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Clinical pain and experimental pain sensitivity in progressive supranuclear palsy
Parkinsonism and Related Disorders 18 (2012) 606e608
Contents lists available at SciVerse ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Short communication
Clinical pain and experimental pain sensitivity in progressive supranuclear palsy Maria Stamelou a, b, *, Helena Dohmann a, Juliane Brebermann a, Evangelia Boura a, Wolfgang H. Oertel a, Günter Höglinger a, Jens C. Möller a, c, Veit Mylius a, d a
Department of Neurology, Philipps University, Marburg, Germany Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, UCL, Queen Square, London WC1B 3BG, UK c Neurocentro della Svizzera Italiana, Ente Ospedaliero Cantonale, Lugano, Switzerland d Service de Physiologie - Explorations Fonctionnelles, Hôpital Henri-Mondor, AP-HP, Université Paris 12, France b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 1 September 2011 Received in revised form 8 November 2011 Accepted 9 November 2011
Objective: We aimed to assess spinal nociception and experimental pain sensitivity in progressive supranuclear palsy-Richardson’s syndrome (PSP-R) compared to patients with Parkinson’s disease (PD) and healthy controls (HC). Methods: Spinal nociception as measured by the nociceptive flexion reflex (NFR) and experimental pain sensitivity as measured by heat and electrical pain thresholds were determined in non-demented, nondepressed, probable PSP-R patients (N ¼ 8), PD patients (N ¼ 19) and 17 HC. Results: PSP-R patients exhibited lower electrical pain thresholds and a tendency for lower NFR thresholds as compared to HC. No significant differences between PSP-R and PD patients were found with respect to experimentally-induced pain. However, significantly less PSP-R than PD patients reported disease-related pain. Conclusions: Degeneration of the descending inhibitory control system within the brainstem in PSP-R might lead to increased experimental pain sensitivity while frontal cortical deterioration may alter self-estimation of pain. Ó 2011 Elsevier Ltd. All rights reserved.
Keywords: Progressive supranuclear palsy Parkinson’s disease Nociception Pain sensitivity Nociceptive flexion reflex
1. Introduction Progressive supranuclear palsy (PSP) belongs to the tauopathies and is an atypical parkinsonian syndrome, characterized in its classical presentation by axial rigidity, postural instability, supranuclear gaze palsy and frontal dementia (now referred as PSPRichardson syndrome, PSP-R), while various further phenotypes have been described [1]. The role of clinically relevant pain in PSP has been addressed up to now only in questionnaire studies, in which 35e67,5% of PSP patients report pain and discomfort [2,3]. However, questionnaire studies are limited since confounding factors such as intake of pain-modifying drugs (for example amitriptyline, which is recommended in PSP), depression and cognitive decline, were not taken into consideration.
* Corresponding author. Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, UCL, Queen Square, London WC1B 3BG, UK. Tel.: þ44 203 108 0023. E-mail address: [email protected] (M. Stamelou). 1353-8020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.parkreldis.2011.11.010
On the other hand in Parkinson’s disease (PD), pain has been reported in up to 83% of the patients in questionnaire studies [4]. Increased experimental pain sensitivity during the “off” phase, possibly attributed to reduced central dopaminergic activation, diminished descending dopaminergic control or altered nociception at the spinal level seems to account for the high prevalence of reported pain in PD [5,6]. The increased pain sensitivity in PD patients becomes significant during the course of disease and has been found to be further augmented in patients with PD-related pain [5]. The aims of this study are 1. to investigate for the first time experimental pain sensitivity and spinal nociception in PSP as a possible correlate for the reported pain, by monitoring confounding factors such as cognitive function, mood and medication. 2. To compare the obtained results with those from PD patients and assess if the differences found could account for the higher prevalence of reported pain in PD compared to PSP.
M. Stamelou et al. / Parkinsonism and Related Disorders 18 (2012) 606e608 2. Methods 2.1. Participants Patients with probable PSP [7], probable PD and healthy controls (HC) free of systemic, neurological or psychiatric diseases were identified at the Dept. of Neurology of Philipps University Marburg. The phenotype of PSP was classified as PSP-R according to published criteria [1]. The study protocol was approved by the local IRB of the University of Marburg. Informed consent was obtained from all subjects. Exclusion criteria were pain-related diseases; acute or chronic pain of any other origin; conditions affecting pain sensitivity (e.g. neuropathy, neurological and psychiatric disorders); pain-modifying medication (e.g. analgesics, antidepressants, opioids, antineuropathic drugs, neuroleptics, long-lasting dopamine agonists, other dopaminergic medication on the day of the examination); depression as assessed by the Montgomery Åsberg Depression Rating Scale (MADRS) for PSP and the geriatric depression score (GDS) for all subjects; dementia as assessed by mini mental status examination (MMSE) (data not shown). 2.2. Clinical assessment The control group was pain free and pain in patients was classified into the five previously described different forms, as described elsewhere [6]. The participants rated their pain on a horizontal visual analogue scale (VAS), which was labeled with verbal anchors from 0 no sensation’ (0) to 0 extremely strong pain’ (100) with a verbal anchor in-between of 0 slightly painful’ (50). Moreover, they completed a pain questionnaire on their clinical pain (e.g. frequency, duration, localization and relation to medication). The Hoehn and Yahr (H&Y) stage and the Unified Parkinson’s Disease Rating Scale (UPDRS) motor score (part III) were assessed in all patients in the “on-phase” and the Frontal assessment battery (FAB) additionally in PSP patients. 2.3. Pain threshold and NFR threshold assessment Electrical stimulation and EMG recording were performed using a standard electro-diagnostic device (Viking IV D; Cardinal Health, Dublin, Ohio, USA) with modified software. Thermal pain was measured using a Peltier based contact stimulation device (Medoc TSA-2001, Ramat Yishai, Israel) with a 30 46 mm2 contact thermode. For determination of heat pain thresholds, subjects were seated upright in an armchair. For further examination participants lay supine on an examination table with knees flexed at 130 by using a pillow. The investigation took place in the morning after overnight withdrawal of all dopaminergic medication at 6e9 am (medication-defined “off” state) and had lasted 1e2 h. In order to localize the sural nerve for reflex stimulation sural neurography was performed on the more affected side in PD patients and on the left side in the control group. For recording of the nociceptive flexion reflex (NFR) and the assessment of electrical pain thresholds, surface electrodes were attached at the same localization as for sural nerve neurography at the calf. The recording electrode was attached ipsilateral over the short head of the biceps femoris muscle, and the reference electrode was fixed near the tendon of the biceps femoris muscle at the head of the fibula. The background for the NFR and its clinical application is described elsewhere [6]. NFR thresholds were assessed using the up-down staircase method. Stimulation intensity was increased in 3 mA increments until the flexion reflex RIII component was detected for the first time. Next, we lowered the stimulus intensity in 2 mA steps until the reflex disappeared. Subsequently, steps of 1 mA were used, and the procedure was repeated until the reflex appeared and subsided two more times. Mean values of three peaks (current intensity that just elicited a reflex) and three troughs (current intensity that no longer elicited a reflex) determined the reflex threshold. The electrical pain threshold was then determined by using the same stimulus paradigm and the same staircase method as during the NFR threshold measurement
607
but with a subjective estimation of pain (painful or non-painful sensation). Thermal heat pain thresholds were measured by a thermode applied to the forearm contralateral to the stimulated sural nerve by using the method of adjustments. Participants were instructed to indicate the point at which the sensation of warmth turned into pain by tapping two mouse keys that increased or decreased stimulus intensity, respectively. Two trials were performed to familiarize the subjects with the procedure before the threshold was determined three times. The means of the three trials were used for further analysis. 2.4. Statistical analysis For statistical analysis the Statistical Package for the Social Sciences (SPSS) version 17 was used. MANOVA was applied to assess the effect of the factor ‘disease (PSP-R, PD and HC)’ on the NFR and the electrical and heat pain thresholds. Post-hoc tests corrected for multiple comparisons were performed by using a Bonferroni adjustment or the Tamhan-T2 test if no homogeneity of the variances was seen. Chisquare test (corrected for continuity) was employed to detect significant influences of disease (PSP-R vs. PD) on the occurrence of clinical pain. Simple group comparisons of the descriptive statistics were conducted using Student’s t-tests for independent variables. Descriptive statistics were given as mean standard deviation and statistical significance was set to a ¼ 0.05.
3. Results 3.1. Study population The clinical characteristics of HC and PSP-R and PD patients are presented in Table 1. The different distribution of the sex is not thought to significantly influence the results, since gender differences in pain perception vanish during aging [8]. H&Y stage was found to be higher in the PSP-R group as compared to the PD group; still all patients were independently mobile and there was no significant difference in the UPDRS III in “on”. As expected, disease duration tended to be shorter in the PSP-R group when compared to the PD patients. No significant differences were found between PSP-R and PD with regard to dopaminergic treatment. PSP-R patients scored 13 2 in the FAB (worst: 0 to best:18). 3.2. Subjective pain perception and spinal nociception in PSP-R 16/19 PD patients (84%) suffered from clinical pain. Of these 74% showed musculoskeletal, 13% back pain, 4% dystonia-associated pain and 9% akathitic discomfort. Significant fewer PSP-R patients (3/8, 38%) reported clinical pain (x2 ¼ 6.417, df ¼ 1, P ¼ 0.011) of musculoskeletal origin. MANOVA revealed a main effect of ‘disease (PSP-R, PD vs. HC)0 [F(6,80) ¼ 5.081; P < 0.001] with significant effects for NFR thresholds [F(2,41) ¼ 8.670; P ¼ 0.001] and electrical pain thresholds [F(2,41) ¼ 4.986; P ¼ 0.012]. A tendency for an effect of ‘disease’ on heat pain thresholds was detected [F(2,41) ¼ 2.966; P ¼ 0.063]. Post-hoc analyses adjusted for multiple comparisons revealed significantly lower electrical pain thresholds in PSP-R patients as compared to HC and a tendency for lower electrical
Table 1 Clinical characteristics of PSP-R and PD patients and HC and descriptive statistics and comparisons of the heat and electrical pain thresholds and NFR thresholds of PSP-R patients compared to PD patients and HC.
Age(yrs) Disease duration (yrs) H&Y stage (1e5) UPDRS III in “On” L-dopa in mg Electrical pain threshold, mA NFR threshold, mA Heat pain threshold, C
PSP-R (N ¼ 8)
PD (N ¼ 19)
HC (N ¼ 17)
PD vs. HC
PSP-R vs. HC
PSP-R vs. PD
4 F/4 M
6 F/13 M
11 F/6 M
P
P
P
0.130 e e e e 0.156 0.001* 0.844
0.135 e e e e 0.006* 0.091 0.173
0.52 0.068 <0.05* 0.091 0.471 0.054 0.630 0.066
67.3 3.4 2.7 30.3 575 5.2 12.8 46.3
7.4 2.7 1.0 14.0 710 1.5 4.3 1.1
68.7 6.7 1.8 22.4 831 7.9 10.6 44.9
4.6 6.2 0.7 9.0 873 4.0 4.7 1.7
71.4 e e e e 11.9 18.3 45.2
5.7
7.4 7.0 1.0
Data are given as mean SD, * significant after Bonferroni or Tamhan-T2 post-hoc adjustment, tendencies are underlined. Significant differences are given in Bold.
608
M. Stamelou et al. / Parkinsonism and Related Disorders 18 (2012) 606e608
pain thresholds as compared to PD patients (Table 1). NFR thresholds tended to be lower in PSP-R patients as compared to HC. Patients suffering from PSP-R tended to exhibit higher heat pain thresholds as compared to the PD group. PD patients had lower NFR thresholds compared to HC as shown already in previous studies [5,6], whereas other differences in experimental thresholds did not reach the level of significance in the current study. 4. Discussion The main result of the present study is that non-demented, nondepressed PSP-R patients exhibited significantly lower electrical pain thresholds compared to HC. Spinal nociception measured by the NFR tended to be increased compared to HC, supporting the finding of lower electrical pain thresholds. This finding might be due to the fact that the midbrain and periaqueductal gray (PAG) are typically compromised by pathophysiological changes in PSP [9]. The PAG is one of the important centers for descending spinal control receiving input from the dorsolateral prefrontal cortex and projecting to the Ncl. raphe magnus and to the dorsal horn. Thus, a deterioration of the descending inhibitory systems could lead to increased nociception and electrical pain sensitivity. Spinal pathological alterations in nociceptive dorsal horn layers as observed in PD are not likely to contribute since they are less pronounced in PSP patients, who rather exhibit pathophysiological changes within the anterior and anteriolateral spinal cord [10]. In line with previous publications 84% of our PD but only 38% of our PSP-R patients reported pain [2e4]. However, PSP-R patients showed a tendency towards higher heat pain thresholds compared to PD patients. The lower frequency of reported pain in PSP-R (despite the lower electrical pain threshold) and the relatively increased heat pain thresholds which require a self-adjustment method and therefore a more active contribution of the patient might be due to their incipient frontal impairment, which may diminish verbal and non-verbal pain communication [2,11]. Previous studies revealed a reduced ability to reliably report experimentally-induced pain in demented patients, while nociception at the spinal level as well as pain perception on the level of facial pain-related expressions were still preserved [11]. It is conceivable that in more advanced PSP stages the frontal impairment may lead to even less reported pain and also to elevated pain tolerance, as shown in patients with frontotemporal dementia [12]. Moreover, it is conceivable that frontal impairment could contribute to less reporting also of other sensory modalities but this is speculative and needs to be further studied. In summary, this is the first study to assess experimental pain sensitivity and nociception in PSP-R. The limitation of these preliminary results is the small number of patients, which does
not allow examining the role of clinical pain on experimental pain sensitivity. Further experimental studies are needed to validate these results on a larger number of PSP patients including different phenotypes, while functional neuroimaging studies could be of help to reveal the underlying pathophysiology of these findings. Funding M. Stamelou receives a Research Grant from the EFNS. V. Mylius receives a Research Grant of the Prof. Schmidtmann Foundation in Marburg, Germany. Competing interests None declared. Acknowledgments None declared. References [1] Williams DR, de Silva R, Paviour DC, Pittman A, Watt HC, Kilford L, et al. Characteristics of two distinct clinical phenotypes in pathologically proven progressive supranuclear palsy: Richardson’s syndrome and PSP-parkinsonism. Brain a journal Neurology 2005;128:1247e58. [2] Schrag A, Sheikh S, Quinn NP, Lees AJ, Selai C, Mathias C, et al. A comparison of depression, anxiety, and health status in patients with progressive supranuclear palsy and multiple system atrophy. Mov Disord 2010;25:1077e81. [3] Winter Y, Spottke AE, Stamelou M, Cabanel N, Eggert K, Hoglinger GU, et al. Health-related quality of life in multiple system atrophy and progressive supranuclear palsy. Neurodegener Dis 2011;8:438e46. [4] Beiske AG, Loge JH, Ronningen A, Svensson E. Pain in Parkinson’s disease: prevalence and characteristics. Pain 2009;141:173e7. [5] Mylius V, Brebermann J, Dohmann H, Engau I, Oertel WH, Moller JC. Pain sensitivity and clinical progression in Parkinson’s disease. Mov Disord; 2011. [6] Mylius V, Engau I, Teepker M, Stiasny-Kolster K, Schepelmann K, Oertel WH, et al. Pain sensitivity and descending inhibition of pain in Parkinson’s disease. J Neurol Neurosurg Psychiatry 2009;80:24e8. [7] Litvan I, Agid Y, Calne D, Campbell G, Dubois B, Duvoisin RC, et al. Clinical research criteria for the diagnosis of progressive supranuclear palsy (SteeleRichardson-Olszewski syndrome): report of the NINDS-SPSP international workshop. Neurology 1996;47:1e9. [8] Mylius V, Kunz M, Hennighausen E, Lautenbacher S, Schepelmann K. Effects of ageing on spinal motor and autonomic pain responses. Neurosci Lett. 2008; 446:129e32. Avalilable at: http://www.ncbi.nlm.nih.gov/pubmed/18832010. [9] Aiba I, Hashizume Y, Yoshida M, Okuda S, Murakami N, Ujihira N. Relationship between brainstem MRI and pathological findings in progressive supranuclear palsyestudy in autopsy cases. J Neurol Sci 1997;152:210e7. [10] Iwasaki Y, Yoshida M, Hashizume Y, Hattori M, Aiba I, Sobue G. Widespread spinal cord involvement in progressive supranuclear palsy. Neuropathology 2007;27:331e40. [11] Kunz M, Mylius V, Scharmann S, Schepelman K, Lautenbacher S. Influence of dementia on multiple components of pain. Eur J Pain 2009;13:317e25. [12] Carlino E, Benedetti F, Rainero I, Asteggiano G, Cappa G, Tarenzi L, et al. Pain perception and tolerance in patients with frontotemporal dementia. Pain 2010;151:783e9.
Contents lists available at SciVerse ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Short communication
Clinical pain and experimental pain sensitivity in progressive supranuclear palsy Maria Stamelou a, b, *, Helena Dohmann a, Juliane Brebermann a, Evangelia Boura a, Wolfgang H. Oertel a, Günter Höglinger a, Jens C. Möller a, c, Veit Mylius a, d a
Department of Neurology, Philipps University, Marburg, Germany Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, UCL, Queen Square, London WC1B 3BG, UK c Neurocentro della Svizzera Italiana, Ente Ospedaliero Cantonale, Lugano, Switzerland d Service de Physiologie - Explorations Fonctionnelles, Hôpital Henri-Mondor, AP-HP, Université Paris 12, France b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 1 September 2011 Received in revised form 8 November 2011 Accepted 9 November 2011
Objective: We aimed to assess spinal nociception and experimental pain sensitivity in progressive supranuclear palsy-Richardson’s syndrome (PSP-R) compared to patients with Parkinson’s disease (PD) and healthy controls (HC). Methods: Spinal nociception as measured by the nociceptive flexion reflex (NFR) and experimental pain sensitivity as measured by heat and electrical pain thresholds were determined in non-demented, nondepressed, probable PSP-R patients (N ¼ 8), PD patients (N ¼ 19) and 17 HC. Results: PSP-R patients exhibited lower electrical pain thresholds and a tendency for lower NFR thresholds as compared to HC. No significant differences between PSP-R and PD patients were found with respect to experimentally-induced pain. However, significantly less PSP-R than PD patients reported disease-related pain. Conclusions: Degeneration of the descending inhibitory control system within the brainstem in PSP-R might lead to increased experimental pain sensitivity while frontal cortical deterioration may alter self-estimation of pain. Ó 2011 Elsevier Ltd. All rights reserved.
Keywords: Progressive supranuclear palsy Parkinson’s disease Nociception Pain sensitivity Nociceptive flexion reflex
1. Introduction Progressive supranuclear palsy (PSP) belongs to the tauopathies and is an atypical parkinsonian syndrome, characterized in its classical presentation by axial rigidity, postural instability, supranuclear gaze palsy and frontal dementia (now referred as PSPRichardson syndrome, PSP-R), while various further phenotypes have been described [1]. The role of clinically relevant pain in PSP has been addressed up to now only in questionnaire studies, in which 35e67,5% of PSP patients report pain and discomfort [2,3]. However, questionnaire studies are limited since confounding factors such as intake of pain-modifying drugs (for example amitriptyline, which is recommended in PSP), depression and cognitive decline, were not taken into consideration.
* Corresponding author. Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, UCL, Queen Square, London WC1B 3BG, UK. Tel.: þ44 203 108 0023. E-mail address: [email protected] (M. Stamelou). 1353-8020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.parkreldis.2011.11.010
On the other hand in Parkinson’s disease (PD), pain has been reported in up to 83% of the patients in questionnaire studies [4]. Increased experimental pain sensitivity during the “off” phase, possibly attributed to reduced central dopaminergic activation, diminished descending dopaminergic control or altered nociception at the spinal level seems to account for the high prevalence of reported pain in PD [5,6]. The increased pain sensitivity in PD patients becomes significant during the course of disease and has been found to be further augmented in patients with PD-related pain [5]. The aims of this study are 1. to investigate for the first time experimental pain sensitivity and spinal nociception in PSP as a possible correlate for the reported pain, by monitoring confounding factors such as cognitive function, mood and medication. 2. To compare the obtained results with those from PD patients and assess if the differences found could account for the higher prevalence of reported pain in PD compared to PSP.
M. Stamelou et al. / Parkinsonism and Related Disorders 18 (2012) 606e608 2. Methods 2.1. Participants Patients with probable PSP [7], probable PD and healthy controls (HC) free of systemic, neurological or psychiatric diseases were identified at the Dept. of Neurology of Philipps University Marburg. The phenotype of PSP was classified as PSP-R according to published criteria [1]. The study protocol was approved by the local IRB of the University of Marburg. Informed consent was obtained from all subjects. Exclusion criteria were pain-related diseases; acute or chronic pain of any other origin; conditions affecting pain sensitivity (e.g. neuropathy, neurological and psychiatric disorders); pain-modifying medication (e.g. analgesics, antidepressants, opioids, antineuropathic drugs, neuroleptics, long-lasting dopamine agonists, other dopaminergic medication on the day of the examination); depression as assessed by the Montgomery Åsberg Depression Rating Scale (MADRS) for PSP and the geriatric depression score (GDS) for all subjects; dementia as assessed by mini mental status examination (MMSE) (data not shown). 2.2. Clinical assessment The control group was pain free and pain in patients was classified into the five previously described different forms, as described elsewhere [6]. The participants rated their pain on a horizontal visual analogue scale (VAS), which was labeled with verbal anchors from 0 no sensation’ (0) to 0 extremely strong pain’ (100) with a verbal anchor in-between of 0 slightly painful’ (50). Moreover, they completed a pain questionnaire on their clinical pain (e.g. frequency, duration, localization and relation to medication). The Hoehn and Yahr (H&Y) stage and the Unified Parkinson’s Disease Rating Scale (UPDRS) motor score (part III) were assessed in all patients in the “on-phase” and the Frontal assessment battery (FAB) additionally in PSP patients. 2.3. Pain threshold and NFR threshold assessment Electrical stimulation and EMG recording were performed using a standard electro-diagnostic device (Viking IV D; Cardinal Health, Dublin, Ohio, USA) with modified software. Thermal pain was measured using a Peltier based contact stimulation device (Medoc TSA-2001, Ramat Yishai, Israel) with a 30 46 mm2 contact thermode. For determination of heat pain thresholds, subjects were seated upright in an armchair. For further examination participants lay supine on an examination table with knees flexed at 130 by using a pillow. The investigation took place in the morning after overnight withdrawal of all dopaminergic medication at 6e9 am (medication-defined “off” state) and had lasted 1e2 h. In order to localize the sural nerve for reflex stimulation sural neurography was performed on the more affected side in PD patients and on the left side in the control group. For recording of the nociceptive flexion reflex (NFR) and the assessment of electrical pain thresholds, surface electrodes were attached at the same localization as for sural nerve neurography at the calf. The recording electrode was attached ipsilateral over the short head of the biceps femoris muscle, and the reference electrode was fixed near the tendon of the biceps femoris muscle at the head of the fibula. The background for the NFR and its clinical application is described elsewhere [6]. NFR thresholds were assessed using the up-down staircase method. Stimulation intensity was increased in 3 mA increments until the flexion reflex RIII component was detected for the first time. Next, we lowered the stimulus intensity in 2 mA steps until the reflex disappeared. Subsequently, steps of 1 mA were used, and the procedure was repeated until the reflex appeared and subsided two more times. Mean values of three peaks (current intensity that just elicited a reflex) and three troughs (current intensity that no longer elicited a reflex) determined the reflex threshold. The electrical pain threshold was then determined by using the same stimulus paradigm and the same staircase method as during the NFR threshold measurement
607
but with a subjective estimation of pain (painful or non-painful sensation). Thermal heat pain thresholds were measured by a thermode applied to the forearm contralateral to the stimulated sural nerve by using the method of adjustments. Participants were instructed to indicate the point at which the sensation of warmth turned into pain by tapping two mouse keys that increased or decreased stimulus intensity, respectively. Two trials were performed to familiarize the subjects with the procedure before the threshold was determined three times. The means of the three trials were used for further analysis. 2.4. Statistical analysis For statistical analysis the Statistical Package for the Social Sciences (SPSS) version 17 was used. MANOVA was applied to assess the effect of the factor ‘disease (PSP-R, PD and HC)’ on the NFR and the electrical and heat pain thresholds. Post-hoc tests corrected for multiple comparisons were performed by using a Bonferroni adjustment or the Tamhan-T2 test if no homogeneity of the variances was seen. Chisquare test (corrected for continuity) was employed to detect significant influences of disease (PSP-R vs. PD) on the occurrence of clinical pain. Simple group comparisons of the descriptive statistics were conducted using Student’s t-tests for independent variables. Descriptive statistics were given as mean standard deviation and statistical significance was set to a ¼ 0.05.
3. Results 3.1. Study population The clinical characteristics of HC and PSP-R and PD patients are presented in Table 1. The different distribution of the sex is not thought to significantly influence the results, since gender differences in pain perception vanish during aging [8]. H&Y stage was found to be higher in the PSP-R group as compared to the PD group; still all patients were independently mobile and there was no significant difference in the UPDRS III in “on”. As expected, disease duration tended to be shorter in the PSP-R group when compared to the PD patients. No significant differences were found between PSP-R and PD with regard to dopaminergic treatment. PSP-R patients scored 13 2 in the FAB (worst: 0 to best:18). 3.2. Subjective pain perception and spinal nociception in PSP-R 16/19 PD patients (84%) suffered from clinical pain. Of these 74% showed musculoskeletal, 13% back pain, 4% dystonia-associated pain and 9% akathitic discomfort. Significant fewer PSP-R patients (3/8, 38%) reported clinical pain (x2 ¼ 6.417, df ¼ 1, P ¼ 0.011) of musculoskeletal origin. MANOVA revealed a main effect of ‘disease (PSP-R, PD vs. HC)0 [F(6,80) ¼ 5.081; P < 0.001] with significant effects for NFR thresholds [F(2,41) ¼ 8.670; P ¼ 0.001] and electrical pain thresholds [F(2,41) ¼ 4.986; P ¼ 0.012]. A tendency for an effect of ‘disease’ on heat pain thresholds was detected [F(2,41) ¼ 2.966; P ¼ 0.063]. Post-hoc analyses adjusted for multiple comparisons revealed significantly lower electrical pain thresholds in PSP-R patients as compared to HC and a tendency for lower electrical
Table 1 Clinical characteristics of PSP-R and PD patients and HC and descriptive statistics and comparisons of the heat and electrical pain thresholds and NFR thresholds of PSP-R patients compared to PD patients and HC.
Age(yrs) Disease duration (yrs) H&Y stage (1e5) UPDRS III in “On” L-dopa in mg Electrical pain threshold, mA NFR threshold, mA Heat pain threshold, C
PSP-R (N ¼ 8)
PD (N ¼ 19)
HC (N ¼ 17)
PD vs. HC
PSP-R vs. HC
PSP-R vs. PD
4 F/4 M
6 F/13 M
11 F/6 M
P
P
P
0.130 e e e e 0.156 0.001* 0.844
0.135 e e e e 0.006* 0.091 0.173
0.52 0.068 <0.05* 0.091 0.471 0.054 0.630 0.066
67.3 3.4 2.7 30.3 575 5.2 12.8 46.3
7.4 2.7 1.0 14.0 710 1.5 4.3 1.1
68.7 6.7 1.8 22.4 831 7.9 10.6 44.9
4.6 6.2 0.7 9.0 873 4.0 4.7 1.7
71.4 e e e e 11.9 18.3 45.2
5.7
7.4 7.0 1.0
Data are given as mean SD, * significant after Bonferroni or Tamhan-T2 post-hoc adjustment, tendencies are underlined. Significant differences are given in Bold.
608
M. Stamelou et al. / Parkinsonism and Related Disorders 18 (2012) 606e608
pain thresholds as compared to PD patients (Table 1). NFR thresholds tended to be lower in PSP-R patients as compared to HC. Patients suffering from PSP-R tended to exhibit higher heat pain thresholds as compared to the PD group. PD patients had lower NFR thresholds compared to HC as shown already in previous studies [5,6], whereas other differences in experimental thresholds did not reach the level of significance in the current study. 4. Discussion The main result of the present study is that non-demented, nondepressed PSP-R patients exhibited significantly lower electrical pain thresholds compared to HC. Spinal nociception measured by the NFR tended to be increased compared to HC, supporting the finding of lower electrical pain thresholds. This finding might be due to the fact that the midbrain and periaqueductal gray (PAG) are typically compromised by pathophysiological changes in PSP [9]. The PAG is one of the important centers for descending spinal control receiving input from the dorsolateral prefrontal cortex and projecting to the Ncl. raphe magnus and to the dorsal horn. Thus, a deterioration of the descending inhibitory systems could lead to increased nociception and electrical pain sensitivity. Spinal pathological alterations in nociceptive dorsal horn layers as observed in PD are not likely to contribute since they are less pronounced in PSP patients, who rather exhibit pathophysiological changes within the anterior and anteriolateral spinal cord [10]. In line with previous publications 84% of our PD but only 38% of our PSP-R patients reported pain [2e4]. However, PSP-R patients showed a tendency towards higher heat pain thresholds compared to PD patients. The lower frequency of reported pain in PSP-R (despite the lower electrical pain threshold) and the relatively increased heat pain thresholds which require a self-adjustment method and therefore a more active contribution of the patient might be due to their incipient frontal impairment, which may diminish verbal and non-verbal pain communication [2,11]. Previous studies revealed a reduced ability to reliably report experimentally-induced pain in demented patients, while nociception at the spinal level as well as pain perception on the level of facial pain-related expressions were still preserved [11]. It is conceivable that in more advanced PSP stages the frontal impairment may lead to even less reported pain and also to elevated pain tolerance, as shown in patients with frontotemporal dementia [12]. Moreover, it is conceivable that frontal impairment could contribute to less reporting also of other sensory modalities but this is speculative and needs to be further studied. In summary, this is the first study to assess experimental pain sensitivity and nociception in PSP-R. The limitation of these preliminary results is the small number of patients, which does
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