B. Neundörfer

Patterns of cortical reorganization in complex regional pain syndrome

Objective: To use magnetoencephalography to assess possible cortical reorganization in the primary somatosensory cortex (S1) of patients with complex regional pain syndrome (CRPS). Background: Patterns of pain and sensory symptoms in CRPS may indicate plastic changes of the CNS. Methods: Magnetic source imaging was used to explore changes in the cortical representation of digits (D) 1 and 5 in relation to the lower lip on the unaffected and affected CRPS side in 12 patients. Results: The authors found a significant shrinkage of the extension of the cortical hand representation for the CRPS affected side. The center of the hand was shifted toward the cortical representation of the lip. The cortical reorganization correlated with the amount of CRPS pain (r = 0.792), as measured by the McGill questionnaire, and the extent of mechanical hyperalgesia (r = 0.860). Using multiple regression analysis, the best predictor for the plastic changes was found to be mechanical hyperalgesia. Additionally, S1 sources following tactile stimulation were significantly increased on the CRPS side compared to the unaffected limb. Conclusions: This study showed reorganization of the S1 cortex contralateral to the CRPS affected side. The reorganization appeared to be linked to complaints of neuropathic pain.

Cortical reorganization during recovery from complex regional pain syndrome

Objective: To characterize reorganization of the primary somatosensory cortex (S1) during healing process in complex regional pain syndrome (CRPS). Background: Recently, the authors showed extensive reorganization of the S1 cortex contralateral to the CRPS affected side. Predictors for these plastic changes were CRPS pain and the extent of mechanical hyperalgesia. It is unclear how these S1 changes develop following successful therapy. Methods: The authors used magnetic source imaging to explore changes in the cortical representation of digits (D) 1 and 5 in relation to the lower lip on the unaffected and affected CRPS side in 10 patients during a year or more of follow-up. Results: Cortical reorganization reversed coincident with clinical improvement. A reduction of CRPS pain correlated with recovery from cortical reorganization. Conclusions: Changes of the somatotopic map within the S1 cortex may depend on CRPS pain and its recovery.

Facilitated neurogenic inflammation in complex regional pain syndrome

&NA; Complex regional pain syndrome (CRPS) is characterized by a variety of clinical features including spontaneous pain and hyperalgesia. Increased neuropeptide release from peripheral nociceptors has been suggested as a possible pathophysiologic mechanism triggering the combination of trophic changes, edema, vasodilatation and pain. In order to verify the increased neuropeptide release in CRPS, electrically induced neurogenic vasodilatation and protein extravasation were evaluated in patients and controls. We performed a prospective study on 10 patients with acute and untreated CRPS and 10 matched healthy controls. Neurogenic inflammation was elicited by strong transcutaneous electrical stimulation via intradermal microdialysis capillaries which simultaneously enabled measurement of protein extravasation. Laser‐Doppler scanning was used to assess axon reflex vasodilatation. Axon reflex vasodilatation was significantly increased in CRPS patients (438±68% of baseline vs. 306±52%; P<0.05) and transcutaneous electrical stimulation provoked protein extravasation only in the patients (before, 0.28±0.03 mg/ml; during stimulation, 0.34±0.04 mg/ml), whereas protein concentration steadily declined during stimulation in the healthy controls (before, 0.23±0.04 mg/ml; during stimulation, 0.18±0.04; P<0.001). The time course of electrically induced protein extravasation in the patients resembled the one observed following application of exogenous substance P (SP). We conclude that neurogenic inflammation is facilitated in CRPS. Our results suggest an increased releasability of neuropeptides in CRPS.

Loss of pain perception in diabetes is dependent on a receptor of the immunoglobulin superfamily

Molecular events that result in loss of pain perception are poorly understood in diabetic neuropathy. Our results show that the receptor for advanced glycation end products (RAGE), a receptor associated with sustained NF-kappaB activation in the diabetic microenvironment, has a central role in sensory neuronal dysfunction. In sural nerve biopsies, ligands of RAGE, the receptor itself, activated NF-kappaBp65, and IL-6 colocalized in the microvasculature of patients with diabetic neuropathy. Activation of NF-kappaB and NF-kappaB-dependent gene expression was upregulated in peripheral nerves of diabetic mice, induced by advanced glycation end products, and prevented by RAGE blockade. NF-kappaB activation was blunted in RAGE-null (RAGE(-/-)) mice compared with robust enhancement in strain-matched controls, even 6 months after diabetes induction. Loss of pain perception, indicative of long-standing diabetic neuropathy, was reversed in WT mice treated with soluble RAGE. Most importantly, loss of pain perception was largely prevented in RAGE(-/-) mice, although they were not protected from diabetes-induced loss of PGP9.5-positive plantar nerve fibers. These data demonstrate, for the first time to our knowledge, that the RAGE-NF-kappaB axis operates in diabetic neuropathy, by mediating functional sensory deficits, and that its inhibition may provide new therapeutic approaches.

Lifetime Cost of Ischemic Stroke in Germany: Results and National Projections From a Population-Based Stroke Registry The Erlangen Stroke Project

Background and Purpose— The number of stroke patients and the healthcare costs of strokes are expected to rise. The objective of this study was to determine the direct costs of first ischemic stroke and to estimate the expected increase in costs in Germany. Methods— An incidence-based, bottom-up, direct-cost-of-ischemic-stroke study from the third-party payer’s perspective was performed, incorporating 10-year survival data and 5-year resource use data from the Erlangen Stroke Registry. Discounted lifetime year 2004 costs per case were obtained and applied to the expected age and sex evolution of the German resident population in the period 2006 to 2025. Results— The overall cost per first-year survivor of first-ever ischemic stroke was estimated to be 18 517 euros (EUR). Rehabilitation accounted for 37% of this cost, whereas in subsequent years outpatient care was the major cost driver. Discounted lifetime cost per case was 43 129 EUR overall and was higher in men (45 549 EUR) than in women (41 304 EUR). National projections for the period 2006 to 2025 showed 1.5 million and 1.9 million new cases of ischemic stroke in men and women, respectively, at a present value of 51.5 and 57.1 billion EUR, respectively. Conclusions— The number of stroke patients and the healthcare costs of strokes in Germany will rise continuously until the year 2025. Therefore, stroke prevention and reduction of stroke-related disability should be made priorities in health planning policies.

Differentiation of Parkinson's disease and multiple system atrophy in early disease stages by means of I-123-MIBG-SPECT

BACKGROUND Differential diagnosis between idiopathic Parkinsons disease (PD) and multiple system atrophy (MSA) is often difficult in early disease stages. Since MSA is misdiagnosed as PD in more than 20% of the early stages, there is need for methods refining the differentiation of the two disease entities. In PD postganglionic involvement of the autonomic nervous system (ANS) predominates whereas in MSA the ANS is mainly affected in its preganglionic structures. The functional integrity of postganglionic cardiac sympathetic neurons can be investigated using I-123-metaiodobenzylguanidine-single photon emission computed tomography (MIBG-SPECT). OBJECTIVES We investigated whether I-123-MIBG-SPECT allows to differentiate between early stages of PD and MSA in patients not yet requiring L-dopa therapy. METHODS Thirty patients (10 PD and 20 MSA patients) underwent MIBG-SPECT and evaluation of heart rate variability (HRV). Patients on any medication interfering with MIBG-accumulation were excluded from the study. Cardiac perfusion was evaluated by myocardial scintigraphy. RESULTS The median cardiac MIBG uptake was significantly decreased in PD as well as MSA patients compared to controls (P<0.001). However, in the PD group MIBG uptake was significantly lower than in MSA (P=0.03). Even in PD patients without clinical signs of autonomic failure, MIBG uptake was significantly lower than in MSA patients (P=0.03). Analysis of heart rate parameters did not differentiate between PD and MSA patients. The median coefficient of variation was significantly smaller in PD and MSA patients compared to control subjects. CONCLUSIONS Our study shows that MIBG-SPECT identifies autonomic cardiac dysfunction in very early stages of both, PD and MSA. More importantly, the technique facilitates differentiation of MSA and PD in the early stages. The different pathology with prominent peripheral, postganglionic sympathetic dysfunction in PD and primarily central and preganglionic lesions in MSA accounts for a lower MIBG uptake in PD compared to MSA patients.

Brain processing during mechanical hyperalgesia in complex regional pain syndrome: a functional MRI study

&NA; Complex Regional Pain Syndromes (CRPS) are characterized by a triad of sensory, motor and autonomic dysfunctions of still unknown origin. Pain and mechanical hyperalgesia are hallmarks of CRPS. There are several lines of evidence that central nervous system (CNS) changes are crucial for the development and maintenance of mechanical hyperalgesia. However, little is known about the cortical structures associated with the processing of hyperalgesia in pain patients. This study describes the use of functional magnetic resonance imaging (fMRI) to delineate brain activations during pin‐prick hyperalgesia in CRPS. Twelve patients, in whom previous quantitative sensory testing revealed the presence of hyperalgesia to punctuate mechanical stimuli (i.e. pin‐prick hyperalgesia), were included in the study. Pin‐prick‐hyperalgesia was elicited by von‐Frey filaments at the affected limb. For control, the identical stimulation was performed on the unaffected limb. fMRI was used to explore the corresponding cortical activations. Mechanical stimulation at the unaffected limb was non‐painful and mainly led to an activation of the contralateral primary somatosensory cortex (S1), insula and bilateral secondary somatosensory cortices (S2). The stimulation of the affected limb was painful (mechanical hyperalgesia) and led to a significantly increased activation of the S1 cortex (contralateral), S2 (bilateral), insula (bilateral), associative‐somatosensory cortices (contralateral), frontal cortices and parts of the anterior cingulate cortex. The results of our study indicate a complex cortical network activated during pin‐prick hyperalgesia in CRPS. The underlying neuronal matrix comprises areas not only involved in nociceptive, but also in cognitive and motor processing.

Neurologic manifestations of cerebral air embolism as a complication of central venous catheterization.

Objective, Patients, and Methods: A severe case of cerebral air embolism after unintentional central venous catheter disconnection was the impetus for a systematic literature review (1975‐1998) of the clinical features of 26 patients (including our patient) with cerebral air embolism resulting from central venous catheter complications. Results: The jugular vein had been punctured in eight patients and the subclavian vein, in 12 patients. Embolism occurred in four patients during insertion, in 14 patients during unintentional disconnection, and in eight patients after removal and other procedures. The total mortality rate was 23%. Two types of neurologic manifestations may be distinguished: group A (n = 14) presented with encephalopathic features leading to a high mortality rate (36%); and group B (n = 12) presented with focal cerebral lesions resulting in hemiparesis or hemianopia affecting mostly the right hemisphere, with a mortality rate as high as 8%. In 75% of patients, an early computed tomography indicated air bubbles, proving cerebral air embolism. Hyperbaric oxygen therapy was performed in only three patients (12%). A cardiac defect, such as a patent foramen ovale was considered the route of right to left shunting in 6 of 15 patients (40%). More often, a pulmonary shunt was assumed (9 of 15 patients; 60%). For the remainder, data were not available. Conclusion: When caring for critically ill patients needing central venous catheterization, nursing staff and physicians should be aware of this potentially lethal complication.

Telemedicine in Emergency Evaluation of Acute Stroke: Interrater Agreement in Remote Video Examination With a Novel Multimedia System

Background and Purpose— In acute stroke care, rapid but careful evaluation of patients is mandatory but requires an experienced stroke neurologist. Telemedicine offers the possibility of bringing such expertise quickly to more patients. This study tested for the first time whether remote video examination is feasible and reliable when applied in emergency stroke care using the National Institutes of Health Stroke Scale (NIHSS). Methods— We used a novel multimedia telesupport system for transfer of real-time video sequences and audio data. The remote examiner could direct the set-top camera and zoom from distant overviews to close-ups from the personal computer in his office. Acute stroke patients admitted to our stroke unit were examined on admission in the emergency room. Standardized examination was performed by use of the NIHSS (German version) via telemedicine and compared with bedside application. Results— In this pilot study, 41 patients were examined. Total examination time was 11.4 minutes on average (range, 8 to 18 minutes). None of the examinations had to be stopped or interrupted for technical reasons, although minor problems (brightness, audio quality) with influence on the examination process occurred in 2 sessions. Unweighted &kgr; coefficients ranged from 0.44 to 0.89; weighted &kgr; coefficients, from 0.85 to 0.99. Conclusions— Remote examination of acute stroke patients with a computer-based telesupport system is feasible and reliable when applied in the emergency room; interrater agreement was good to excellent in all items. For more widespread use, some problems that emerge from details like brightness, optimal camera position, and audio quality should be solved.

Normative values of vibratory perception in 530 children, juveniles and adults aged 3–79 years

Impaired vibratory perception is an early and frequent finding in various neuropathies. Quantitative vibratory threshold assessment refines the diagnosis of neuropathies but is based on psychophysical techniques requiring patient cooperation. Large, age and sex matched normative data bases are needed to better identify abnormal vibratory perception. In this study vibratory perception was tested at the second metacarpal bone and above the first metatarsal bone of 530 children, juveniles and adults aged 3.3-79.2 years. Thresholds assessed with a 128 Hz graded Rydel-Seiffer tuning fork, TF, were compared to three Vibrameter values, the vibration perception thresholds, VPT, determined with increasing vibration stimuli, the vibration disappearance threshold, VDT, determined with decreasing supraliminal stimuli, and the vibration threshold VT which equals the mean of VPT and VDT. The influence of gender, age, body height, weight and skin temperature at the tested site on thresholds was studied. Retest reliability was tested in 73 children aged 3.3-6.9 years and in 20 volunteers aged 5.2-66.1 years who were also tested for the influence of pretest skin warming on thresholds and for differences between results of the left and right body side. TF, VPT, VDT, VT were closely correlated with each other (Spearman: -0.67<Rs<-0.47; P<0.01). The skin temperature, body side, weight and height did not influence thresholds. In adults, thresholds increased with age and were higher in men above the age of 50 than in women of the same age. Thresholds at the feet were higher than at the hands (Wilcoxon: P<0.001). Retest reliability was high and did not depend on the retest interval. The study provides important normative data for the widespread use of quantitative vibration testing.