Margarete Weber

The important role of neuropeptides in complex regional pain syndrome

Objective: To test the contribution of neurogenic inflammation and neuropeptide release to the pathophysiology of complex regional pain syndrome (CRPS). Background: CRPS is characterized by edema and increased skin temperature, sympathetic dysfunction and pain, or hyperalgesia. This investigation was prompted by a recent study by the authors that suggested a facilitated neurogenic inflammation in CRPS. Methods: In addition to physical examination, calcitonin gene-related peptide (CGRP) serum concentrations were measured using a radioimmunoassay (RIA) for human CGRP in 19 patients with acute CRPS, on the affected and unaffected sides (n = 13), before and 9 months after therapy (n = 9). In addition, an age- and sex-matched group of 16 healthy controls was investigated. Results: In blood from the cubital vein, CGRP levels in patients with CRPS (122.2 ± 14.6 pmol/L) were increased (controls 83.8 ± 6.7 pmol/L, p < 0.03). There was no difference between the affected and unaffected sides. There was, however, a reduction of serum CGRP after therapy (acute disease: 141.2 ± 18.5 pmol/L, after therapy 106.7 ± 11.3 pmol/L, p < 0.005); absolute CGRP levels then no longer differed from controls. Increased serum CGRP was correlated to the incidence of nerve lesions (p < 0.02) and hyperhidrosis (p < 0.04). There was no correlation to other clinical symptoms, duration of CRPS, or pain. However, normalization of CGRP after therapy was accompanied by clinical improvement of local inflammatory signs, but not by pain reduction. Conclusions: Increased systemic CGRP levels in patients with acute CRPS suggest neurogenic inflammation as a pathophysiologic mechanism contributing to vasodilation, edema, and increased sweating. However, pain and hyperalgesia, in particular in chronic stages, were independent of increased neuropeptide concentration.

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.

Substance-P-induced protein extravasation is bilaterally increased in complex regional pain syndrome

Pain, mechanical hyperalgesia, edema, increased skin temperature, and skin reddening are characteristic symptoms of acute complex regional pain syndrome (CRPS). We have recently demonstrated facilitated neurogenic inflammation on the affected limb. To further elucidate the underlying mechanisms, exogenous substance P (SP) in ascending concentrations (10(-9), 10(-8), 10(-7), 10(-6) M) was intradermally applied to the affected and the unaffected limbs, respectively, in two groups of 11 CRPS patients each using the microdialysis technique. Fourteen healthy volunteers served as controls for SP application, and 9 volunteers and 10 patients served as controls for saline perfusion. Dialysate protein content was measured photometrically to assess plasma protein extravasation. Significant differences in dialysate protein content were found after 10(-9) M SP (affected side, 98.4 +/- 8.4% of baseline value; unaffected side, 104.4 +/- 5.6%; controls, 70.7 +/- 4.1%; P < 0.005) and after 10(-6) M SP (affected, 169.7 +/- 24.2%; unaffected, 189.4 +/- 19.1%; controls, 122.2 +/- 12.0%; P < 0.05). While 10(-9) M SP induced no protein extravasation in controls, it provoked protein extravasation in 6 of 11 patients on the affected and in 5 of 11 patients on the unaffected side (P < 0.01). We conclude that SP-induced plasma protein extravasation is increased in CRPS patients on both the affected and unaffected limbs. The underlying mechanism might be impaired SP inactivation. Thus, our results further support the hypothesis that neurogenic inflammation plays an important role in the initiation of CRPS.

Experimental tissue acidosis leads to increased pain in complex regional pain syndrome (CRPS).

&NA; The aim of this study was to investigate the role of local acidosis in the generation of pain in complex regional pain syndrome (CRPS). We investigated ten patients with CRPS of the upper extremity with a mean duration of the disease of 43 weeks (range 4–280 weeks) and ten control subjects for sensitivity to infusion of fluids with low pH (pH 6.1). Another group of five CRPS patients and three healthy controls was investigated using the same protocol but neutral infusion fluid (pH 7.4). A motorized syringe pump was installed for a constant infusion of synthetic interstitial fluid (SIF, either acidified (pH 6.1) or neutral) into the skin at the back of the hands and, thereafter, into the interosseus I muscle on both sides. A flow rate of 30 ml/h was chosen for intradermal and 7.5 ml/h for intramuscular infusion over a period of 10 min. The magnitude of pain was rated on an electronic visual analogue scale. Patients were requested to give their ratings every 10 s during the whole stimulation period. The ratings were normalized as fractions of individual grand mean values. We found significantly increased pain perception during infusion of acidified SIF on the affected side in CRPS patients. Low pH fluid into the skin was significantly more painful between 4 and 6 min (ipsi 1.27 normalized rating (NR) (0.19–1.94), contra 0.31 NR (0.03–0.51), P<0.02) and between 8 and 10 min (ipsi 1.38 NR (0.19–1.94), contra 0.08 NR (0–0.27), P<0.03) on the affected side, while analysis over the whole stimulation period just failed to reach statistical significance (ipsi 281 area under the curve (AUC) (187–834), contra 87 AUC (28–293), P=0.059). Low pH infusion into the muscle was significantly more painful on the affected side during the whole infusion time (ipsi 861 AUC (308–1377), contra 190 AUC (96–528), P<0.01). The quality of the deep pain during infusion into the muscle was described by the patients as very similar to the CRPS‐related pain. In controls we found no side differences of pain intensity during low pH stimulation. Neutral SIF evoked no pain at all, neither in CRPS patients (ipsi 0 AUC, contra 0 AUC) nor in healthy controls. Our results suggest that hyperalgesia to protons is present in patients with CRPS. Further, we could demonstrate that pain is not only restricted to the skin but is also generated in deep somatic tissue of the affected limb.

Increased skin lactate in complex regional pain syndrome: Evidence for tissue hypoxia?

Article abstract To investigate oxygen metabolism in complex regional pain syndrome (CRPS), the authors measured skin lactate via dermal microdialysis performed on patients with CRPS (n = 11) and healthy control subjects (n = 11). In addition, they measured blood lactate. Although venous lactate was unaltered, skin lactate was increased in patients with CRPS (2.95 mmol/L; control subjects 1.74 mmol/L; p < 0.005). These results suggest enhanced anaerobic glycolysis, probably as a result of chronic tissue hypoxia.

Laser scanning tomography of the optic nerve vs CSF opening pressure in idiopathic intracranial hypertension

The authors investigated 17 patients with idiopathic intracranial hypertension (IIH), correlating laser scanning tomography of the optic nerve with CSF opening pressure. The decrease in papilla volume and papilla height showed a linear correlation with the opening pressure of the CSF (r = 0.59, p < 0.001; r = 0.63, p < 0.001). If the CSF opening pressure is higher than 20 cm water, an increase of 5 cm water CSF pressure corresponds to a papilla volume increase of 0.95 mm3 as well as a papilla height increase of 0.34 mm.

SHOULD ASPIRIN BE DISCONTINUED FOR DIAGNOSTIC LUMBAR PUNCTURE

effect in two patients. If treatment is necessary, a tentative course of SSRIs is recommended. In a recent open-label study, rivastigmine improved behavioral symptoms in patients with FTLD and reduced caregiver burden. If SSRIs are ineffective in controlling the core features of MBI, rivastigmine may provide a therapeutic option. Awareness of the concept of MBI prevents stigmatization of a patient with a probable organic brain disease as a psychiatric patient. Proper diagnosis in an early stage may reduce patient and caregiver stress.

Complex regional pain syndrome: an actual survey

Complex regional pain syndrome – in the past called sympathetic reflex dystrophy – is, in its pathophysiology, still not fully understood. However, research in the last few years has led to a better understanding of the illness and the beginning of a pathophysiologically- orientated therapy. The core hypothesis is based on neuropeptide release, neurogenic inflammation and its sympathetic dependence. Therapy should be based on current pathophysiological concepts regarding CRPS and neuropathic pain and could thereby lead to a good outcome of the illness.

Persistent amnesia following right-sided vertebral artery dissection

Sirs: A 30-year-old right-handed man was admitted to our hospital after his first epileptic seizure. He reported that he had changed vision and was very confused and uncooperative. On examination he was awake, but disorientated, had retrograde amnesia and a left upper quadrant visual field loss. Past medical history yielded several chiropractic manipulations of the cervical spine within months before admission. He was a heavy smoker, drank one pint of beer daily and was taking cannabis regularly, speed and amphetamine only occasionally. His white blood cell count was elevated (19,900/μL), urine tests for benzodiazepines, cannabinoides and amphetamine were positive. Cerebrospinal fluid obtained by lumbar puncture was normal as was a first cranial computed tomography (CT). Ultrasound sonography showed right vertebral artery dissection, which was confirmed by CT angiography (figure). Ophthalmological examination confirmed the left upper quadrant visual field defect. A repeat of CT one day later showed right temporooccipital infarction including parts of the hippocampus and small left temporooccipital infarction, indicating involvement of both posterior cerebral arteries (PCA). Neuropsychological testing yielded a verbal IQ of 88, consistent with the patient’s schooling. Wechsler Memory Scale (WMS) showed a markedly reduced memory index (MI) of 60. Verbal and visual memory functions were equally impaired. Remote recall was most markedly reduced including verbal and visual memory functions. Drawing was unimpaired. A copy of the Rey-Osterrieth figure was accurate (36 points), but reproduction after 10 minutes nearly impossible (4 points). Five months later magnetic resonance imaging (MRI) showed infarction within the territory of the right PCA including the posterior part of the hippocampus with a minimal residuum on the left side. Neuropsychological testing now yielded a markedly improved MI of 77 with nearly unchanged scores in subtests testing visual memory functions (MI 69). However, the verbal memory score had increased (MI 86). Delayed recall relating to visual memory was unchanged, but verbal delayed recall was clearly improved corresponding with the MRI findings. Copying of the ReyOsterrieth figure was unchanged (36 vs. 4 points). Amnesia is a well-known symptom following PCA infarction [1, 10], as are disorders of consciousness, confusion or bewilderment [3–5]. However, amnesic stroke following vertebral artery dissection has only been described once previously as transient amnesia [7]. As with our patient, onset of symptoms is often delayed for hours or days [6]. We found vertebral artery dissection presenting with persistent amnesia as the only salient symptom. Other symptoms of vertebral artery dissection such as head or neck pain, cerebellar or brainstem dysfunction [1, 2, 5–7] were absent. Only a mild contralateral visual field defect could be detected. There was no apparent impairment of color discrimination. We regard cervical spine manipulation as the most likely cause in this patient [9], although other possible risk factors existed as well. Within five months of follow-up amnesia improved gradually, most of which consisted of verbal memory functions. This suggests a recovery especially within the territory of the dominant left PCA which is supposed to be responsible for verbal memory functions and for vulnerability to global amnesia [8]. In fact, MRI after five months showed only minor abnormalities in the left PCA territory, whereas a larger persistent infarction could be seen on the right side. Acute amnesia as a leading or solitary symptom should be regarded as a possible sign of vertebral artery dissection, especially in patients with a recent history of cervical spine manipulation. Transient global amnesia presents with a duration of less than one day and usually lacks accompanying signs and symptoms. LETTER TO THE EDITORS

Migraine-like headache as the presenting symptom of basilar artery occlusion

Abstract If migraine or a migrainelike headache and stroke occur together, it is difficult to determine whether migraine is the cause of the stroke or stroke is the cause of symptomatic migraine. We report the case of a 19-year-old woman without a history of migraine who presented with a migraine-like headache, nausea and desire for tranquility and dimmed lighting. Initial neurological examination, computed tomography and cerebrospinal fluid analysis were normal, leading to the presumptive diagnosis of first manifestation of migraine. Persistence of dizziness and transient diplopia, however, prompted a magnetic resonance imaging examination, which revealed major stroke in the posterior circulation due to occlusion of the basilar artery. The symptoms resolved spontaneously and treatment with antiplatelet inhibitor was prescribed. Smoking and use of oral contraceptives were identified as vascular risk factors. Stroke in the posterior circulation due to occlusion of the basilar artery may show rather inconspicuous symptoms and provoke migrainous headache.