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//-->833PAPERLonglasting antalgic effects of daily sessions of repetitivetranscranial magnetic stimulation in central and peripheralneuropathic painE M Khedr, H Kotb, N F Kamel, M A Ahmed, R Sadek, J C Rothwell...............................................................................................................................See Editorial Commentary, p 761J Neurol Neurosurg Psychiatry2005;76:833–838. doi: 10.1136/jnnp.2004.055806See end of article forauthors’ affiliations.......................Correspondence to:Dr E M Khedr, Departmentof Neurology, AssiutUniversity Hospital, Assiut,Egypt; Emankhedr99@yahoo.comReceived 7 October 2004Revised version received29 November 2004Accepted2December2004.......................Background and objective:A single session of repetitive transcranial magnetic stimulation (rTMS) overmotor cortex had been reported to produce short term relief of some types of chronic pain. The presentstudy investigated whether five consecutive days of rTMS would lead to longer lasting pain relief inunilateral chronic intractable neuropathic pain.Patients and methods:Forty eight patients with therapy resistant chronic unilateral pain syndromes (24each with trigeminal neuralgia (TGN) and post-stroke pain syndrome (PSP)) participated. Fourteen fromeach group received 10 minutes real rTMS over the hand area of motor cortex (20 Hz, 10610 s trains,intensity 80% of motor threshold) every day for five consecutive days. The remaining patients receivedsham stimulation. Pain was assessed using a visual analogue scale (VAS) and the Leeds assessment ofneuropathic symptoms and signs (LANSS) scale, before, after the first, fourth, and fifth sessions, and twoweeks after the last session.Results:No significant differences were found in basal pain ratings between patients receiving real- andsham-rTMS. However, a two factor ANOVA revealed a significant ‘‘¡ TMS’’6‘‘time’’ interactionindicating that real and sham rTMS had different effects on the VAS and LANSS scales. Post hoc testingshowed that in both groups of patients, real-rTMS led to a greater improvement in scales than sham-rTMS,evident even two weeks after the end of the treatment. No patient experienced adverse effects.Conclusion:These results confirm that five daily sessions of rTMS over motor cortex can producelonglasting pain relief in patients with TGN or PSP.timulation of the motor cortex for the treatment ofcertain forms of refractory neurogenic pain has attractedmuch interest in recent years. Tsubokawaet al1firstshowed that central post-stroke pain could be reduced bymeans of chronic motor cortex stimulation (MCS) throughimplanted epidural electrodes. Further studies proved thatMCS could also relieve trigeminal neuropathic pain andcentral pain in Wallenberg’s syndrome.2 3However, suchtreatments are invasive and the outcome varies from patientto patient. A number of studies have shown that a singlesession of repetitive transcranial magnetic stimulation(rTMS) can relieve pain transiently in some patients withchronic neuropathic pain,4–6although others have found theeffect to be small and not significant.7The question we address here is whether the duration ofpain relief can be extended by repeated application of rTMSevery day for five days. Lefaucheuret al8reported that painwas well controlled in a single patient with drug resistantneuropathic pain for 16 months by monthly sessions ofmotor cortex rTMS. In contrast, Topperet al9failed to see anylong term therapeutic effect of three weeks’ daily parietalcortex rTMS in two patients with pain due to longstandingunilateral avulsion of the lower cervical roots even thoughpain was reduced for 10 minutes in the same individualsafter a single session of rTMS. We have extended thesestudies to a much larger group of patients using rTMS overthe conventional motor cortex site.SMarch 2004. The study included 48 patients with unilateralchronic neuropathic pain; 24 had trigeminal neuralgia (TGN)as a peripheral neuropathic pain, and 24 had post-stroke pain(PSP) as a central type of neuropathic pain. All patients hadbeen treated with various medications, including anti-convulsants, narcotic or non-narcotic analgesics and anti-depressants, without satisfactory pain control. Three of thepatients with TGN had persistent pain even after micro-vascular decompression.Clinically, the diagnosis of TGN was based on the criteria ofthe International Association for the Study of Pain.10Sixteenwomen and eight men (mean (SD) age 51.5 (10.7) years) hadTGN with mean duration of illness of 39 (31) months. Painwas commonly evoked by trivial stimuli, including washing,shaving, smoking, talking, and brushing the teeth, but couldalso occur spontaneously.The clinical diagnosis of PSP was based on history ofcerebrovascular stroke (haemorrhagic or thromboembolic).Ten women and 14 men (mean age 52.3 (10.3) years) hadPSP with mean duration of illness of 18 (17) months. Allpatients with PSP had minor motor deficits. Twelve hadthalamic infarction, six had thalamic haemorrhage, four hadlateral medullary syndrome, and two had parietal infarctionas documented by CT scan of the brain. The patientscomplained of a spontaneous, abnormally painful sensationof great intensity that they described as burning, tearing, ordeep-boring, mostly in the face and upper limb and trunkAbbreviations:ADM, abductor digiti minimi; CT, computedtomography; LANSS, Leeds assessment of neuropathic symptoms andsigns; MCS, motor cortex stimulation; PSP, post-stroke pain; RMT, restingmotor threshold; rTMS, repetitive transcranial magnetic stimulation;TGN, trigeminal neuralgia; VAS, visual analogue scalePATIENTS AND METHODSPatientsWe conducted this study at the Department of Neurology,with participation of the Chronic Pain Unit, at AssiutUniversity Hospital, Assiut, Egypt, between March 2003 andwww.jnnp.com834Khedr, Kotb, Kamel, et alarea (spontaneous painful dysaesthesia). Neurological exam-ination revealed an increased threshold for pinprick andthermal sensation in the painful area in all patients and adecrease in tactile and/or vibration sensations of varyingdegrees in some patients. All patients had minor motordeficit.We excluded patients with intracranial metallic devices orwith pacemakers or any other device. We also excluded thosewith extensive myocardial ischaemia and those known tohave epilepsy. All patients participated in the study aftergiving written informed consent and the local ethicalcommittee of Assiut University Hospital approved theexperimental procedure.The baseline assessment consisted of a full history andneurological examination followed by instruction in the useof a visual analogue scale (VAS). Each patient then providedtwo VAS ratings, and the mean was taken. After this thepatients were assessed by the examiner using the Leedsassessment of neuropathic symptoms and signs (LANSS)pain scale, which is based on analysis of sensory descriptionand bedside examination of sensory dysfunction.11Measuresof VAS and LANSS were taken at each follow up point.Patients were randomly assigned to one of the two groups,depending on the day of the week on which they wererecruited. One group (consisting of patients recruited onSaturday to Monday) received real-rTMS and the other group(recruited on Tuesday to Thursday) received sham-rTMS.PreparationThe patient sat in a comfortable chair and was asked to relaxas much as possible. Electromyography (EMG) recordingsfrom the contralateral abductor digiti minimi (ADM) musclewere acquired with silver-silver chloride surface electrodes,using a muscle belly-tendon set-up, with a 3 cm diametercircular ground electrode placed on the wrist. A DantecKeypoint electromyograph was used to collect the signal(Dantec, Skovlunde, Denmark). EMG parameters included abandpass of 20–1000 Hz and a recording time window of200 ms. TMS was performed with a commercially available90 mm figure of eight coil connected to Mag-Lite r25stimulator (Dantec Medical, Skovelund, Denmark).Determination of resting motor thresholdFirst we determined the optimal scalp location from whichTMS evoked motor potentials of greatest amplitude in theADM. We used a constant suprathreshold stimulus intensityand moved the figure of eight coil systematically in 1 cmsteps to determine the scalp position from where TMS evokedmotor potentials of maximum peak to peak amplitude in thetarget muscle. The coil was positioned tangentially to thescalp and oriented so that the induced electrical currentswould flow approximately perpendicular to the centralsulcus, at a 45˚angle from the mid-sagittal line.12Singlepulse TMS was then delivered to the optimal location startingat suprathreshold intensity and decreasing in steps of 2% ofthe stimulator output. Relaxation and EMG signals weremonitored for 20 ms prior to stimulation. The resting motorthreshold (RMT) was defined as the minimal intensityrequired to elicit motor evoked potentials of 50mVpeak topeak amplitude in five out of 10 consecutive trials.13Theoptimal scalp location and coil orientation was marked usinga red marker to reuse for daily rTMS.Repetitive transcranial magnetic stimulationA few studies have investigated the best parameters to use forrTMS mediated relief of pain. Epidural stimulation usuallyemploys submotor threshold pulses at,40Hz. All previousrTMS studies have used subthreshold intensities, usually setat 80% RMT. However, different groups have used differentfrequencies. Lefaucheuret al4found 10 Hz to be moreeffective than 0.5 Hz. In contrast, Rollniket al7used 20 Hz.In a preliminary investigation we examined whether 20 HzrTMS may be more effective than 10 Hz (both at 80% RMT)over a non-blinded two day treatment session. Since 20 Hzseemed marginally more effective, we elected to use 20 Hz,80% RMT stimulation in the main study.Real-rTMS involved applying a train of rTMS once perminute for 10 minutes. Each train consisted of 200 pulses at20 Hz and 80% RMT (total duration of 10 s) applied througha figure of eight coil over the identified motor cortical areacorresponding to the hand of the painful side. The treatmentwas repeated every day for five consecutive days. Sham-rTMSwas applied using the same parameters but with the coilelevated and angled away from the head to reproduce someof the subjective sensation of rTMS and yet avoid inductionof current in the brain.14However, since none of the patientshad experienced rTMS previously they were unaware ofwhich stimulation was real and which was sham. During therTMS, all patients wore earplugs to protect the ears fromthe acoustic artefact associated with the discharge of thestimulation coil.Follow upPatients were followed up after the first, fourth, and fifthrTMS session, and 15 days after the last session, using theVAS and LANSS scales. The second author evaluated thesemeasures blindly—that is, without knowing the type ofrTMS.Data analysisPain level was assessed at baseline, after the first, fourth, andfifth rTMS session, and 15 days after the last session usingthe VAS and LANSS scales. Values for both patient groups(TGN and PSP) and each rating scale (VAS and LANSS) wereanalysed in separate two factor analysis of variance (ANOVA)with ‘‘time after start of treatment’’ and ‘‘¡ rTMS’’ as mainfactors. The Greenhouse–Geisser correction of degrees offreedom was used when necessary to correct non-sphericityof data. The percentage modification of the pain level wascalculated from the scores measured before and after therTMS sessions, both real and sham, by the followingequation:(post-rTMS2pre-rTMS pain scores)6100/pre-rTMS painscorefor VAS and LANSS. Individual effects of rTMS were alsoclassified into three categories:NNNgood—reduction of pain score by>70%satisfactory—reduction of pain score by>40–69%poor—reduction of pain score by,40%.15RESULTSThere was no significant difference between the VAS andLANSS scores of the real and sham groups at baseline.However, fig 1 shows that the scores of the patients whoreceived real-rTMS decreased more over the course of thetreatment than those who received sham-TMS. This wasconfirmed in a two factor repeated measures ANOVAseparately in each group of patients with ‘‘time of assess-ment’’ and ‘‘¡ rTMS’’ as main factors. In both the TGN andPSP groups, there was a significant interaction between‘‘time’’ and ‘‘¡ rTMS’’ for both the VAS and LANSS scores(TGN VASF1.5,32.1= 4.7, p = 0.025; TGN LANSSF1.8,39= 11.3,p,0.001; PSP VASF1.6,34.4= 26.6, p,0.001; PSP LANSSF1.3,28.8= 25.5, p,0.001). Post hoc testing showed that therewww.jnnp.comrTMS in trigeminal neuralgia and post-stroke pain syndrome83510.07.5TGN – VAS scores30TGN – LANSS scoresVAS score5.02.50.0VAS scoreRealShamPSP – VAS scores201010.07.530PSP – LANSS scoresVAS score5.02.50.0VAS scorePrePost 1Post 2Post 3 2 weeks2010PrePost 1Post 2Post 3 2 weeksFigure 1Changes in mean pain rating scores (visual analogue scale (VAS) and Leeds assessment of neuropathic symptoms and signs (LANSS) painscale) at the five assessment points for the two groups of patients. The first assessment was immediately prior to commencing repetitive transcranialmagnetic stimulation (rTMS) treatment (Pre), the second (Post 1) was immediately after the first session of rTMS, and then after the fourth (Post 2) andfifth (Post 3) rTMS sessions, and 15 days (2 weeks) after the last session. As the data show the mean scores of the patients who received real-rTMSdecreased more over the course of the treatment than those who received sham-TMS. In both, the trigeminal neuralgia (TGN) and post-stroke pain(PSP) groups, there was a significant interaction between ‘‘time’’ and ‘‘¡ rTMS’’ for both the VAS and LANSS scores (see text for details). In bothgroups of patients improvement was greatest in those receiving real-TMS.8TGN – real VAS8TGN – sham VASNo of patients4No of patients123456789106642212345678910VAS scores8VAS scores8TGN – real LANSSTGN – sham LANSSNo of patients4No of patients66422PrePost1–23–45–67–89–1011–1213–1415–1617–1819–2021–2223–241–23–45–67–89–1011–1213–1415–1617–1819–2021–22VAS scores23–24VAS scoresFigure 2The distribution of rating scores among patients with trigeminal neuralgia (TGN). The graphs compare baseline data with that at the time ofmaximum effect immediately after the last treatment session. Although pain scores decreased after real repetitive transcranial magnetic stimulation(rTMS), the effect was greater in some individuals than others. So even after real-rTMS, a few patients were still in the baseline range.www.jnnp.com836Khedr, Kotb, Kamel, et al8PSP – real VAS8PSP – sham VASNo of patients4No of patients123456789106642212345678910VAS scores8VAS scores8PSP – real LANSSPSP – sham LANSSNo of patients4No of patients66422PrePost9–1011–1213–1415–1617–1819–2021–2223–241–23–45–67–811–1213–1415–1617–1819–2021–22VAS scores23–241–23–45–67–89–10VAS scoresFigure 3The distribution of rating scores among patients with post-stroke pain (PSP). The graphs compare baseline data with that at the time ofmaximum effect immediately after the last treatment session. Although pain scores decreased after real repetitive transcranial magnetic stimulation(rTMS), the effect was greater in some individuals than others. So even after real-rTMS, a few patients were still in the baseline range.was a significant decrease in pain ratings at all time pointsafter real rTMS compared with baseline (pairedttests;p,0.05) in both groups of patients. There was no change inLANSS ratings after sham-rTMS in the PSP group althoughthere was a small decrease in the patients’ VAS scores afterthe fourth and fifth sessions and at two weeks’ follow up.Both LANSS and VAS scores decreased in the TGN groupafter the fourth and fifth sessions and at two weeks’follow up.Since there were no obvious differences in the results ofpatients with PSP and TGN, we grouped the data and tookthe mean of both rating scales to calculate the percentagereduction in pain ratings produced by rTMS. In the real-rTMSgroup pain decreased by 45% compared with baselinemeasures at the end of the fifth treatment session and wasstill reduced by 40% two weeks later. In contrast, pain ratingsin the sham group declined only by 5% and 2%, respectively(p,0.001 comparing the percent reduction after real andsham treatments).Figures 2 and 3 show how treatment changed thedistribution of rating scores in the patients with TGN andPSP, respectively. Data at baseline are compared with that atthe time of maximum effect immediately after the lasttreatment session. Real rTMS decreases the pain ratings, butit is also clear that the effect is greater in some individualsthan others, with a small number of patients in each groupremaining in the baseline range, even after real rTMS.Tables 1 and 2 summarise outcomes after the fifth treatmentsession and two weeks later.DISCUSSIONEpidural electrical MCS has been reported to amelioratesymptoms in some patients with intractable chronic pain ofcentral and peripheral origin.16However,,30%of operatedpatients fail to respond so that there is a need to developpredictive tools to select patients for treatment.17 18TMS is arelatively new technology that offers the possibility of testingwhether patients will respond to direct cortical stimulation bymeasuring their response to a period of non-invasive corticalstimulation. Repetitive TMS appears to stimulate motorcortex in a way similar to that produced by epiduralstimulation,19and can transiently reduce pain in some groupsof patients with neuropathic pain.4The present data suggestthat rTMS at 20 Hz given every day for five days can reducepain ratings in patients with TGN and PSP for at least twoweeks after the end of treatment. We conclude that repeatedTable 1Individual effect on LANSS ratings of repetitive transcranial magnetic stimulation(rTMS) immediately after the last session and at two weeks’ follow up. Values are n (%)After the fifth sessionSubgroupTGN realTGN shamPSP realPSP shamPoor3849(21.4)(80)(28.6)(90)Satisfactory4281(28.6)(20)(57.2)(10)Good72(50)(0)(14.3)(0)Two weeks after the last sessionPoor7869(50)(80)(42.9)(90)Satisfactory4261(28.6)(20)(42.9)(10)Good32(21.4)(0)(14.3)(0)LANSS, Leeds assessment of neuropathic symptoms and signs; PSP, post-stroke pain; TGN, trigeminal neuralgia.www.jnnp.comrTMS in trigeminal neuralgia and post-stroke pain syndrome837Table 2Individual effect on visual analogue scale (VAS) ratings of repetitive transcranialmagnetic stimulation (rTMS) immediately after the last session and at two weeks’ follow up.Values are n (%)After the fifth sessionSubgroupTGN realTGN shamPSP realPSP shamPoor4639(28.6)(60)(21.4)(90)Satisfactory7 (50)4 (40)10 (71.4)1(10)Good31(21.4)(0)(7.2)(0)Two weeks after the last sessionPoor6 (42.9)8 (80)5 (35.7)10 (100)Satisfactory527(35.7)(20)(50)(0)Good32(21.4)(0)(14.3)(0)PSP, post-stroke pain; TGN, trigeminal neuralgia.sessions of rTMS over the motor cortex may be, at least insome groups of patients, an effective way of providingrelatively lasting relief of painful symptoms, and a screeningprocedure in others who might benefit from implantation ofa chronic stimulating device.There is a great deal of evidence that sessions of rTMS canlead to after effects on the excitability of the human cerebralcortex14and that repeated applications can prolong theduration of the effect even in healthy subjects.20In view ofthese results, rTMS over the dorsolateral prefrontal cortex hasbeen applied therapeutically with varying degrees of successto treat depressed and psychotic patients.21–23In addition,rTMS of the motor cortex has been used to amelioratedystonic symptoms24and bradykinesia in Parkinson’sdisease.25Relatively few studies have investigated the effect of TMSin relief of chronic pain. Initial studies showed that a singlesession of rTMS over the motor cortex could lead to shortterm relief of pain4–6in most cases. In the present study wetested whether repeated sessions of rTMS might prolong thecontrol of pain. To our knowledge there are only two otherprevious studies on this topic. Topperet al9reported nopermanent reduction of pain in two patients with phantomlimb pain-like syndrome after daily sessions of 10 Hz rTMSover the parietal cortex for three consecutive weeks. However,the pathophysiological basis of phantom limb pain-likesyndrome may be different from other types of neuropathicpain. In addition, other successful studies of rTMS in painrelief have used the motor cortex as the target site rather thanthe parietal cortex. A second study of repeated rTMS in pain8reported that neuropathic pain in a single patient was wellcontrolled by monthly sessions of rTMS over the motor cortexat 10 Hz. The present study used MCS in a daily regimen andfound clear effects on pain ratings that outlasted treatmentfor up to two weeks.A small placebo effect was found after the fourth treatmentsession in both groups of patients, particularly in the VASscores. Lefaucheuret al5found a similar sham effect, andindeed it would be unusual for there to be no placebo effect atall in a study such as this. However, the important point isthat the effect of real-rTMS was much greater than that ofthe sham condition in both groups of patients and for bothrating scales.In the present study, the effects built up rather slowly,being only mild immediately after the initial session on thefirst day, but quite clear when tested immediately after thefourth session, and much greater than the placebo effect ofsham stimulation. This is consistent with Lefaucheuret al’s4original observation that pain relief after a single session wasoptimal two to four days after rTMS. Plegeret al6recordedsome pain relief 30 seconds after rTMS, but this intensifiedafter 45 minutes. Since we assessed pain immediately afterthe first session, we may have missed the time of optimalresponse. However, by day 4, the effects were clear. Anotherexplanation for the absence of significant pain relief after thefirst session could be related to the duration of the session inthe present study, which was 10 minutes as compared with20 minutes used in some of previous studies.4 5 7 8The mean degree of pain reduction (,45% in both ratingscales) that we observed was both greater and longer lastingthan has been reported in other studies. Although we cannotbe certain of the reasons, it seems likely that this due to thecombination of a larger number of rTMS pulses per session(2000 compared with 1000 of Lefaucheuret al4or 400 ofTopperet al9) plus the repeated sessions at daily intervals.Another explanation could be related to the site of pain. Mostof our patients had either facial pain (TGN) or facial plusupper limb dysaesthesia (PSP). We applied rTMS over thehand area, which lies between the representation of theface and the arm. It might have been that stimulation herecould have spread readily to both sites, as proposed byLefaucheuret al,5and given a good overall reduction inpain ratings. Interestingly, there was a range in the responseof individual patients: from excellent to virtually nothing.Precisely why this should occur is unknown, but since asimilar range of responsiveness is seen after chroniccortical stimulation it was not entirely unexpected. Onepossibility is that the mechanism of pain relief relies onactivation of corticothalamic projections9that may bedamaged in some of the patients. Nevertheless, the fact thatrTMS can probe the range of interindividual effects makesit a good tool to screen patients for potential chronicimplantation.The mechanisms responsible for the effect of MCS on painare still unknown. Several authors have observed an increaseof cerebral blood flow in the ipsilateral thalamus, orbito-frontal and cingulate gyri, and in the upper brain stem duringMCS16. As noted above it may be that activity in theprojections to the thalamic nuclei from the motor andpremotor cortices is modulated by rTMS entailing a cascadeof synaptic events in pain related structures receivingafferents from these nuclei, including the medial thalamus,anterior cingulate, and upper brain stem.Our results are compatible with previous work showingthat direct electrical stimulation of motor cortex withimplanted electrodes is an effective treatment in somepatients for control of chronic deafferentation or neuro-pathic pain.26 27Here we show that repeated daily sessions ofrTMS are able to mimic these effects in patients with TGNand PSP......................Authors’ affiliationsE M Khedr, N F Kamel, M A Ahmed, R Sadek,Department ofNeurology, Assiut University Hospital, Assiut, EgyptH Kotb,Department of Anaesthesiology, Assiut University Hospital,Assiut, EgyptJ C Rothwell,Sobell Research Department of Motor Neuroscience andMovement Disorders, National Hospital for Neurology andNeurosurgery, London, UKCompeting interests: none declaredwww.jnnp.com [ Pobierz całość w formacie PDF ]