Dynamic posturography and posturographic training for Parkinson's disease in a routine clinical setting.

BACKGROUND: Postural instability in Parkinson's disease (PD) often is ill-responsive to drugs and DBS. Physiotherapy is recommended but practicability and cost effectiveness are debatable. RESEARCH QUESTION: Can a simple 'plug and play' posturography system produce clinically meaningful measures and elicit postural motor learning in PD patients? METHODS: 40 moderately affected PD patients in a general neurology outpatient clinic who complained of postural instability were included to practice shifts and stabilization of the center of pressure (COP) in a low intensity (once weekly 20-25 minutes over 6 weeks) dynamic posturographic training using the Biodex balance systemTM. Average deviations from mean COP position and from the center of the base of support (BOS) with different degrees of visual feedback in static and dynamic posturographic tasks other than the training tasks, the Berg-Balance-Scale (BBS) and patient self-ratings (FES-I, ABC scale) were assessed before and after training. RESULTS: Posturographic performance was significantly better with eyes open than closed and more so with explicit visual feedback of COP position (p < 0.005). Only with this latter type of feedback and only the deviation form the BOS in dynamic and static posturography was significantly correlated with BBS and UPDRS III (p < 0.001). The deviation from the BOS under explicit visual feedback significantly improved after training (p < 0.005) whereas BBS, FES-I and ABC-scale did not. SIGNIFICANCE: Our posturography procedures were well applicable as a routine clinical tool. They yielded clinically valid measures when COP position was visible and directional shifts from the BOS centre were quantified. Our training was effective for this posturographic measure only. Its significance as a predictor for clinical efficacy of higher intensity and longer term training schedules is hypothesized and warrants further studies.

Neuroimaging Of Cold Allodynia Reveals A Central Disinhibition Mechanism Of Pain.

PURPOSE: Allodynia refers to pain evoked by physiologically innocuous stimuli. It is a disabling symptom of neuropathic pain following a lesion within the peripheral or central nervous system. In fact, two different pathophysiological mechanisms of cold allodynia (ie, hypersensitivity to innocuous cold) have been proposed. The peripheral sensitization of nociceptive neurons can produce cold allodynia, which can be induced experimentally by a topical application of menthol. An alternative mechanism involves reduced inhibition of central pain processing by innocuous cold stimuli. A model to induce the latter type of allodynia is the conduction block of peripheral A-fiber input. PATIENTS AND METHODS: In the presented study, functional MRI was used to analyze these two different experimental models of cold allodynia. In order to identify the underlying cerebral activation patterns of both mechanisms, the application of menthol and the induction of a mechanical A-fiber blockade were studied in healthy volunteers. RESULTS: The block-induced cold allodynia caused significantly stronger activation of the medial polymodal pain processing pathway, including left medial thalamus, anterior cingulate cortex, and medial prefrontal cortex. In contrast, menthol-induced cold allodynia caused significantly stronger activity of the left lateral thalamus as well as the primary and secondary somatosensory cortices, key structures of the lateral discriminative pathway of pain processing. Mean pain intensity did not differ between both forms of cold allodynia. CONCLUSION: Experimental cold allodynia is mediated in different cerebral areas depending on the underlying pathophysiology. The activity pattern associated with block-induced allodynia confirms a fundamental integration between painful and non-painful temperature sensation, ie, the cold-induced inhibition of cold pain.

Sensitized vasoactive C-nociceptors: key fibers in peripheral neuropathic pain.

INTRODUCTION: Multiple mechanisms are involved in the development and persistence of neuropathic pain. Some patients with nerve damage will remain painless and develop a "loss of function" phenotype, whereas others develop painful neuropathies. OBJECTIVES: The aim of this study is to investigate the role of a peripheral nervous system sensitization by analyzing patients with and without pain. METHODS: The topical application of capsaicin was investigated in peripheral nociceptors. Two groups of patients (painful vs painless) with length-dependent neuropathies and small-fiber impairment were tested. Quantitative sensory testing was assessed before and after topical application of 0.6% capsaicin in the affected skin. In addition, blood perfusion measurements and an axon reflex flare assessment were performed. RESULTS: Quantitative testing revealed that heat hyperalgesia was induced in all patients and volunteers (P < 0.01) without observing any significant differences between patient groups. By contrast, the extent of the axon reflex flare reaction (P < 0.01) as well as the blood perfusion (P < 0.05) was significantly greater in patients with pain than in neuropathy patients not experiencing pain. CONCLUSION: Hyperexcitable vasoactive nociceptive C fibers might contribute to pain in peripheral neuropathies and therefore may serve as a key player in separating into a painless or painful condition.

Short Report: TRPV1-polymorphism 1911 A>G alters capsaicin-induced sensory changes in healthy subjects.

BACKGROUND: C-fibers express transient receptor potential (TRP) channels. These high-voltage gated channels function as integrators of different physical stresses (e.g. heat, protons, ATP). Additionally channel activation can be induced by capsaicin. Topically applied, capsaicin elicits burning pain, heat and mechanical hyperalgesia and serves as a human surrogate model for pain. It was suggested that the TRPV1-variant rs8065080 (1911A>G) plays a pivotal role in patients with neuropathic pain syndromes. We investigated the effect of this TRPV1-SNP on thermal sensitivity and superficial skin perfusion in 25 healthy subjects. METHODS AND FINDINGS: Nine subjects being homozygous TRPV1 wild type (AA), 8 heterozygous (AG) and 8 homozygous variant (GG) carriers were selected out of a pool of genotyped healthy individuals. Under physiological conditions (no capsaicin application), there was no statistical significant difference in thermal thresholds or skin perfusion between carriers of different TRPV1 1199A>G genotypes. However, intra-individual calculations (Δ% pre vs. post capsaicin) revealed (1) less warm-detection in AA/AG (-82.1%) compared to GG (-13.1%) and (2) a gain of heat pain sensitivity in AA/AG (+22.2%) compared to GG carriers (+15.6%) after adjustment for perfusion measurements ((1)p = 0.009, (2)p = 0.021). CONCLUSION: Presence of homozygous variant TRPV1 genotype (GG) demonstrated less capsaicin-induced warm hypoesthesia in warm-detection and less capsaicin-induced heat pain sensitivity suggesting an altered channel function. This demonstrates not only the functional influence of TRPV1 rs8065080 polymorphism itself; it further more underpins the relevance of genotyping-based approaches in both patients and surrogate models of neuropathic pain in healthy volunteers.

Harlequin Syndrome After Thoracic Paravertebral Block.

Harlequin syndrome is characterized by the sudden onset of unilateral facial flushing and sweating, often preceded by exercise, excessive heat, or, rarely, regional anesthesia. Although the exact mechanism remains unclear, it is often referred to as transient or permanent interruption of the sympathetic nervous system. We present a case of Harlequin syndrome without Horner syndrome in a patient with unilateral right-sided facial flushing that started shortly after a left-sided thoracic paravertebral nerve block for a mastectomy. We discuss the interruption of the sympathetic and parasympathetic nervous system and the levels of spinal nerve block associated with a thoracic paravertebral nerve block.

Somatotopic mismatch of hand representation following stroke: is recovery possible?

Well-organized somatotopic representation of the hand is required to interpret input from cutaneous mechanoreceptors. Previous reports have identified patients with various distortions of somatotopic representation after stroke. Importantly, those patients were investigated years after the stroke, indicating that afferent signal regained access to the cortical circuits; however, further plastic changes, which would re-establish somatotopic order and ability to correctly localize tactile stimuli, did not follow. Thus, it was not known whether somatotopic organization could be restored in such patients and whether there is a potential for new rehabilitation strategies. This is the first case report demonstrating normalization of somatotopic representation.

Local anaesthetic sympathetic blockade for complex regional pain syndrome.

BACKGROUND: This is an update of the original Cochrane review published in The Cochrane Library, 2005, Issue 4, on local anaesthetic blockade (LASB) of the sympathetic chain used to treat complex regional pain syndrome (CRPS). OBJECTIVES: To assess the efficacy of LASB for the treatment of pain in CRPS and to evaluate the incidence of adverse effects of the procedure. SEARCH METHODS: We updated searches of the Cochrane Pain, Palliative and Supportive Care Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) on the Cochrane Library (Issue 11 of 12, 2012), MEDLINE (1966 to 22/11/12), EMBASE (1974 to 22/11/12), LILACS (1982 to 22/11/12), conference abstracts of the World Congresses of the International Association for the Study of Pain (1995 to 2010), and various clinical trial registers (inception to 2012). We also searched bibliographies from retrieved articles for additional studies. SELECTION CRITERIA: We considered for inclusion randomised controlled trials (RCTs) that evaluated the effect of sympathetic blockade with local anaesthetics in children or adults with CRPS. DATA COLLECTION AND ANALYSIS: The outcomes of interest were reduction in pain intensity levels, the proportion who achieved moderate or substantial pain relief, the duration of pain relief, and the presence of adverse effects in each treatment arm. MAIN RESULTS: We included an additional 10 studies (combined n = 363) in this update. Overall we include 12 studies (combined n = 386). All included studies were assessed to be at high or unclear risk of bias.Three small studies compared LASB to placebo/sham. We were able to pool the results from two of these trials (intervention n = 23). Pooling did not demonstrate significant short-term benefit for LASB (in terms of the risk of a 50% reduction of pain scores).Of two studies that investigated LASB as an addition to rehabilitation treatment, the only study that reported pain outcomes demonstrated no additional benefit from LASB.Eight small randomised studies compared sympathetic blockade to another active intervention. Most studies found no difference in pain outcomes between sympathetic block and other active treatments.Only five studies reported adverse effects, all with minor effects reported. AUTHORS' CONCLUSIONS: This update has found similar results to the original systematic review. There remains a scarcity of published evidence to support the use of local anaesthetic sympathetic blockade for CRPS. From the existing evidence it is not possible to draw firm conclusions regarding the efficacy or safety of this intervention but the limited data available do not suggest that LASB is effective for reducing pain in CRPS.

Cutaneous noradrenaline measured by microdialysis in complex regional pain syndrome during whole-body cooling and heating.

Complex regional pain syndrome (CRPS) is characterised by autonomic, sensory, and motor disturbances. The underlying mechanisms of the autonomic changes in CPRS are unknown. However, it has been postulated that sympathetic inhibition in the acute phase with locally reduced levels of noradrenaline is followed by an up-regulation of alpha-adrenoceptors in chronic CRPS leading to denervation supersensitivity to catecholamines. This exploratory study examined the effect of cutaneous sympathetic activation and inhibition on cutaneous noradrenaline release, vascular reactivity, and pain in CRPS patients and in healthy volunteers. Seven patients and nine controls completed whole-body cooling (sympathetic activation) and heating (sympathetic inhibition) induced by a whole-body thermal suit with simultaneous measurement of the skin temperature, skin blood flow, and release of dermal noradrenaline. CRPS pain and the perceived skin temperature were measured every 5 min during thermal exposure, while noradrenaline was determined from cutaneous microdialysate collected every 20 min throughout the study period. Cooling induced peripheral sympathetic activation in patients and controls with significant increases in dermal noradrenaline, vasoconstriction, and reduction in skin temperature. The main findings were that the noradrenaline response did not differ between patients and controls or between the CRPS hand and the contralateral unaffected hand, suggesting that the evoked noradrenaline release from the cutaneous sympathetic postganglionic fibres is preserved in chronic CRPS patients.

Somatotopic mismatch following stroke: a pathophysiological condition escaping detection.

Clinical evaluation of somatosensory deficits in stroke patients is very limited and usually does not include testing of somatotopic organisation, which is a prerequisite for meaningful interpretation of sensory input and sensorimotor control. Detailed tactile testing of the left hand of a 54-year-old patient suffering from sensory deficit and central pain after a right-sided stroke revealed severe distortion of somatotopic sensory maps as evidenced by incorrect localisation of the point stimuli. Unlike previously reported gross somatotopic remapping taking place within reduced representational space after lesion, this is the first case report revealing chaotic scrambled somatosensory maps. While the incidence of such scrambled somatotopic representation of tactile input is not yet known in stroke patients, current observations indicate that in-depth investigations of somatotopic organisation of affected area may reveal the underlying cause for various functional deficits including central pain. Thus, new rehabilitation strategies may need to be developed specifically for such patients.

A case of pain, motor impairment, and swelling of the arm after acute herpes zoster infection.

Complex regional pain syndrome (CRPS) and postherpetic neuralgia (PHN) represent neuropathic pain syndromes that may appear with similar clinical signs and symptoms. Medical history and clinical distribution of symptoms and signs (PHN typically at the thorax; CRPS typically at the limbs) is obvious in most cases, helping to discriminate between both disorders. Here, we present a patient suffering from CRPS II following PHN of one upper extremity. This case demonstrates that both etiology and part of the body affected by a neuropathy influence the pain phenotype.

Pains in Parkinson disease--many syndromes under one umbrella.

Pain is a nonmotor symptom that substantially affects the quality of life of at least one-third of patients with Parkinson disease (PD). Interestingly, patients with PD frequently report different types of pain, and a successful approach to distinguish between these pains is required so that effective treatment strategies can be established. Differences between these pains are attributable to varying peripheral pain mechanisms, the role of motor symptoms in causing or amplifying pain, and the role of PD pathophysiology in pain processing. In this Review, we propose a four-tier taxonomy to improve classification of pain in PD. This taxonomy assigns nociceptive, neuropathic and miscellaneous pains to distinct categories, as well as further characterization into subcategories. Currently, treatment of pain in PD is based on empirical data only, owing to a lack of controlled studies. The facultative symptom of 'dopaminergically maintained pain' refers to pain that benefits from antiparkinson medication. Here, we also present additional pharmacological and nonpharmacological treatment approaches, which can be targeted to a specific pain following classification using our taxonomy.

Topical high-concentration (40%) menthol-somatosensory profile of a human surrogate pain model.

UNLABELLED: Cold hyperalgesia is 1 of the characteristic signs in neuropathic pain. Topical application of menthol has been proposed as model to study cold hyperalgesia. The aim of this psychophysical study was to characterize the human surrogate of neuropathic pain of topical menthol application by using a standardized and validated protocol of quantitative sensory testing (QST). Additionally, we assessed the course of the signs elicited by menthol application over time. High-concentration 40% L-menthol was applied topically on hairy skin in 12 healthy subjects. Standardized psychophysical tests (QST) assessing 13 parameters including thermal and mechanical detection and pain thresholds were obtained before and every 45 minutes after menthol removal up to 4 hours after menthol application. Menthol decreased the cold pain threshold, mechanical pain threshold, and increased the mechanical pain sensitivity in all subjects displaying cold and mechanical pinprick hyperalgesia. In all subjects, an area of secondary pinprick hyperalgesia could be determined. Within the observation time, the decreased cold pain threshold increased continuously, whereas the signs of primary and secondary pinprick hyperalgesia remained stable. The data suggest that topical 40% menthol application is a useful model for studies of cold hyperalgesia and pinprick hyperalgesia in humans. PERSPECTIVE: This study establishes the topical application of high-concentration 40% menthol as a useful stable model for studies of cold hyperalgesia and pinprick hyperalgesia in humans. The provided long-term data are important for psychophysical and pharmacological research in humans and provide us with insights on experimental cold and mechanical hyperalgesia.

Transient receptor potential channel polymorphisms are associated with the somatosensory function in neuropathic pain patients.

Transient receptor potential channels are important mediators of thermal and mechanical stimuli and play an important role in neuropathic pain. The contribution of hereditary variants in the genes of transient receptor potential channels to neuropathic pain is unknown. We investigated the frequency of transient receptor potential ankyrin 1, transient receptor potential melastin 8 and transient receptor potential vanilloid 1 single nucleotide polymorphisms and their impact on somatosensory abnormalities in neuropathic pain patients. Within the German Research Network on Neuropathic Pain (Deutscher Forscbungsverbund Neuropathischer Schmerz) 371 neuropathic pain patients were phenotypically characterized using standardized quantitative sensory testing. Pyrosequencing was employed to determine a total of eleven single nucleotide polymorphisms in transient receptor potential channel genes of the neuropathic pain patients and a cohort of 253 German healthy volunteers. Associations of quantitative sensory testing parameters and single nucleotide polymorphisms between and within groups and subgroups, based on sensory phenotypes, were analyzed. Single nucleotide polymorphisms frequencies did not differ between both the cohorts. However, in neuropathic pain patients transient receptor potential ankyrin 1 710G>A (rs920829, E179K) was associated with the presence of paradoxical heat sensation (p = 0.03), and transient receptor potential vanilloid 1 1911A>G (rs8065080, I585V) with cold hypoalgesia (p = 0.0035). Two main subgroups characterized by preserved (1) and impaired (2) sensory function were identified. In subgroup 1 transient receptor potential vanilloid 1 1911A>G led to significantly less heat hyperalgesia, pinprick hyperalgesia and mechanical hypaesthesia (p = 0.006, p = 0.005 and p<0.001) and transient receptor potential vanilloid 1 1103C>G (rs222747, M315I) to cold hypaesthesia (p = 0.002), but there was absence of associations in subgroup 2. In this study we found no evidence that genetic variants of transient receptor potential channels are involved in the expression of neuropathic pain, but transient receptor potential channel polymorphisms contributed significantly to the somatosensory abnormalities of neuropathic pain patients.

Central pain syndromes.

Central pain is a chronic neuropathic pain disorder that develops as a direct consequence of a lesion within the central nervous system. The most common causes for central pain are vascular lesions to the brain and the spinal cord, multiple sclerosis, and spinal cord injury. Clinically, central pain typically develops with a delay after the lesion. The pain typically is localized in an area of abnormal sensitivity corresponding to the preceding central lesion. Spontaneous pain and also evoked pains can be found. Pathophysiologically, ectopic neural activity and hyperexcitability are driven by pathological facilitatory and disinhibitory processes. In addition to medical history and clinical examination, diagnosis of central pain is based on imaging and electrophysiological techniques, including quantitative sensory testing, to confirm a central lesion and for identification of the underlying disease. Management of central pain mainly based on pharmacological treatment still is a great challenge, but evidence points to efficacy of antidepressants, anticonvulsants, and opioids.

Vasomotor disturbances in complex regional pain syndrome--a review.

Complex regional pain syndromes (CRPS) are characterized by vascular disturbances primary affecting the microcirculation in the distal part of the involved extremity. In the acute stage inhibited sympathetic vasoconstriction and exaggerated neurogenic inflammation driven by central and peripheral mechanisms, respectively, seem to be the major pathophysiological mechanisms inducing vasodilation. During the chronic course of the disease as well as early in some patients vasoconstriction dominates the clinical picture induced by changes in the microcirculation itself such as endothelial dysfunction or vascular hyperreactivity, whereas sympathetic vasoconstrictor activity returns and neurogenic inflammation is less severe. It can be suggested that the interaction between different mechanisms underlying vasomotor disturbances as well as the severity of each single mechanism in the individual patient have a great impact on the variety of the overall clinical picture in CRPS. Irrespective of the underlying pathophysiology, measurements of skin temperature differences between the affected and the contralateral extremity can serve as a diagnostic tool in CRPS, in particular when sensitivity and specificity is increased by considering dynamic alterations in skin temperature asymmetries.

Neuropathic pain: diagnosis, pathophysiological mechanisms, and treatment.

Neuropathic pain develops as a result of lesions or disease affecting the somatosensory nervous system either in the periphery or centrally. Examples of neuropathic pain include painful polyneuropathy, postherpetic neuralgia, trigeminal neuralgia, and post-stroke pain. Clinically, neuropathic pain is characterised by spontaneous ongoing or shooting pain and evoked amplified pain responses after noxious or non-noxious stimuli. Methods such as questionnaires for screening and assessment focus on the presence and quality of neuropathic pain. Basic research is enabling the identification of different pathophysiological mechanisms, and clinical assessment of symptoms and signs can help to determine which mechanisms are involved in specific neuropathic pain disorders. Management of neuropathic pain requires an interdisciplinary approach, centred around pharmacological treatment. A better understanding of neuropathic pain and, in particular, of the translation of pathophysiological mechanisms into sensory signs will lead to a more effective and specific mechanism-based treatment approach.

Influence of deep brain stimulation and levodopa on sensory signs in Parkinson's disease.

To examine the effects of levodopa (L-dopa) and deep brain stimulation of the subthalamic nucleus (STN-DBS) on sensory symptoms and signs in Parkinson's disease (PD). Seventeen patients with PD were included. (1) Presence of sensory symptoms and (2) effects of L-dopa and STN-DBS on sensory symptoms and signs [assessed by quantitative sensory testing (QST)] were examined 6 months after starting STN-DBS. In addition, in 12 of these patients, presence of sensory symptoms prior and post STN-DBS was compared. Pain was most frequently nociceptive. In about 30-40%, pain and sensory symptoms were associated with PD motor symptoms. In most of these cases, pain responded to L-dopa. Intensity of pain was reduced post STN-DBS compared to pre STN-DBS. L-Dopa had no influence on detection thresholds, whereas STN-DBS improved thermal detection thresholds. However, thermal and mechanical pain thresholds were uninfluenced by L-dopa or STN-DBS. Although some patients reported an improvement of pain with STN-DBS or L-dopa, objectively pain sensitivity as assessed by QST was not altered by STN-DBS or L-dopa suggesting that there is no evidence for a direct modulation of central pain processing by L-dopa or STN-DBS.

Role of sympathetic nervous system in activity-induced cerebral perfusion.

Several studies have suggested that autonomic neural control plays a role in regulation of cerebral blood flow (CBF), although the exact role of the sympathetic nervous system on CBF remains debated. The effects of sympathetic innervation on activity-induced cerebral perfusion changes in humans have not been studied. The aims of this study were therefore (a) to investigate patients with an "intrinsic" sympathetic deficit after stroke and healthy controls with regard to activity-induced cerebral perfusion changes, and (b) to investigate possible differences in functional CBF regulation between the anterior and posterior circulation. Cerebral blood flow velocity in the medial cerebral artery (MCA) and posterior cerebral artery (PCA) was investigated in 21 healthy controls and 17 patients with Wallenberg's syndrome using transcranial Doppler sonography during cortical activation of MCA and PCA territories, respectively. Patients with a central sympathetic deficit had a prolonged decrease of resistance in the MCA and showed a slower and less pronounced decrease of resistance in the PCA upon cortical activation. No difference was observed between the side with and without sympathetic deficit. Results suggest that (a) sympathetic efferents are involved in economisation of activity-induced changes of cerebral perfusion in the anterior circulation, (b) activity-induced sympathetic regulation of blood flow differs between the anterior and posterior vascular territories in humans and (c) a possible resting sympathetic tonus on extraparenchymal vessel might exist in the posterior circulation.