The results for the overall patient group and sub-groups were presented as absolute numbers and percentages. The χ2-test and Fisher’s exact test were used to analyze the association between categorical variables. For continuous variables with normal distribution and non-normal distribution, the t-test and Mann-Whitney U test were used, respectively. Binary logistic regression analyses were performed to adjust for various factors such as age, sex, and etiology laboratory test result. The relationship between variables was examined by Spearson’s correlation coefficient. All statistical analyses were performed by the Statistical Package for Social Sciences 11.0 software. P<0.05 was considered statistically significant.
6
Ⅲ. Results
Of the 58 patients interviewed, four patients were subsequently excluded due todementia (n = 2) and refusal to study consent (n = 2). The results of 48 patients who reported pain and 6 patients who did not have pain were analyzed (Figure 6).
A. General characteristics ofpatients with NTNC myelopathy
Demographics and clinical characteristics of patients with pain are summarized in Table 1. In pain(+) group, the mean (±standard deviation [SD])patient age was 46.2±11.5 years;
27 patients (56.3%) were men. Eighteen (37.5%) patients had recurrent myelopathy and six (12.5%) patients had diabetes mellitus (DM). Median (range) initial and current Expanded Disability Status Scale (EDSS) scores were 3.0(0-9) and 2.2 (0-7.5), respectively. The majority of cases had idiopathic etiology (n=36, 75%), and the most common level of lesion was in the thoracic cord (n=23, 47.9%). In six patients who did not have pain, the mean (±SD) age was 36.5±21.7 years; 4 patients were men. Median (range) initial and current EDSS score were 3.5 (2-8) and 3 (0-9). Current EDSS score of three patients were 0, while another 3 patients showed the score over 6. Unlike the pain (+) group, the most common etiology in the pain (-) group was NMO (n=3, 50%) without statistical significance due to low number of patients. Thoracic cord was also the most common level(n= 4, 66.7%) in pain (-) group.
B. Pain profiles
In total, 41 (85.4%) patients stated that pain initiated during the first 3 months of myelopathy onset. Median (range)pain duration was 52 (3.5-162) months and the median (range) SF-MPQ score was 12 (1-34). Thirty five (72.9%) patients reported continuous pain throughout the day. The most common words used by patients to describe their pain wereexhausting, gnawing and heavyin order.
7
Non-neuropathic pain (LANSS score < 12) was present in 32 (66%) patients and was more common than neuropathic pain (33%). In all cases of neuropathic pain, below-level neuropathic pain was the most frequently reported (in 93.7% of patients), followed by at-level neuropathic pain(37.5%); only one patient reported above-at-level neuropathic pain (data not shown).
C. Pair-wise comparisons between non-neuropathic and neuropathic pain groups
Mean (±SD) age was statistically significantly lower in patients with neuropathic pain than in patients with non-neuropathic pain (39.1 ± 12.5 vs. 49.8 ± 9.3, P = 0.002).
However, overall median pain score (assessed by SF-MPQ) was statistically significantly higher in patients with neuropathic pain (8 vs 17.5, P = 0.004). There were no statistically significant differences in the other variables including gender, DM, etiology of myelopathy, CSF study, pain duration, total SF-36 score, and HADS score between the two pain groups (Table 2).
Similar to the all types of pain, the most common descriptions for neuropathic pain were gnawing, exhausting and heavy. However, in the presence of neuropathic pain, shooting, stabbing, and aching were used statistically significantly more than for overall pain (Table 3).
D. Predictors for neuropathic pain
A binary logistic regression was performed to evaluate the predictive factors for the development of neuropathic pain in NTNC myelopathy. The following factors were entered into the model: (1) age of myelopathy onset > 40 year old, (2) gender, (3) etiology, idiopathic or non-idiopathic, (4) initial EDSS score. The results showed that onset age under 40, non-idiopathic etiology were independent predictors of the occurrence of neuropathic pain (Table 4) The Nagelkerke R2 value was 0.383, suggesting a strong association between neuropathic pain and the independent variables in the regression analysis.
8 E. Effect of pain on quality of life
Both the SF-MPQ and LANSS scores showed significant correlation with SF-36 scores adjusted by age, sex, presence of DM, and current EDSS scores (r = -0.624, P< 0.0001 for SF-MPQ; r = -0.357, P = 0.017 for LANSS). However, SF-MPQ scores, which indicated total pain, showed a higher correlation with SF-36 scores than the LANSS scores (Figure 7).
F. Pain response to treatment
Patients were divided into two groups based on their PGIC score; those with no improvement or worsening pain (score ≤ 2) and those with improvement of pain after treatment (score > 2). Patients showing clinical improvementwith treatment were female (n=16, 55.2%), non-idiopathic etiology (n=11, 37.9%) or long lesion (n=18, 62.1%). But the presence of diabetes was related to poor pain treatment response (Table 5).
9
Ⅳ. Discussion
In this study, almost all patients with NTNC myelopathy reported chronic pain and one third of the pain had neuropathic features. Patients with neuropathic pain were younger and had higher SF-MPQ scores than those with non-neuropathic pain. Being aged under 40 and having non-idiopathic etiology were independent predictive factors for the development of neuropathic pain. Patients responded well to pain treatment tended to be ofthe female gender, have non-idiopathic etiology, and have a lesion length longer than 3 vertebral segments. In contrast,the presence of diabetes was related to poor response to pain treatment.
It is common for patients with myelopathy to develop serious and often life-threatening complications after the acute phase has passed. Chronic pain, a common secondary complication following SCI, has a wide reported range of prevalence, ranging from 11 to 94%(Defrin et al., 2001). Recent studies have shown that more than 80% of patients with SCIexperience pain (Siddall et al., 2003)and a third of them rated the pain as severe(Cruz-Almeida et al., 2005).Several studies of non-traumatic myelopathy have reported a 20 to 60% prevalence of chronic pain (New et al., 2002; Pidcock et al., 2007;
Werhagen et al., 2007).Pain after idiopathic myelitis is generally considered rare (Laffey et al., 1999);however, one study found that 75% of patients with ATM had acute pain;
chronic pain developed in 54% of patients(Pidcock et al., 2007).Furthermore, recent studies have reported frequent pain and pain related quality of life impairment in patients with demyelinating myelopathy including NMO and MS(Solaro et al., 2004; Kanamori et al., 2011; Qian et al., 2012).In the present study, 88.9% of NTNC myelopathy patients interviewed reported pain. Patients without pain were classified as either of two groups;
EDSS score 0 or severely disabled status (EDSS ≥ 6.5) with no sensory function at all.
There were no significant differences in epidemiological or clinical data between patients with pain and without pain.
Numerous studies have found that pain typically occurs within the first 6 months of myelopathy(Ravenscroft et al., 2000; Norrbrink Budh et al., 2003b; Henwood and Ellis, 2004), though in some studies it has been reported within the first year (Stormer et al.,
10
1997).The present results show that 80% of pain began within the first 3 months of disease onset; earlier than that reported in the previous myelopathy pain studies(Miguel and Kraychete, 2009).This difference is assumed to be due to the inclusion of non-traumatic, non-compressive causes of myelopathy inthe present study. At the onset of NTNC myelopathy, many patients complain of sensory symptoms, in contrast to traumatic myelopathy where motor symptoms are most frequently reported.According to previous studies, almost all patients with myelopathy pain report continuous pain, which is usually intensified in the evening(Demirel et al., 1998; Celik et al., 2012).Similarly, 35 (72.9%) patients in the present studyalso reported continuous pain. The various descriptions of pain have included pricking, tingling, and tiring(Stormer et al., 1997;
Finnerup et al., 2001; Celik et al., 2012). In contrast, the most frequently used pain descriptions in our data included exhausting, gnawing and heavy. This difference may be due to variations in patient populations between studies, or cultural differences in pain perception.
Nociceptive pain is the most common type of myelopathy pain both in the acute and chronic phase(Siddall et al., 2003).It can be identified by location (above- or at-lesion level in patients with complete spinal cord damage) and by pain features (aching, dull, worse with activities)(Siddall et al., 1997).Shoulder pain due to acute phase trauma or overuse, muscle weakness, and spasticity, in the chronic phase is common(Akbar et al., 2011). Pain related to spasms, muscle contractures, and pain in the back and wrist are also examples of nociceptive pain(Finnerup, 2013).Nociceptive pain is less severe than the other types andusually presents early on following the onset of disease or trauma(Siddall et al., 2003).In NTNC myelopathy, unlike traumatic SCI, there is no injury or compression to the structures surrounding the spinal cord.Therefore, neuropathic pain could be considered more common than nociceptive pain in NTNC myelopathy. However, the present study revealed that 32 (67%) patients had non-neuropathic pain (LANSS score <12). We speculate that this result had several causes, Firstly, we only evaluated pain in the chronic phase. After the acute stage of myelopathy, nociceptive pain due to weakness, overuse, and spasticityincreases naturally. Secondly, patients with NTNC myelopathy are older than those with traumatic SCI(Burney et al.,
11
1993; New et al., 2002). Even if we excluded patients who experienced pain from other diseases, the elderly would have more pain-causing problems such as arthritis or muscle cramps. These factors could affect the majority of our patients having NTNC myelopathy with non-neuropathic pain.
There are two types of neuropathic pain in myelopathy: myelopathy-related neuropathic pain and other neuropathic pain. Myelopathy-related neuropathic pain is further classified as either at-level or below-level neuropathic pain. Other neuropathic pain describes pain which is not a direct consequence of myelopathy (e.g. post-thoracostomy pain, and pain due to carpal tunnel syndrome fromwheelchair use), which may occur above-, at-, or below- lesion level(Finnerup, 2013).
The mechanisms of myelopathy-related neuropathic pain are multiple and not yet fully understood. At-level neuropathic paincould result from a lesion in the nerve roots or spinal cord, whilebelow-level neuropathic pain is considered as central pain due to spinal cord lesions, suggesting a different underlying cause.At-level neuropathic paincan be initiated early following damage and it therefore appears to share some of the characteristics of nociceptive pain. However, at-level neuropathic pain is more likely to be described as severe, and persists despite treatment. Below-level neuropathic paingenerally occurs later than nociceptive or at-level neuropathic pain and is also described as severe and excruciating. Neuroplasticity is an important component of the spontaneous recovery from a myelopathy; however, it can generate negative consequences such as spasticity, autonomic dysreflexia, and neuropathic pain(Brown and Weaver, 2012).Increasing evidence has indicated that neuroplasticity may limit the effects of experimental myelopathy therapy due to undesired results such as neuropathic pain(Brown and Weaver, 2012).Central sensitization is considered to be the main cellular change responsible for central neuropathic pain and manifests as a decrease in pain thresholds, increased response to synaptic input, and expansion of receptor fields(Woolf, 2011). Additionally, an imbalance between descending inhibitory activity and facilitation, and the loss of dorsal interneuron containing inhibitory function may contribute to central sensitization(Gwak and Hulsebosch, 2011).
The aim of this present study was to determine which factors predict the development
12
of neuropathic pain in NTNC myelopathy. While many studies have shown neuropathic pain to be a common and serious problem following myelopathy, the understanding of the factors associated with its development is limited.
In this study, several variables were significantly related to the development of neuropathic pain after the onset of myelopathy. First, the age of patients in the neuropathic pain group was significantly lower than that of the non-neuropathic group.
Generally, old age is known as a predictor for persistent neuropathic pain(Jung et al., 2004; Kehlet et al., 2006; Werhagen et al., 2007; Margot-Duclot et al., 2009).Numerous studies have shown that increasing age is a predictive factor for chronic pain following surgery(White et al., 1997), illness(Dworkin, 1997), or injury(Baldwin et al., 1996). This may be due to age related changes in endogenous pain control mechanism at the central level(Washington et al., 2000; Gibson and Helme, 2001; Edwards et al., 2003; Karp et al., 2008).In contrast, age and neuropathic pain following SCI have not been found to be related(Ravenscroft et al., 2000; Norrbrink Budh et al., 2003a; Nakipoglu-Yuzer et al., 2013).Furthermore, one study found that myelopathy-related neuropathic pain was mainly observed in patients aged between 30 and 39 years, but there was no correlation with age and pain severity (Werhagen et al., 2004).
With regard to age, binary logistic regression analysis confirmed findings of the paired comparison analysis, showing that onset age below 40 is an independent predictive factor for the development of neuropathic pain. Additionally, known etiologywas anothersignificant predictor for neuropathic pain. While the mechanisms of neuropathic pain in myelopathy are not yet fully understood, a recent study found a marked difference in the effectiveness of diffuse noxious inhibitory control (DNIC) between a group of healthy participants aged between 40 to 55 years old and a group of patients aged between 20 and 35 years (Lariviere et al., 2007).DNIC, which is also referred to as bulbospinal endogenous pain control mechanism, is one of the most understood descending inhibitory pain mechanisms. It has been suggested that pain perception and endogenous pain modulation function decline by middle age and continue to deteriorate thereafter (Lariviere et al., 2007). The present findings support this because there was a significantly higher occurrence of neuropathic pain in patients under the age of 40.
13
One study reported that 55.4% of patients with myelopathy related neuropathic pain are tetraplegic(Widerstrom-Noga et al., 2001).Another study failed to find a relationship between the existence of pain and the level of lesion or completeness of injury, although below-level neuropathic pain was more common in patients with tetraplegia(Siddall et al., 2003).It has also been documented that there is no relationship between patient demographics and myelopathy features, pain score, localization, or severity(Ullrich et al., 2008).Furthermore, another study failed to find a relationship between completeness of injury and the type of pain(Yap et al., 2003). Patients with malignant etiology of myelopathy have been shown to experience neuropathic pain more frequently than other etiologic subgroups. In the present study, non-idiopathic etiology such as multiple sclerosis, neuromyelitis optica, and infection was associated with a higher frequency of neuropathic pain. However, these patients tended to show a better response to treatment than those with idiopathic myelopathy (as assessed by PGIC score), though the reason for these results is presently unknown. While there was no relationship found between recurrence of myelopathy and the PGIC score, targeted therapy according to the etiology would reduce pain intensity, even if further neuropathic pain occurred.
Myelopathy pain is intense and constant, aggravated by various stimuli encountered during daily activities, and interferes with quality of life beyond just the limiting of motor functions. In one study, 70% of patients with myelopathy reported that pain affected their life to a great extent(Werhagen et al., 2004) and in another report, more than 90% of such patients stated that their pain interfered with daily activities(Finnerup et al., 2001).Furthermore, numerous other studies have found that the health related quality of life of patients with neuropathic pain is worse than in those with non-neuropathic pain(Smith et al., 2007; Smith and Torrance, 2012).In the present study, both SF-MPQ and LANSS scores showed a significant correlation with SF-36 scores after adjustment for age, sex, presence of DM, and current EDSS score. In contrast to previous studies, SF-MPQ scores exhibited a higher correlation to SF-36 than LANSS scores. This may be because nociceptive pain is the most common type of pain during myelopathy, and secondly, a relatively low number of patients were included in this study.
The adoption of a broad approach is essential for the treatment of myelopathy pain.
14
The classification of pain type, its underlying mechanisms, and the consideration of the multidimensional aspects of pain is also required. In surveys of medical treatments, simple analgesics including non-steroidal anti-inflammatory drugs have been the most frequently used to treat overall myelopathy pain(Finnerup et al., 2001; Nakipoglu-Yuzer et al., 2013; Yamashita et al., 2014).While these drugs are effective at relieving nociceptive pain, they may be ineffective for treating neuropathic pain. Instead, anticonvulsants such as gabapentin andpregabalin, as well as antidepressants such as amitriptyline and duloxetine, could be effective treatments of myelopathy-related neuropathic pain. Gabapentin was the most frequently used medication by the patients in this study.
A major limitation of this study is that consecutive patients were not enrolled.
Therefore, since the case series could be confounded by a selection bias, an accurate prevalence of pain could not be reported. Additionally, despite careful clinical examination and use of various questionnaires for pain assessment, it can be difficult to clearly differentiate between nociceptive and neuropathic pain. Furthermore, the LANSS pain scale might not to be a suitable tool for evaluating the neuropathic pain in myelopathy, despite its widespread use for classifying myelopathy pain.
15
Ⅴ. Conclusion
In this study, the characteristics of chronic pain in NTNC myelopathy were assessed and the predictive factors for development of neuropathic pain were investigated. The age at myelopathy onset and etiology of myelopathy were related to the occurrence of neuropathic pain. A significant relationship was also found between pain and quality of life. This research focused on chronic pain in NTNC myelopathy, which has been relatively poorly studied in comparison to traumatic or compressive SCI. These findings enhance the understanding of pain in NTNC myelopathy and may contribute to the advancement of research in this field and the development of effective treatment.
16 Table 1. Clinical characteristics of patients
Pain (+)
Abbreviations: SD, standard deviation; DM, Diabetes mellitus; EDSS, Expanded Disability Status Scale; NMO, Neuromyelitis optica; MS, Multiple sclerosis
17 Length of lesion,median (range) 3.5 (1-24) 3.5 (1-17) 0.680
Onset to pain, median (range) 0 (0-5) 0 (0-9) 0.905
Median painduration (range) 54 (3.5-160) 31 (5-166) 0.485 Median SF-MPQ (range) 8 (2-34) 17.5 (1-26) 0.004 Median SF-36 (range) 73.2 (49.4-104.3) 70.5 (50.3-102.1) 0.101
Median HADS (range) 15 (1-29) 18.5 (2-29) 0.306
Abbreviations: LANSS, Leeds assessment of neuropathic symptoms and signs; SD, standard deviation; DM, Diabetes mellitus; NMO, Neuromyelitis optica; MS, Multiple sclerosis; CSF, Cerebrospinal fluid; MPQ, short form McGill pain questionnaire; SF-36, short form 36; HADS, Hospital anxiety depression scales
18
Table 3.Pain descriptors used in patients with myelopathy Overall pain Abbreviations: LANSS, Leeds assessment of neuropathic symptoms and signs
19
Table 4. Predictive factors for occurrence of neuropathic pain
Variables OR (95% CI) p-value
Sex 2.899 (0.549-15.315) 0.210
Age < 40 16.596 (3.044-90.477) 0.001
Non-idiopathic etiology 2.126 (1.373-12.116) 0.049
Initial EDSS 0.909 (0.657-1.258) 0.565
20
Table 5. The Patients’ Global Impression of Change (PGIC) after treatment of pain PGIS ≤2
(n=19)
PGIS >2
(n=29) p-vaule Onset age (mean±SD) 46.6 ± 12.0 46.0 ± 11.5 0.867 Sex
0.049
Female, n (%) 5(26.3) 16 (55.2)
Male, n (%) 14 (73.7) 13 (44.8)
DM (+), n (%) 5 (26.3) 1 (3.4) 0.019
Initial EDSS, median (range) 3 (1-7) 2.5 (0-9) 0.622 Initial sensory level (+), n (%) 15 (78.9) 22 (75.9) 0.804
Recurrence (+), n (%) 6 (31.6) 12 (41.4) 0.493
Non-idiopathic etiology, n (%) 1 (5.3) 11 (37.9) 0.011 Length of lesion > 3, n (%) 6 (31.6) 18 (62.1) 0.039 Pain duration ≥ 3yr, n (%) 8 (42.1) 20 (69.0) 0.065
21
Figure 1.Korean version of Short Form McGill Pain Questionnaire.
22
Figure 2.Korean version of Leeds Assessment of Neuropathic Symptoms and Signs pain scale.
23
Figure 3.Korean version of Short Form 36 Health Survey (1).
24
Figure 3.Korean version of Short Form 36 Health Survey (2).
25
Figure 3.Korean version of Short Form 36 Health Survey (3).
26
Figure 4.Korean version of Hospital Anxiety and Depression Scale.
27
Figure 5.Korean version of Patients’ Global Impression of Change scale.
28
Figure 6.Flowchart of patient recruitment and participation.
29
Figure 7.Relationship between quality of life and total pain score (A) and neuropathic pain score (B) after adjusted by age, sex, DM, current EDSS score (r=-0.624, p<0.0001 for SF-MPQ; r=-0.357, p=0.017 for LANSS).
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