPSP with mean reduction of spontaneous pain by 30% [88]. In this trial it was also effective in cold allodynia but not on mechanical allodynia. Several open label studies have suggested the benefit of gabapentine in post stroke pain [89]. A study including 307 patients with peripheral and central neuropathic pain, 9 of them had CPSP, reported an overall effect of gabapentine titrated to 2400 mg/d over 8 weeks [90]. However, patients previously unresponsive to gabapentine were not included in this study and it is not clear if all the patients had neuropathic pain. Gabapentine may be effective in several pain components including pain paroxysms, and brush/cold induced allodynia related to both peripheral and central lesion [89]. The doses used vary from 1200–3600 mg with optimal dose of 1800 mg/d [91]. Most side effects occur during titration and include dizziness, somnolence, and weight gain on long-term use.

Zonisamide was found to be useful in a report of two patients with posterolateral thalamic infarcts [92]. Topiramate and valproate have not been found to be useful in central and neuropathic pain [93,94]. Results are awaited from a multi-Center, randomized, double-blind, placebo controlled trial evaluating the efficacy and safety of the newer antiepileptic drug, Pregabalin (http://clinicaltrials.gov/ct2/show/ NCT00313820), in CPSP. Opioids: On the basis of several controlled studies it has been suggested that opioids may relieve neuropathic pain provided sufficient doses are administered. Analgesic doses in neuropathic pain are twice that needed for reliving nociceptive pain [95]. Three randomized double-blind placebo controlled trials have evaluated opioids in central pain. In a trial of 15 patients with CPSP and spinal cord injury pain, IV morphine did not result in significant relief compared to controls, however, 46% patients had significant benefit from acute administration of the drug and most were relieved with sustained release morphine even after 1 month [96]. Morphine was effective in relieving brush induced allodynia in spinal cord injury pain [97]. These results suggest that IV morphine is effective in certain types of neuropathic pain, especially brush induced allodynia. Oral opioids are also effective in a subgroup of patients with central pain. However, benefit of opioids is maintained in less than 20% over 1–2 years [96]. Intravenous tramadol infusion was reported to be effective in a patient with CPSP of 10 years' duration refractory to CBZ and amitryptiline [98]. Intravenous naloxone was found to be of no value in alleviating the pain of CPSP in a randomized controlled trial against saline [99]. Methadone, a fourth line agent for use in chronic neuropathic pain, has not been evaluated in controlled studies for use in CPSP. Antiarrhythmics: Local anesthetics and their derivatives (antiarrhythmics) are sodium channel blockers. These compounds relieve spontaneous pain, mechanical dynamic and static allodynia. Thermally evoked pain is relieved to a lesser extent [100]. Lidocaine is the most effective agent available for central pain but it has to be administered intravenously. In a double-blind randomized placebo controlled trial on 16 subjects with central pain, 6 of whom had CPSP; lidocaine significantly improved the quality of spontaneous pain in 69% patients compared to 38% in placebo. Pain relief persisted up to 45 min after injection. It also reduced brush induced allodynia and mechanical hyperalgesia. However thermal allodynia and hyperalgesia were not significantly relieved [101]. After 7 days of study, 12 patients received mexiletine 200 mg/d which was titrated to 400 mg– 800 mg/d. Mexiletine which is an oral analogue of lidocaine was not as effective as lidocaine in the management of central pain. Two patients discontinued because of side effects. The efficacy of IV lidocaine may not translate into effective oral treatment by mexiletine. N-methyl-d-aspartate (NMDA) antagonists: Intravenous ketamine produced improvement in a CPSP patient unresponsive to other therapies [102]. Maintenance doses of specially compounded oral ketamine (50 mg three times per day) and oral diazepam (5 mg three times per day) were used to allay the dysphoria associated with ketamine administration. Other long-term pain medicines were subsequently withdrawn and reduced levels of pain and increased functionality were reported at 9 month follow up. The problem of a narrow therapeutic window offsets the use of ketamine in the clinical routine setting. 8.2. Non-pharmacological approaches Dorsal root entry zone (DREZ) lesions: Treatment options for patients refractory to conservative measures include dorsal root entry zone (DREZ) lesions and spinal cord stimulation [7]. Although spinal and trigeminal Nucleus Caudalis DREZ operations have been shown to be effective in the treatment of intractable pain syndromes, especially spinal cord CP [7], these have not been systematically evaluated in CPSP.

G. Kumar, C.R. Soni / Journal of the Neurological Sciences 284 (2009) 10–17

Motor cortex stimulation: Tsubokawa et al. [103] were the first to demonstrate that electrical stimulation of the motor cortex resulted in a reduction of pain in patients with CPSP. Subsequent results of the use of motor cortex stimulation to alleviate pain in patients with central pain have varied, with responses in several small studies ranging up to 100% [104,105]. Nguyen et al. [106] obtained a 77% response rate using somatosensory evoked potentials to confirm the position of stimulating electrodes. Deep brain stimulation has been effective in thalamic stroke syndrome [107]. MRI data has revealed that there is functional reorganization in ongoing phantom limb pain and can provide physiological basis for the efficacy of cortical stimulation [108]. Present status of use of this modality is limited to neurosurgical pain management centers for the exceptional CPSP patient that fails to respond to everything else. Repetitive transcranial magnetic stimulation (r TMS) is a noninvasive motor cortex stimulation technique that has been shown to be effective in CPSP and may produce longlasting pain relief [110], however, it is not as effective in brainstem strokes [111]. Deep brain stimulation (DBS) may be used in very select patients, especially when paraplegia is present [7]. It is unwise to ablate certain areas of the brain because of limited knowledge of the long term effects of ablation and a minimal understanding of CP's pathophysiology. The concern is that ablation might produce deficits or worsen existing pain.[49] Overall DBS has been disappointing for CPSP [112]. Vestibular Caloric Stimulation (VCS): There is report of relief of thalamic CPSP with VCS in 2 patients [113]. Transcutaneous electrical nerve stimulation (TENS) is occasionally helpful, especially acupuncture-like or low-frequency TENS [114]. Supplementing pharmacologic therapy with either standard TENS or low-frequency TENS and with psychosocial support in the form of family education is useful. Counseling helps to explain to family members why patients are in such pain and limited in their activities, even though nothing outwardly may appear to be wrong with them [7]. 9. Conclusion CPSP is a relatively under reported complication of stroke and often overshadowed by motor complications such as weakness, spasticity and aphasia. There is a wide spectrum of CPSP and in some patients it can be severe and disabling. Both pharmacological and non-pharmacological treatments are tried with variable success. However, most evidence is based on a small number of patients underscoring the need for further research. Primary outcome measures that are important for the patients and their families–such as dependency, and quality of life–should be evaluated. 10. Glossary 10.1. Interoceptive cortex Dorsal insular cortex embedded in which are the cortical representations of several highly resolved, distinct sensations, including temperature, pain, itch, muscular and visceral sensations, sensual touch and other feelings from the body. It contains a sensory representation of the small-diameter afferent activity that relates to the physiological condition of the entire body [55]. References [1] Merskey HM, Bogduk N. Classification of chronic pain. 2nd ed. Seattle: IASP Press; 1994. [2] Tasker RR. Microelectrode findings in the thalamus in chronic pain and other conditions. Stereotact Funct Neurosurg 2001;77(1–4):166–8. [3] Devor M. Neuropathic pain and injured nerve: peripheral mechanisms. Br Med Bull 1991 Jul;47(3):619–30. [4] Widar M, Ahlstrom G. Disability after a stroke and the influence of long-term pain on everyday life. Scand J Caring Sci 2002 Sep;16(3):302–10.

15

[5] Jensen MP, Chodroff MJ, Dworkin RH. The impact of neuropathic pain on health-related quality of life: review and implications. Neurology 2007 Apr 10;68(15):1178–82. [6] Appelros P. Prevalence and predictors of pain and fatigue after stroke: a population-based study. Int J Rehabil Res 2006 Dec;29(4):329–33. [7] Gonzales GR. Central pain: diagnosis and treatment strategies. Neurology 1995 Dec;45(12 Suppl 9):S11–6 discussion S35–6. [8] Gonzales GR. Suicide in central pain patients [abstract]. Neurology 1994;44 (suppl2):A318. [9] Gentry C. Where does it hurt? Wall Street J 1999:R6. [10] Zorowitz RD, Smout RJ, Gassaway JA, Horn SD. Usage of pain medications during stroke rehabilitation: the Post-Stroke Rehabilitation Outcomes Project (PSROP). Top Stroke Rehabil 2005;12(4):37–49 Fall. [11] Davis RA, Stokes JW. Neurosurgical attempts to relieve thalamic pain. Surg Gynecol Obstet 1966 Aug;123(2):371–84. [12] Bowsher D. Sensory consequences of stroke. Lancet 1993 Jan 16;341(8838):156. [13] Glader EL, Stegmayr B, Johansson L, Hulter-Asberg K, Wester PO. Differences in longterm outcome between patients treated in stroke units and in general wards: a 2-year follow-up of stroke patients in Sweden. Stroke 2001 Sep;32(9):2124–30. [14] Sulch D, Melbourn A, Perez I, Kalra L. Integrated care pathways and quality of life on a stroke rehabilitation unit. Stroke 2002 Jun;33(6):1600–4. [15] Pullen R, Harlacher R, Pientka L, Fusgen I. [The elderly stroke patient — observations 18 months after the event]. Z Gerontol Geriatr 1999 Oct;32(5):358–63. [16] Jonsson AC, Lindgren I, Hallstrom B, Norrving B, Lindgren A. Prevalence and intensity of pain after stroke: a population based study focusing on patients' perspectives. J Neurol Neurosurg Psychiatry 2006 May;77(5):590–5. [17] Leijon G, Boivie J, Johansson I. Central post-stroke pain—neurological symptoms and pain characteristics. Pain 1989 Jan;36(1):13–25. [18] Nasreddine ZS, Saver JL. Pain after thalamic stroke: right diencephalic predominance and clinical features in 180 patients. Neurology 1997 May;48(5):1196–9. [19] Bogousslavsky J, Regli F, Uske A. Thalamic infarcts: clinical syndromes, etiology, and prognosis. Neurology 1988 Jun;38(6):837–48. [20] Graff-Radford NR, Damasio H, Yamada T, Eslinger PJ, Damasio AR. Nonhaemorrhagic thalamic infarction. Clinical, neuropsychological and electrophysiological findings in four anatomical groups defined by computerized tomography. Brain Jun 1985;108(Pt 2):485–516. [21] Samuelsson M, Samuelsson L, Lindell D. Sensory symptoms and signs and results of quantitative sensory thermal testing in patients with lacunar infarct syndromes. Stroke 1994 Nov;25(11):2165–70. [22] Paciaroni M, Bogousslavsky J. Pure sensory syndromes in thalamic stroke. Eur Neurol 1998;39(4):211–7. [23] Kumral E, Evyapan D, Balkir K, Kutluhan S. Bilateral thalamic infarction. Clinical, etiological and MRI correlates. Acta Neurol Scand 2001 Jan;103(1):35–42. [24] Kawahara N, Sato K, Muraki M, Tanaka K, Kaneko M, Uemura K. CT classification of small thalamic hemorrhages and their clinical implications. Neurology 1986 Feb;36(2):165–72. [25] Kumral E, Kocaer T, Ertubey NO, Kumral K. Thalamic hemorrhage. A prospective study of 100 patients. Stroke 1995 Jun;26(6):964–70. [26] Mori S, Sadoshima S, Ibayashi S, Fujishima M, Iino K. Impact of thalamic hematoma on six-month mortality and motor and cognitive functional outcome. Stroke 1995 Apr;26(4):620–6. [27] Chung CS, Caplan LR, Han W, Pessin MS, Lee KH, Kim JM. Thalamic haemorrhage. Brain 1996 Dec;119(Pt 6):1873–86. [28] Kim JS, Bae YH. Pure or predominant sensory stroke due to brain stem lesion. Stroke 1997 Sep;28(9):1761–4. [29] MacGowan DJ, Janal MN, Clark WC, Wharton RN, Lazar RM, Sacco RL, et al. Central poststroke pain and Wallenberg's lateral medullary infarction: frequency, character, and determinants in 63 patients. Neurology Jul 1997;49(1):120–5. [30] Kameda W, Kawanami T, Kurita K, Daimon M, Kayama T, Hosoya T, et al. Lateral and medial medullary infarction: a comparative analysis of 214 patients. Stroke 2004 Mar;35(3):694–9. [31] Nakazato Y, Yoshimaru K, Ohkuma A, Araki N, Tamura N, Shimazu K. [Central poststroke pain in Wallenberg syndrome]. No To Shinkei 2004 May;56(5):385–8. [32] Kim JS, Choi-Kwon S. Sensory sequelae of medullary infarction: differences between lateral and medial medullary syndrome. Stroke 1999 Dec;30(12):2697–703. [33] Widar M, Ek AC, Ahlstrom G. , Coping with long-term pain after a stroke. J Pain Symptom Manage 2004 Mar;27(3):215–25. [34] Canavero S, Bonicalzi V. Central pain of brain origin: epidemiology and clinical features. Central pain syndrome: pathophysiology, diagnosis and management. 1 ed. Cambridge: Cambridge University Press; 2007. p. 9–99. [35] Fields HL, Adams JE. Pain after cortical injury relieved by electrical stimulation of the internal capsule. Brain 1974 Mar;97(1):169–78. [36] Michel D, Laurent B, Convers P, Garcia-Larrea L, Le Bas JF, Mauguiere F, et al. Cortical pain. Clinical, electrophysiologic and topographic study of 12 cases. Rev Neurol (Paris) 1990;146(6–7):405–14. [37] Bowsher D, Leijon G, Thuomas KA. Central poststroke pain: correlation of MRI with clinical pain characteristics and sensory abnormalities. Neurology 1998 Nov;51(5):1352–8. [38] Garcia-Larrea L, Peyron R, Mertens P, Gregoire MC, Lavenne F, Le Bars D, et al. Electrical stimulation of motor cortex for pain control: a combined PET-scan and electrophysiological study. Pain 1999 Nov;83(2):259–73. [39] Lenz FA, Lee JI, Garonzik IM, Rowland LH, Dougherty PM, Hua SE. Plasticity of pain-related neuronal activity in the human thalamus. Prog Brain Res 2000;129:259–73. [40] Bromm B, Frieling A, Lankers J. Laser-evoked brain potentials in patients with dissociated loss of pain and temperature sensibility. Electroencephalogr Clin Neurophysiol 1991 Jul–Aug;80(4):284–91.

16

G. Kumar, C.R. Soni / Journal of the Neurological Sciences 284 (2009) 10–17

[41] Garcia-Larrea L, Convers P, Magnin M, Andre-Obadia N, Peyron R, Laurent B, et al. Laser-evoked potential abnormalities in central pain patients: the influence of spontaneous and provoked pain. Brain 2002 Dec;125(Pt 12):2766–81. [42] Mauguiere F, Desmedt JE. Thalamic pain syndrome of Dejerine–Roussy. Differentiation of four subtypes assisted by somatosensory evoked potentials data. Arch Neurol 1988 Dec;45(12):1312–20. [43] Beric A. Central pain: “new” syndromes and their evaluation. Muscle Nerve 1993 Oct;16(10):1017–24. [44] Beric A, Dimitrijevic MR, Lindblom U. Central dysesthesia syndrome in spinal cord injury patients. Pain 1988 Aug;34(2):109–16. [45] Nauta HJ, Hewitt E, Westlund KN, Willis Jr WD. Surgical interruption of a midline dorsal column visceral pain pathway. Case report and review of the literature. J Neurosurg 1997 Mar;86(3):538–42. [46] Hirshberg RM, Al-Chaer ED, Lawand NB, Westlund KN, Willis WD. Is there a pathway in the posterior funiculus that signals visceral pain? Pain 1996 Oct;67(2–3):291–305. [47] Triggs WJ, Beric A. Dysaesthesiae induced by physiological and electrical activation of posterior column afferents after stroke. J Neurol Neurosurg Psychiatry 1994 Sep;57(9):1077–80. [48] Peyron R, Garcia-Larrea L, Gregoire MC, Costes N, Convers P, Lavenne F, et al. Haemodynamic brain responses to acute pain in humans: sensory and attentional networks. Brain 1999 Sep;122(Pt 9):1765–80. [49] Pagni CA. Central pain due to spinal cord and brain stem damage. In: Wall PD, Melzack R, editors. Textbook of pain. Edinburg: Churchill Livingstone; 1989. p. 634–55. [50] Head H, Holmes G. Researches into sensory disturbances from cerebral lesions. Brain 1911;34:102–254. [51] Jeanmonod D, Magnin M, Morel A. Low-threshold calcium spike bursts in the human thalamus. Common physiopathology for sensory, motor and limbic positive symptoms. Brain Apr 1996;119(2):363–75. [52] Ralston 3 rd HJ, Ralston DD. Medial lemniscal and spinal projections to the macaque thalamus: an electron microscopic study of differing GABAergic circuitry serving thalamic somatosensory mechanisms. J Neurosci 1994 May;14 (5 Pt 1):2485–502. [53] Melzack R, Loeser JD. Phantom body pain in paraplegics: evidence for a central “pattern generating mechanism” for pain. Pain 1978 Feb;4(3):195–210. [54] Craig AD. A new view of pain as a homeostatic emotion. Trends Neurosci 2003 Jun;26(6):303–7. [55] Craig AD. How do you feel? Interoception: the sense of the physiological condition of the body. Nat Rev Neurosci 2002 Aug;3(8):655–66. [56] Bowsher D. Central pain: clinical and physiological characteristics. J Neurol Neurosurg Psychiatry 1996 Jul;61(1):62–9. [57] Rinaldi PC, Young RF, Albe-Fessard D, Chodakiewitz J. Spontaneous neuronal hyperactivity in the medial and intralaminar thalamic nuclei of patients with deafferentation pain. J Neurosurg 1991 Mar;74(3):415–21. [58] Lenz FA, Kwan HC, Martin R, Tasker R, Richardson RT, Dostrovsky JO. 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 1994 Oct;72(4):1570–87. [59] Peyron R, Garcia-Larrea L, Deiber MP, Cinotti L, Convers P, Sindou M, et al. Electrical stimulation of precentral cortical area in the treatment of central pain: electrophysiological and PET study. Pain 1995 Sep;62(3):275–86. [60] Wiesenfeld-Hallin Z, Aldskogius H, Grant G, Hao JX, Hokfelt T, Xu XJ. Central inhibitory dysfunctions: mechanisms and clinical implications. Behav Brain Sci 1997 Sep;20(3):420–5 discussion 35-513. [61] Craig AD, Reiman EM, Evans A, Bushnell MC. Functional imaging of an illusion of pain. Nature 1996 Nov 21;384(6606):258–60. [62] Craig AD, Bushnell MC. The thermal grill illusion: unmasking the burn of cold pain. Science 1994;265:252–5. [63] Hirato M, Horikoshi S, Kawashima Y, Satake K, Shibasaki T, Ohye C. The possible role of the cerebral cortex adjacent to the central sulcus for the genesis of central (thalamic) pain—a metabolic study. Acta Neurochir Suppl (Wien) 1993;58:141–4. [64] Andersen G, Vestergaard K, Ingeman-Nielsen M, Jensen TS. Incidence of central post-stroke pain. Pain 1995 May;61(2):187–93. [65] Widar M, Samuelsson L, Karlsson-Tivenius S, Ahlstrom G. Long-term pain conditions after a stroke. J Rehabil Med 2002 Jul;34(4):165–70. [66] Schmahmann JD. Vascular syndromes of the thalamus. Stroke 2003 Sep;34(9): 2264–78. [67] Oliveira RA, Teixeira MJ. Central poststroke pain: clinical-encephalic imaging correlations. 10th World Congress on Pain, Book of Abstracts. Seattle, WA: IASP Press; 2002. A96-P2. [68] Kameyama M. Vascular lesions of the thalamus on the dominant and nondominant side. Appl Neurophysiol 1976;39(3–4):171–7. [69] Greenspan JD, Ohara S, Sarlani E, Lenz FA. Allodynia in patients with post-stroke central pain (CPSP) studied by statistical quantitative sensory testing within individuals. Pain 2004 Jun;109(3):357–66. [70] Schott B, Laurent B, Mauguiere F. [Thalamic pain: critical study of 43 cases]. Rev Neurol (Paris) 1986;142(4):308–15. [71] Wessel K, Vieregge P, Kessler C, Kompf D. Thalamic stroke: correlation of clinical symptoms, somatosensory evoked potentials, and CT findings. Acta Neurol Scand 1994 Sep;90(3):167–73. [72] Kim JS. Central post-stroke pain or paresthesia in lenticulocapsular hemorrhages. Neurology 2003 Sep 9;61(5):679–82. [73] Hansson P. Post-stroke pain case study: clinical characteristics, therapeutic options and long-term follow-up. Eur J Neurol 2004 Apr;11(Suppl 1):22–30. [74] Kim JS. Delayed-onset ipsilateral sensory symptoms in patients with central poststroke pain. Eur Neurol 1998 Nov;40(4):201–6.

[75] Willoch F, Schindler F, Wester HJ, Empl M, Straube A, Schwaiger M, et al. Central poststroke pain and reduced opioid receptor binding within pain processing circuitries: a [11C]diprenorphine PET study. Pain 2004 Apr;108(3):213–20. [76] Bassetti C, Bogousslavsky J, Regli F. Sensory syndromes in parietal stroke. Neurology 1993 Oct;43(10):1942–9. [77] Schmahmann JD, Leifer D. Parietal pseudothalamic pain syndrome. Clinical features and anatomic correlates. Arch Neurol 1992 Oct;49(10):1032–7. [78] Bowsher D, Brooks J, Enevoldson P. Central representation of somatic sensations in the parietal operculum (SII) and insula. Eur Neurol 2004;52(4):211–25. [79] Lhermitte J. Physiologie des ganglions centraux. Les corps stries. La couche optique. Les formations sousthalamiques. In: Binet R, editor. Traité de Physiologie Normale et Pathologique. Paris: Masson; 1933. p. 357–402. [80] Tasker RR, de Carvallho G, Dostrovsky JO. The history of central pain syndromes, with observations concerning pathophysiology and treatment. In: Casey KL, editor. Pain and central nervous system disease: the central pain syndromes. New York: Raven Press; 1991. p. 31–58. [81] Garcin R. La douleur dans les affections organiques du systeme nerveux central. Rev Neurol (Paris) 1937;68:105–53. [82] Riddoch G. The clinical features of central pain. Lancet 1938;1:1093–8. [83] Bowsher D. Stroke and central poststroke pain in an elderly population. J Pain 2001 Oct;2(5):258–61. [84] Leijon G, Boivie J. Central post-stroke pain—a controlled trial of amitriptyline and carbamazepine. Pain 1989 Jan;36(1):27–36. [85] Bowsher D. Central post-stroke (‘thalamic syndrome’) and other central pains. Am J Hosp Palliat Care 1999 Jul–Aug;16(4):593–7. [86] Shimodozono M, Kawahira K, Kamishita T, Ogata A, Tohgo S, Tanaka N. Reduction of central poststroke pain with the selective serotonin reuptake inhibitor fluvoxamine. Int J Neurosci 2002 Oct;112(10):1173–81. [87] McQuay H, Carroll D, Jadad AR, Wiffen P, Moore A. Anticonvulsant drugs for management of pain: a systematic review. BMJ 1995 Oct 21;311(7012):1047–52. [88] Vestergaard K, Andersen G, Gottrup H, Kristensen BT, Jensen TS. Lamotrigine for central poststroke pain: a randomized controlled trial. Neurology 2001 Jan 23;56(2):184–90. [89] Attal N, Brasseur L, Parker F, Chauvin M, Bouhassira D. Effects of gabapentin on the different components of peripheral and central neuropathic pain syndromes: a pilot study. Eur Neurol 1998 Nov;40(4):191–200. [90] Serpell MG. Gabapentin in neuropathic pain syndromes: a randomised, doubleblind, placebo-controlled trial. Pain 2002 Oct;99(3):557–66. [91] Backonja M, Glanzman RL. Gabapentin dosing for neuropathic pain: evidence from randomized, placebo-controlled clinical trials. Clin Ther 2003 Jan;25(1): 81–104. [92] Takahashi Y, Hashimoto K, Tsuji S. Successful use of zonisamide for central poststroke pain. J Pain 2004 Apr;5(3):192–4. [93] Canavero S, Bonicalzi V, Paolotti R. Lack of effect of topiramate for central pain. Neurology 2002 Mar 12;58(5):831–2. [94] Drewes AM, Andreasen A, Poulsen LH. Valproate for treatment of chronic central pain after spinal cord injury. A double-blind cross-over study. Paraplegia 1994 Aug;32(8):565–9. [95] Benedetti F, Vighetti S, Amanzio M, Casadio C, Oliaro A, Bergamasco B, et al. Dose– response relationship of opioids in nociceptive and neuropathic postoperative pain. Pain 1998 Feb;74(2–3):205–11. [96] Attal N, Guirimand F, Brasseur L, Gaude V, Chauvin M, Bouhassira D. Effects of IV morphine in central pain: a randomized placebo-controlled study. Neurology 2002 Feb 26;58(4):554–63. [97] Eide PK, Stubhaug A, Stenehjem AE. Central dysesthesia pain after traumatic spinal cord injury is dependent on N-methyl-d-aspartate receptor activation. Neurosurgery 1995 Dec;37(6):1080–7. [98] Iranami H, Yamazaki A, Hatano Y. Tramadol challenge for relief of intractable central poststroke pain. Mayo Clin Proc 2006 Apr;81(4):566. [99] Bainton T, Fox M, Bowsher D, Wells C. A double-blind trial of naloxone in central post-stroke pain. Pain 1992 Feb;48(2):159–62. [100] Sakurai M, Kanazawa I. Positive symptoms in multiple sclerosis: their treatment with sodium channel blockers, lidocaine and mexiletine. J Neurol Sci 1999 Jan 15;162(2):162–8. [101] Attal N, Gaude V, Brasseur L, Dupuy M, Guirimand F, Parker F, et al. Intravenous lidocaine in central pain: a double-blind, placebo-controlled, psychophysical study. Neurology 2000 Feb 8;54(3):564–74. [102] Vick PG, Lamer TJ. Treatment of central post-stroke pain with oral ketamine. Pain 2001 May;92(1–2):311–3. [103] Tsubokawa T, Katayama Y, Yamamoto T, Hirayama T, Koyama S. Chronic motor cortex stimulation for the treatment of central pain. Acta Neurochir Suppl (Wien) 1991;52:137–9. [104] Hosobuchi Y. Motor cortical stimulation for control of central deafferentation pain. Adv Neurol 1993;63:215–7. [105] Katayama Y, Fukaya C, Yamamoto T. Poststroke pain control by chronic motor cortex stimulation: neurological characteristics predicting a favorable response. J Neurosurg 1998 Oct;89(4):585–91. [106] Nguyen JP, Lefaucheur JP, Decq P, Uchiyama T, Carpentier A, Fontaine D, et al. Chronic motor cortex stimulation in the treatment of central and neuropathic pain. Correlations between clinical, electrophysiological and anatomical data. Pain 1999 Sep;82(3):245–51. [107] Katayama Y, Yamamoto T, Kobayashi K, Kasai M, Oshima H, Fukaya C. Motor cortex stimulation for post-stroke pain: comparison of spinal cord and thalamic stimulation. Stereotact Funct Neurosurg 2001;77(1–4):183–6. [108] Roux FE, Ibarrola D, Lazorthes Y, Berry I. Chronic motor cortex stimulation for phantom limb pain: a functional magnetic resonance imaging study: technical case report. Neurosurgery 2001 Mar;48(3):681–7 discussion 7–8. [109] Dejerine J, Roussy G. Le syndrome thalamique. Rev Neurol 1906;12:521–32.

G. Kumar, C.R. Soni / Journal of the Neurological Sciences 284 (2009) 10–17 [110] Khedr EM, Kotb H, Kamel NF, Ahmed MA, Sadek R, Rothwell JC. Longlasting antalgic effects of daily sessions of repetitive transcranial magnetic stimulation in central and peripheral neuropathic pain. J Neurol Neurosurg Psychiatry 2005;76:833–8. [111] Lefaucheur JP, Drouot X, Menard-Lefaucheur I, Zerah F, Bendib B, Cesaro P, Keravel Y, Nguyen JP. Neurogenic pain relief by repetitive transcranial magnetic cortical stimulation depends on the origin and the site of pain. J Neurol Neurosurg Psychiatry 2004;75:612–6.

17

[112] Rasche D, Rinaldi PC, Young RF, Tronnier VM. Deep brain stimulation for the treatment of various chronic pain syndromes. Neurosurg Focus 2006 Dec 15;21 (6):E8. [113] Ramachandran VS, McGeoch PD, Williams L, Arcilla G. Rapid relief of thalamic pain syndrome induced by vestibular caloric stimulation. Neurocase 2007 Jun;13 (3):185–8. [114] Leijon G, Boivie J. Central post-stroke pain–the effect of high and low frequency TENS. Pain 1989 Aug;38(2):187–91.