Disappearance of central thalamic pain syndrome after contralateral parietal lobe lesion: implications for therapeutic brain stimulation

Pain 98 (2002) 325–330 www.elsevier.com/locate/pain

Clinical note

Disappearance of central thalamic pain syndrome after contralateral parietal lobe lesion: implications for therapeutic brain stimulation C. Helmchen a,*, M. Lindig b, D. Petersen c, V. Tronnier d a

Department of Neurology, Medical University of Lu¨beck, Ratzeburger Allee 160, D-23538 Lu¨beck, Germany Department of Anesthesiology, Medical University of Lu¨beck, Ratzeburger Allee 160, D-23538 Lu¨beck, Germany c Department of Neuroradiology, Medical University of Lu¨beck, Ratzeburger Allee 160, D-23538 Lu¨beck, Germany d Department of Neurosurgery, University of Heidelberg, Germany b

Received 11 January 2002; accepted 26 April 2002

Abstract At present there is hardly any appropriate therapy for central pain syndromes available. We report on a unique case of a central thalamic pain syndrome that did not respond to any therapy but disappeared after an additional contralateral parietal lobe lesion. This example indicates that lesions affecting the bilateral balance of thalamo-parietal circuits may lead to pain relief in patients with central pain syndrome, which probably constitutes a bilateral disorder of functional plasticity. This should be taken into account in chronic brain stimulation for persistent pain states. q 2002 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved. Keywords: Central pain syndrome; Neural plasticity; Brain stimulation

1. Introduction Central pain is a chronic severely disabling pain syndrome following central nervous system (CNS), e.g. thalamic lesions. Since its pathomechanism is unknown, therapeutic options are often poor. Deep brain (periventricular grey, thalamus) stimulation and more recently motor cortex stimulation have been shown to be effective in pain alleviation for some chronic pain disorders (Davis et al., 2000; Kumar et al., 1990; Peyron et al., 2000b). Thus, target areas of potential functional inactivation have to be clearly delineated. In contrast to the usually performed brain stimulation ipsilateral to the lesion, potential benefit of contralateral stimulation might derive from the following clinical observation of a patient with a central pain syndrome following a left thalamic lesion which disappeared with a new contralateral parietal lobe lesion. 2. Case report 2.1. Medical history and examination This 60-year old patient suffered from two episodes of * Corresponding author. Tel.: 149-451-500-2927; fax: 149-451-5002489. E-mail address: [email protected] (C. Helmchen).

acute neurological deficits within 2 years, first in June 1999 and, second, in April 2001, which are described in the following. (1) In 1999 he noticed a sudden weakness and numbness of his left arm and leg. On neurological examination there was a severe left-sided spastic hemiparesis (MRC 3) with hyperreflexia and a left extensor plantar response. Sensory examination revealed impaired light touch, pinprick, vibration, position sense and two-point-discrimination on the left side. Thermal sensation was abnormal, i.e. he could not differentiate between warm and cold stimuli within a range of more than 458C (0–458C). Even 498C sustained (20 s) temperature applied at the finger tips of his left hand was not appreciated. At that time there was no spontaneous pain or allodynia, neither tactile nor cold and warm thermoallodynia. Sensory examination was normal and particularly normal thermal sensation in his right hand. CCT revealed a hemorrhage in the right posterolateral thalamus extending medially to the wall of the third ventricle that resolved over the next few weeks. About 3 months later he noticed the gradual onset of a throbbing dysaesthetic pain on his left side, particularly in his left arm. The constant spontaneous pain had a burning aching quality with an intensity of on average 80 on a visual analog scale (VAS 0–100) which was severely unpleasant leading to partial disability. It was aggravated by movements and cold stimuli. On neurological examination he showed an improved left-

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sided hemiparesis (MRC 4) but sustained hemihypesthesia and -hypalgesia and – as a new sign – allodynia, both mechano- as well as cold and warm thermoallodynia. He could still not differentiate between warm and cold stimuli. Thermal stimulation applied at the fingertips and thenar muscles as assessed by a commercial thermode (Peltier thermode; TSA II, Medoc Inc., Israel) revealed a warm threshold at 408C on his right hand. On the affected left hand even 498C was not noticed as warm or even painful. In addition to the spastic muscle tone in his left arm there was some focal abducting dystonic component of the left hand. Clinical follow up-examination within the next 1.5 years did not show any significant change in clinical findings. Ten months later CCT showed complete resolution of the former hemorrhage with a circumscribed hypodense lesion in the posterior right thalamus clearly involving the posterolateral nuclei. Magnetic resonance imaging (MRI) additionally showed few subcortical parietal and frontal lesions [in the centrum semiovale, not involving the anterior cingulate cortex (ACC)] suggestive of small infarctions probably resulting from ipsilateral carotid artery occlusive disease, which was confirmed by doppler and duplex sonography (right 50%, left 70% stenosis). He received acetylsalicylic acid (300 mg/die) for secondary stroke prevention. Various pharmacological and physical therapy did not substantially improve this central pain syndrome. Medication included antidepressant (amitryptiline, clomipramine, melperone), anticonvulsive (gabapentine, carbamazepine), antispastic (baclofen) agents with a sufficient dose and duration (at least 8 weeks each trial) and in addition various analgesics (paracetamole, flupirtine, tramadol, hydromorphine, naloxone, polamidone). Behavioral therapy and psychotherapy included Jacobson’s progressive muscle relaxation, apart from extensive physiotherapy and occupational training. Intravenous lidocaine infusion could not be applied due to cardiac failure. Since all these therapies did not achieve remarkable pain relief, ipsilesional therapeutic brain stimulation was considered. (2) In 2001, almost 2 years after the right thalamic hemorrhage, he suddenly suffered once again from acute onset of numbness and coordination problems on his right side, predominantly affecting his right arm. While washing his hands he noticed four important changes: first, he could not appreciate warm temperature on his right hand any longer. Secondly, on his left arm he was now able to differentiate between warm and cold water. Thirdly, cold water particularly did not elicit allodynic pain any longer and, finally, the spontaneous aching central pain on his left side disappeared. In fact, for the first time since the right thalamic hemorrhage he thought he would be released from his long-lasting pain syndrome on his left side. On examination he presented with a profound sensory deficit on his right side: position sensation was virtually lost in his right fingers, only positional changes of the hand joints could be partly noticed. Additionally, there

was moderate hemihypesthesia but severe hypalgesia and warm and cold thermhypesthesia on his right side but no allodynia. In his right leg he could not distinguish warm and cold stimuli, however, position sense was only slightly reduced in his right leg. In contrast to previous examinations he could now differentiate warm and cold stimuli in his left hand. There was no allodynia any longer, neither mechanical nor thermal. Moreover, he could discriminate two temperatures as close as 58C apart. There was still sustained left hemidys- and hypesthesia, particularly in the left arm. Simultaneous tactile but not thermal stimulation was localized to the right arm. In addition there was some transient dysphasia and dyslexia. The remaining neurological examination showed the previously described deficit on the left side but was otherwise normal. Thermal threshold analysis (Peltier thermode) revealed no thermal sensation, from 0 up to 508C in his right hand. He also did not recognize the stimuli as painful or unpleasant. In contrast, in his left hand he now noticed a cold thermal stimulus of 28C as intensively cold and 498C as warm but not painful. Over the course of the following 2 months sensory deficits largely improved on the right side: hypesthesia, hypalgesia and thermhypesthesia clearly improved but position sense remained very poor. Concomitantly, spontaneous central pain and – to a smaller degree – cold thermallodynia redeveloped on the left side and still increased over the following months. It still persists almost 1 year after the parietal stroke. However, there was neither warm thermonor mechano-allodynia on the left side. On the right side spontaneous pain or allodynia had not yet developed. 2.2. Investigations Noxious stimulation and determination of thermal heat and pain thresholds were performed with a commercial Peltier thermode (TSA II, Medoc Inc., Israel) with a 3 £ 3 cm thermo-conducting surface applied at the finger tips or thenar muscles for a variable duration (up to 20 s). Somatosensory-evoked potentials (SEP) showed bilaterally still normal N20 latencies on median nerve stimulation but prolonged P40-latencies on right tibial nerve stimulation (57.8 ms). Serial (three times within 1 year) MRI investigations were performed at 1.5 T (Siemens Symphony, Erlangen, Germany; standard head coil) with axial T1-weighted spin echo and proton-density (pdw)-/T2-weighted fast spin echo and sagittal T1- weighted gradient-echo three-dimensional (3D) sequences. The right-sided hemorrhage (Fig. 1A) resolved within the next months leaving a hemosiderin-containing right posterior thalamic lesion (Fig. 1B, axial slice, T1-weighted spin echo sequence). There was no new lesion in the right hemisphere on subsequent cranial MRI investigations. After the new sensory impairment on his right side almost 2 years later MRI (Fig. 1C, D) showed a left hemispheric postcentral parietal ischemic infarction (5 £ 4 £ 5 cm) that involved

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Fig. 1. Brain images of the patient at two different intervals are shown: (A) at the time of the initial right thalamic hemorrhage (CCT), and (B–D), 2 years after the initial hemorrhage (MRI). The hemorrhage (A) resolved within the next months leaving a hemosiderin-containing right posterior thalamic lesion (B, axial slice, T1-weighted spin echo sequence). The parietal lesion, that abolished the central pain syndrome on the left side of the body, is shown in selected (non-contiguous) axial T1 images (C) and sagittal (D) T1-weighted gradient-echo 3D images: it involved the postcentral and supramarginal gyrus including primary (SI) and secondary somatosensory (SII) cortex at the parietal operculum in the upper bank of the Sylvian fissure. (C) Shows the horizontal extent of the parietal lesion, which did not involve the anterior cingulate gyrus. It did involve a small medial portion of the posterior insular cortex (C) and the external capsule but it spared the anterior insula, internal capsule and the left thalamus. The right thalamic lesion was unchanged to the previous MRI and there was no additional lesion on the right side. Abbreviations: Th, thalamus; SI, primary somatosensory cortex; SII, secondary somatosensory cortex; CS, central sulcus; pINS, posterior insular cortex.

the postcentral and supramarginal gyrus including the primary (SI) and secondary somatosensory (SII) cortex, the external capsule and a very small portion of the posterior insular cortex but it spared the anterior insula, anterior cingulum, internal capsule, motor cortex, and the left thalamus. Doppler and duplex sonography detected complete occlusion of the left medial cerebral artery as the most likely reason of an arterioarterial embolus causing this parietal infarction.

3. Discussion Based on the shortage of effective treatments for central pain syndromes we present for the first time that bilateral

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changes of activity in the thalamo-parietal circuits may effectively abolish central pain. Since parietal lesions themselves can elicit central pain syndromes (Peyron et al., 2000a), it is of particular interest that it was a contralateral parietal lesion that abolished central thalamic pain in our patient which might shed light into future strategies of brain stimulation. According to the structural lesion site, the time course and the quality of pain, this neuropathic pain in our patient can be classified as thalamic central pain syndrome (CPSP). CPSP is defined as a pain syndrome following a lesion or dysfunction of the CNS (Mersky and Bogduk, 1994). One of the important causes are vascular lesions (infarctions, hemorrhages). About 60% of all chronic post-stroke pain syndromes (CPSP) have lesions affecting the thalamus (Bowsher et al., 1998) that is typically located in the ventroposterior thalamus (VMpo) (Bogousslavsky et al., 1988), which was involved in our patient. This region receives particularly dense spinothalamic projections in primates (Boivie, 1979; Craig, 2000) and accordingly there is recent electrophysiological evidence from single cell recordings of thermosensitive and nociceptive neurons in the VMpo in humans (Lenz and Dougherty, 1998). However, spontaneous thalamic burst activity has not only been found in patients with chronic CPSP but also in non-pain patients (Radhakrishnan et al., 1999) indicating that this activity is not specifically related to pain. Clinically, most patients with CPSP in fact have spinothalamic lesions (Cassinari and Pagni, 1969; Bowsher et al., 1998; Pagni, 1998) and therefore most of them have sensory abnormalities, particularly in dorsolateral medullary infarction (Wallenberg’s syndrome, Fitzek et al., 2001) and posterolateral thalamic lesions (Bowsher et al., 1998) as in our patient. The latency that CPSP needs to develop usually takes weeks to months (three in our patient) and probably reflects regional neuronal plasticity or reorganization that has not been studied in detail yet. CPSP may disappear in some of the patients spontaneously but continues in most of the patients for many years (Boivie et al., 1999). 3.1. Pathomechanism of post-stroke thalamic pain syndromes Therefore, one of the possible pathomechanisms in the evolution of CPSP is thalamic sensory deafferentiation since the effective thalamic output from the ventrocaudal thalamus to the cortex is affected by somatosensory deafferentation in pain patients (Davis et al., 1996). Under normal conditions, sensory stimuli usually evoke inhibitory thalamic activity (Roberts et al., 1992), which, however, is particularly susceptible to pathological changes (Ralston et al., 1996). Consequently, numerous imaging studies have focussed on changes in thalamic activity in chronic neuropathic pain syndromes, with controversial results, ranging from hyper- (Cesaro et al., 1991; Peyron et al., 1998) to hypoactivity (Casey, 1999; Peyron et al., 2000b) contralat-

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eral to the affected limb. More recently, it has been suggested that pathological hypoactivity in the resting hemithalamus masks an underlying hyperresponsiveness to noxious stimulation (Casey, 2000). Thus, there are several lines of evidence for changes of thalamocortical processing of noxious information in CPSP patients. Possible explanations encompass (i) loss of lowthreshold mechanoreceptive thalamic neurons (reflecting a sensory-nociceptive imbalance) with subsequent increase of nociceptive neuronal output, (ii) reduced tonic inhibition of thalamic or cortical nociceptive neurons, and/or (iii) unmasking or strengthening of nociceptive pathways (Davis et al., 1996). Other hypotheses involve disruption of thermosensory integration and the loss of cold inhibition of burning pain (Craig, 1998), long term potentiation, and removal of inhibition on medial thalamic nuclei exerted by the reticular thalamic nucleus leading to hypersensitivity and spontaneous pain as has been shown with SPECT (Cesaro et al., 1991). These mechanisms have to be considered to explain the two different pain syndromes in our patient, i.e. spontaneous central pain and the severe thermo-allodynia, and their disappearance after the new contralesional parietal lesion. Evidence for a causal relationship comes from the time course of CPSP in our patient: with the onset of the left parietal lesion, there were severe sensory deficits on the right side of the body but both the thalamic spontaneous pain and allodynia on the left side of the body immediately disappeared. Severe impairment of SEPs over the left parietal lobe indicated the functional impairment of the somatosensory cortex. Over the following course of 2 months sensory impairment significantly improved and concomitantly CPSP on the left side redeveloped and increased again. Finally, apart from the parietal lesion there was no other new lesion which could explain the pain relief. The thalamic lesion in our patient involved the right VMpo but the anterior cingulum, ipsilateral primary motor cortex, parietal (SI and SII) and insular cortex were spared. However, thalamocortical fibers may have been disrupted. Apart from thalamocortical projections to SI and SII and the insular cortex, the medial and intralaminar thalamic nuclei send efferents to the ACC (Vogt and Pandya, 1987). In contrast to normal subjects, CPSP patients, e.g. with dorsolateral medullary (Peyron et al., 1998) or parietal lesions (Peyron et al., 2000a), do not show ACC activation, neither during spontaneous or allodynic pain nor during noxious stimuli. This reduced or absent ACC activation has been proposed to reflect CPSP since pain relief by deep brain stimulation has normalized the ACC response to noxious stimuli (Peyron et al., 2000b). The decreased ACC activation probably reflects increased inhibition of ACC, which is possibly elicited by a loss of inhibition of medial thalamic nuclei (Cesaro et al., 1991) by lesions of the inhibitory thalamic interneurons of the VMpo. Decreased ACC activation has also been found to be concomitant with amplified thalamic responses to innocuous stimuli and may clinically

explain allodynia (Peyron et al., 2000b). Thus, the parietal lesion in our patient may have temporarily altered the balance of bilateral thalamo-parietal circuits and possibly abolished central pain by changing the output to ACC. Evidence for this hypothesis should come from future imaging studies. 3.2. Bilateral mechanisms of neural circuits involved in pain perception: implications for brain stimulation Our current knowledge about bilateral activations following noxious or allodynic stimuli in normal subjects (Casey et al., 2001; Baron et al., 1999; Coghill et al., 1999) or patients with chronic neuropathic pain syndromes (Hsieh et al., 1995; May et al., 1998) has not been sufficiently considered in therapeutic strategies for CPSP, particularly in DBS. Up to now all therapeutic attempts of brain stimulation to treat CPSP have been focussed on ipsilateral brain stimulation, either thalamic (Tsubokawa et al., 1985), periventricular or periaqueductal DBS (Tasker and Vilela-Filho, 1995) or, more recently, motor cortex stimulation (Tsubokawa et al., 1991; Katayama et al., 1998; Garcia-Larrea et al., 1999). Specifically, apart from its effects on the thalamus, pain relief following electrical stimulation of the motor cortex is thought to be exerted largely by activation of the ACC, prefrontal cortex and upper brainstem but not via parietal somatosensory cortex stimulation (Garcia-Larrea et al., 1999). Stimulation of the parietal cortex has yet not been found to be effective in pain relief but rather elicits pain while excising the postcentral gyrus resulting in pain relief (Penfield and Jaspers, 1954; Erickson et al., 1952). Parietal cortex excitation may elicit contralateral painful sensations (Helmchen et al., 2000) but parietal lesions may also generate CPSP (Peyron et al., 2000a). Unlike the latter patient (Peyron et al., 2000a) the parietal lesion in our patient abolished a sustained CPSP due to a previous right thalamic lesion. There is one previous report on a patient with CPSP due to a left thalamic infarction that disappeared with a subsequent ipsilateral small ischemic lesion in the left corona radiata, interrupting the thalamo-parietal connections (Soria and Fine, 1991). Thus, not only ipsi- but also contra-lateral imbalance in thalamo-parietal circuits may be crucial for CPSP. The finding that pain relief was associated with a contralateral parietal lesion provides clinical support for experimental data that pain processing in the human brain during noxious stimulation in normal subjects is a bilateral, distributed mechanism (Coghill et al., 1999; Casey et al., 2001). There are several lines of evidence that not only contralateral but also ipsilateral nociception and thermesthesia are processed in a non-serial but parallel way in patients with parietal cortical lesions subserving different functions of pain-related perception and behavior independently (Knecht et al., 1996). Ipsilateral activation of pain-related areas has therefore been thought to represent a bilateral cortical representation of pain perception and there is increasing evidence

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from various neuropathic pain syndromes including CPSP that the hemisphere ipsilateral to the stimulation site is activated even stronger, e.g. in ipsilateral thalamus and SI (Peyron et al., 2000a; Ertl-Wagner et al., 2000). If plastic reorganization of somatosensory circuits underlies this activation it appears feasible that a parietal lesion ipsilateral to the affected body side abolishes CPSP as in our patient. The parietal lesion involved the postcentral and supramarginal gyrus including SI and SII but it clearly spared the ipsilateral left thalamus. Thus, the lesion of the left somatosensory cortex probably affected cortico-thalamic fibers and changed the balance of both thalamic relay nuclei and presumably their output to ACC. Finally, a small dorsomedial part of insular cortex was also lesioned. The insular cortex is crucially involved in the thermosensory integration but lesions usually elicit CPSP (Craig et al., 2000). Therefore we consider it unlikely that this quite medially located posterior insular lesion caused the pain relief in our patient. In conclusion, this unique example indicates that lesions affecting the bilateral balance of thalamo-parietal circuits may lead to pain relief in patients with CPSP which probably constitutes a bilateral disorder of functional plasticity which has to be taken into account in therapeutic brain stimulation. References Baron R, Baron Y, Disbrow E, Roberts TPL. Brain processing of capsaicininduced secondary hyperalgesia: a functional MRI study. Neurology 1999;54:548–557. Bogousslavsky J, Regli F, Uske A. Thalamic infarcts: clinical syndromes, etiology, and prognosis. Neurology 1988;38:837–848. Boivie J. An anatomical reinvestigation of the termination of the spinothalamic tract in the monkey. J Comp Neurol 1979;186:343–369. Boivie J. Central pain. In: Wall PD, Melzack R, editors. Textbook of pain, 4th ed.. London: Churchill Livingstone, 1999. pp. 879–912. Bowsher D, Leijon G, Thuomas KA. Central poststroke pain: correlation of MRI with clinical pain characteristics and sensory abnormalities. Neurology 1998;51:1352–1358. Casey KL. Forebrain mechanisms of nociception and pain: analysis through imaging. Proc Natl Acad Sci USA 1999;96:7668–7674. Casey KL. Concepts of pain mechanisms: the contribution of functional imaging of the human brain. In: Sandku¨ hler J, Bromm B, Gebhart GF, editors. Nervous system plasticity and chronic pain, Progress in brain research, 129. Amsterdam: Elsevier, 2000. pp. 277–288. Casey KL, Morrow TJ, Lorenz J, Minoshima S. Temporal and spatial dynamics of human forebrain activity during heat pain: analysis by positron emission tomography. J Neurophysiol 2001;85:951–959. Cassinari V, Pagni CA. Central pain. A neurosurgical survey, . Cambridge, MA: Harvard University Press, 1969 p. 1–192. Cesaro P, Mann MW, Moretti JL, Defer G, Roualdes B, Nguyen JP, Degos JD. Central pain and thalamic hyperactivity: a single photon emission computerized tomographic study. Pain 1991;47:329–336. Coghill RC, Sang CN, Maisog JM, Iadarola MJ. Pain intensity processing within the human brain: a bilateral, distributed mechanism. J Neurophysiol 1999;82:1934–1943. Craig AD. A new version of the thalamic disinhibition hypothesis of central pain. Pain Forum 1998;7:1–14. Craig AD. The functional anatomy of lamina I and its role in post-stroke central pain. In: Sandku¨ hler J, Bromm B, Gebhart GF, editors. Nervous

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