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Central poststroke pain: A population-based study
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PAIN 152 (2011) 818–824
www.elsevier.com/locate/pain
Central poststroke pain: A population-based study Henriette Klit a, Nanna Brix Finnerup a,⇑, Grethe Andersen b, Troels Staehelin Jensen a,b a b
Danish Pain Research Center, Aarhus University Hospital, Norrebrogade 44, Building 1A, DK-8000 Aarhus C, Denmark Department of Neurology, Aarhus University Hospital, Norrebrogade 44, Building 10, DK-8000 Aarhus C, 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
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Article history: Received 27 September 2010 Received in revised form 17 December 2010 Accepted 17 December 2010
Keywords: Neuropathic pain Central pain Stroke Allodynia Hyperalgesia Classification
a b s t r a c t Central poststroke pain (CPSP) is a specific pain condition arising as a direct consequence of a cerebrovascular lesion. There is limited knowledge about the epidemiology and clinical characteristics of this often neglected but important consequence of stroke. In this population-based study, a questionnaire was sent out to all (n = 964) stroke patients identified through the Danish National Indicator Project Stroke Database in Aarhus County, Denmark, between March 2004 and February 2005. All surviving patients who fulfilled 4 questionnaire criteria for possible CPSP (n = 51) were selected for further clinical examination, and their pain was classified by using stringent and well-defined criteria and a detailed, standardized clinical examination. The minimum prevalence of definite or probable CPSP in this population is 7.3% and the prevalence of CPSP-like dysesthesia or pain is 8.6%. Pinprick hyperalgesia was present in 57%, cold allodynia in 40%, and brush-evoked dysesthesia in 51% of patients with CPSP. Because of its negative impact on quality of life and rehabilitation, pain is an important symptom to assess in stroke survivors. Ó 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
1. Introduction Pain after stroke includes a heterogeneous group of conditions including hemiplegic shoulder pain, pain due to spasticity, headache, joint pain, and a specific disorder termed central poststroke pain (CPSP) [13]. Although poststroke pains are common, they are an often neglected consequence of cerebral stroke [13], with a negative impact on the quality of life in this group of patients, who already have other major handicaps, such as motor weakness, ataxia, and aphasia [8,26]. For other medical complications after stroke, see Kumar et al. [17]. CPSP is a specific pain condition in which pain is assumed to be the result of a lesion of the normal pain pathways. CPSP was previously defined as ‘‘a neuropathic pain syndrome following stroke characterized by pain and sensory abnormalities in parts of the body that correspond to the cerebrovascular lesion where no other obvious nociceptive, psychogenic, and peripheral neurogenic origin for the pain is present’’ [1,18]. On the basis of a new proposed general definition of neuropathic pain [23], CPSP is now defined as ‘‘pain arising as a direct consequence of a cerebrovascular lesion of the somatosensory system in the central nervous system (CNS)’’ [16]. This new definition raises questions about the epidemiology and clinical characteristics of CPSP as opposed to other types of poststroke pain. Reduced pain and/or temperature sensation, together with allodynia (ie, pain elicited by nonnoxious stimuli) or dysesthesia (ie, ⇑ Corresponding author. Tel.: +45 8949 3455; fax: +45 8949 3269. E-mail address: fi[email protected] (N.B. Finnerup).
spontaneous or evoked unpleasant but not painful sensations) in the painful body parts are characteristic features of central pain [1,2,5,6,15,16,18,24]. The sensory loss to thermal and pinprick stimuli is considered to represent damage to the spinothalamic pathways, whereas the hypersensitivity phenomena allodynia and/or dysesthesia may represent a neuronal hyperexcitability [9]. Previous studies of CPSP are mainly based on retrospectively collected data from neurology, pain, or rehabilitation clinics, and not all studies include a clinical examination with well-defined diagnostic criteria of CPSP [9,25]. The lack of stringent criteria for CPSP is reflected in the reported prevalence rates ranging from 1–12% [1,14]. The objectives of the present study were to identify patients with CPSP in a population-based study using a questionnaire; to verify the diagnosis by a clinical examination; and to describe the characteristics of CPSP in the identified population. 2. Methods 2.1. Recruitment of stroke patients Stroke patients were identified through the Danish National Indicator Project Stroke Database (NIP, http://www.nip.dk), a database in which all hospitalized patients diagnosed with a stroke according to the World Health Organization ICD-10 criteria have been registered since January 2003. The NIP database contains information on risk factors, severity, and treatment of stroke. Patients with intracerebral hemorrhage (I61), cerebral infarction (I63), and unspecified stroke (I64) were included in the study. A questionnaire was sent out in October 2006 to all surviving
0304-3959/$36.00 Ó 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.pain.2010.12.030
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not complete the screening questions on chronic pain (n = 12) were not included in the study. Information on stroke diagnosis (ICD-10) and stroke severity (Scandinavian Stroke Scale, SSS) [19] was retrieved from the NIP database. Results of the questionnaire study will be published elsewhere (Klit et al., personal communication). 2.3. Identification of CPSP in the questionnaire On the basis of the questionnaires, a suspicion of CPSP was based on 4 predefined criteria that we termed ‘‘questionnaire criteria’’ (Table 1) [16]. 2.4. Clinical examination
Fig. 1. Study flowchart.
patients registered in the database in Aarhus County, Denmark, between March 2004 and February 2005 (n = 964) (Fig. 1). A reminder was sent to those who had not responded after 1 month. In cases of unclear or missing responses to items in the questionnaire, participants were contacted by telephone. 2.2. Study design The questionnaire had items on demographics, stroke, pain history, abnormal sensation, development of chronic pain, and quality of life. Chronic pain was defined as constant or remitting pain present for more than 3 months. Patients were asked about the development of chronic pain at or after the time of stroke onset. The pain section included screening questions about the development of headache, shoulder pain, other joint pain, pain because of increased muscle stiffness/spasms, and ‘‘other pain,’’ ie, pain not caused by any of the above. The subjects were asked to draw the areas of abnormal sensation and ‘‘other pain’’ on body charts. Patients who denied a stroke episode (n = 24) and patients who could
All patients who fulfilled the questionnaire criteria were contacted between May 2008 and June 2009. Patients who reported poststroke pain or dysesthesia, or who could not be interviewed by telephone were invited to participate in a clinical examination. The examination included a medical history, a pain drawing, a standardized pain interview, a Danish version of the 10-item DN4 [3], questions on pain interference, and sensory testing. A sensory screening standardized for bedside examination was performed bilaterally for static and dynamic touch, pinprick, and cold stimuli. The examination of sensory function in our laboratory has been described previously [10,11,21]. In brief, a cotton swab was used to examine for touch sensation, a monofilament (Semmes Weinstein Touch Test monofilaments No. 5.88, Stoelting, IL) for pinprick sensation, a brush (Somedic SENSELab brush 05, Hörby, Sweden) for dynamic allodynia, and a metal roller (developed at DPRC) at room temperature (approximately 20 °C) for cold sensation. For each sensory modality, the sensation was noted as ‘‘abolished,’’ ‘‘diminished,’’ ‘‘normal,’’ or ‘‘increased’’ compared to the unaffected mirror body part, and the findings were indicated on a body chart. The presence of evoked dysesthesia, allodynia, and sensations of spreading or aftersensations was noted for each modality. The areas and intensities of maximum evoked pain were recorded. A detailed sensory examination was performed in the painful area with the contralateral area serving as a control area. All telephone interviews and clinical examinations were performed by the same physician (HK). Medical records from the
Table 1 Diagnostic criteria for identification of CPSP patients. Method of identification Criteria for identification of patients with CPSP
Study group
Questionnaire criteria
Best clinical judgment
1. Development of pain after stroke onset not attributed to Best clinical judgment on the basis of medical headache, increased muscle stiffness/spasms, shoulder records, history, imaging, pain drawing, pain pain, or other joint pain (ie, ‘‘other pain’’) interview and clinical findings by 2 experts 2. Overlap between the areas of abnormal sensation and other pain 3. An anatomically plausible distribution of the indicated areas of altered sensation or pain, ie, either a unilateral or crossed head/body distributiona 4. No other obvious cause of the pain
Questionnaire population (n = 608)
All examined patients (n = 51)
Grading system of Klit et al. [16]a A. Exclusion of other likely causes of pain B. Pain with a neuroanatomically plausible distribution C. A history suggestive of stroke D. A neuroanatomically plausible distribution confirmed by clinical findings E. A relevant vascular lesion on imaging. Possible CPSP = A+B+C Probable CPSP = A+B+C+D or E Definite CPSP = A + B + C + D and E All examined patients (n = 51)
Abbreviation: CPSP, central poststroke pain. Patients with suspected CPSP (n = 67) were identified from the questionnaire using the questionnaire criteria. A total of 51 of these patients were examined. Examined patients with CPSP were identified by use of (1) best clinical judgment and (2) the proposed grading system for CPSP. a Based on a new proposed definition of neuropathic pain by Treede et al. [23].
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hospital admittance at the time of stroke onset and results of computed tomographic or magnetic resonance imaging scans were obtained for all patients participating in the clinical examination. 2.5. Classification of examined patients At the end of data collection, all available information (including history, medical records, pain drawings, imaging, and clinical findings) was anonymized and reviewed independently by 2 neuropathic pain experts (TSJ and NBF). Patients were categorized as having definite CPSP, probable CPSP (ie, other causes of pain could not be excluded), CPSP-like dysesthesia (ie, unpleasant sensory symptoms, but no pain), or no CPSP on the basis of best clinical judgment [21]. In case of disagreement, the 2 expeorts conferred and a consensus was reached. The examined patients were also classified according to a proposed grading system for CPSP [16] by a third author (HK), based on the new grading system for neuropathic pain published by Treede et al. [23] (Table 1). According to this system, termed the ‘‘grading system,’’ CPSP is defined as ‘‘possible,’’ ‘‘probable,’’ or ‘‘definite’’. In the case of major disagreement between the clinical categorization and the grading system (n = 3), all the available information was reviewed again by 3 of the authors (TSJ, NBF, and HK) and a consensus classification was reached (‘‘consensus classification’’). 2.6. Ethics The study was conducted in accordance with the Helsinki Declaration, and informed consent was obtained before the examination. The study was approved by the regional research ethics committee (the Central Denmark Region Committee on Biomedical Research Ethics, ID 20060083) and by the Danish Data Protection Agency (ID 2006-41-6779). 2.7. Statistical analysis Statistical analysis was performed by Intercooled Stata version 9.1 software (StataCorp, College Station, TX). Data are presented
as mean and SD with 95% confidence intervals or as median and 10% and 90% percentiles (p10–90) where appropriate. Parametric data were analyzed by the Student t test. Nonparametric data were analyzed by Mann–Whitney and Kruskal–Wallis (rank sum) tests. Dichotomous data were analyzed by the Pearson v2 test and the Fisher exact test. P values of less than .05 were considered statistically significant. 3. Results Questionnaires were mailed to 964 stroke patients (457 women and 507 men), 644 questionnaires were returned, and 608 stroke patients (63.1%) were included in the study (Fig. 1). Development of novel chronic pain since onset of stroke was reported by 38.8% (Klit et al., personal communication). A total of 67 patients fulfilled the 4 predefined criteria for suspected CPSP (Fig. 2), corresponding to an incidence of suspected CPSP of 11.0% in the questionnaire population. At the time of follow-up, 12 of the 67 stroke patients suspected of CPSP were deceased, pain had resolved in 2 patients, and 2 patients were excluded from the clinical examination, 1 due to lack of consent and 1 due to severe aphasia (Fig. 1). The remaining patients suspected of CPSP (n = 51; 24 men, 27 women) all participated in the clinical examination. Thirty-three patients were examined in their own private homes and 18 at the Danish Pain Research Center. ‘‘Best clinical judgment’’ was used to categorize 24 patients as definite CPSP, 10 probable CPSP, 6 CPSP-like dysesthesia, and 11 no CPSP. Discrepancies between experts were seen in 22 cases (43.1%), with subsequent agreement after consensus discussion. When the grading system for CPSP was used, 25 patients were categorized as definite CPSP, 11 as probable CPSP, and 15 as no CPSP (including CPSP-like dysesthesia). Thus, of 51 patients categorized as possible CPSP in the questionnaire, 66.7% (78.4% including CPSPlike dysesthesia) were classified as definite or probable CPSP in the clinical judgment. Twenty-one subjects had definite CPSP, and 34 patients had either definite and/or probable CPSP in both the grading system
Fig. 2. Questionnaire criteria for identification of suspected central poststroke pain. Each circle illustrates one of the criteria, and the diagram illustrates how the criteria overlap. Criterion 1 is presence of poststroke pain not due to spasticity/spasms, headache, shoulder pain, or other joint pain. Criterion 2 is an overlap between the areas of abnormal sensation and other pain, as indicated by the patient on body chart in the questionnaire. Criterion 3 is an anatomically plausible distribution of the indicated areas of altered sensation or pain, ie, either a unilateral or crossed head/body distribution. Criterion 4 is the exclusion of other causes of pain in the patients fulfilling the first 3 criteria. Two patients were excluded on the basis of these criteria.
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Supplementary material). Thus, according to the consensus classification, 21 patients (41%) were classified as having definite CPSP, 14 (27%) probable CPSP, 6 (12%) dysesthesia, and 10 (20%) no CPSP. In the following, CPSP refers to examined patients with definite or probable CPSP (n = 35) according to the consensus classification. The demographics of the examined patients are listed in Table 3. The median age was 67.8 years (range 38.1–92.2 years), and the median time from stroke to examination was 4.4 years (range 3.3–5.7 years). There seemed to be an overrepresentation of strokes located to the thalamus and the brain stem in patients with definite CPSP (Table 3), but numbers are small. Evoked dysesthesia or allodynia and a high DN4 score (P4) were significantly more common in patients classified as definite or possible CPSP as compared to patients with CPSP-like dysesthesia or no CPSP. Only patients that fulfilled the questionnaire criteria were invited for the clinical examination including the DN4. A total of 33 of 51 (65%) of these had a high DN4 score (Table 3). With DN4 used as the test and clinical consensus as the gold standard, the sensitivity of the DN4 was 0.80, the specificity was 0.69, and the positive predictive value was 0.85 (Table 3). Two of the patients classified as not having CPSP reported that they had previously had pain (n = 1) or dysesthesia (n = 1) compatible with CPSP. In patients categorized as either definite or probable CPSP, 15 of 26 (58%) had a high score on the Leeds Assessment of Neuropathic Symptoms and Signs pain scale (S-LANNS) in the questionnaire. The clinical characteristics and categorization of each examined patient are provided in Supplementary Table 1. In Supplementary Table 2, examined patients with CPSP (n = 35) are compared to patients with development of pain (n = 169) but not suspected of CPSP from the questionnaire. Patients with CPSP
and the clinical categorization. Fourteen patients were categorized as having either dysesthesia or no CPSP in both systems of categorization. The agreement between the 2 applied systems of categorization was 94.1% (n = 48) (j = 0.86). Three patients in which there was disagreement between the 2 systems (Table 2) were reviewed by 3 of the authors, and a consensus classification was reached (details on these 3 patients are available in the
Table 2 Agreement between best clinical judgment and grading system for CPSP. Proposed grading system for CPSP
Definite Probable Not Total
Definite/probable Not Total
Clinical categorization
Total
Definite
Probableb
Dysesthesia or no CPSP
21 3 0 24
3 7 1 11
1 1 14a 16
25 11 15 51
Definite/possiblec
Dysesthesia or no CPSPa
34 1 35
2 14 16
36 15 51
Abbreviation: CPSP, central poststroke pain. a Best clinical judgment identified 6 patients with CPSP-like dysesthesia; these patients are included in the 14 patients. The kappa value for agreement between best clinical judgement and grading system for CPSP was j = 0.86. A kappa value of 0.61–0.80 is ‘‘good’’ or ‘‘substantial’’ agreement, and >0.80 is ‘‘almost perfect’’ agreement. b j = 0.72. c j = 0.86.
Table 3 Demographics at time of examination of the 51 examined patients categorized according to the consensus classification. Characteristic
All
Definite CPSP
Probable CPSP
CPSP-like dysesthesia
No CPSP
Examined subjects, n (%) Age at time of examination, y, median (range) Time from stroke, y, median (range)
51 (100%) 67.8 (38.1–92.2) 4.4 (3.3–5.7)
21 (41.2%) 66.6 (38.1–79.5) 4.3 (3.3–5.7)
14 (27.5%) 65.8 (49.6–89.6) 4.3 (3.6–4.8)
6 (11.8%) 67.1 (53.3–81.6) 4.5 (3.9–4.8)
10 (19.6%) 71.0 (59.3–92.2) 4.4 (4.1–5.1)
Sex Male Female Modified Rankin scale (0–5), median (range)
24 (47.1%) 27 (52.9%) 2 (1–4)
10 (47.6%) 11 (42.4%) 2 (1–4)
5 (35.7%) 9 (64.3%) 2 (1–4)
4 (66.7%) 2 (33.3%) 1.5 (0–3)
5 (50.0%) 5 (50.0%) 2 (1–3)
Stroke type Infarction Hemorrhage
43 (84.3%) 8 (15.7%)
16 (76.2%) 5 (23.8%)
13 (92.9%) 1 (7.1%)
6 (100%) 0
8 (80.0%) 2 (20.0%)
Imaging modalityb CT (n) MRI (n)
48 17
18 11
14 1
6 3
10 2
12 4 2 7 23 1 4 (0–7) 5 (2–6) 33 (65%) 27 (53%)
0 4 2 4 11 0 5 (3–9) 5 (3–7) 15 (71%) 12 (57%)
8 0 0 2 3 1c 4 (2–6) 5 (4–6) 13 (93%) 10 (71%)
1 0 0 0 3 0 0 3 2 1
3 0 0 1 6 0 3.5 (0–7) 3 (0.5–6) 3 (30%) 4 (40%)
30 (59%)
18 (86%)
10 (71%)
2 (33%)
Stroke localizationa,b Not evident on scan (CT only) (n) Brain stema (n) Thalamusa (n) Basal gangliaa (n) Hemispherea (n) Cerebelluma (n) Pain scores, NRS (0–10), median (range) (p10–p90)b DN4 score (0–10), median (range) (p10–p90)b DN4 P4, n (%)b Development of other poststroke pain, ie, headache, shoulder pain or pain due to spasticity or spasms, n (%) Evoked allodynia and/or dysesthesia on sensory examination, n (%)b
(0–0) (1–5) (33%) (17%)
0 (0%)
Abbreviations: CPSP, central poststroke pain; CT, computed tomography; MRI, magnetic resonance imaging; NRS, numeric rating scale. Data are based on medical records, imaging, pain interview, and sensory examination. Evoked dysesthesia and/or allodynia were significantly more common in patients classified as definite or possible CPSP compared to patients with CPSP-like dysesthesia or no CPSP (P < .001, Fisher’s exact test). There were more patients with a high DN4 score (P4) in the groups with definite or possible CPSP than in the groups with CPSP-like dysesthesia or no CPSP (P = .003, Fisher’s exact test). All patients were scanned at admission with CT, MRI, or both. a Localization as described by radiologist or in medical records. The definition of basal ganglia may vary and may in some cases include the thalamus. b Significant difference between groups (P < .005, v2 exact or Kruskal–Wallis test). c Patient underwent CT only; other lesion probable.
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were significantly younger (median age 62.5 vs. 69.8 years, P = .008) and less likely to report depression (20.6 vs. 40.0%, P = .034) than patients without suspected CPSP. There was no significant difference between the 2 groups with respect to sex, use of daily pain medication, pain interference, or self-rated overall quality of life and health. Pain characteristics of the patients with CPSP are summarized in Supplementary Table 3 and Fig. 3. The onset of pain was within 3 months in 60%. Daily pain was frequent (71%), and pain was often spontaneous or both spontaneous and evoked, whereas evoked pain only was less common. The median pain intensity within the last week was moderate, ie, 5 on a numeric rating scale (NRS, 0 ‘‘no pain,’’ and 10 ‘‘worst imaginable pain’’), but 66% of these patients had an NRS score of 4 or more. In general, the pain interfered only a little with general activities, mood, sleep, and enjoyment of life, but there was a great variation between patients. A total of 54% of these patients had an interference score of 4 or more (0–10, with 0 indicating ‘‘does not interfere’’ and 10 indicating ‘‘completely interferes’’) on general activities, 49% on mood and sleep, and 40% on enjoyment of life. In 23% of the patients, the pain had decreased over time since onset in either intensity or distribution, while 34% reported increase in pain. The most common pain descriptors were ‘‘burning’’ and ‘‘painful cold,’’ while the sensory descriptors in the painful area included ‘‘tingling,’’ ‘‘pins and needles,’’ and ‘‘numbness.’’ Only 6 patients reported itching. Other words used in free text were ‘‘sore/aching’’ and ‘‘pressing/squeezing.’’ A total of 63% of the patients with CPSP had developed other poststroke pain conditions concomitantly. All CPSP patients had abnormal sensory findings, and all had hyposensitivity to at least one modality. A combination of hyperand hyposensitivity in one or more sensory modalities on clinical sensory examination was found in 86% of the patients with CPSP. A few patients had hyposensitivity as the only finding (14%). A total of 66% of the patients had allodynia or hyperalgesia, and 80% either allodynia or evoked dysesthesia in at least one modality. Allodynia for cold (40%), pinprick hyperalgesia (57%) and dysesthesia in response to cold (66%), brush (51%), and touch (40%) were common findings. Sensations of spreading and aftersensations were found in 29% and 34% of the patients, respectively. There were no patients with normal sensory examination for cold and pinprick. Of the 35 patients categorized as having CPSP, 28 patients received one of the following types of medication daily (R, n = 14) or on demand (OD, n = 14): nonsteroidal anti-inflammatory drugs (6 OD), paracetamol (9 R, 14 OD); weak opioids (2 R, 4 OD), strong opioids (1 R); antiepileptic drugs, including gabapentin, pregabalin, and lamotrigine (7 R); tricyclic antidepressants (2 R); selective serotonin reuptake inhibitors or serotonin noradrenaline reuptake inhibitors (10 R). Nine patients had tried and abandoned some type of pain medication in the past; this included gabapentin (n = 3), pregabalin (n = 2), lamotrigine (n = 2), tricyclic antidepressants (n = 2), and other drugs (n = 8), including NSAIDS, paracetamol, tramadol, and oxycodone.
4. Discussion This population-based study of poststroke pain used stringent and well-defined criteria, a validated approach, and a detailed, standardized clinical examination to estimate the prevalence of CPSP and describe its clinical characteristics. On the basis of a population-based questionnaire, patients who fulfilled 4 questionnaire criteria for possible CPSP (see Section 2) (11%) were selected for further clinical examination. With the addition of a clinical examination, definite CPSP was present in 3.5%, definite or probable in 5.8%, and CPSP-like pain or dysesthesia in 6.7% of the original questionnaire study population according to the consensus
classification. If we assume that the frequency of CPSP was the same in the deceased and excluded patients with suspected CPSP (n = 14), this corresponds to an estimated minimum prevalence of definite CPSP in 4.4%, definite or probable CPSP in 7.3%, and CPSP-like dysesthesia or pain in 8.6%. The response rate in this study was 63.1%. We have no information on the pain states in patients who did not respond. If it is assumed that none of them experienced pain, the corresponding percentage of patients with definite or probable CPSP would be 4.6%. Also, the criteria used in the questionnaire have not been validated, and thus we may have overlooked patients with CPSP from the questionnaire. Because there is no uniform definition of CPSP and no objective findings that can differentiate CPSP from other pain conditions, the diagnosis is one of exclusion. This lack of a gold standard for CPSP, as well as for other neuropathic pain conditions [16,23], makes it difficult to validate the findings. We attempted to verify the diagnosis of CPSP by 2 different methods. First, patients were categorized on the basis of best overall clinical judgment, based on all available information, including history and sensory findings. Second, patients were categorized according to the proposed grading system for CPSP. This approach implies a risk of a circular argumentation because some of the findings included in the questionnaire criteria are also weighted high in the grading system, and possibly also in the best clinical judgment. Despite this limitation, this approach has been used before in validation studies [4,11,21], and there are no simple measures to exclude the possible effect of circular argumentation in studies without a predefined gold standard. Screening instruments have been suggested to help in the diagnosis of neuropathic pain. In this study, we found a specificity of 0.8 and a sensitivity of 0.69 compared to the clinical examination as the gold standard. Questionnaires may aid in the decision, but because patients may experience non-stroke-related neuropathic pain and may have paraesthesia and dysesthesia in addition to a nociceptive pain, the diagnosis of neuropathic pain should always be based on a neurological examination. As in other studies of CPSP [2,24], we found that all patients had abnormal pain and temperature sensibility, supporting the notion that a lesion of the spinothalamic tract is necessary for the development of CPSP. Importantly, there was no a priori requirement for abnormality in temperature or pinprick sensation. The present study also confirms that allodynia, aftersensations, and spreading sensations are common findings in patients with CPSP [1,2,12], These signs are assumed to reflect a neuronal hyperexcitability in the nervous system [2,24]. Although the underlying mechanisms for such hyperexcitability are unknown, one possibility is disinhibition due to a specific lesion of the central nervous system (for review, see Klit et al. [16]). Our study shows that other concomitant poststroke pain conditions are common in patients with CPSP (63%). Chronic pain is common in stroke survivors, and figures as high as 55% have been reported [20,22], but it is not known whether the frequency of nociceptive pain or other types of neuropathic pain is higher in patients with CPSP. It is possible that this high number may be due to the relatively high age of the subjects, large number of comorbidities and medications, and other types of pain that may be a consequence of the stroke, such as spasm-related pain and shoulder pain. This complicates the diagnosis of CPSP and is reflected by the fact that many of our patients were categorized as probable CPSP because other causes of pain could not be excluded with certainty. In this study, patients with CPSP often reported moderate pain intensities and CPSP generally only interfered little with daily activities, mood, sleep, and enjoyment of life. In previous studies of CPSP, patients have reported moderate to severe pain intensity [7,12,18] and pain as a great burden. Some of these studies may
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Fig. 3. Pain drawings of the examined patients, grouped according to the consensus classification, showing pain localization. The patients were asked to draw all chronic pain, defined as constant or remitting pain with a duration of at least 3 months that had developed at or after stroke onset. Patients were asked to indicate their pain in both the affected and unaffected side, regardless of whether the pain was judged to be stroke related or not. The patients were asked to describe each different pain type separately, including intensity, provoking factors, and descriptors. At the time of classification, we identified possible poststroke pain on the basis of these pain drawings in combination with medical records, pain interview, clinical findings, and imaging.
be biased toward more severe cases because they are based on outpatient neurological or pain clinics. In the present study, almost one-fourth reported an improvement of CPSP over time, and in 5 patients with suspected CPSP, the pain (n = 4) or dysesthesia
(n = 1) had resolved within 4 years after stroke. Many patients attributed this reduction of pain to a general adjustment where they get used to the pain, but it may also reflect that CPSP is a dynamic condition in which the symptoms fluctuate or change over
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time. There is a need for further prospective studies to investigate the natural history of CPSP. In conclusion, the best estimated prevalence of definite or probable CPSP is 7.3% in this study. If dysesthesia is included, the prevalence is 8.6%. All patients with CPSP had sensory hyposensitivity to at least one modality and often had sensory hypersensitivity with cold- or touch-evoked pain or dysesthesia and pinprick hyperalgesia. Conflict of interest statement The authors have no conflicts of interest. Acknowledgments H.K. is supported by the Ludvig and Sara Elsass Foundation. N.B.F. and T.S.J. are supported by the Velux Foundation and the Danish Medical Research Council. We thank research secretary Helle Obenhausen Andersen for language revision. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.pain.2010.12.030. References [1] Andersen G, Vestergaard K, Ingeman-Nielsen M, Jensen TS. Incidence of central post-stroke pain. Pain 1995;61:187–93. [2] Boivie J, Leijon G, Johansson I. Central post-stroke pain – a study of the mechanisms through analyses of the sensory abnormalities. Pain 1989;37:173–85. [3] 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). Pain 2005;114:29–36. [4] Bouhassira D, Attal N, Fermanian J, Alchaar H, Gautron M, Masquelier E, Rostaing S, Lanteri-Minet M, Collin E, Grisart J, Boureau F. Development and validation of the Neuropathic Pain Symptom Inventory. Pain 2004;108:248–57. [5] Bowsher D. Central pain: clinical and physiological characteristics. J Neurol Neurosurg Psychiatry 1996;61:62–9.
[6] Bowsher D. Stroke and central poststroke pain in an elderly population. J Pain 2001;2:258–61. [7] Bowsher D, Leijon G, Thuomas KA. Central poststroke pain: correlation of MRI with clinical pain characteristics and sensory abnormalities. Neurology 1998;51:1352–8. [8] 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. [9] Finnerup NB. A review of central neuropathic pain states. Curr Opin Anaesthesiol 2008;21:586–9. [10] Finnerup NB, Johannesen IL, Fuglsang-Frederiksen A, Bach FW, Jensen TS. Sensory function in spinal cord injury patients with and without central pain. Brain 2003;126:57–70. [11] Gottrup H, Andersen J, Arendt-Nielsen L, Jensen TS. Psychophysical examination in patients with post-mastectomy pain. Pain 2000;87:275–84. [12] Greenspan JD, Ohara S, Sarlani E, Lenz FA. Allodynia in patients with poststroke central pain (CPSP) studied by statistical quantitative sensory testing within individuals. Pain 2004;109:357–66. [13] Jensen TS, Lenz FA. Central post-stroke pain: a challenge for the scientist and the clinician. Pain 1995;61:161–4. [14] 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;77:590–5. [15] Kim JS. Post-stroke pain. Expert Rev Neurother 2009;9:711–21. [16] Klit H, Finnerup NB, Jensen TS. Central post-stroke pain: clinical characteristics, pathophysiology, and management. Lancet Neurol 2009;8:857–68. [17] Kumar S, Magdy HS, Caplau LR. Medical complications after stroke. Lancet Neurol 2010;9:105–18. [18] Leijon G, Boivie J, Johansson I. Central post-stroke pain – neurological symptoms and pain characteristics. Pain 1989;36:13–25. [19] Lindenstrom E, Boysen G, Waage Christiansen L, á Rogvi Hansen B, Würtzen Nielsen P. Reliability of Scandinavian Neurological Stroke Scale. Cerebrovasc Dis 1991;1:103–7. [20] 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. [21] Rasmussen PV, Sindrup SH, Jensen TS, Bach FW. Symptoms and signs in patients with suspected neuropathic pain. Pain 2004;110:461–9. [22] Sackley C, Brittle N, Patel S, Ellins J, Scott M, Wright C, Dewey ME. The prevalence of joint contractures, pressure sores, painful shoulder, other pain, falls, and depression in the year after a severely disabling stroke. Stroke 2008;39:3329–34. [23] Treede RD, Jensen TS, Campbell JN, Cruccu G, Dostrovsky JO, Griffen JW, Hansson P, Hughes P, Nurmikko T, Serra J. Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology 2008;70:1630–5. [24] 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. Pain 1995;61:177–86. [25] 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. [26] Widar M, Ahlstrom G, Ek AC. Health-related quality of life in persons with long-term pain after a stroke. J Clin Nurs 2004;13:497–505.
PAIN 152 (2011) 818–824
www.elsevier.com/locate/pain
Central poststroke pain: A population-based study Henriette Klit a, Nanna Brix Finnerup a,⇑, Grethe Andersen b, Troels Staehelin Jensen a,b a b
Danish Pain Research Center, Aarhus University Hospital, Norrebrogade 44, Building 1A, DK-8000 Aarhus C, Denmark Department of Neurology, Aarhus University Hospital, Norrebrogade 44, Building 10, DK-8000 Aarhus C, 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 27 September 2010 Received in revised form 17 December 2010 Accepted 17 December 2010
Keywords: Neuropathic pain Central pain Stroke Allodynia Hyperalgesia Classification
a b s t r a c t Central poststroke pain (CPSP) is a specific pain condition arising as a direct consequence of a cerebrovascular lesion. There is limited knowledge about the epidemiology and clinical characteristics of this often neglected but important consequence of stroke. In this population-based study, a questionnaire was sent out to all (n = 964) stroke patients identified through the Danish National Indicator Project Stroke Database in Aarhus County, Denmark, between March 2004 and February 2005. All surviving patients who fulfilled 4 questionnaire criteria for possible CPSP (n = 51) were selected for further clinical examination, and their pain was classified by using stringent and well-defined criteria and a detailed, standardized clinical examination. The minimum prevalence of definite or probable CPSP in this population is 7.3% and the prevalence of CPSP-like dysesthesia or pain is 8.6%. Pinprick hyperalgesia was present in 57%, cold allodynia in 40%, and brush-evoked dysesthesia in 51% of patients with CPSP. Because of its negative impact on quality of life and rehabilitation, pain is an important symptom to assess in stroke survivors. Ó 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
1. Introduction Pain after stroke includes a heterogeneous group of conditions including hemiplegic shoulder pain, pain due to spasticity, headache, joint pain, and a specific disorder termed central poststroke pain (CPSP) [13]. Although poststroke pains are common, they are an often neglected consequence of cerebral stroke [13], with a negative impact on the quality of life in this group of patients, who already have other major handicaps, such as motor weakness, ataxia, and aphasia [8,26]. For other medical complications after stroke, see Kumar et al. [17]. CPSP is a specific pain condition in which pain is assumed to be the result of a lesion of the normal pain pathways. CPSP was previously defined as ‘‘a neuropathic pain syndrome following stroke characterized by pain and sensory abnormalities in parts of the body that correspond to the cerebrovascular lesion where no other obvious nociceptive, psychogenic, and peripheral neurogenic origin for the pain is present’’ [1,18]. On the basis of a new proposed general definition of neuropathic pain [23], CPSP is now defined as ‘‘pain arising as a direct consequence of a cerebrovascular lesion of the somatosensory system in the central nervous system (CNS)’’ [16]. This new definition raises questions about the epidemiology and clinical characteristics of CPSP as opposed to other types of poststroke pain. Reduced pain and/or temperature sensation, together with allodynia (ie, pain elicited by nonnoxious stimuli) or dysesthesia (ie, ⇑ Corresponding author. Tel.: +45 8949 3455; fax: +45 8949 3269. E-mail address: fi[email protected] (N.B. Finnerup).
spontaneous or evoked unpleasant but not painful sensations) in the painful body parts are characteristic features of central pain [1,2,5,6,15,16,18,24]. The sensory loss to thermal and pinprick stimuli is considered to represent damage to the spinothalamic pathways, whereas the hypersensitivity phenomena allodynia and/or dysesthesia may represent a neuronal hyperexcitability [9]. Previous studies of CPSP are mainly based on retrospectively collected data from neurology, pain, or rehabilitation clinics, and not all studies include a clinical examination with well-defined diagnostic criteria of CPSP [9,25]. The lack of stringent criteria for CPSP is reflected in the reported prevalence rates ranging from 1–12% [1,14]. The objectives of the present study were to identify patients with CPSP in a population-based study using a questionnaire; to verify the diagnosis by a clinical examination; and to describe the characteristics of CPSP in the identified population. 2. Methods 2.1. Recruitment of stroke patients Stroke patients were identified through the Danish National Indicator Project Stroke Database (NIP, http://www.nip.dk), a database in which all hospitalized patients diagnosed with a stroke according to the World Health Organization ICD-10 criteria have been registered since January 2003. The NIP database contains information on risk factors, severity, and treatment of stroke. Patients with intracerebral hemorrhage (I61), cerebral infarction (I63), and unspecified stroke (I64) were included in the study. A questionnaire was sent out in October 2006 to all surviving
0304-3959/$36.00 Ó 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.pain.2010.12.030
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not complete the screening questions on chronic pain (n = 12) were not included in the study. Information on stroke diagnosis (ICD-10) and stroke severity (Scandinavian Stroke Scale, SSS) [19] was retrieved from the NIP database. Results of the questionnaire study will be published elsewhere (Klit et al., personal communication). 2.3. Identification of CPSP in the questionnaire On the basis of the questionnaires, a suspicion of CPSP was based on 4 predefined criteria that we termed ‘‘questionnaire criteria’’ (Table 1) [16]. 2.4. Clinical examination
Fig. 1. Study flowchart.
patients registered in the database in Aarhus County, Denmark, between March 2004 and February 2005 (n = 964) (Fig. 1). A reminder was sent to those who had not responded after 1 month. In cases of unclear or missing responses to items in the questionnaire, participants were contacted by telephone. 2.2. Study design The questionnaire had items on demographics, stroke, pain history, abnormal sensation, development of chronic pain, and quality of life. Chronic pain was defined as constant or remitting pain present for more than 3 months. Patients were asked about the development of chronic pain at or after the time of stroke onset. The pain section included screening questions about the development of headache, shoulder pain, other joint pain, pain because of increased muscle stiffness/spasms, and ‘‘other pain,’’ ie, pain not caused by any of the above. The subjects were asked to draw the areas of abnormal sensation and ‘‘other pain’’ on body charts. Patients who denied a stroke episode (n = 24) and patients who could
All patients who fulfilled the questionnaire criteria were contacted between May 2008 and June 2009. Patients who reported poststroke pain or dysesthesia, or who could not be interviewed by telephone were invited to participate in a clinical examination. The examination included a medical history, a pain drawing, a standardized pain interview, a Danish version of the 10-item DN4 [3], questions on pain interference, and sensory testing. A sensory screening standardized for bedside examination was performed bilaterally for static and dynamic touch, pinprick, and cold stimuli. The examination of sensory function in our laboratory has been described previously [10,11,21]. In brief, a cotton swab was used to examine for touch sensation, a monofilament (Semmes Weinstein Touch Test monofilaments No. 5.88, Stoelting, IL) for pinprick sensation, a brush (Somedic SENSELab brush 05, Hörby, Sweden) for dynamic allodynia, and a metal roller (developed at DPRC) at room temperature (approximately 20 °C) for cold sensation. For each sensory modality, the sensation was noted as ‘‘abolished,’’ ‘‘diminished,’’ ‘‘normal,’’ or ‘‘increased’’ compared to the unaffected mirror body part, and the findings were indicated on a body chart. The presence of evoked dysesthesia, allodynia, and sensations of spreading or aftersensations was noted for each modality. The areas and intensities of maximum evoked pain were recorded. A detailed sensory examination was performed in the painful area with the contralateral area serving as a control area. All telephone interviews and clinical examinations were performed by the same physician (HK). Medical records from the
Table 1 Diagnostic criteria for identification of CPSP patients. Method of identification Criteria for identification of patients with CPSP
Study group
Questionnaire criteria
Best clinical judgment
1. Development of pain after stroke onset not attributed to Best clinical judgment on the basis of medical headache, increased muscle stiffness/spasms, shoulder records, history, imaging, pain drawing, pain pain, or other joint pain (ie, ‘‘other pain’’) interview and clinical findings by 2 experts 2. Overlap between the areas of abnormal sensation and other pain 3. An anatomically plausible distribution of the indicated areas of altered sensation or pain, ie, either a unilateral or crossed head/body distributiona 4. No other obvious cause of the pain
Questionnaire population (n = 608)
All examined patients (n = 51)
Grading system of Klit et al. [16]a A. Exclusion of other likely causes of pain B. Pain with a neuroanatomically plausible distribution C. A history suggestive of stroke D. A neuroanatomically plausible distribution confirmed by clinical findings E. A relevant vascular lesion on imaging. Possible CPSP = A+B+C Probable CPSP = A+B+C+D or E Definite CPSP = A + B + C + D and E All examined patients (n = 51)
Abbreviation: CPSP, central poststroke pain. Patients with suspected CPSP (n = 67) were identified from the questionnaire using the questionnaire criteria. A total of 51 of these patients were examined. Examined patients with CPSP were identified by use of (1) best clinical judgment and (2) the proposed grading system for CPSP. a Based on a new proposed definition of neuropathic pain by Treede et al. [23].
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hospital admittance at the time of stroke onset and results of computed tomographic or magnetic resonance imaging scans were obtained for all patients participating in the clinical examination. 2.5. Classification of examined patients At the end of data collection, all available information (including history, medical records, pain drawings, imaging, and clinical findings) was anonymized and reviewed independently by 2 neuropathic pain experts (TSJ and NBF). Patients were categorized as having definite CPSP, probable CPSP (ie, other causes of pain could not be excluded), CPSP-like dysesthesia (ie, unpleasant sensory symptoms, but no pain), or no CPSP on the basis of best clinical judgment [21]. In case of disagreement, the 2 expeorts conferred and a consensus was reached. The examined patients were also classified according to a proposed grading system for CPSP [16] by a third author (HK), based on the new grading system for neuropathic pain published by Treede et al. [23] (Table 1). According to this system, termed the ‘‘grading system,’’ CPSP is defined as ‘‘possible,’’ ‘‘probable,’’ or ‘‘definite’’. In the case of major disagreement between the clinical categorization and the grading system (n = 3), all the available information was reviewed again by 3 of the authors (TSJ, NBF, and HK) and a consensus classification was reached (‘‘consensus classification’’). 2.6. Ethics The study was conducted in accordance with the Helsinki Declaration, and informed consent was obtained before the examination. The study was approved by the regional research ethics committee (the Central Denmark Region Committee on Biomedical Research Ethics, ID 20060083) and by the Danish Data Protection Agency (ID 2006-41-6779). 2.7. Statistical analysis Statistical analysis was performed by Intercooled Stata version 9.1 software (StataCorp, College Station, TX). Data are presented
as mean and SD with 95% confidence intervals or as median and 10% and 90% percentiles (p10–90) where appropriate. Parametric data were analyzed by the Student t test. Nonparametric data were analyzed by Mann–Whitney and Kruskal–Wallis (rank sum) tests. Dichotomous data were analyzed by the Pearson v2 test and the Fisher exact test. P values of less than .05 were considered statistically significant. 3. Results Questionnaires were mailed to 964 stroke patients (457 women and 507 men), 644 questionnaires were returned, and 608 stroke patients (63.1%) were included in the study (Fig. 1). Development of novel chronic pain since onset of stroke was reported by 38.8% (Klit et al., personal communication). A total of 67 patients fulfilled the 4 predefined criteria for suspected CPSP (Fig. 2), corresponding to an incidence of suspected CPSP of 11.0% in the questionnaire population. At the time of follow-up, 12 of the 67 stroke patients suspected of CPSP were deceased, pain had resolved in 2 patients, and 2 patients were excluded from the clinical examination, 1 due to lack of consent and 1 due to severe aphasia (Fig. 1). The remaining patients suspected of CPSP (n = 51; 24 men, 27 women) all participated in the clinical examination. Thirty-three patients were examined in their own private homes and 18 at the Danish Pain Research Center. ‘‘Best clinical judgment’’ was used to categorize 24 patients as definite CPSP, 10 probable CPSP, 6 CPSP-like dysesthesia, and 11 no CPSP. Discrepancies between experts were seen in 22 cases (43.1%), with subsequent agreement after consensus discussion. When the grading system for CPSP was used, 25 patients were categorized as definite CPSP, 11 as probable CPSP, and 15 as no CPSP (including CPSP-like dysesthesia). Thus, of 51 patients categorized as possible CPSP in the questionnaire, 66.7% (78.4% including CPSPlike dysesthesia) were classified as definite or probable CPSP in the clinical judgment. Twenty-one subjects had definite CPSP, and 34 patients had either definite and/or probable CPSP in both the grading system
Fig. 2. Questionnaire criteria for identification of suspected central poststroke pain. Each circle illustrates one of the criteria, and the diagram illustrates how the criteria overlap. Criterion 1 is presence of poststroke pain not due to spasticity/spasms, headache, shoulder pain, or other joint pain. Criterion 2 is an overlap between the areas of abnormal sensation and other pain, as indicated by the patient on body chart in the questionnaire. Criterion 3 is an anatomically plausible distribution of the indicated areas of altered sensation or pain, ie, either a unilateral or crossed head/body distribution. Criterion 4 is the exclusion of other causes of pain in the patients fulfilling the first 3 criteria. Two patients were excluded on the basis of these criteria.
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Supplementary material). Thus, according to the consensus classification, 21 patients (41%) were classified as having definite CPSP, 14 (27%) probable CPSP, 6 (12%) dysesthesia, and 10 (20%) no CPSP. In the following, CPSP refers to examined patients with definite or probable CPSP (n = 35) according to the consensus classification. The demographics of the examined patients are listed in Table 3. The median age was 67.8 years (range 38.1–92.2 years), and the median time from stroke to examination was 4.4 years (range 3.3–5.7 years). There seemed to be an overrepresentation of strokes located to the thalamus and the brain stem in patients with definite CPSP (Table 3), but numbers are small. Evoked dysesthesia or allodynia and a high DN4 score (P4) were significantly more common in patients classified as definite or possible CPSP as compared to patients with CPSP-like dysesthesia or no CPSP. Only patients that fulfilled the questionnaire criteria were invited for the clinical examination including the DN4. A total of 33 of 51 (65%) of these had a high DN4 score (Table 3). With DN4 used as the test and clinical consensus as the gold standard, the sensitivity of the DN4 was 0.80, the specificity was 0.69, and the positive predictive value was 0.85 (Table 3). Two of the patients classified as not having CPSP reported that they had previously had pain (n = 1) or dysesthesia (n = 1) compatible with CPSP. In patients categorized as either definite or probable CPSP, 15 of 26 (58%) had a high score on the Leeds Assessment of Neuropathic Symptoms and Signs pain scale (S-LANNS) in the questionnaire. The clinical characteristics and categorization of each examined patient are provided in Supplementary Table 1. In Supplementary Table 2, examined patients with CPSP (n = 35) are compared to patients with development of pain (n = 169) but not suspected of CPSP from the questionnaire. Patients with CPSP
and the clinical categorization. Fourteen patients were categorized as having either dysesthesia or no CPSP in both systems of categorization. The agreement between the 2 applied systems of categorization was 94.1% (n = 48) (j = 0.86). Three patients in which there was disagreement between the 2 systems (Table 2) were reviewed by 3 of the authors, and a consensus classification was reached (details on these 3 patients are available in the
Table 2 Agreement between best clinical judgment and grading system for CPSP. Proposed grading system for CPSP
Definite Probable Not Total
Definite/probable Not Total
Clinical categorization
Total
Definite
Probableb
Dysesthesia or no CPSP
21 3 0 24
3 7 1 11
1 1 14a 16
25 11 15 51
Definite/possiblec
Dysesthesia or no CPSPa
34 1 35
2 14 16
36 15 51
Abbreviation: CPSP, central poststroke pain. a Best clinical judgment identified 6 patients with CPSP-like dysesthesia; these patients are included in the 14 patients. The kappa value for agreement between best clinical judgement and grading system for CPSP was j = 0.86. A kappa value of 0.61–0.80 is ‘‘good’’ or ‘‘substantial’’ agreement, and >0.80 is ‘‘almost perfect’’ agreement. b j = 0.72. c j = 0.86.
Table 3 Demographics at time of examination of the 51 examined patients categorized according to the consensus classification. Characteristic
All
Definite CPSP
Probable CPSP
CPSP-like dysesthesia
No CPSP
Examined subjects, n (%) Age at time of examination, y, median (range) Time from stroke, y, median (range)
51 (100%) 67.8 (38.1–92.2) 4.4 (3.3–5.7)
21 (41.2%) 66.6 (38.1–79.5) 4.3 (3.3–5.7)
14 (27.5%) 65.8 (49.6–89.6) 4.3 (3.6–4.8)
6 (11.8%) 67.1 (53.3–81.6) 4.5 (3.9–4.8)
10 (19.6%) 71.0 (59.3–92.2) 4.4 (4.1–5.1)
Sex Male Female Modified Rankin scale (0–5), median (range)
24 (47.1%) 27 (52.9%) 2 (1–4)
10 (47.6%) 11 (42.4%) 2 (1–4)
5 (35.7%) 9 (64.3%) 2 (1–4)
4 (66.7%) 2 (33.3%) 1.5 (0–3)
5 (50.0%) 5 (50.0%) 2 (1–3)
Stroke type Infarction Hemorrhage
43 (84.3%) 8 (15.7%)
16 (76.2%) 5 (23.8%)
13 (92.9%) 1 (7.1%)
6 (100%) 0
8 (80.0%) 2 (20.0%)
Imaging modalityb CT (n) MRI (n)
48 17
18 11
14 1
6 3
10 2
12 4 2 7 23 1 4 (0–7) 5 (2–6) 33 (65%) 27 (53%)
0 4 2 4 11 0 5 (3–9) 5 (3–7) 15 (71%) 12 (57%)
8 0 0 2 3 1c 4 (2–6) 5 (4–6) 13 (93%) 10 (71%)
1 0 0 0 3 0 0 3 2 1
3 0 0 1 6 0 3.5 (0–7) 3 (0.5–6) 3 (30%) 4 (40%)
30 (59%)
18 (86%)
10 (71%)
2 (33%)
Stroke localizationa,b Not evident on scan (CT only) (n) Brain stema (n) Thalamusa (n) Basal gangliaa (n) Hemispherea (n) Cerebelluma (n) Pain scores, NRS (0–10), median (range) (p10–p90)b DN4 score (0–10), median (range) (p10–p90)b DN4 P4, n (%)b Development of other poststroke pain, ie, headache, shoulder pain or pain due to spasticity or spasms, n (%) Evoked allodynia and/or dysesthesia on sensory examination, n (%)b
(0–0) (1–5) (33%) (17%)
0 (0%)
Abbreviations: CPSP, central poststroke pain; CT, computed tomography; MRI, magnetic resonance imaging; NRS, numeric rating scale. Data are based on medical records, imaging, pain interview, and sensory examination. Evoked dysesthesia and/or allodynia were significantly more common in patients classified as definite or possible CPSP compared to patients with CPSP-like dysesthesia or no CPSP (P < .001, Fisher’s exact test). There were more patients with a high DN4 score (P4) in the groups with definite or possible CPSP than in the groups with CPSP-like dysesthesia or no CPSP (P = .003, Fisher’s exact test). All patients were scanned at admission with CT, MRI, or both. a Localization as described by radiologist or in medical records. The definition of basal ganglia may vary and may in some cases include the thalamus. b Significant difference between groups (P < .005, v2 exact or Kruskal–Wallis test). c Patient underwent CT only; other lesion probable.
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were significantly younger (median age 62.5 vs. 69.8 years, P = .008) and less likely to report depression (20.6 vs. 40.0%, P = .034) than patients without suspected CPSP. There was no significant difference between the 2 groups with respect to sex, use of daily pain medication, pain interference, or self-rated overall quality of life and health. Pain characteristics of the patients with CPSP are summarized in Supplementary Table 3 and Fig. 3. The onset of pain was within 3 months in 60%. Daily pain was frequent (71%), and pain was often spontaneous or both spontaneous and evoked, whereas evoked pain only was less common. The median pain intensity within the last week was moderate, ie, 5 on a numeric rating scale (NRS, 0 ‘‘no pain,’’ and 10 ‘‘worst imaginable pain’’), but 66% of these patients had an NRS score of 4 or more. In general, the pain interfered only a little with general activities, mood, sleep, and enjoyment of life, but there was a great variation between patients. A total of 54% of these patients had an interference score of 4 or more (0–10, with 0 indicating ‘‘does not interfere’’ and 10 indicating ‘‘completely interferes’’) on general activities, 49% on mood and sleep, and 40% on enjoyment of life. In 23% of the patients, the pain had decreased over time since onset in either intensity or distribution, while 34% reported increase in pain. The most common pain descriptors were ‘‘burning’’ and ‘‘painful cold,’’ while the sensory descriptors in the painful area included ‘‘tingling,’’ ‘‘pins and needles,’’ and ‘‘numbness.’’ Only 6 patients reported itching. Other words used in free text were ‘‘sore/aching’’ and ‘‘pressing/squeezing.’’ A total of 63% of the patients with CPSP had developed other poststroke pain conditions concomitantly. All CPSP patients had abnormal sensory findings, and all had hyposensitivity to at least one modality. A combination of hyperand hyposensitivity in one or more sensory modalities on clinical sensory examination was found in 86% of the patients with CPSP. A few patients had hyposensitivity as the only finding (14%). A total of 66% of the patients had allodynia or hyperalgesia, and 80% either allodynia or evoked dysesthesia in at least one modality. Allodynia for cold (40%), pinprick hyperalgesia (57%) and dysesthesia in response to cold (66%), brush (51%), and touch (40%) were common findings. Sensations of spreading and aftersensations were found in 29% and 34% of the patients, respectively. There were no patients with normal sensory examination for cold and pinprick. Of the 35 patients categorized as having CPSP, 28 patients received one of the following types of medication daily (R, n = 14) or on demand (OD, n = 14): nonsteroidal anti-inflammatory drugs (6 OD), paracetamol (9 R, 14 OD); weak opioids (2 R, 4 OD), strong opioids (1 R); antiepileptic drugs, including gabapentin, pregabalin, and lamotrigine (7 R); tricyclic antidepressants (2 R); selective serotonin reuptake inhibitors or serotonin noradrenaline reuptake inhibitors (10 R). Nine patients had tried and abandoned some type of pain medication in the past; this included gabapentin (n = 3), pregabalin (n = 2), lamotrigine (n = 2), tricyclic antidepressants (n = 2), and other drugs (n = 8), including NSAIDS, paracetamol, tramadol, and oxycodone.
4. Discussion This population-based study of poststroke pain used stringent and well-defined criteria, a validated approach, and a detailed, standardized clinical examination to estimate the prevalence of CPSP and describe its clinical characteristics. On the basis of a population-based questionnaire, patients who fulfilled 4 questionnaire criteria for possible CPSP (see Section 2) (11%) were selected for further clinical examination. With the addition of a clinical examination, definite CPSP was present in 3.5%, definite or probable in 5.8%, and CPSP-like pain or dysesthesia in 6.7% of the original questionnaire study population according to the consensus
classification. If we assume that the frequency of CPSP was the same in the deceased and excluded patients with suspected CPSP (n = 14), this corresponds to an estimated minimum prevalence of definite CPSP in 4.4%, definite or probable CPSP in 7.3%, and CPSP-like dysesthesia or pain in 8.6%. The response rate in this study was 63.1%. We have no information on the pain states in patients who did not respond. If it is assumed that none of them experienced pain, the corresponding percentage of patients with definite or probable CPSP would be 4.6%. Also, the criteria used in the questionnaire have not been validated, and thus we may have overlooked patients with CPSP from the questionnaire. Because there is no uniform definition of CPSP and no objective findings that can differentiate CPSP from other pain conditions, the diagnosis is one of exclusion. This lack of a gold standard for CPSP, as well as for other neuropathic pain conditions [16,23], makes it difficult to validate the findings. We attempted to verify the diagnosis of CPSP by 2 different methods. First, patients were categorized on the basis of best overall clinical judgment, based on all available information, including history and sensory findings. Second, patients were categorized according to the proposed grading system for CPSP. This approach implies a risk of a circular argumentation because some of the findings included in the questionnaire criteria are also weighted high in the grading system, and possibly also in the best clinical judgment. Despite this limitation, this approach has been used before in validation studies [4,11,21], and there are no simple measures to exclude the possible effect of circular argumentation in studies without a predefined gold standard. Screening instruments have been suggested to help in the diagnosis of neuropathic pain. In this study, we found a specificity of 0.8 and a sensitivity of 0.69 compared to the clinical examination as the gold standard. Questionnaires may aid in the decision, but because patients may experience non-stroke-related neuropathic pain and may have paraesthesia and dysesthesia in addition to a nociceptive pain, the diagnosis of neuropathic pain should always be based on a neurological examination. As in other studies of CPSP [2,24], we found that all patients had abnormal pain and temperature sensibility, supporting the notion that a lesion of the spinothalamic tract is necessary for the development of CPSP. Importantly, there was no a priori requirement for abnormality in temperature or pinprick sensation. The present study also confirms that allodynia, aftersensations, and spreading sensations are common findings in patients with CPSP [1,2,12], These signs are assumed to reflect a neuronal hyperexcitability in the nervous system [2,24]. Although the underlying mechanisms for such hyperexcitability are unknown, one possibility is disinhibition due to a specific lesion of the central nervous system (for review, see Klit et al. [16]). Our study shows that other concomitant poststroke pain conditions are common in patients with CPSP (63%). Chronic pain is common in stroke survivors, and figures as high as 55% have been reported [20,22], but it is not known whether the frequency of nociceptive pain or other types of neuropathic pain is higher in patients with CPSP. It is possible that this high number may be due to the relatively high age of the subjects, large number of comorbidities and medications, and other types of pain that may be a consequence of the stroke, such as spasm-related pain and shoulder pain. This complicates the diagnosis of CPSP and is reflected by the fact that many of our patients were categorized as probable CPSP because other causes of pain could not be excluded with certainty. In this study, patients with CPSP often reported moderate pain intensities and CPSP generally only interfered little with daily activities, mood, sleep, and enjoyment of life. In previous studies of CPSP, patients have reported moderate to severe pain intensity [7,12,18] and pain as a great burden. Some of these studies may
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Fig. 3. Pain drawings of the examined patients, grouped according to the consensus classification, showing pain localization. The patients were asked to draw all chronic pain, defined as constant or remitting pain with a duration of at least 3 months that had developed at or after stroke onset. Patients were asked to indicate their pain in both the affected and unaffected side, regardless of whether the pain was judged to be stroke related or not. The patients were asked to describe each different pain type separately, including intensity, provoking factors, and descriptors. At the time of classification, we identified possible poststroke pain on the basis of these pain drawings in combination with medical records, pain interview, clinical findings, and imaging.
be biased toward more severe cases because they are based on outpatient neurological or pain clinics. In the present study, almost one-fourth reported an improvement of CPSP over time, and in 5 patients with suspected CPSP, the pain (n = 4) or dysesthesia
(n = 1) had resolved within 4 years after stroke. Many patients attributed this reduction of pain to a general adjustment where they get used to the pain, but it may also reflect that CPSP is a dynamic condition in which the symptoms fluctuate or change over
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time. There is a need for further prospective studies to investigate the natural history of CPSP. In conclusion, the best estimated prevalence of definite or probable CPSP is 7.3% in this study. If dysesthesia is included, the prevalence is 8.6%. All patients with CPSP had sensory hyposensitivity to at least one modality and often had sensory hypersensitivity with cold- or touch-evoked pain or dysesthesia and pinprick hyperalgesia. Conflict of interest statement The authors have no conflicts of interest. Acknowledgments H.K. is supported by the Ludvig and Sara Elsass Foundation. N.B.F. and T.S.J. are supported by the Velux Foundation and the Danish Medical Research Council. We thank research secretary Helle Obenhausen Andersen for language revision. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.pain.2010.12.030. References [1] Andersen G, Vestergaard K, Ingeman-Nielsen M, Jensen TS. Incidence of central post-stroke pain. Pain 1995;61:187–93. [2] Boivie J, Leijon G, Johansson I. Central post-stroke pain – a study of the mechanisms through analyses of the sensory abnormalities. Pain 1989;37:173–85. [3] 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). Pain 2005;114:29–36. [4] Bouhassira D, Attal N, Fermanian J, Alchaar H, Gautron M, Masquelier E, Rostaing S, Lanteri-Minet M, Collin E, Grisart J, Boureau F. Development and validation of the Neuropathic Pain Symptom Inventory. Pain 2004;108:248–57. [5] Bowsher D. Central pain: clinical and physiological characteristics. J Neurol Neurosurg Psychiatry 1996;61:62–9.
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