The characteristics of chronic central pain after traumatic brain injury

Pain 131 (2007) 330–340 www.elsevier.com/locate/pain

The characteristics of chronic central pain after traumatic brain injury Hadas Ofek a

a,b

, Ruth Defrin

a,*

Department of Physical Therapy, School of Health Professions, Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv 69978, Israel b Loewenstein Hospital Rehabilitation Center, Raanana, Israel Received 28 January 2007; received in revised form 11 June 2007; accepted 15 June 2007

Abstract Central pain following traumatic brain injury (TBI) has not been studied in depth. Our purpose was to conduct a systematic study of patients with TBI suffering from chronic central pain, and to describe the characteristics of the central pain. Groups were TBI patients with (TBIP) and without central pain (TBINP) and healthy controls. TBI patients with other pain mechanisms were excluded from the study. Participants underwent quantitative somatosensory testing in the painful and pain-free body regions. Thresholds for warmth, cold, heat-pain, touch and graphesthesia were measured and pathologically evoked pain (allodynia, hyperpathia and wind-up pain) evaluated. Chronic pain was mapped and characterized. Chronic pain developed at a relatively late onset (6.6 ± 9 months) was almost exclusively unilateral and reported as pricking, throbbing and burning. Although both TBIP and TBINP exhibited a significant reduction in thermal and tactile sensations compared to controls, thermal sensations in the painful regions of TBIP were significantly more impaired than pain-free regions in the same patients (p < 0.01) and in TBINP (p < 0.01). Painful regions also exhibited very high rates of allodynia, hyperpathia and exaggerated wind-up. The characteristics of the chronic pain resembled those of other central pain patients although TBIP displayed several unique features. The sensory profile indicated that damage to the pain and temperature systems is a necessary but not sufficient condition for the development of chronic central pain following TBI. Neuronal hyperexcitability may be a contributing factor to the chronic pain.  2007 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. Keywords: Traumatic brain injury; Chronic pain; Central pain; Quantitative somatosensory testing

1. Introduction Traumatic brain injury (TBI), also termed acquired brain injury, occurs when a sudden, blunt or penetrating trauma causes damage to the brain. Some common disabilities developing following TBI include problems with cognition, sensory processing, motor performance, communication and behavioral or mental health. Symptoms of TBI can be mild, moderate or severe, depending on the extent of damage to the brain (Thurman, 2001). Chronic pain is one of the consequences of TBI. The overall prevalence of chronic pain in patients with TBI varies between 22% and 95%, depending on the source

*

Corresponding author. Tel.: +972 3 6405431; fax: +972 3 6405436. E-mail address: [email protected] (R. Defrin).

(Uomoto and Esselman, 1993; Beetar et al., 1996; Lahz and Bryant, 1996; Alfano et al., 2000). Chronic pain is reported to occur throughout the body, the head being the most common site of pain and the focus of the majority of studies. Several authors report a negative relationship between the frequency of headache and injury severity (Yamaguchi, 1992; Uomoto and Esselman, 1993; Beetar et al., 1996; Lahz and Bryant, 1996), namely that headache prevails predominantly amongst patients with mild rather than moderate–severe TBI. The prevalence of chronic pain in other body regions has been found to be similar in patients with mild and with moderate–severe TBI (Lahz and Bryant, 1996). Chronic pain in patients with TBI can originate from a number of sources. In some instances the pain is a direct result of tissue injuries inflicted during the event causing the TBI, such as bone fractures and dislocations, cervical

0304-3959/$32.00  2007 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.pain.2007.06.015

H. Ofek, R. Defrin / Pain 131 (2007) 330–340

injuries, soft tissue trauma and peripheral nerve or plexus damage. Chronic pain can also originate from secondary consequences of the trauma, e.g., pressure palsies, periarticular new bone formation, spasticity, deep venous thrombosis and abnormal posture (Cosgrove et al., 1989; Cooper, 1993; Gellman et al., 1996; Ivanhoe and Hartman, 2004; Walker, 2004). In most of these instances, the chronic pain is located in body regions that are associated with known tissue damage or abnormality. However, there are instances in which chronic pain is located in body regions that have not been injured during the trauma or were not associated with any pathology. It is possible that the chronic pain in these body regions is of central origin, namely ‘‘central pain’’. Central pain is pain caused by a lesion or dysfunction in the central nervous system (Merskey and Bogduk, 1994). Central pain due to spinal cord injury and brain stroke is well documented (Beric’ et al., 1988; Boivie, 1999; Defrin et al., 2001; Finnerup et al., 2003) and recently, studies on central pain following multiple sclerosis were published (Osterberg et al., 2005; Svendsen et al., 2005). However, central pain following TBI is only briefly mentioned in three case report studies (Barraguer-Bordas et al., 1993; Khoshyomn et al., 2004; Son et al., 2006). The authors observed that the nature of chronic pain in body regions that were not injured during the trauma causing the TBI resembled central pain features. The purpose of this investigation was to study patients with central pain following TBI, aiming to (a) characterize the chronic pain; (b) explore the sensory profile of these body regions with quantitative somatosensory testing. 2. Methods 2.1. Subjects Three groups were included in the study: (1) 15 patients with TBI who suffer chronic pain (mean age 28 yrs ± 10), (2) 16 patients with TBI who do not suffer pain (24 yrs ± 6) and (3) 15 pain-free healthy volunteers (26 yrs ± 6). All patients with TBI were recruited from the Loewenstein Rehabilitation Center, Ra’anana, Israel. They were either inpatients of the head trauma wards (mean duration of hospitalization at the ward is 12 months) or outpatients in the outpatient program (during the 2-year period of the study, a total of 250 inpatients and outpatients were at the hospital). Inclusion criteria for all patients with TBI were: (1) diagnosis of TBI determined by a complete neurological evaluation and CT and/or MRI scans, (2) a minimum duration of 5 months after injury, (3) no evidence for neurological and systemic diseases (e.g., diabetes, Parkinson’s disease), (4) no prior psychiatric illnesses, (5) communication and understanding capabilities, assessed by clinical examination and application of the LOTCA test (Katz et al., 1989), carried

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out by the occupational and speech therapists of the hospital. An additional inclusion criterion for group 1 was chronic pain in body regions without signs of local injury (e.g., fractures, burns and wounds), peripheral neuropathy and related spinal injury. Diagnosis and exclusion of orthopedic, neurological and other problems in the chronic pain regions as mentioned above was based on clinical examination and tests (e.g., MRI) according to need. Inpatients and outpatients with TBI, who report suffering from chronic pain, undergo such examinations routinely and the information collected during the diagnosis procedure is updated in the medical records. After reviewing the medical records of patients and inpatients with chronic pain, and excluding those with actual or suspected local peripheral or spinal cause, we further excluded patients who did not fulfill the inclusion criteria mentioned above. The remaining patients were then randomly approached and asked if they were willing to participate in the study. Except for two patients who were not able to participate due to personal reasons, all patients who were approached agreed to participate. Seventeen patients were then tested. After one testing session, two patients were dropped from the study: one subject was unable to follow our instructions; the other complained that the stimulation aggravated his pain. Recruitment was terminated after 15 TBI patients with chronic pain (TBIP) completed the testing. TBI patients without chronic pain (TBINP) who fulfilled the exclusion criteria were then recruited and matched as far as possible for sex, age, severity of TBI, type and duration of TBI. Normal controls were students and workers of the Tel-Aviv University, matched for sex and age to the TBI patients. Informed consent was obtained from all participants after they received a full explanation of the goals and protocols of the study. Experiments were approved both by the Tel-Aviv University and the Loewenstein Rehabilitation Center Human Rights Committees. Testing took place in a quiet room. The subjects were seated in a comfortable armchair with the tested limb supported on a holder. All subjects were trained for the sensory testing before the actual testing had started. For all subjects, testing was conducted on the hands and legs of both sides of the body (right and left). It should be pointed out that sensory testing is not an objective measure of sensory disturbances and is based on subjects’ report. 2.2. Equipment 2.2.1. Thermal stimulator Thermal stimuli were delivered using a Peltier-based, computerized thermal stimulator (TSA 2001, Medoc Inc., Israel) with a 3 · 3 cm contact probe. The principles of the Peltier stimulator have been described elsewhere (Fruhstorfer et al., 1976; Wilcox and Giesler, 1984; Verdugo and Ochoa, 1992). 2.2.2. von Frey filaments Mechanical stimuli were applied with Semmes-Weinstein Monofilaments. The kit is comprised of 20 calibrated monofilaments, with sizes ranging between 1.65 and 6.65. Each filament is attached to a plastic holder. Vertical pressure applied

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with the handle induces a calibrated force ranging between 0.008 and 300 gm, respectively (Johansson et al., 1980; BellKrotoski and Tomancik, 1987). 2.3. Data collection Patients with TBI underwent an extensive interview about the causes and circumstances of injury, age at injury, the nature of chronic pain, its location, time of pain onset after injury, its dynamics, factors ameliorating or exacerbating it, etc. Information obtained in the interview was cross-checked with their medical records. Data regarding the location of TBI were extracted from CT/MRI scans performed 24–48 h and 1 month after the injury (MRI; 1.5 Tesla scanners, with various sequences including: fluid-attenuated inversion recovery, T2-weighted spin echo, T2* weighted gradient echo, SPGR and/or T1 GAD, according to need. CT; axial scanning with brain parenchyma, soft tissue and/or bone windows according to need). Severity of injury was determined according to Glasgow Coma Scale-GCS (Jennett and Teasdale, 1976) and duration of Post-Traumatic Unconsciousness-PTU (Cooper, 1993; Vogelbaum et al., 1998). 2.4. Quantitative somatosensory testing (QST) 2.4.1. Thermal testing Thermal thresholds were measured with the thermal stimulator, using the method of Limits. For warmth (WS) and cold (CS) sensation threshold determination, subjects received 4 successive, increasing or decreasing stimuli, starting from an adaptation temperature of 32 C, at a rate of 2 C/s with inter-stimulus intervals of 15 s. The subject was asked to press a switch at the first warm or cold sensation perceived, at which point the temperature was recorded by the computer. WS and CS thresholds were the average reading of 4 successive stimuli of increasing or decreasing temperature, respectively. Warm and cold stimuli were applied in random order. Following each and every stimulus, the subject was asked to report the quality of sensation perceived. For heat-pain threshold (HP) determination subjects received 4 successive stimuli starting from an adaptation temperature of 32 C at a rate of 2 C/s. A minimal interval of 30 s was kept between successive stimuli in the same session, in order to avoid possible sensitization or suppression of cutaneous receptors (Yarnitsky and Ochoa, 1990; Defrin et al., 2001). The subject was asked to press a switch at the first pain sensation perceived. The subject was also asked to report the quality of pain perceived. HP threshold was the average reading of 4 successive stimuli of increasing temperature. 2.4.2. Light touch and graphesthesia The threshold of light touch was evaluated with the von Frey filaments. With the subject blind folded, the examiner applied the hairs in an increasing order, starting from the smallest filament. The subject was asked to report the minute he perceived touch. At that point he was asked to localize the stimulus perceived. The threshold for light touch was the calibrated force of the monofilament first perceived. Graphesthesia testing consisted of identification of a number or a geometric shape, which was traced on the skin with a monofilament No. 4.74. A four-point rank order scale was

constructed for graphesthesia (Lahuerta et al., 1990; Defrin et al., 2001), as follows: 0 = complete loss of identification of the shape drawn on the skin, 1 = vague sensation of the moving trace on the skin with no identification of the above (both ranks 0 and 1 were considered as loss of graphesthesia), 2 = decreased sensation (hypoesthesia) of the trace with identification of the above, 3 = normal sensation of graphesthesia. 2.4.3. Allodynia Static allodynia was examined by a single application of a von Frey filament (filament No. 4.74); dynamic allodynia was tested by gently dragging the same filament along the patient’s limb. In both instances the patient was asked to report the quality of sensation evoked by the stimulus. If the stimulus elicited painful sensation the subject was asked to rank its intensity on a Visual Analog Scale (VAS) (Ochoa and Yarnitsky, 1993; Defrin et al., 2001). 2.4.4. Mechanical wind-up pain Mechanical wind-up was measured with a von Frey filament No. 6.65. The examiner applied the filament 4 consecutive times to the surface of the skin at two different rates; every 3 s and every 10 s (0.3 and 0.1 Hz), the latter of which as a control. The patient was asked to rate the intensity of pain following the 1st and 4th stimuli on a VAS. The first stimulus of the series produced no pain or minimal pain sensation. When wind-up occurred, the fourth stimulus evoked considerable pain (Price et al., 1992; Defrin et al., 2001). 2.4.5. Hyperpathia Hyperpathia was tested by heating the skin, from an adaptation temperature of 35 C at a rate of 2 C/s. Emergence of a sudden, strong painful sensation, which persisted after stimulation was turned off, was defined as hyperpathia. The subjects were asked to rate the intensity of hyperpathic pain on a VAS (Defrin et al., 2001). 2.5. The Mc’Gill pain questionnaire All patients with chronic pain filled out the Mc’Gill pain questionnaire (MPQ) (Melzack, 1975). The MPQ provides a quantitative evaluation of the patient’s pain experience with a separate measure of its sensory, affective and cognitive dimensions (for a full description, see Melzack and Torgerson, 1971; Melzack, 1975; Defrin et al., 1999). Three quantitative parameters were derived: the pain rating index (PRI)-based on summing the values of the words chosen by the subject from the list, the number of words chosen (NWC) from that list and pain intensity (at present and when it is worse) on a 5-word/number ordinal scale. 2.6. Spasticity Spasticity was evaluated with the Modified Ashworth Test (MAT) (Bohannon and Smith, 1987). The examiner passively moved various parts of the hand and leg (e.g., the knee) back and forth at least five times and evaluated the degree of resistance to the movement on a scale from 0 to 4. A score of 0 was defined as no resistance and indicated normal tone and a score of 4 was defined as maximal resistance and indicated rigidity.

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2.7. Data processing Data were processed with SAS software. Mixed effects models were used to evaluate the differences between the groups (TBI patients with and without chronic pain, healthy controls), body sides within and between groups and between painful and pain-free body regions of TBI patients with chronic pain. In those body regions with complete sensory loss, a cut-off value was assigned for each modality to allow for average calculations. The values used were means + 2 standard deviations of normal WS and HP threshold and means 2 standard deviations of normal CS threshold (Defrin et al., 2002). The independent variables in the models were: threshold for warmth, cold, heat-pain and touch (continuous variables), graphesthesia, static and dynamic allodynia, wind-up pain, hyperpathia and spasticity (categorical variables). The models included main effects and interactions as well as pair-wise comparisons. In order to present the differences between the two TBI groups with regard to the pathological sensations (static allodynia, dynamic allodynia, wind-up pain and hyperpathia) a ‘‘sensory profile’’ of 5 categories was created based on the frequency of the sensations; the ‘‘worst’’ profile was defined as ‘‘the presence of all 4 pathological sensations’’ (1 1 1 1) whereas in the ‘‘best’’ profile was defined as no pathological sensations present’’ (0 0 0 0). In between the two extremes are different combinations of sensations. p-values <0.05 were considered significant.

3. Results 3.1. Group and injury characterization Tables 1 and 2 present information on the TBI and functional status of patients with chronic pain (Table 1) and patients without chronic pain (Table 2). There

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were no significant differences between the groups in sex distribution, age, duration and severity of TBI, the, mechanism of injury and motor/mobility status. All participants were relatively young at the time of injury, most of them had severe to moderate TBI caused mainly by a blunt hit on the head. There were no significant differences between any of the TBI groups and between healthy controls in age (mean age 26, range 19–46 years) and sex distribution (3 females, 12 males). Table 3 presents the distribution of brain injuries of patients with TBI. The pain group exhibited higher rate of injuries in the parietal cortex (p = 0.04) and in the corpus callosum area (p = 0.05) compared with the control group. 3.2. Characterization of the chronic pain 3.2.1. Onset and duration of pain Chronic pain first appeared at a mean onset time of 6.6 ± 9 months after injury (range 0.5–30 m) and remained up to the time of the study. Forty percent of patients reported that pain developed within the first month after injury, 50% reported that pain developed between 2 and 12 months after injury and in 10%, pain appeared after 12 months. Mean duration of chronic pain in the group is 16 months (range 6–66 m). 3.2.2. Location of pain Fig. 1 shows the location of chronic pain in 15 participants. In 14 patients (93%) chronic pain was restricted to one body side; on the right side in 10 patients and on the left side in 5 patients. One patient reported having pain more centrally in the lower back region in addition to the pain in one body side (patient No. 6).

Table 1 Characterization of TBI patients with chronic pain (TBIP) Subject

Age at injury

Sex

Duration of injury (m)

Type of injury

GCS

Duration PTU (d)

Cause of injury

Motor status

Mobility

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Mean (SD)

29 34 22 24 37 20 31 19 26 48 21 25 21 39 54 30 (10)

Male Male Male Male Male Male Male Male Male Male Female Male Male Male Female

14 40 26 10 26 32 5 6 96 15 18 7 5 40 20 24 (23)

Blunt Blunt Blunt Blunt Penetrating Blunt Blunt Blunt Blunt Blunt Penetrating Blunt Blunt Blunt Blunt

6 3 3 4 4 un 5 6 3 9 un 14 un 5 4 4.6 (2)

21 un 14 un un un 7 30 30 14 14 0 0 7 30 15 (11)

MVA MVA MVA MVA GS MVA FOH MVA MVA FOH GS MVA MVA MVA MVA

Mild Rt HP Db HP Rt > Lf Rt HP + AT NMD Lf HP NMD Mild Lf HP Db HP Db HP + AT Mild Rt HP Rt HP NMD NMD Mild Rt HP Db HP Lf > Rt

IW WU AsT IW WU IW AsT IW IW IW AsT IW IW AsT WU

GCS, Glasgow Coma Scale; PTU, Post-Traumatic Unconsciousness; m, months; d, days; un, unknown; MVA, motor vehicle accident; GS, gun shot; FOH, fall of height; Rt, right; Lf, left; Db, double; >, one side more than the other; HP, hemiparesis; AT, ataxia; NMD, no motor deficit; IW, independent walker; WU, wheelchair user; AsT, assisted technology.

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Table 2 Characterization of TBI patients without chronic pain (TBINP) Subject

Age at injury

Sex

Duration of injury (m)

Type of injury

GCS

Duration of PTU (d)

Cause of injury

Motor status

Mobility

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

20 19 34 22 28 38 21 27 26 19 21 20 19 19 21 20 24 (6)

Female Female Male Male Male Male Male Male Female Male Male Female Male Male Male Male

17 10 39 6 80 12 14 5 15 11 5 21 7 16 8 10 18 (19)

Blunt Blunt Blunt Blunt Blunt Blunt Blunt Blunt Blunt Blunt Blunt Blunt Blunt Blunt Penetrating Blunt

3 3 3 3 3 7 3 5 4 7 5 4 6 3 un un 4 (1.5)

14 30 un 2 un 7 12 7 40 23 5 10 un 30 7 30 16 (12)

MVA MVA MVA MVA MVA MVA MVA MVA MVA MVA MVA MVA MVA MVA GS MVA

Mild Lf HP Db HP Lf > Rt Lf HP Mild Rt HP Db HP + AT NMD Rt HP Lf HP Rt HP Mild Rt HP Mild Rt HP Db HP + AT Lf HP + AT Db HP Lf HP Db HP + AT

IW AsT AsT AsT WU IW AsT AsT AsT IW IW WU AsT WU AsT WU

GCS, Glasgow Coma Scale; PTU, Post-Traumatic Unconsciousness; m, months; d, days; un, unknown; MVA, motor vehicle accident; GS, gun shot; FOH, fall of height; Rt, right; Lf, left; Db, double; >, one side more than the other; HP, hemiparesis; AT, ataxia; NMD, no motor deficit; IW, independent walker; WU, wheelchair user; AsT, assisted technology.

Interestingly, chronic pain was present in the body side exhibiting a more severe motor (see Table 1) and sensory dysfunction (as described in Section 3.3.1.). Chronic pain was dispersed across several body regions (mean of 5 body regions per patient). Painful body regions most frequently reported were: knee area (93%), shoulder (80%), foot (73%), hand (53%), thigh (46%), lower back (46%), upper back (40%), head and face (40%), arm (33%). Two patients reported having pain on the entire body side. 3.2.3. Intensity and quality Pain intensity was measured with the VAS (0–10) and with the PPI scale (1–5) of the MPQ. At the day testing was conducted, mean VAS score was 2.8 ± 2 and median PPI score was 2. Patients reported that the intensity Table 3 Number (%) of brain regions with visible traumatic lesion in TBI patients with (TBIP) and without (TBINP) chronic paina Brain injury location

TBIP (n = 15)

TBINP (n = 16)

p-value

Parietal cortex Frontal cortex Ventricle hemorrhage/enlargement Traumatic axonal injury Subarachnoid hemorrhage Temporal cortex Corpus callosum Brain stem Subdural Hematoma Basal ganglia Cerebellum Occipital lobe

8 8 7 7 6 6 3 2 2 2 1 1

3 10 4 11 7 6 0 4 2 1 1 3

0.04 0.60 0.20 0.21 0.83 0.61 0.05 0.36 0.94 0.50 0.96 0.31

a

(53) (53) (46) (46) (40) (40) (27) (13) (13) (13) (7) (7)

(19) (62) (25) (69) (44) (37) (0) (25) (12) (6) (6) (19)

Based on CT/MRI conducted in the acute and sub-acute phase.

of pain at its worse was 5 (1–5), i.e., most intense pain. Mean NWC and PRI calculated from the MPQ were 6.5 ± 3 and 17.5 ± 8, respectively. Many patients reported that the pain prevented them from concentrating on work – ‘‘it doesn’t let the brain work’’; that the pain is exhausting, excruciating, irritating, ‘‘like real torture’’ or ‘‘like non-stop exertion’’. Additional descriptors reported by patients were: ‘‘pounding/throbbing’’ ‘‘pressing’’, ‘‘burning’’, ‘‘cutting’’ and ‘‘muscular effort-like’’. According to the MPQ, pain quality most frequently selected by TBI patients was ‘‘pricking’’ (53%). Other pain descriptors were ‘‘cool’’, ‘‘cold’’, ‘‘freezing’’, ‘‘troublesome’’, ‘‘numb’’ and ‘‘wretched’’ (33%), ‘‘pressing’’ (26%), ‘‘hot’’ (20%) and ‘‘burning’’ (20%). In many instances, patients reported that different qualities exist within different painful body regions. 3.2.4. Aggravating and alleviating and factors All patients (100%) reported that physical effort (active movement) exacerbates the chronic pain. Other aggravating factors were: cold weather (60%), fatigue (40%), touch (26%), tension (26%), immobilization (20%) and electrical nerve stimulation (20%). Pain was alleviated by relaxation or rest (60%), heating or warm weather (40%), massage (20%). Four patients (26%) reported that pain medications were helpful. 3.3. Quantitative somatosensory testing 3.3.1. Thermal sensations Fig. 2 presents average (±SE) threshold values for WS (A), CS (B) and HP (C) measured in the hands

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Both TBINP and TBIP exhibited higher thermal thresholds than those measured in the normal control group: for hands (WS p < 0.001 and p < 0.001, CS p < 0.01 and p < 0.001, HP p < 0.01 and p < 0.001) and legs (WS p < 0.01 and p < 0.001, CS p < 0.01 and p < 0.001, HP p < 0.01 and p < 0.001). However in TBINP, thermal thresholds of one body side were similar to those of the other side, but in TBIP, the two body sides presented a different sensory profile. That is, in TBIP the thresholds of WS, CS and HP in painful hands and legs were significantly higher than in the pain-free hands and legs (WS p < 0.0001 and p < 0.0001; CS p < 0.0001 and p < 0.001; HP p < 0.01 and p < 0.05, respectively). The thresholds of WS, CS and HP in the painful hands and legs of TBIP were also significantly higher than those measured in pain-free regions of TBINP (WS p < 0.05 and p < 0.05; CS p < 0.0001 and p < 0.001; HP p < 0.05 and p < 0.01, respectively). The interactions group type * body side for hands and legs were significant for WS (p < 0.01 and p < 0.01, respectively), CS (p < 0.001 and p < 0.01, respectively) and HP (p < 0.01 and p < 0.05, respectively). This means that the differences in WS, CS and HP thresholds between the two body sides of TBIP were significantly larger than in TBINP (in the latter group the thresholds in the two body sides were similar). All (100%) TBIP exhibited abnormal thermal thresholds in their painful body regions compared with only 7 (44%) TBINP.

Fig. 1. Location of chronic pain in intact body regions of patients with TBI.

and legs of the two body sides of healthy controls, patients without chronic pain (TBINP) and in painful and pain-free body regions of patients with chronic pain (TBIP).

3.3.2. Touch and graphesthesia Fig. 3 presents average (±SE) threshold values for light touch (A) and median (±SE) scores of graphesthesia (B) measured in the hands and legs of the two body sides of healthy controls, patients without chronic pain (TBINP) and in painful and pain-free body regions of patients with chronic pain (TBIP). The thresholds for touch of both TBINP and TBIP were higher than those in normal controls, in the hands (p < 0.05 and p < 0.05, respectively) and legs (p < 0.01 and p < 0.05, respectively) (A). Graphesthesia scores of TBINP and TBIP were slightly lower than normal values but the differences did not reach significance levels in either hands or legs (B). In contrast to thermal thresholds, touch and graphesthesia were similarly affected in TBINP and TBIP. That is, in both groups touch thresholds in both hands were similar, but in both groups one leg presented a higher touch threshold than the other leg (p < 0.05 and p < 0.05, respectively) with no significant differences between the groups (Fig. 3a). Similarly, in both groups graphesthesia scores were similar in the two hands but more affected in one leg than the other (p < 0.05, p < 0.05, respectively) with no significant differences between the groups (Fig. 3b). Accordingly, the

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H. Ofek, R. Defrin / Pain 131 (2007) 330–340 48 46

Painfree side in TBIP and TBINP Painful side in TBIP, painfree side in TBINP

35

*

**

Mean CS threshold ( C)

44 42 40 38 **

36

**

30

o

Mean WS threshold (oC)

*

Painfree side in TBIP and TBINP Painful side in TBIP, painfree in TBINP

**

25

20

*

*

15 34 32

Control-h Control-l

TBINP-h TBIP-h TBINP-l TBIP-l

10

Control-h Control-l

Body regions

c

TBINP-h TBIP-h TBINP-l

TBIP-l

Body regions

54

Painfree side in TBIP and TBINP Painful side in TBIP, painfree side in TBINP

52

*

Mean HP threshold (oC)

*

50 48 46

** **

44 42 40

Control-h Control-l

TBINP-h TBIP-h TBINP-l

TBIP-l

Body regions

Fig. 2. Threshold of warm sensation (WS) (a), cold sensation (CS) (b) and heat-pain sensation (HP) (c) in hands (h) and legs (l) of patients with (TBIP) and without (TBINP) chronic pain and in normal controls. In TBINP and controls both sides are pain-free, in TBIP one side is painful (grey bars) and the other side, is pain-free (black bars). Thermal thresholds of both TBI groups were higher than in normal controls (**p < 0.001 and p < 0.001, respectively). Thermal thresholds in the painful regions of TBIP were higher than pain-free regions of the same patients (*WS p < 0.0001 and p < 0.0001, CS p < 0.0001 and p < 0.001, HP p < 0.01 and p < 0.05, for hands and legs, respectively) and of TBINP (*WS p < 0.05 and p < 0.05, CS p < 0.0001 and p < 0.001, HP p < 0.05 and p < 0.01, respectively). Values denote group means ± SE.

interaction group * body side for touch and for graphesthesia was not significant. 3.3.3. Abnormal sensations Data on abnormal sensation were collected both in the interview and during testing. All TBIP reported that they have allodynia as opposed to none of the TBINP (p < 0.001). The patients reported that the stimuli inflicting pain include cold temperature (e.g., cold water and cold air of air-conditioning), crude touch, physical effort and movement. TBIP also reported having disesthesias (27%) that felt-like streams of cold and electric-like sensations. Parasthesias were reported by patients of both groups but more frequently by TBIP (53% of TBIP and 6% of TBINP, p < 0.01). Table 4 describes the frequencies of abnormal sensations evoked during testing in the painful and pain-free body sides of TBIP and TBINP. TBIP exhibited very high rates of all the abnormal sensations that were rarely found in TBINP. In TBIP, the incidence of the abnormal sensations in the painful body side was significantly higher than that of the, pain-free side (p < 0.001 for

every sensation tested) and compared with both body sides of TBINP (p < 0.001, for every sensation tested). In contrast, there were no differences in the frequency of abnormal sensations between the two body sides of TBINP. Table 5 presents the ‘‘pathological sensory profile’’ of patients with TBI, according to the frequency of the pathological sensations tested. In the ‘‘worst’’ profile all 4 pathological sensations were present (1 1 1 1) whereas in the ‘‘best’’ profile none of the pathological sensations were present (0 0 0 0). The majority of TBIP (87%) had a worst–bad profile, none had a ‘‘best’’ profile whereas the majority of TBINP (81%) had a best–good profile (p < 0.01) (Table 5). 3.4. Spasticity There were no significant differences between the groups in the MAS scores. Mean scores for the hands of TBIP and TBINP were 0 (range 0–3) and 0 (1–3), respectively. Mean scores for the legs of TBIP and TBINP were 0 (range 0–4) and 1 (1–3), respectively.

H. Ofek, R. Defrin / Pain 131 (2007) 330–340 4

Painfree side in TBIP and TBINP Painful side in TBIP, painfree side in TBINP

Mean touch threshold

* *

3

2

**

**

1

0 Control-h Control-l

TBINP-h TBIP-h TBINP-l TBIP-l

Body regions

Median graphesthesia score

4

Painfree side in TBIP and TBINP Painful side in TBIP, painfree side in TBINP

3

2

1

0 Control-h Control-l

TBINP-h TBIP-h TBINP-l TBIP-l

Body regions

Fig. 3. Threshold for touch (a) and graphesthesia scores (b) in hands (h) and legs (l) of patients with (TBIP) and without (TBINP) chronic pain and in normal controls. In TBINP and controls both sides are pain-free, in TBIP one side is painful (grey bars) and the other side, is pain-free (black bars). The threshold for touch of both TBI groups was higher than in normal controls (**p < 0.05 and p < 0.01, for hands and legs, respectively) and the scores of graphesthesia were slightly lower although not significantly so. Touch and graphesthesia were similarly affected in TBINP and TBIP with one leg exhibiting increased sensory loss compared with the other leg (*p < 0.05 and p < 0.05, respectively). Values denote group means ± SE (a) and median (b).

4. Discussion Our aim was to study the pain characteristics and the sensory profile of patients with TBI suffering from chronic central pain. To date, only three case studies have described central pain in patients with TBI. Chronic pain in patients with TBI was restricted to one body side, which was significantly more affected

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with regard to motor and sensory function than the pain-free side. In the two patients with penetrating injuries causing a unilateral TBI, the pain was located on the side of the body that was contralateral to the TBI side, as also reported in three case reports of TBI patients with central pain (Barraguer-Bordas et al., 1993; Khoshyomn et al., 2004; Son et al., 2006). The pain developed within several weeks to months after injury and then persisted with fluctuations of its intensity. Chronic pain intensity varied between moderate to severe and its quality was mainly a pricking, throbbing, pressing and pounding in nature with occasional thermal sensation. These characteristics resemble those of the case reports mentioned above and the 3 patients examined by Bowsher (1996). Sensory testing revealed that TBI patients with and without chronic pain (TBIP and TBINP, respectively) presented a significant loss of thermal sensibility compared with healthy controls. However, TBIP exhibited a non-symmetrical loss in that painful regions were significantly more affected than pain-free regions. In contrast, the sensory loss exhibited by TBINP was symmetrical and to a lesser degree. A similar, non-symmetrical dysfunction of pain and temperature sensations was also observed in two patients who developed central pain 24 and 6 months following TBI (Khoshyomn et al., 2004; Son et al., 2006). In addition to the loss of thermal sensations, the painful body regions of TBIP exhibited very high rates of abnormally evoked pain; allodynia, hyperpathia and exaggerated wind-up, as also recorded in other case reports (Barraguer-Bordas et al., 1993; Bowsher, 1996; Khoshyomn et al., 2004; Son et al., 2006). These characteristics resemble those of central pain developing after spinal cord injury (SCI), stroke and multiple sclerosis (MS). Central pain in the latter three instances has the following characteristics: (a) relatively late onset, (b) moderate to severe intensity, (c) burning, pricking and pressing quality and (d) exacerbation by changes in environmental temperature, mood and physical conditions (e.g., Vestergaard et al., 1995; Bowsher, 1996; Eide et al., 1996; Beric’ et al., 1988; Boivie, 1999; Defrin et al., 2001; Finnerup et al., 2003; Hansson, 2004; Osterberg et al., 2005). In addition, a reduction in pain and temperature sensations and a high frequency

Table 4 Incidence (%) of abnormal sensations in painful and pain-free body sides of TBI patients with (TBIP) and without (TBINP) chronic pain TBIP

Hyperpathia Static allodynia Dynamic allodynia Wind-up pain

TBINP

Painful side

Pain-free side

p-value*

One side

Other side

p-value*

100**

27 0 0 33

p < 0.001 p < 0.001 p < 0.001 p < 0.001

44 6 6 25

25 0 0 25

NS NS NS NS

60** 47** 93**

p-values *, comparisons within groups (between body sides); **, p < 0.001 comparisons between groups.

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Table 5 Frequency (%) of pathological sensations in TBIP and TBINP divided into categories of ‘‘best’’ to ‘‘worst’’ Neurological profile

0 ‘‘Best’’

1 ‘‘Good’’

2

3 ‘‘Bad’’

4 ‘‘Worst’’

Total

TBIP TBINP

0 (0) 8 (50)

0 (0) 5 (31)

2 (13) 2 (13)

6 (40) 1 (6)

7 (47) 0 (0)

15 (100) 16 (100)

Best, no pathological sensations present; 1, only one type of pathological sensation present, etc.; Worst, all pathological sensations present.

of pathologically evoked pain is typical of painful regions in patients with SCI (Eide et al., 1996; Beric’ et al., 1988; Boivie, 1999; Defrin et al., 2001; Finnerup et al., 2003), stroke (Boivie et al., 1989; Vestergaard et al., 1995; Bowsher, 1996, 1998; Boivie, 1999; Greenspan et al., 2004) and MS (Osterberg et al., 2005). There are important clinical implications in the finding that central pain in patients with TBI manifest in body regions not associated with local or spinal injury. TBI patients exhibit many other problems such as motor dysfunction, cognitive deficits, behavioral changes and emotional distress (Vogelbaum et al., 1998; Sherman et al., 2006). Central pain, because it occurs in seemingly intact body regions, is often ignored or deemed to be symptomatic of a cognitive/affective disorder and receives inadequate treatment. Therefore, we propose that a diagnosis of central pain should be considered when TBI patients present clinical features similar to those presented here. Several lines of treatment can be offered including antidepressants, anticonvulsants and lidocaine (for review, see Beniczky et al., 2005; Finnerup et al., 2005; Hulsebosch, 2005; Frese et al., 2006). It should be emphasized that the treatment of central pain is difficult and patients should be carefully and systematically monitored for efficacy and side effects. It should also be pointed out that chronic pain may be of psychogenic origin and it is important that this factor be taken into consideration in the evaluation of therapeutic measures. Since all painful regions exhibited a significant reduction in pain and temperature sensations but not necessarily that of touch and graphesthesia, it appears that damage to the pain and temperature system is essential for the development of central pain in TBI patients. The damage can occur below, at and/or above the thalamic level as our patients exhibit brain injuries in various locations. Perhaps the relatively high frequency of parietal damage may have some inference on the level of damage but this information was obtained from MRI conducted in the acute and sub-acute phase and may not reflect the chronic phase of the TBI. Damage to the pain and temperature system is certainly not a sufficient condition for the occurrence of central pain since both TBIP and TBINP presented disturbances in these sensations. It is possible that a critical degree of damage is necessary to initiate central pain, as TBIP presented a more extensive sensory loss than did TBINP. Alternatively, an imbalance between ipsi- and contralateral body sides in the extent of damage to pain

and temperature pathways may be necessary as such an imbalance is present only in TBIP and not in TBINP. An example of this kind of imbalance was recently described in patients with central pain following syringomyelia (Ducreux et al., 2006). The possibility that hyperexcitability and hyper-reactivity of the nervous system is necessary for the occurrence of central pain is supported by the very high incidence of allodynia, hyperpathia and exaggerated wind-up sensations in TBIP, which rarely occurred in TBINP. Electrophysiological recordings (Lenz et al., 1994, 1987; Tasker et al., 1992) and brain scans (Ness et al., 1998; Casey et al., 1999; Peyron et al., 2000; Pattany et al., 2002) do confirm that deafferented neurons in the thalamus and somatosensory cortex of patients with central pain may undergo plastic changes and become hyperexcitable. These neurons burst spontaneously with epileptiform discharges coinciding with complaints of pain, and are hypersensitive to stimulation. Spontaneous bursts and hypersensitivity might underlie the spontaneous pain and the abnormal sensations which were found in TBIP in this study. The delayed onset of chronic pain is interesting and difficult to explain. Conceivably, hyperexcitability occurs in response to the damage inflicted on the pain system (due to the TBI) resulting in a reactive loss of inhibitory mechanisms. This could explain the delayed onset of chronic pain coinciding with the development of a critical level of hyperexcitability. Despite the resemblance in characteristics between the patients tested herein and patients with central pain tested in other studies, some clinical features appear to be unique to TBI patients. Usually the quality of this pain is one of pricking and pounding/throbbing; only 20% of patients reported burning pain which is more frequently present in SCI patients (e.g., Defrin et al., 2001; Finnerup et al., 2003) and post-stroke patients (e.g., Bowsher, 1996; Hansson, 2004) with central pain. In addition, 100% of the TBI patients had movement allodynia, which is not common in SCI patients with central pain (Defrin et al., 2001; Finnerup et al., 2003) although it was reported by 20% of post-stroke patients with central pain (Bowsher, 1996). Variations in the characteristics of central pain among patients are likely due to variations in the injury site or in the etiology of injury. It would therefore be interesting to study patients with central pain of different etiologies under similar conditions to uncover the common as well as the unique features in this population.

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It is noteworthy that our study included patients with blunt or penetrating TBIs. Blunt injuries differ from penetrating injuries in that they are usually more severe and affect a greater area of the brain, often leaving the skull undamaged. A penetrating object causes local damage to skull and brain, leaving the rest of the brain relatively unaffected. Despite such differences, the two patients with penetrating injuries did not exhibit distinct features from patients with blunt injuries except for a slightly lower number of painful regions.

Acknowledgments The authors thank Dr. Ofer Keren from the Department of Brain Injury Rehabilitation, Loewenstein Rehabilitation Hospital, for his support and assistance in this work. Part of this work was funded by the Rosin foundation.

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