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Early evoked pain or dysesthesia is a predictor of central poststroke pain
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PAIN 155 (2014) 2699–2706
www.elsevier.com/locate/pain
Early evoked pain or dysesthesia is a predictor of central poststroke pain Henriette Klit a,b,⇑, Anne P. Hansen a, Ninna S. Marcussen a, Nanna B. Finnerup a, Troels S. Jensen a,b a b
Danish Pain Research Center, Aarhus University, Aarhus, Denmark Department of Neurology, Aarhus University Hospital, Aarhus, Denmark
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
a r t i c l e
i n f o
Article history: Received 29 June 2014 Received in revised form 26 September 2014 Accepted 29 September 2014
Keywords: Central neuropathic pain Central poststroke pain Pain Predictors Stroke
a b s t r a c t Central poststroke pain (CPSP) is a central neuropathic pain condition caused by a cerebrovascular lesion affecting the central somatosensory nervous system. Once developed, CPSP is difficult to treat, so there is an interest in identifying stroke patients at risk for the development of CPSP. This study examined if sensory abnormalities, including evoked dysesthesia, allodynia, or hyperalgesia to static and dynamic touch, cold, and pinprick, at stroke onset are a predictor for the development of CPSP. Consecutive stroke patients were recruited from a large prospective study of poststroke pain in Aarhus, Denmark, between 2007 and 2008. Patients underwent a structured pain interview and a standardized sensory examination within 4 days of admission, and a structured telephone interview was conducted after 3 and 6 months. Patients who developed poststroke pain in the affected side without any other plausible cause were classified as having possible CPSP. A total of 275 stroke patients completed the study, and 29 patients (10.5%) were classified as having possible CPSP. The diagnosis was confirmed by a clinical examination in 15 of 17 patients, corresponding to a prevalence of 8.3%. The presence of allodynia, hyperalgesia, or dysesthesia in response to the sensory examination at stroke onset increased the odds for CPSP at 6 months by 4.6 (odds ratio; 95% confidence interval 1.5–13.9). The combination of reduced or absent sensation to pinprick or cold and early evoked pain or dysesthesia at onset increased odds by 8.0 (odds ratio; 95% confidence interval 2.6–24.8). In conclusion, early evoked pain or dysesthesia is a predictor for CPSP. Ó 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
1. Introduction Central poststroke pain (CPSP) is a central neuropathic pain condition caused by a vascular lesion of the central somatosensory nervous system [16]. It is characterized by pain and sensory abnormalities in the body parts that correspond to the injured brain area. The incidence of this devastating condition, which is associated with both reduced quality of life and increased mortality [7,27], is estimated to be 7% to 8% in stroke survivors [1,19]. The condition is often refractory to treatment, and it is thus important to identify patients who are at risk for the development of CPSP in order to follow these patients more carefully, inform them about central pain, initiate treatment, and conduct prophylactic treatment studies in the future. The underlying mechanisms of CPSP are not known, but abnormal spinothalamocortical tract function [23,34], loss of inhibition ⇑ Corresponding author at: Danish Pain Research Center, Aarhus University Hospital, Norrebrogade 44, Building 1A, DK-8000 Aarhus C, Denmark. Tel.: +45 7846 3287; fax: +45 7846 3269. E-mail address: [email protected] (H. Klit).
[6,9,11,12,14], central sensitization [37], and neuroplastic changes [24,28,29] are all mechanisms that have been implicated in this and other central neuropathic pain conditions. Central sensitization is defined as an increased responsiveness of nociceptive neurons in the central nervous system (CNS) to their normal or subthreshold afferent input [1]. Neuropathic pain is characterized by negative and/or positive symptoms and signs. It may be spontaneous (ongoing or intermittent) or evoked, and it may be associated with nonpainful dysesthesia or paresthesia [5,34]. The negative signs in CPSP include loss or reduction of thermal and pinprick sensibility, while positive symptoms and signs are pain or unpleasantness evoked by touch, pressure, or thermal stimuli. This dual combination of loss and hypersensitivity in the affected area is usually explained by loss of input to a population of CNS neurons participating in the processing of somatosensory information, and at the same time hyperexcitability in the same or other neurons within the CNS [14,19]. Our previous studies have shown that sensory hypersensitivity in the affected body parts may occur already at onset of stroke [1,19], but it is unclear if this sensory hypersensitivity presenting as hyperalgesia, dysesthesia, or allodynia is a risk factor for the
http://dx.doi.org/10.1016/j.pain.2014.09.037 0304-3959/Ó 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
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subsequent development of pain. In 2 recent studies, early sensory hypersensitivity was found to predict later onset of central neuropathic pain (below-level pain) in patients with spinal cord injury [10,38]. In this prospective study, we aimed to determine if stroke patients with early evoked pain or dysesthesia, defined as findings of allodynia, hyperalgesia, or dysesthesia in response to the sensory examination at stroke onset, have an increased risk of developing CPSP. 2. Methods 2.1. Patient recruitment We included stroke patients admitted consecutively to the Stroke Unit of the Department of Neurology, Aarhus University Hospital, Aarhus, Denmark, between February and September 2007 and between February and July 2008 (Fig. 1). Inclusion criteria were age of 18 years or above, informed consent, and a diagnosis of stroke according to the World Health Organization criteria (ICD-10 codes: I61, I63, I64.9, I67.6, and I67.7). Exclusion criteria were a diagnosis of trasient ischemic attack (TIA) (G45.9) or subarachnoid
hemorrhage (I60.9), inability to communicate, severe dementia, or pronounced somnolence. Results on pain development are reported elsewhere [13]. All included patients underwent a structured interview and a standardized bedside sensory examination within the first 4 days of admission (initial examination), including sensory testing for dysesthesia, allodynia, and hyperalgesia. Dysesthesia is defined as an unpleasant abnormal sensation, whether spontaneous or evoked; allodynia as pain due to a stimulus that does not normally provoke pain; and hyperalgesia as increased pain from a stimulus that normally provokes pain [26]. To determine the presence of these phenomena, we used static and dynamic touch, cold, and pinprick stimulation (in the following called evoked pain or dysesthesia) [13]. The interview included questions about pain conditions before the stroke and the presence of spontaneous and evoked pain or dysesthesia at or after stroke onset. Medical records from the hospital admission and results of computed tomography (CT) and/or magnetic resonance imaging (MRI) scans were obtained. All initial examinations were done by 1 of 2 investigators (APH or NSM). A structured follow-up telephone interview was conducted 3 and 6 months after stroke onset. The interview included questions
Fig. 1. Flow chart of study.
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about the status of the pain reported in the previous interview, pain experienced within the last week, and the presence of spontaneous and evoked pain or dysesthesia. Only patients who completed the 6-month follow-up were included in the study. After the 6-month follow-up, patients were classified as having possible CPSP, other poststroke pain, or no poststroke pain on the basis of the data from the initial examination and the interviews at the admission and the 3- and 6-month follow-up. Information about early evoked dysesthesia or pain was not used to classify the patients. Patients were identified as having ‘‘possible CPSP’’ on the basis of the proposed grading system for neuropathic pain [20,33] if they fulfilled the following 3 criteria: (1) onset of pain at or after stroke onset, (2) pain located in the stroke-affected side of the body, and (3) no other plausible cause of the pain (including poststroke shoulder pain isolated to the shoulder region) [13]. The affected side was confirmed post hoc on the basis of information from medical records on symptoms and signs at stroke onset and CT or MRI results. If the affected side could not be identified with certainty (n = 10), both sides were included as affected. Early evoked pain or dysesthesia was considered relevant if: (1) it was unilateral or asymmetrical, (2) it was found in the affected side of the body, and (3) its onset was after the stroke, or if onset was uncertain. In order to confirm the diagnosis, all patients identified with possible CPSP were invited to participate in a clinical examination (follow-up examination). The examination included a standardized interview, a bedside sensory examination, and thermal sensory testing. Patients were interviewed about medical history, medication, and pain, which was assessed with 4 items from the Brief Pain Inventory (general activity, mood, sleep, and enjoyment of life) [8] and a Danish version of the 10-item DN4 [4], and patients were asked to complete a pain drawing. On the basis of all the available information, except for information on early evoked pain or dysesthesia, patients were classified as having definite CPSP or no CPSP according to the proposed grading system for neuropathic pain [33]. All follow-up examinations were performed by a physician (HK) who had not participated in the initial examination. Patients who were classified as having definite CPSP based on the grading system for neuropathic pain at the follow-up examination, including patients who fulfilled the criteria for definite neuropathic pain but in whom other causes of pain could not be excluded, are referred to as definite CPSP patients in the following. 2.2. Sensory examination At both examinations, a cotton ball was used to examine for static touch sensation, a von Frey monofilament (monofilament No. 5.88; Semmes Weinstein Touch Test, Stoelting, IL, USA) for pinprick sensation, a brush (Somedic, Hörby, Sweden) for dynamic touch, and a metal roller for cold sensation (initial examination: a metal roll at 20 °C [Somedic, Hörby, Sweden]; follow-up examination: metal roll at room temperature). Sensation to each stimulus was noted as absent, diminished, normal, or increased compared to the unaffected mirror body part. In those cases where the affected side could not be determined on the basis of the sensory examination alone, the history and the result of the brain scan determined the affected side. Sensory findings were indicated on a body chart. The presence of evoked dysesthesia, allodynia, and hyperalgesia to each stimulus was noted, and the intensities of evoked pain and dysesthesia were scored on an 11-point (0 = no pain, 10 = worst possible pain) numeric rating scale (NRS). The initial examination was conducted bilaterally on the front of the forearm, thenar, cheek, shin, and the dorsum of the foot, while the entire front of the body, or in a few cases (for practical reasons) only parts of the body, were examined at the follow-up examination.
At the clinical follow-up examination, sensory thermal testing (TSA 2001; Medoc Thermotest, Ramat Yishai, Israel) was conducted with a 3 3 cm2 thermode, a baseline temperature of 32 °C, a rate of change of 1 °C/s for detection and 5 °C/s for pain thresholds, and cutoff values at 0 °C and 50 °C. Cold detection threshold (CDT), warm detection threshold (WDT), cold pain threshold (CPT), and heat pain threshold (HPT) were determined on the affected side (in an area of pain, either cheek, forearm, or shin) and on the corresponding contralateral side (average of 3 measurements). A side difference of P2 °C in detection thresholds, P10.3 °C in cold pain thresholds, and P4.2 °C in heat pain thresholds were considered abnormal [30]. 2.3. Ethics The study was conducted in accordance with the Helsinki Declaration. Written and oral information was given, and informed consent was obtained before both the initial and the follow-up examination. The study was approved by the regional research ethics committee (20060116) and by the Danish Data Protection Agency (2006-41-6900). 2.4. Statistical analysis Statistical analysis was performed by Intercooled Stata software, version 9.2 (StataCorp, College Station, TX, USA). Data are presented as mean and standard deviation (SD) with 95% confidence intervals (CI) or as median with range where appropriate. Parametric data were analyzed by Student’s t test. Nonparametric data were analyzed using by Mann-Whitney and Kruskal-Wallis (rank sum) tests. Dichotomous data were analyzed by Pearson’s chi-square (v2) test and Fisher’s exact test. Odds ratios (OR) are presented with 5% and 95% CI. P values less than .05 were considered statistically significant. 3. Results In total, 299 stroke patients were included in the prospective study, and 275 patients (153 men, 122 women) completed the 6month follow-up (Fig. 1). The mean age of the patients was 65.6 (SD 13.0) years. Detailed information including stroke characteristics are reported elsewhere [13]. After the 6-month follow-up interview, 29 patients (11 men) were classified as having possible CPSP, corresponding to an incidence of 10.5% (mean age 60.4 [SD 9.39] years) [13]. In 25 of these 29 patients, the pain was located in an area with sensory abnormalities confirmed by the initial examination at stroke onset. Possible CPSP was more common after lesions affecting the left side compared with the right (20/ 138 vs 8/126, P = .032). Seventeen of 29 patients with possible CPSP agreed to participate in the follow-up examination. In the remaining 12 patients,
Table 1 Number of patients (N = 275) with evoked pain or dysesthesia and median (range) intensity on the NRS (0–10). Stimulus
Brush Light touch Cold thermo rolla Pinprick Total (n = 42)
Evoked pain
Evoked dysesthesia
n
n
NRS
12 5 21 9 33
4 4 5 4
0 0 3 12 13
NRS
5 (4–9) 5 (1–10)
(1–8) (2–5) (1–10) (2–5)
a Only 1 patient with cold-evoked pain and 4 with cold-evoked dysesthesia also had brush-evoked dysesthesia, suggesting that cold-evoked hypersensitivity is not only related to the touch of the thermal roll.
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Table 2 OR for the development of CPSP.a Item
Predictor
95% 95% CI
Sens (%)
4.6
1.5– 13.9
10 (4.1%)
3.6
0.7– 18.3 0.7– 18.3 1.7– 31.6 0.6– 59.3 0.4– 8.3 1.0– 15.1 0.6– 8.8 0.3– 21.2 3.7– 46.6 5.9– 633 2.1– 18.6 1.5– 12.3 1.3– 15.9 0.8– 6.2 2.1– 17.7 1.8– 104.6 2.0– 26.1 3.7– 46.6 2.6– 24.8 NA
Definite CPSP (n = 15), n (%)
Not suspected of CPSP (n = 246), n (%)
Primary outcome 1 Early evoked pain or dysesthesia at examination
6 (40%)
31 (12.6%)
Secondary outcomes 1a Early evoked pain (allodynia or hyperalgesia) at examination
2 (13%)
OR
1b
Early evoked pain or dysesthesia to 1 or more stimuli
2 (13%)
10 (4.1%)
3.6
*
Early pain or dysesthesia to brush at examination
3 (20%)
8 (3.3%)
7.4
*
Early pain or dysesthesia to touch at examination
1 (7%)
3 (1.2%)
5.7
*
Early pain or dysesthesia to cold at examination
2 (13%)
20 (8.1%)
1.7
*
Early dysesthesia or hyperalgesia to pinprick at examination
3 (20%)
15 (6.1%)
3.9
*
2
Reported spontaneous pain or unpleasantness at onset
3 (20%)
24 (9.8%)
2.3
2a
Reported spontaneous pain* at onset
1 (7%)
7 (2.9%)
2.4
3
Reported pain or dysesthesia evoked by touch or cold at onset
5 (33%)
9 (3.7%)
13.2
3a
Reported pain evoked by touch or cold at onset
3 (20%)
1 (0.4%)
61.3
2 or 3
Reported spontaneous pain or unpleasantness or reported dysesthesia or pain evoked by touch or cold at onset Reported spontaneous pain or unpleasantness or reported or evoked dysesthesia or pain at onset Reported or evoked pain
7 (47%)
30 (12.2%)
6.3
8 (53%)
52 (21.1%)
4.3
4 (27%)
18 (7.3%)
4.6
7 (47%)
71 (28.9%)
2.2
5
Early hyperesthesia at examination (including evoked dysesthesia or pain) Early anesthesia at examination
8 (53%)
39 (15.9%)
6.1
6
Hypo- or anesthesia to 1 or more stimuli at examination
14 (93%)
125 (50.8%)
13.6
6a
Hypo- or anesthesia to cold or pinprick at examination
12 (80%)
88 (35.8%)
7.2
1 and 5
Early evoked pain/dysesthesia and anesthesia at examination
5 (33%)
9 (3.7%)
13.2
1 and 6a
Early evoked pain/dysesthesia and reduced/abolished sensation to cold or pinprick at examination Abnormal sensory findings at examination, either hyper-, hypo, or anesthesia
6 (40%)
19 (7.7%)
8.0
15 (100%)
149 (60.6%)
1, 2 or 3 1a or 2a 4
4 or 6
NA
Spec (%)
PPV (%)
Acc (%)
16
96
40
85
17
95
13
91
17
95
13
91
27
95
20
92
25
95
7
93
9
95
13
87
17
95
20
90
11
95
20
86
13
95
7
92
36
96
33
93
75
95
20
95
19
96
47
85
13
97
53
77
18
95
27
89
9
96
47
70
17
97
53
82
10
99
93
52
12
98
80
64
36
96
33
93
24
96
40
89
9
100
100
43
OR = odds ratio; CPSP = central poststroke pain; CI = confidence interval; PPV = positive predictive value; sens = sensitivity; spec = specificity; acc = accuracy. * Reported spontaneous pain not including pain due to headache or evoked pains. a Comparison between reported symptoms and sensory findings on the initial examination at stroke onset correlated to the later classification as definite CPSP, confirmed by a clinical examination (n = 15) compared to patients not suspected of CPSP (n = 246).
pain had disappeared in 2 patients, 8 patients declined participation, and 2 patients were lost to follow-up (Fig. 1). The median time from the stroke to the follow-up examination was 32.4 months (range 6.2–36.6 months). At the follow-up examination, the patients were classified as follows: definite (n = 15, including 4 patients in whom other causes of pain could not be excluded), not CPSP (n = 1, poststroke shoulder pain), and no longer pain (CPSP-like dysesthesia, n = 1). In total, 15 of the 17 examined patients were classified as having definite CPSP. This corresponds to a minimum prevalence of clinically confirmed definite CPSP in 5.9% of patients within 6 months after stroke. If patients in whom other causes of pain could not be excluded are omitted, the corresponding prevalence is 4.3%. If we expect those without response to have the same prevalence, it corresponds to a prevalence of 8.3% (15/19 29/275). The sensory findings and reported symptoms and pain of the 15 patients with definite CPSP are summarized in Fig. 3 and Supplementary Tables 1–3.
3.1. Predictors of CPSP Definite CPSP confirmed by the clinical follow-up examination was considered to be the outcome measure. The 15 patients with definite CPSP were compared with the 246 (275 29) patients without possible CPSP (Fig. 1). 3.2. Primary outcome measure: early evoked dysesthesia or pain Early evoked pain or dysesthesia to brush, touch, cold, or pinprick stimulation was found in 53 of 275 patients. Relevant evoked pain or dysesthesia was identified in 42 patients (15.3%), while the remaining 11 findings were nonrelevant, ie, bilateral and symmetrical (n = 3), in the unaffected side (n = 6), or had onset before stroke (n = 2). Of these 42 patients, 13 had allodynia or hyperalgesia, and 29 patients had only evoked dysesthesia. The findings and the intensity of evoked pain or dysesthesia to the 4 stimuli are summarized in Table 1.
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Of the 42 patients with early evoked pain or dysesthesia, 5 were later classified as having possible CPSP but were not available for follow-up, 31 were not suspected of having CPSP, and 6 were later classified as having definite CPSP (Fig. 1). Early evoked pain or dysesthesia was found in 37.9% (11 of 29) of the patients with possible CPSP compared to 12.6% (31 of 246) of the patients not suspected of having CPSP (P < .001, v2). This corresponds to an OR of 4.2 (95% CI 1.8–9.8) of developing possible CPSP in patients with early evoked pain or dysesthesia. In patients with definite CPSP, early evoked pain or dysesthesia was seen in 6 (40.0%) of 15, corresponding to an OR of 4.6 (95% CI 1.5–13.9), with a positive predictive value of 40%, a sensitivity of 16%, a specificity of 96%, and an accuracy of 85% (Table 2, item 1; Fig. 2). Of the 6 patients with early evoked pain or dysesthesia who later developed definite CPSP, 1 patient had pinprick dysesthesia (NRS 5), 1 had pinprick hyperalgesia (NRS not done), 1 had cold allodynia (NRS 4), 1 had brush dysesthesia (NRS 7), 1 had a combination of dysesthesia to brush (NRS 4), touch (NRS 4), and pinprick (NRS 4), and 1 had a combination of dysesthesia to brush (NRS 8) and cold (NRS 3) (Supplementary Table 1). The presence of early evoked pain or dysesthesia in combination with reduced or absent sensation to cold or pinprick increased the odds for central poststroke pain at 6 months by 8.0 (OR; 95% CI 2.6–24.8) (Table 2, items 1 and 6a). 3.3. Secondary outcome measures: other symptoms and signs Secondary outcomes are presented in Table 2. Patients who reported pain evoked by touch or cold at onset were more likely to be classified as having definite CPSP at follow-up (OR 61.3; 95% CI 5.9–633) (Table 2, item 3a). Patients with decreased or absent sensation, ie, hypo- or anesthesia to 1 or more stimuli, were also more likely to be classified as having CPSP (OR 13.6; 95% CI 1.8–104.6) (Table 2, item 6). There was also a significant correlation between the presence of early anesthesia and CPSP (OR 6.1; 95% CI 2.1–17.7) (Table 2, item 5). Patients with reduced or absent sensation to pinprick or cold, indicating abnormal spinothalamocortical tract function, were also more likely to be classified with CPSP (OR 7.2; 95% CI 2.0–26.1) (Table 2, item 6a; Fig. 3). We found no correlation between the presence of early hyperesthesia and the development of CPSP (OR 2.2; 95% CI 0.8–6.2) (Table 2, item 4). Reported spontaneous pain or unpleasantness at the initial interview (item 2) was not significantly correlated to CPSP, whereas there was a significant correlation between
Fig. 2. Frequency of early evoked dysesthesia or pain in patients with and without CPSP at 6-month follow-up. ⁄P < .001.
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reported touch- or cold-evoked dysesthesia or pain in the affected side and CPSP (OR 13.2; 95% CI 3.7–46.6) (Table 2, item 3). The combination of early evoked pain and dysesthesia and absent sensation to 1 or more stimuli at the time of the initial examination increased the OR for developing CPSP to 13.2 (95% CI 3.7–46.6) with a sensitivity of 36% and a specificity of 96% (accuracy 93%) (Table 2, items 1 and 5). 4. Discussion Our previous studies have indicated that CPSP is more common in patients with somatosensory deficits [1,19]. In this prospective study, we found that the presence of evoked dysesthesia, allodynia, or hyperalgesia in the affected side of the body within 4 days of stroke onset was a predictor for the development of CPSP within 6 months after stroke onset (OR 4.6; 95% CI 1.5–13.9). Other early predictors include patient-reported evoked pain and dysesthesia and sensory abnormalities at the initial examination. A hallmark of neuropathic pain is the combination of negative and positive signs [15]. Importantly, we found that the combination of early evoked pain or dysesthesia and absent sensation to 1 or more stimuli at the time of the initial examination increased the OR for developing CPSP (OR 13.2; 95% CI 3.7–46.6). It has previously been shown that evoked dysesthesia and allodynia are present in most patients with CPSP [2,3,5], but to our knowledge, ours is the first study to compare early sensory findings to the subsequent development of CPSP in a prospective manner. We found that early evoked pain or dysesthesia was present within 4 days of stroke onset in 15% of the patients. Findings of evoked dysesthesia or pain may in some, but not all, cases reflect neuronal hyperexcitability, ie, an excessive reaction of the neurons to stimuli [18]. In some patients, these symptoms were present early or immediately after stroke onset. The presence of dysesthesia and allodynia in CPSP patients may reflect central sensitization [11], which has been proposed as one of the mechanisms underlying this pain condition [17,20,34]. Consistent with the present findings, recent studies have shown that early sensory hypersensitivity and allodynia are predictors for below-level central pain in patients with spinal cord injury. Zeilig et al. [38] found that dynamic mechanical allodynia, temporal summation of pain, and hyperpathia predicted central pain, while Finnerup et al. [10] found that brush, cold, warm, and single or repetitive pinprick predicted central pain, of which cold-evoked pain or dysesthesia was the best predictor. The authors suggested that this neuronal hyperexcitability, which may develop after damage to the spinothalamic tracts, develops gradually and precedes the development of spontaneous central pain [10,38]. In line with these findings, we found that early pain or dysesthesia to brush and the combination of early evoked pain or dysesthesia and decreased or absent sensation to cold or pinprick, which may be interpreted as an indication of damage to the spinothalamic tracts, significantly predicted development of central pain. The presence of early evoked pain or dysesthesia is not a perfect predictor for the development of CPSP. The sensitivity, specificity, and accuracy of early evoked dysesthesia or pain was 16%, 96%, and 85%, respectively, indicating that other mechanisms are involved. In accordance with the present study, not all patients in the studies on spinal cord injury pain who developed central pain had early sensory hypersensitivity. A high prevalence of CPSP has been reported after lesions affecting the posterior parts of the thalamus and the lateral medulla [22,25,32]. While the study by Sprenger et al. [32] focused on structural changes within the thalamus as a risk factor for CPSP, this study found that early clinical hypersensitivity in the body part corresponding to the affected brain lesion represents a predictor for subsequent development of CPSP. It is possible that
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Fig. 3. Area of sensory abnormalities at onset (left) compared to areas of sensory abnormalities (middle) and pain (right) at follow-up examination in patients with definite CPSP.
a combination of early sensory findings combined with information on the localization of the lesion, such as specific areas within the thalamus [32], may prove to be an even better predictor. Laserevoked potentials or functional neuroimaging could also be of value in identifying high-risk patients in future preemptive treatment studies. To date, only one study has been published on prophylactic treatment of CPSP [22]. In this prophylactic study, a
total of 39 patients with thalamic stroke were randomized to receive either amitriptyline or placebo. Only 7 of 39 patients developed CPSP; unfortunately, the study did not have sufficient statistical power to show any beneficial effect. In the present study, we found an estimated minimum prevalence of clinically confirmed definite CPSP in 5.9% of patients within 6 months after stroke and a prevalence of definite CPSP
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without other possible causes of pain in 4.3%. It can be difficult to determine if a patient with poststroke pain has CPSP. We applied clearly defined criteria in order to do this. The prevalence found in this study corresponds to other population-based studies using this and other methods of identification [1,19,35]. Unlike some of the previous epidemiologic studies on CPSP, patients with dysesthesia only were not included in the present study. If these patients had been included, the reported prevalence of CPSP would have been higher. The present study has some shortcomings. Twelve of 29 patients with possible CPSP were not available for the clinical follow-up examination. However, because CPSP was confirmed by the clinical examination in 15 of the 17 patients with possible CPSP, we assume that the frequency of CPSP was the same in the patients who did not participate in the follow-up examination. This corresponds to an estimated minimum prevalence of definite CPSP in 8.3% (15/19 27/275), and in 5.7% (11/19 27/275) of definite CPSP patients in whom other causes of pain could be excluded, in line with previously published estimates of the prevalence of CPSP [1,19]. It may be argued that patients with early evoked dysesthesia or pain have CPSP with early onset, and that the signs simply reflect a disease that is already present. However, only 1 patient had spontaneous pain at onset (Supplementary Table 1). In order not to tire out the acute stroke patients, the initial sensory examination was only performed in the face and in the distal limbs. Thus, we do not have detailed topographical data. Information on the topographical distribution of sensory findings could be an additional source of predictors. It was not always possible retrospectively to determine whether a sensory finding was caused by the present stroke, a previous stroke, or other neurologic disease such as neuropathy. In cases of uncertainty, the sensory findings were categorized as new. CPSP due to a previous stroke was not evaluated in this study because only pain with onset after the current stroke was described. Although all patients classified as definite CPSP fulfilled the diagnostic criteria according to the proposed grading system for neuropathic pain, we could not clinically rule out that other (peripheral) diseases were contributing to the pain in a small subset of patients. These patients were classified as patients with CPSP in whom other causes of pain could not be excluded. Including these patients in the study implies a risk of overestimating the prevalence of CPSP. The last follow-up in the prospective study was at 6 months. The onset of CPSP is within 6 months after stroke in the majority of patients [1,36]. In the study by Andersen [1], only 3 of 207 patients developed CPSP after 6 months. However, there are case reports in the literature indicating a later onset, and it is therefore possible that we have overlooked cases with late onset. We cannot rule out the notion that some of the patients with poststroke shoulder pain may have had a localized type of CPSP in the shoulder region. Thus, there is a risk of underreporting the incidence of CPSP [21,31]. Interestingly, at the time of follow-up, pain had disappeared in 3 of the 29 patients with possible CPSP. This confirms our previous finding that CPSP may diminish or disappear over time in some patients [18]. Relevant early evoked pain or dysesthesia was found in 15% of the stroke patients. Early evoked pain or dysesthesia was found to be a significant factor for the development of CPSP, indirectly suggesting that central sensitization may be an underlying pathophysiologic mechanism. Because of the increased risk, a close follow-up of patients with early evoked pain or dysesthesia is recommended in order to identify and treat potential pain. Future clinical studies on the prevention of this pain condition could be based on patients with early hypersensitivity, preferably if other factors related to CPSP can be identified.
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Conflict of interest The authors report no conflict of interest. Acknowledgments The authors thank Helle O. Andersen for editing help. This work was supported by the Velux Foundation, the Danish Medical Association Research Fund, a Hoejmosegaard Grant, and a scholarship from Aarhus University. The funding sources had no involvement or role in the collection, analysis, or interpretation of the data or in the writing of this article or the decision to submit it for publication. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.pain.2014.09.037. References [1] Andersen G, Vestergaard K, Ingeman-Nielsen M, Jensen TS. Incidence of central post-stroke pain. PAINÒ 1995;61:187–93. [2] Attal N, Cruccu G, Baron R, Haanpää M, Hansson P, Jensen TS, Nurmikko T. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol 2010;17:e1113–88. [3] Boivie J, Leijon G, Johansson I. Central post-stroke pain – a study of the mechanisms through analyses of the sensory abnormalities. PAINÒ 1989;37:173–85. [4] Bouhassira D, Attal N, Alchaar H, Boureau F, Brochet B, Bruxelle J, Cunin G, Fermanian J, Ginies P, Grun-Overdyking A, Jafari-Schluep H, Lantéri-Minet M, Laurent B, Mick G, Serrie A, Valade D, Vicaut E. Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4). PAINÒ 2005;114:29–36. [5] Bowsher D. Central pain: clinical and physiological characteristics. J Neurol Neurosurg Psychiatry 1996;61:62–9. [6] Cesaro P, Mann MW, Moretti JL, Defer G, Roualdes B, Nguyen JP, Degos JD. Central pain and thalamic hyperactivity: a single photon emission computerized tomographic study. PAINÒ 1991;47:329–36. [7] Choi-Kwon S, Choi JM, Kwon SU, Kang DW, Kim JS. Factors that affect the quality of life at 3 years post-stroke. J Clin Neurol 2006;2:34–41. [8] Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singapore 1994;23:129–38. [9] Craig AD, Bushnell MC. The thermal grill illusion: unmasking the burn of cold pain. Science 1994;265:252–5. [10] Finnerup NB, Norrbrink C, Trok K, Piehl F, Johannesen IL, Sorensen JC, Jensen TS, Werhagen L. Phenotypes and predictors of pain following traumatic spinal cord injury: a prospective study. J Pain 2014;15:40–8. [11] Garcia-Larrea L, Convers P, Magnin M, Andre-Obadia N, Peyron R, Laurent B, Mauguiere F. Laser-evoked potential abnormalities in central pain patients: the influence of spontaneous and provoked pain. Brain 2002;125:2766–81. [12] Garcia-Larrea L, Maarrawi J, Peyron R, Costes N, Mertens P, Magnin M, Laurent B. On the relation between sensory deafferentation, pain and thalamic activity in Wallenberg’s syndrome: a PET-scan study before and after motor cortex stimulation. Eur J Pain 2006;10:677–88. [13] Hansen AP, Marcussen NS, Klit H, Andersen G, Finnerup NB, Jensen TS. Pain following stroke: a prospective study. Eur J Pain 2012;16:1128–36. [14] Head H, Holmes G. Sensory disturbances from cerebral lesions. Brain 1911;34:102–254. [15] Jensen TS, Baron R. Translation of symptoms and signs into mechanisms in neuropathic pain. PAINÒ 2003;102:1–8. [16] Jensen TS, Baron R, Haanpaa M, Kalso E, Loeser JD, Rice AS, Treede RD. A new definition of neuropathic pain. PAINÒ 2011;152:2204–5. [17] Jensen TS, Lenz FA. Central post-stroke pain: a challenge for the scientist and the clinician. PAINÒ 1995;61:161–4. [18] Jensen TS, Finnerup NB. Allodynia and hyperalgesia in neuropathic pain: clinical manifestations and mechanisms. Lancet Neurol 2014;13:924–35. [19] Klit H, Finnerup NB, Andersen G, Jensen TS. Central poststroke pain: a population-based study. PAINÒ 2011;152:818–24. [20] Klit H, Finnerup NB, Jensen TS. Central post-stroke pain: clinical characteristics, pathophysiology, and management. Lancet Neurol 2009;8:857–68. [21] Klit H, Finnerup NB, Jensen TS. Defining post-stroke pain: diagnostic challenges. Lancet Neurol 2010;9:344–5 [Authors’ reply]. [22] Lampl C, Yazdi K, Roper C. Amitriptyline in the prophylaxis of central poststroke pain. Preliminary results of 39 patients in a placebo-controlled, long-term study. Stroke 2002;33:3030–2. [23] Leijon G, Boivie J, Johansson I. Central post-stroke pain – neurological symptoms and pain characteristics. PAINÒ 1989;36:13–25. [24] Lenz FA, Gracely RH, Baker FH, Richardson RT, Dougherty PM. Reorganization of sensory modalities evoked by microstimulation in region of the thalamic principal sensory nucleus in patients with pain due to nervous system injury. J Comp Neurol 1998;399:125–38.
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Ò
H. Klit et al. / PAIN 155 (2014) 2699–2706
[25] MacGowan DJ, Janal MN, Clark WC, Wharton RN, Lazar RM, Sacco RL, Mohr JP. Central poststroke pain and Wallenberg’s lateral medullary infarction: frequency, character, and determinants in 63 patients. Neurology 1997;49:120–5. [26] Pain terms: a current list with definitions and notes on usage. In: Merskey H, Bogduk N, editors. Classification of chronic pain. Seattle: IASP Press; 1994. p. 209–14. [27] Naess H, Lunde L, Brogger J, Waje-Andreassen U. Post-stroke pain on long-term follow-up: the Bergen stroke study. J Neurol 2010;257:1446–52. [28] Peyron R, Garcia-Larrea L, Gregoire MC, Convers P, Lavenne F, Veyre L, Froment JC, Mauguiere F, Michel D, Laurent B. Allodynia after lateral-medullary (Wallenberg) infarct. A PET study. Brain 1998;121:345–56. [29] Peyron R, Garcia-Larrea L, Gregoire MC, Convers P, Richard A, Lavenne F, Barral FG, Mauguiere F, Michel D, Laurent B. Parietal and cingulate processes in central pain. A combined positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) study of an unusual case. PainÒ 2000;84: 77–87. [30] Rolke R, Baron R, Maier C, Tolle TR, Treede RD, Beyer A, Binder A, Birbaumer N, Birklein F, Botefur IC, Braune S, Flor H, Huge V, Klug R, Landwehrmeyer GB, Magerl W, Maihofner C, Rolko C, Schaub C, Scherens A, Sprenger T, Valet M, Wasserka B. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): standardized protocol and reference values. PainÒ 2006;123:231–43.
[31] Roosink M, Geurts AC, Ijzerman MJ. Defining post-stroke pain: diagnostic challenges. Lancet Neurol 2010;9:344–5. [32] Sprenger T, Seifert CL, Valet M, Andreou AP, Foerschler A, Zimmer C, Collins DL, Goadsby PJ, Tolle TR, Chakravarty MM. Assessing the risk of central post-stroke pain of thalamic origin by lesion mapping. Brain 2012;135:2536–45. [33] Treede RD, Jensen TS, Campbell JN, Cruccu G, Dostrovsky JO, Griffin JW, Hansson P, Hughes R, Nurmikko T, Serra J. Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology 2008;70: 1630–5. [34] Vestergaard K, Nielsen J, Andersen G, Ingeman-Nielsen M, Arendt-Nielsen L, Jensen TS. Sensory abnormalities in consecutive, unselected patients with central post-stroke pain. PainÒ 1995;61:177–86. [35] Weimar C, Kloke M, Schlott M, Katsarava Z, Diener HC. Central poststroke pain in a consecutive cohort of stroke patients. Cerebrovasc Dis 2002;14: 261–3. [36] Widar M, Samuelsson L, Karlsson-Tivenius S, Ahlstrom G. Long-term pain conditions after a stroke. J Rehabil Med 2002;34:165–70. [37] Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. PAINÒ 2011;152:S2–S15. [38] Zeilig G, Enosh S, Rubin-Asher D, Lehr B, Defrin R. The nature and course of sensory changes following spinal cord injury: predictive properties and implications on the mechanism of central pain. Brain 2012;135:418–30.
PAIN 155 (2014) 2699–2706
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Early evoked pain or dysesthesia is a predictor of central poststroke pain Henriette Klit a,b,⇑, Anne P. Hansen a, Ninna S. Marcussen a, Nanna B. Finnerup a, Troels S. Jensen a,b a b
Danish Pain Research Center, Aarhus University, Aarhus, Denmark Department of Neurology, Aarhus University Hospital, Aarhus, Denmark
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
a r t i c l e
i n f o
Article history: Received 29 June 2014 Received in revised form 26 September 2014 Accepted 29 September 2014
Keywords: Central neuropathic pain Central poststroke pain Pain Predictors Stroke
a b s t r a c t Central poststroke pain (CPSP) is a central neuropathic pain condition caused by a cerebrovascular lesion affecting the central somatosensory nervous system. Once developed, CPSP is difficult to treat, so there is an interest in identifying stroke patients at risk for the development of CPSP. This study examined if sensory abnormalities, including evoked dysesthesia, allodynia, or hyperalgesia to static and dynamic touch, cold, and pinprick, at stroke onset are a predictor for the development of CPSP. Consecutive stroke patients were recruited from a large prospective study of poststroke pain in Aarhus, Denmark, between 2007 and 2008. Patients underwent a structured pain interview and a standardized sensory examination within 4 days of admission, and a structured telephone interview was conducted after 3 and 6 months. Patients who developed poststroke pain in the affected side without any other plausible cause were classified as having possible CPSP. A total of 275 stroke patients completed the study, and 29 patients (10.5%) were classified as having possible CPSP. The diagnosis was confirmed by a clinical examination in 15 of 17 patients, corresponding to a prevalence of 8.3%. The presence of allodynia, hyperalgesia, or dysesthesia in response to the sensory examination at stroke onset increased the odds for CPSP at 6 months by 4.6 (odds ratio; 95% confidence interval 1.5–13.9). The combination of reduced or absent sensation to pinprick or cold and early evoked pain or dysesthesia at onset increased odds by 8.0 (odds ratio; 95% confidence interval 2.6–24.8). In conclusion, early evoked pain or dysesthesia is a predictor for CPSP. Ó 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
1. Introduction Central poststroke pain (CPSP) is a central neuropathic pain condition caused by a vascular lesion of the central somatosensory nervous system [16]. It is characterized by pain and sensory abnormalities in the body parts that correspond to the injured brain area. The incidence of this devastating condition, which is associated with both reduced quality of life and increased mortality [7,27], is estimated to be 7% to 8% in stroke survivors [1,19]. The condition is often refractory to treatment, and it is thus important to identify patients who are at risk for the development of CPSP in order to follow these patients more carefully, inform them about central pain, initiate treatment, and conduct prophylactic treatment studies in the future. The underlying mechanisms of CPSP are not known, but abnormal spinothalamocortical tract function [23,34], loss of inhibition ⇑ Corresponding author at: Danish Pain Research Center, Aarhus University Hospital, Norrebrogade 44, Building 1A, DK-8000 Aarhus C, Denmark. Tel.: +45 7846 3287; fax: +45 7846 3269. E-mail address: [email protected] (H. Klit).
[6,9,11,12,14], central sensitization [37], and neuroplastic changes [24,28,29] are all mechanisms that have been implicated in this and other central neuropathic pain conditions. Central sensitization is defined as an increased responsiveness of nociceptive neurons in the central nervous system (CNS) to their normal or subthreshold afferent input [1]. Neuropathic pain is characterized by negative and/or positive symptoms and signs. It may be spontaneous (ongoing or intermittent) or evoked, and it may be associated with nonpainful dysesthesia or paresthesia [5,34]. The negative signs in CPSP include loss or reduction of thermal and pinprick sensibility, while positive symptoms and signs are pain or unpleasantness evoked by touch, pressure, or thermal stimuli. This dual combination of loss and hypersensitivity in the affected area is usually explained by loss of input to a population of CNS neurons participating in the processing of somatosensory information, and at the same time hyperexcitability in the same or other neurons within the CNS [14,19]. Our previous studies have shown that sensory hypersensitivity in the affected body parts may occur already at onset of stroke [1,19], but it is unclear if this sensory hypersensitivity presenting as hyperalgesia, dysesthesia, or allodynia is a risk factor for the
http://dx.doi.org/10.1016/j.pain.2014.09.037 0304-3959/Ó 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
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subsequent development of pain. In 2 recent studies, early sensory hypersensitivity was found to predict later onset of central neuropathic pain (below-level pain) in patients with spinal cord injury [10,38]. In this prospective study, we aimed to determine if stroke patients with early evoked pain or dysesthesia, defined as findings of allodynia, hyperalgesia, or dysesthesia in response to the sensory examination at stroke onset, have an increased risk of developing CPSP. 2. Methods 2.1. Patient recruitment We included stroke patients admitted consecutively to the Stroke Unit of the Department of Neurology, Aarhus University Hospital, Aarhus, Denmark, between February and September 2007 and between February and July 2008 (Fig. 1). Inclusion criteria were age of 18 years or above, informed consent, and a diagnosis of stroke according to the World Health Organization criteria (ICD-10 codes: I61, I63, I64.9, I67.6, and I67.7). Exclusion criteria were a diagnosis of trasient ischemic attack (TIA) (G45.9) or subarachnoid
hemorrhage (I60.9), inability to communicate, severe dementia, or pronounced somnolence. Results on pain development are reported elsewhere [13]. All included patients underwent a structured interview and a standardized bedside sensory examination within the first 4 days of admission (initial examination), including sensory testing for dysesthesia, allodynia, and hyperalgesia. Dysesthesia is defined as an unpleasant abnormal sensation, whether spontaneous or evoked; allodynia as pain due to a stimulus that does not normally provoke pain; and hyperalgesia as increased pain from a stimulus that normally provokes pain [26]. To determine the presence of these phenomena, we used static and dynamic touch, cold, and pinprick stimulation (in the following called evoked pain or dysesthesia) [13]. The interview included questions about pain conditions before the stroke and the presence of spontaneous and evoked pain or dysesthesia at or after stroke onset. Medical records from the hospital admission and results of computed tomography (CT) and/or magnetic resonance imaging (MRI) scans were obtained. All initial examinations were done by 1 of 2 investigators (APH or NSM). A structured follow-up telephone interview was conducted 3 and 6 months after stroke onset. The interview included questions
Fig. 1. Flow chart of study.
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about the status of the pain reported in the previous interview, pain experienced within the last week, and the presence of spontaneous and evoked pain or dysesthesia. Only patients who completed the 6-month follow-up were included in the study. After the 6-month follow-up, patients were classified as having possible CPSP, other poststroke pain, or no poststroke pain on the basis of the data from the initial examination and the interviews at the admission and the 3- and 6-month follow-up. Information about early evoked dysesthesia or pain was not used to classify the patients. Patients were identified as having ‘‘possible CPSP’’ on the basis of the proposed grading system for neuropathic pain [20,33] if they fulfilled the following 3 criteria: (1) onset of pain at or after stroke onset, (2) pain located in the stroke-affected side of the body, and (3) no other plausible cause of the pain (including poststroke shoulder pain isolated to the shoulder region) [13]. The affected side was confirmed post hoc on the basis of information from medical records on symptoms and signs at stroke onset and CT or MRI results. If the affected side could not be identified with certainty (n = 10), both sides were included as affected. Early evoked pain or dysesthesia was considered relevant if: (1) it was unilateral or asymmetrical, (2) it was found in the affected side of the body, and (3) its onset was after the stroke, or if onset was uncertain. In order to confirm the diagnosis, all patients identified with possible CPSP were invited to participate in a clinical examination (follow-up examination). The examination included a standardized interview, a bedside sensory examination, and thermal sensory testing. Patients were interviewed about medical history, medication, and pain, which was assessed with 4 items from the Brief Pain Inventory (general activity, mood, sleep, and enjoyment of life) [8] and a Danish version of the 10-item DN4 [4], and patients were asked to complete a pain drawing. On the basis of all the available information, except for information on early evoked pain or dysesthesia, patients were classified as having definite CPSP or no CPSP according to the proposed grading system for neuropathic pain [33]. All follow-up examinations were performed by a physician (HK) who had not participated in the initial examination. Patients who were classified as having definite CPSP based on the grading system for neuropathic pain at the follow-up examination, including patients who fulfilled the criteria for definite neuropathic pain but in whom other causes of pain could not be excluded, are referred to as definite CPSP patients in the following. 2.2. Sensory examination At both examinations, a cotton ball was used to examine for static touch sensation, a von Frey monofilament (monofilament No. 5.88; Semmes Weinstein Touch Test, Stoelting, IL, USA) for pinprick sensation, a brush (Somedic, Hörby, Sweden) for dynamic touch, and a metal roller for cold sensation (initial examination: a metal roll at 20 °C [Somedic, Hörby, Sweden]; follow-up examination: metal roll at room temperature). Sensation to each stimulus was noted as absent, diminished, normal, or increased compared to the unaffected mirror body part. In those cases where the affected side could not be determined on the basis of the sensory examination alone, the history and the result of the brain scan determined the affected side. Sensory findings were indicated on a body chart. The presence of evoked dysesthesia, allodynia, and hyperalgesia to each stimulus was noted, and the intensities of evoked pain and dysesthesia were scored on an 11-point (0 = no pain, 10 = worst possible pain) numeric rating scale (NRS). The initial examination was conducted bilaterally on the front of the forearm, thenar, cheek, shin, and the dorsum of the foot, while the entire front of the body, or in a few cases (for practical reasons) only parts of the body, were examined at the follow-up examination.
At the clinical follow-up examination, sensory thermal testing (TSA 2001; Medoc Thermotest, Ramat Yishai, Israel) was conducted with a 3 3 cm2 thermode, a baseline temperature of 32 °C, a rate of change of 1 °C/s for detection and 5 °C/s for pain thresholds, and cutoff values at 0 °C and 50 °C. Cold detection threshold (CDT), warm detection threshold (WDT), cold pain threshold (CPT), and heat pain threshold (HPT) were determined on the affected side (in an area of pain, either cheek, forearm, or shin) and on the corresponding contralateral side (average of 3 measurements). A side difference of P2 °C in detection thresholds, P10.3 °C in cold pain thresholds, and P4.2 °C in heat pain thresholds were considered abnormal [30]. 2.3. Ethics The study was conducted in accordance with the Helsinki Declaration. Written and oral information was given, and informed consent was obtained before both the initial and the follow-up examination. The study was approved by the regional research ethics committee (20060116) and by the Danish Data Protection Agency (2006-41-6900). 2.4. Statistical analysis Statistical analysis was performed by Intercooled Stata software, version 9.2 (StataCorp, College Station, TX, USA). Data are presented as mean and standard deviation (SD) with 95% confidence intervals (CI) or as median with range where appropriate. Parametric data were analyzed by Student’s t test. Nonparametric data were analyzed using by Mann-Whitney and Kruskal-Wallis (rank sum) tests. Dichotomous data were analyzed by Pearson’s chi-square (v2) test and Fisher’s exact test. Odds ratios (OR) are presented with 5% and 95% CI. P values less than .05 were considered statistically significant. 3. Results In total, 299 stroke patients were included in the prospective study, and 275 patients (153 men, 122 women) completed the 6month follow-up (Fig. 1). The mean age of the patients was 65.6 (SD 13.0) years. Detailed information including stroke characteristics are reported elsewhere [13]. After the 6-month follow-up interview, 29 patients (11 men) were classified as having possible CPSP, corresponding to an incidence of 10.5% (mean age 60.4 [SD 9.39] years) [13]. In 25 of these 29 patients, the pain was located in an area with sensory abnormalities confirmed by the initial examination at stroke onset. Possible CPSP was more common after lesions affecting the left side compared with the right (20/ 138 vs 8/126, P = .032). Seventeen of 29 patients with possible CPSP agreed to participate in the follow-up examination. In the remaining 12 patients,
Table 1 Number of patients (N = 275) with evoked pain or dysesthesia and median (range) intensity on the NRS (0–10). Stimulus
Brush Light touch Cold thermo rolla Pinprick Total (n = 42)
Evoked pain
Evoked dysesthesia
n
n
NRS
12 5 21 9 33
4 4 5 4
0 0 3 12 13
NRS
5 (4–9) 5 (1–10)
(1–8) (2–5) (1–10) (2–5)
a Only 1 patient with cold-evoked pain and 4 with cold-evoked dysesthesia also had brush-evoked dysesthesia, suggesting that cold-evoked hypersensitivity is not only related to the touch of the thermal roll.
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Table 2 OR for the development of CPSP.a Item
Predictor
95% 95% CI
Sens (%)
4.6
1.5– 13.9
10 (4.1%)
3.6
0.7– 18.3 0.7– 18.3 1.7– 31.6 0.6– 59.3 0.4– 8.3 1.0– 15.1 0.6– 8.8 0.3– 21.2 3.7– 46.6 5.9– 633 2.1– 18.6 1.5– 12.3 1.3– 15.9 0.8– 6.2 2.1– 17.7 1.8– 104.6 2.0– 26.1 3.7– 46.6 2.6– 24.8 NA
Definite CPSP (n = 15), n (%)
Not suspected of CPSP (n = 246), n (%)
Primary outcome 1 Early evoked pain or dysesthesia at examination
6 (40%)
31 (12.6%)
Secondary outcomes 1a Early evoked pain (allodynia or hyperalgesia) at examination
2 (13%)
OR
1b
Early evoked pain or dysesthesia to 1 or more stimuli
2 (13%)
10 (4.1%)
3.6
*
Early pain or dysesthesia to brush at examination
3 (20%)
8 (3.3%)
7.4
*
Early pain or dysesthesia to touch at examination
1 (7%)
3 (1.2%)
5.7
*
Early pain or dysesthesia to cold at examination
2 (13%)
20 (8.1%)
1.7
*
Early dysesthesia or hyperalgesia to pinprick at examination
3 (20%)
15 (6.1%)
3.9
*
2
Reported spontaneous pain or unpleasantness at onset
3 (20%)
24 (9.8%)
2.3
2a
Reported spontaneous pain* at onset
1 (7%)
7 (2.9%)
2.4
3
Reported pain or dysesthesia evoked by touch or cold at onset
5 (33%)
9 (3.7%)
13.2
3a
Reported pain evoked by touch or cold at onset
3 (20%)
1 (0.4%)
61.3
2 or 3
Reported spontaneous pain or unpleasantness or reported dysesthesia or pain evoked by touch or cold at onset Reported spontaneous pain or unpleasantness or reported or evoked dysesthesia or pain at onset Reported or evoked pain
7 (47%)
30 (12.2%)
6.3
8 (53%)
52 (21.1%)
4.3
4 (27%)
18 (7.3%)
4.6
7 (47%)
71 (28.9%)
2.2
5
Early hyperesthesia at examination (including evoked dysesthesia or pain) Early anesthesia at examination
8 (53%)
39 (15.9%)
6.1
6
Hypo- or anesthesia to 1 or more stimuli at examination
14 (93%)
125 (50.8%)
13.6
6a
Hypo- or anesthesia to cold or pinprick at examination
12 (80%)
88 (35.8%)
7.2
1 and 5
Early evoked pain/dysesthesia and anesthesia at examination
5 (33%)
9 (3.7%)
13.2
1 and 6a
Early evoked pain/dysesthesia and reduced/abolished sensation to cold or pinprick at examination Abnormal sensory findings at examination, either hyper-, hypo, or anesthesia
6 (40%)
19 (7.7%)
8.0
15 (100%)
149 (60.6%)
1, 2 or 3 1a or 2a 4
4 or 6
NA
Spec (%)
PPV (%)
Acc (%)
16
96
40
85
17
95
13
91
17
95
13
91
27
95
20
92
25
95
7
93
9
95
13
87
17
95
20
90
11
95
20
86
13
95
7
92
36
96
33
93
75
95
20
95
19
96
47
85
13
97
53
77
18
95
27
89
9
96
47
70
17
97
53
82
10
99
93
52
12
98
80
64
36
96
33
93
24
96
40
89
9
100
100
43
OR = odds ratio; CPSP = central poststroke pain; CI = confidence interval; PPV = positive predictive value; sens = sensitivity; spec = specificity; acc = accuracy. * Reported spontaneous pain not including pain due to headache or evoked pains. a Comparison between reported symptoms and sensory findings on the initial examination at stroke onset correlated to the later classification as definite CPSP, confirmed by a clinical examination (n = 15) compared to patients not suspected of CPSP (n = 246).
pain had disappeared in 2 patients, 8 patients declined participation, and 2 patients were lost to follow-up (Fig. 1). The median time from the stroke to the follow-up examination was 32.4 months (range 6.2–36.6 months). At the follow-up examination, the patients were classified as follows: definite (n = 15, including 4 patients in whom other causes of pain could not be excluded), not CPSP (n = 1, poststroke shoulder pain), and no longer pain (CPSP-like dysesthesia, n = 1). In total, 15 of the 17 examined patients were classified as having definite CPSP. This corresponds to a minimum prevalence of clinically confirmed definite CPSP in 5.9% of patients within 6 months after stroke. If patients in whom other causes of pain could not be excluded are omitted, the corresponding prevalence is 4.3%. If we expect those without response to have the same prevalence, it corresponds to a prevalence of 8.3% (15/19 29/275). The sensory findings and reported symptoms and pain of the 15 patients with definite CPSP are summarized in Fig. 3 and Supplementary Tables 1–3.
3.1. Predictors of CPSP Definite CPSP confirmed by the clinical follow-up examination was considered to be the outcome measure. The 15 patients with definite CPSP were compared with the 246 (275 29) patients without possible CPSP (Fig. 1). 3.2. Primary outcome measure: early evoked dysesthesia or pain Early evoked pain or dysesthesia to brush, touch, cold, or pinprick stimulation was found in 53 of 275 patients. Relevant evoked pain or dysesthesia was identified in 42 patients (15.3%), while the remaining 11 findings were nonrelevant, ie, bilateral and symmetrical (n = 3), in the unaffected side (n = 6), or had onset before stroke (n = 2). Of these 42 patients, 13 had allodynia or hyperalgesia, and 29 patients had only evoked dysesthesia. The findings and the intensity of evoked pain or dysesthesia to the 4 stimuli are summarized in Table 1.
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Of the 42 patients with early evoked pain or dysesthesia, 5 were later classified as having possible CPSP but were not available for follow-up, 31 were not suspected of having CPSP, and 6 were later classified as having definite CPSP (Fig. 1). Early evoked pain or dysesthesia was found in 37.9% (11 of 29) of the patients with possible CPSP compared to 12.6% (31 of 246) of the patients not suspected of having CPSP (P < .001, v2). This corresponds to an OR of 4.2 (95% CI 1.8–9.8) of developing possible CPSP in patients with early evoked pain or dysesthesia. In patients with definite CPSP, early evoked pain or dysesthesia was seen in 6 (40.0%) of 15, corresponding to an OR of 4.6 (95% CI 1.5–13.9), with a positive predictive value of 40%, a sensitivity of 16%, a specificity of 96%, and an accuracy of 85% (Table 2, item 1; Fig. 2). Of the 6 patients with early evoked pain or dysesthesia who later developed definite CPSP, 1 patient had pinprick dysesthesia (NRS 5), 1 had pinprick hyperalgesia (NRS not done), 1 had cold allodynia (NRS 4), 1 had brush dysesthesia (NRS 7), 1 had a combination of dysesthesia to brush (NRS 4), touch (NRS 4), and pinprick (NRS 4), and 1 had a combination of dysesthesia to brush (NRS 8) and cold (NRS 3) (Supplementary Table 1). The presence of early evoked pain or dysesthesia in combination with reduced or absent sensation to cold or pinprick increased the odds for central poststroke pain at 6 months by 8.0 (OR; 95% CI 2.6–24.8) (Table 2, items 1 and 6a). 3.3. Secondary outcome measures: other symptoms and signs Secondary outcomes are presented in Table 2. Patients who reported pain evoked by touch or cold at onset were more likely to be classified as having definite CPSP at follow-up (OR 61.3; 95% CI 5.9–633) (Table 2, item 3a). Patients with decreased or absent sensation, ie, hypo- or anesthesia to 1 or more stimuli, were also more likely to be classified as having CPSP (OR 13.6; 95% CI 1.8–104.6) (Table 2, item 6). There was also a significant correlation between the presence of early anesthesia and CPSP (OR 6.1; 95% CI 2.1–17.7) (Table 2, item 5). Patients with reduced or absent sensation to pinprick or cold, indicating abnormal spinothalamocortical tract function, were also more likely to be classified with CPSP (OR 7.2; 95% CI 2.0–26.1) (Table 2, item 6a; Fig. 3). We found no correlation between the presence of early hyperesthesia and the development of CPSP (OR 2.2; 95% CI 0.8–6.2) (Table 2, item 4). Reported spontaneous pain or unpleasantness at the initial interview (item 2) was not significantly correlated to CPSP, whereas there was a significant correlation between
Fig. 2. Frequency of early evoked dysesthesia or pain in patients with and without CPSP at 6-month follow-up. ⁄P < .001.
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reported touch- or cold-evoked dysesthesia or pain in the affected side and CPSP (OR 13.2; 95% CI 3.7–46.6) (Table 2, item 3). The combination of early evoked pain and dysesthesia and absent sensation to 1 or more stimuli at the time of the initial examination increased the OR for developing CPSP to 13.2 (95% CI 3.7–46.6) with a sensitivity of 36% and a specificity of 96% (accuracy 93%) (Table 2, items 1 and 5). 4. Discussion Our previous studies have indicated that CPSP is more common in patients with somatosensory deficits [1,19]. In this prospective study, we found that the presence of evoked dysesthesia, allodynia, or hyperalgesia in the affected side of the body within 4 days of stroke onset was a predictor for the development of CPSP within 6 months after stroke onset (OR 4.6; 95% CI 1.5–13.9). Other early predictors include patient-reported evoked pain and dysesthesia and sensory abnormalities at the initial examination. A hallmark of neuropathic pain is the combination of negative and positive signs [15]. Importantly, we found that the combination of early evoked pain or dysesthesia and absent sensation to 1 or more stimuli at the time of the initial examination increased the OR for developing CPSP (OR 13.2; 95% CI 3.7–46.6). It has previously been shown that evoked dysesthesia and allodynia are present in most patients with CPSP [2,3,5], but to our knowledge, ours is the first study to compare early sensory findings to the subsequent development of CPSP in a prospective manner. We found that early evoked pain or dysesthesia was present within 4 days of stroke onset in 15% of the patients. Findings of evoked dysesthesia or pain may in some, but not all, cases reflect neuronal hyperexcitability, ie, an excessive reaction of the neurons to stimuli [18]. In some patients, these symptoms were present early or immediately after stroke onset. The presence of dysesthesia and allodynia in CPSP patients may reflect central sensitization [11], which has been proposed as one of the mechanisms underlying this pain condition [17,20,34]. Consistent with the present findings, recent studies have shown that early sensory hypersensitivity and allodynia are predictors for below-level central pain in patients with spinal cord injury. Zeilig et al. [38] found that dynamic mechanical allodynia, temporal summation of pain, and hyperpathia predicted central pain, while Finnerup et al. [10] found that brush, cold, warm, and single or repetitive pinprick predicted central pain, of which cold-evoked pain or dysesthesia was the best predictor. The authors suggested that this neuronal hyperexcitability, which may develop after damage to the spinothalamic tracts, develops gradually and precedes the development of spontaneous central pain [10,38]. In line with these findings, we found that early pain or dysesthesia to brush and the combination of early evoked pain or dysesthesia and decreased or absent sensation to cold or pinprick, which may be interpreted as an indication of damage to the spinothalamic tracts, significantly predicted development of central pain. The presence of early evoked pain or dysesthesia is not a perfect predictor for the development of CPSP. The sensitivity, specificity, and accuracy of early evoked dysesthesia or pain was 16%, 96%, and 85%, respectively, indicating that other mechanisms are involved. In accordance with the present study, not all patients in the studies on spinal cord injury pain who developed central pain had early sensory hypersensitivity. A high prevalence of CPSP has been reported after lesions affecting the posterior parts of the thalamus and the lateral medulla [22,25,32]. While the study by Sprenger et al. [32] focused on structural changes within the thalamus as a risk factor for CPSP, this study found that early clinical hypersensitivity in the body part corresponding to the affected brain lesion represents a predictor for subsequent development of CPSP. It is possible that
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Fig. 3. Area of sensory abnormalities at onset (left) compared to areas of sensory abnormalities (middle) and pain (right) at follow-up examination in patients with definite CPSP.
a combination of early sensory findings combined with information on the localization of the lesion, such as specific areas within the thalamus [32], may prove to be an even better predictor. Laserevoked potentials or functional neuroimaging could also be of value in identifying high-risk patients in future preemptive treatment studies. To date, only one study has been published on prophylactic treatment of CPSP [22]. In this prophylactic study, a
total of 39 patients with thalamic stroke were randomized to receive either amitriptyline or placebo. Only 7 of 39 patients developed CPSP; unfortunately, the study did not have sufficient statistical power to show any beneficial effect. In the present study, we found an estimated minimum prevalence of clinically confirmed definite CPSP in 5.9% of patients within 6 months after stroke and a prevalence of definite CPSP
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without other possible causes of pain in 4.3%. It can be difficult to determine if a patient with poststroke pain has CPSP. We applied clearly defined criteria in order to do this. The prevalence found in this study corresponds to other population-based studies using this and other methods of identification [1,19,35]. Unlike some of the previous epidemiologic studies on CPSP, patients with dysesthesia only were not included in the present study. If these patients had been included, the reported prevalence of CPSP would have been higher. The present study has some shortcomings. Twelve of 29 patients with possible CPSP were not available for the clinical follow-up examination. However, because CPSP was confirmed by the clinical examination in 15 of the 17 patients with possible CPSP, we assume that the frequency of CPSP was the same in the patients who did not participate in the follow-up examination. This corresponds to an estimated minimum prevalence of definite CPSP in 8.3% (15/19 27/275), and in 5.7% (11/19 27/275) of definite CPSP patients in whom other causes of pain could be excluded, in line with previously published estimates of the prevalence of CPSP [1,19]. It may be argued that patients with early evoked dysesthesia or pain have CPSP with early onset, and that the signs simply reflect a disease that is already present. However, only 1 patient had spontaneous pain at onset (Supplementary Table 1). In order not to tire out the acute stroke patients, the initial sensory examination was only performed in the face and in the distal limbs. Thus, we do not have detailed topographical data. Information on the topographical distribution of sensory findings could be an additional source of predictors. It was not always possible retrospectively to determine whether a sensory finding was caused by the present stroke, a previous stroke, or other neurologic disease such as neuropathy. In cases of uncertainty, the sensory findings were categorized as new. CPSP due to a previous stroke was not evaluated in this study because only pain with onset after the current stroke was described. Although all patients classified as definite CPSP fulfilled the diagnostic criteria according to the proposed grading system for neuropathic pain, we could not clinically rule out that other (peripheral) diseases were contributing to the pain in a small subset of patients. These patients were classified as patients with CPSP in whom other causes of pain could not be excluded. Including these patients in the study implies a risk of overestimating the prevalence of CPSP. The last follow-up in the prospective study was at 6 months. The onset of CPSP is within 6 months after stroke in the majority of patients [1,36]. In the study by Andersen [1], only 3 of 207 patients developed CPSP after 6 months. However, there are case reports in the literature indicating a later onset, and it is therefore possible that we have overlooked cases with late onset. We cannot rule out the notion that some of the patients with poststroke shoulder pain may have had a localized type of CPSP in the shoulder region. Thus, there is a risk of underreporting the incidence of CPSP [21,31]. Interestingly, at the time of follow-up, pain had disappeared in 3 of the 29 patients with possible CPSP. This confirms our previous finding that CPSP may diminish or disappear over time in some patients [18]. Relevant early evoked pain or dysesthesia was found in 15% of the stroke patients. Early evoked pain or dysesthesia was found to be a significant factor for the development of CPSP, indirectly suggesting that central sensitization may be an underlying pathophysiologic mechanism. Because of the increased risk, a close follow-up of patients with early evoked pain or dysesthesia is recommended in order to identify and treat potential pain. Future clinical studies on the prevention of this pain condition could be based on patients with early hypersensitivity, preferably if other factors related to CPSP can be identified.
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Conflict of interest The authors report no conflict of interest. Acknowledgments The authors thank Helle O. Andersen for editing help. This work was supported by the Velux Foundation, the Danish Medical Association Research Fund, a Hoejmosegaard Grant, and a scholarship from Aarhus University. The funding sources had no involvement or role in the collection, analysis, or interpretation of the data or in the writing of this article or the decision to submit it for publication. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.pain.2014.09.037. References [1] Andersen G, Vestergaard K, Ingeman-Nielsen M, Jensen TS. Incidence of central post-stroke pain. PAINÒ 1995;61:187–93. [2] Attal N, Cruccu G, Baron R, Haanpää M, Hansson P, Jensen TS, Nurmikko T. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol 2010;17:e1113–88. [3] Boivie J, Leijon G, Johansson I. Central post-stroke pain – a study of the mechanisms through analyses of the sensory abnormalities. PAINÒ 1989;37:173–85. [4] Bouhassira D, Attal N, Alchaar H, Boureau F, Brochet B, Bruxelle J, Cunin G, Fermanian J, Ginies P, Grun-Overdyking A, Jafari-Schluep H, Lantéri-Minet M, Laurent B, Mick G, Serrie A, Valade D, Vicaut E. Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4). PAINÒ 2005;114:29–36. [5] Bowsher D. Central pain: clinical and physiological characteristics. J Neurol Neurosurg Psychiatry 1996;61:62–9. [6] Cesaro P, Mann MW, Moretti JL, Defer G, Roualdes B, Nguyen JP, Degos JD. Central pain and thalamic hyperactivity: a single photon emission computerized tomographic study. PAINÒ 1991;47:329–36. [7] Choi-Kwon S, Choi JM, Kwon SU, Kang DW, Kim JS. Factors that affect the quality of life at 3 years post-stroke. J Clin Neurol 2006;2:34–41. [8] Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singapore 1994;23:129–38. [9] Craig AD, Bushnell MC. The thermal grill illusion: unmasking the burn of cold pain. Science 1994;265:252–5. [10] Finnerup NB, Norrbrink C, Trok K, Piehl F, Johannesen IL, Sorensen JC, Jensen TS, Werhagen L. Phenotypes and predictors of pain following traumatic spinal cord injury: a prospective study. J Pain 2014;15:40–8. [11] Garcia-Larrea L, Convers P, Magnin M, Andre-Obadia N, Peyron R, Laurent B, Mauguiere F. Laser-evoked potential abnormalities in central pain patients: the influence of spontaneous and provoked pain. Brain 2002;125:2766–81. [12] Garcia-Larrea L, Maarrawi J, Peyron R, Costes N, Mertens P, Magnin M, Laurent B. On the relation between sensory deafferentation, pain and thalamic activity in Wallenberg’s syndrome: a PET-scan study before and after motor cortex stimulation. Eur J Pain 2006;10:677–88. [13] Hansen AP, Marcussen NS, Klit H, Andersen G, Finnerup NB, Jensen TS. Pain following stroke: a prospective study. Eur J Pain 2012;16:1128–36. [14] Head H, Holmes G. Sensory disturbances from cerebral lesions. Brain 1911;34:102–254. [15] Jensen TS, Baron R. Translation of symptoms and signs into mechanisms in neuropathic pain. PAINÒ 2003;102:1–8. [16] Jensen TS, Baron R, Haanpaa M, Kalso E, Loeser JD, Rice AS, Treede RD. A new definition of neuropathic pain. PAINÒ 2011;152:2204–5. [17] Jensen TS, Lenz FA. Central post-stroke pain: a challenge for the scientist and the clinician. PAINÒ 1995;61:161–4. [18] Jensen TS, Finnerup NB. Allodynia and hyperalgesia in neuropathic pain: clinical manifestations and mechanisms. Lancet Neurol 2014;13:924–35. [19] Klit H, Finnerup NB, Andersen G, Jensen TS. Central poststroke pain: a population-based study. PAINÒ 2011;152:818–24. [20] Klit H, Finnerup NB, Jensen TS. Central post-stroke pain: clinical characteristics, pathophysiology, and management. Lancet Neurol 2009;8:857–68. [21] Klit H, Finnerup NB, Jensen TS. Defining post-stroke pain: diagnostic challenges. Lancet Neurol 2010;9:344–5 [Authors’ reply]. [22] Lampl C, Yazdi K, Roper C. Amitriptyline in the prophylaxis of central poststroke pain. Preliminary results of 39 patients in a placebo-controlled, long-term study. Stroke 2002;33:3030–2. [23] Leijon G, Boivie J, Johansson I. Central post-stroke pain – neurological symptoms and pain characteristics. PAINÒ 1989;36:13–25. [24] Lenz FA, Gracely RH, Baker FH, Richardson RT, Dougherty PM. Reorganization of sensory modalities evoked by microstimulation in region of the thalamic principal sensory nucleus in patients with pain due to nervous system injury. J Comp Neurol 1998;399:125–38.
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Ò
H. Klit et al. / PAIN 155 (2014) 2699–2706
[25] MacGowan DJ, Janal MN, Clark WC, Wharton RN, Lazar RM, Sacco RL, Mohr JP. Central poststroke pain and Wallenberg’s lateral medullary infarction: frequency, character, and determinants in 63 patients. Neurology 1997;49:120–5. [26] Pain terms: a current list with definitions and notes on usage. In: Merskey H, Bogduk N, editors. Classification of chronic pain. Seattle: IASP Press; 1994. p. 209–14. [27] Naess H, Lunde L, Brogger J, Waje-Andreassen U. Post-stroke pain on long-term follow-up: the Bergen stroke study. J Neurol 2010;257:1446–52. [28] Peyron R, Garcia-Larrea L, Gregoire MC, Convers P, Lavenne F, Veyre L, Froment JC, Mauguiere F, Michel D, Laurent B. Allodynia after lateral-medullary (Wallenberg) infarct. A PET study. Brain 1998;121:345–56. [29] Peyron R, Garcia-Larrea L, Gregoire MC, Convers P, Richard A, Lavenne F, Barral FG, Mauguiere F, Michel D, Laurent B. Parietal and cingulate processes in central pain. A combined positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) study of an unusual case. PainÒ 2000;84: 77–87. [30] Rolke R, Baron R, Maier C, Tolle TR, Treede RD, Beyer A, Binder A, Birbaumer N, Birklein F, Botefur IC, Braune S, Flor H, Huge V, Klug R, Landwehrmeyer GB, Magerl W, Maihofner C, Rolko C, Schaub C, Scherens A, Sprenger T, Valet M, Wasserka B. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): standardized protocol and reference values. PainÒ 2006;123:231–43.
[31] Roosink M, Geurts AC, Ijzerman MJ. Defining post-stroke pain: diagnostic challenges. Lancet Neurol 2010;9:344–5. [32] Sprenger T, Seifert CL, Valet M, Andreou AP, Foerschler A, Zimmer C, Collins DL, Goadsby PJ, Tolle TR, Chakravarty MM. Assessing the risk of central post-stroke pain of thalamic origin by lesion mapping. Brain 2012;135:2536–45. [33] Treede RD, Jensen TS, Campbell JN, Cruccu G, Dostrovsky JO, Griffin JW, Hansson P, Hughes R, Nurmikko T, Serra J. Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology 2008;70: 1630–5. [34] Vestergaard K, Nielsen J, Andersen G, Ingeman-Nielsen M, Arendt-Nielsen L, Jensen TS. Sensory abnormalities in consecutive, unselected patients with central post-stroke pain. PainÒ 1995;61:177–86. [35] Weimar C, Kloke M, Schlott M, Katsarava Z, Diener HC. Central poststroke pain in a consecutive cohort of stroke patients. Cerebrovasc Dis 2002;14: 261–3. [36] Widar M, Samuelsson L, Karlsson-Tivenius S, Ahlstrom G. Long-term pain conditions after a stroke. J Rehabil Med 2002;34:165–70. [37] Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. PAINÒ 2011;152:S2–S15. [38] Zeilig G, Enosh S, Rubin-Asher D, Lehr B, Defrin R. The nature and course of sensory changes following spinal cord injury: predictive properties and implications on the mechanism of central pain. Brain 2012;135:418–30.