MUSCLE ACHES AND CRAMPS SEVERAL YEARS AFTER GUILLAIN-BARRÉ SYNDROME.
Bernsen R.A.J.A.M., de Jager A.E.J., Schmitz P.I.M., van der Meché F.G.A. Dept. Neurology, University Hospital Groningen and Dept. Biostatistics and Dept. Neurology University Hospital and Erasmus University Rotterdam, The Netherlands
OBJECTIVE: To assess the occurrence of muscle aches and cramps after GBS. BACKGROUND: It was our impression that many patients complained of muscle aches and cramps after GBS. DESIGN/ METHOD: Patients who had participated in a clinical trial were reinvestigated 3 to 6 years after onset of the disease by means of a questionnaire and a neurological examination. It was established if they had complains of muscle aches and cramps. Results: Fifty-nine of 122 patients still suffer from muscle aches and cramps. There is a statistical significant relation with objective residual sensory deficit of arms (p<0.01) and legs (p<0.01). Furthermore patients with pure motor GBS suffer significantly less from muscle aches and cramps (p=0.04). CONCLUSION: Muscle aches and cramps are related to sensory deficit and not to motor impairment.
THE ROLE OF THE MITOGEN ACTIVATED PROTEIN KINASE (MAPK) PATHWAY IN INFLAMMATION-INDUCED THERMAL HYPERALGESIA IN THE MOUSE
Sammons M.J., Raval P., Davey P.T., Rogers D.C., Hunter A.J., Parsons A.A., Patel S., Bingham S. Neuroscience research, SmithKline Beecham Pharmaceuticals, Harlow, Essex CM19 5AW, UK.
Peripheral inflammation is associated with hyperalgesia and allodynia. These phenomena are produced via many different mediators acting through distinct signalling pathways. The aim of these studies was to investigate the role of the MAPK pathway in carrageenan-induced thermal hyperalgesia in the mouse. Intraplantar (ipl) carrageenan (carra, 25ul, 2%) or saline was injected into a randomly selected hindpaw in 32 male ICR (25-35g) mice and inflammation and thermal hyperalgesia measured 4hrs later. In a separate experiment mice were perfuse-fixed under terminal anaesthesia 4hrs after ipl carra or saline (n=3 per group) and skin, sciatic nerve, L4 and L5 dorsal root ganglia and spinal cord removed for immunohistochemical localisation of phosphorylated MAPK (P-MAPK). The MAPK inhibitor PD98059 (0.1, 0.3 and lmg/kg; sc) given 30mins pre-carra significantly increased paw withdrawal latencies (PWLs) from 2.6 ± 0.3s to 5.1 ± 0.5s at 1mg/kg (p<0.05, n=8 per group) but had no effect on paw depth (inflammation). PD98059 had no effect on PWLs or paw depth on the side contralateral. to carra administration. 4hrs after carra administration P-MAPK was present in all tissues examined compared to saline treated mice. These data demonstrate that during carra-induced thermal hyperalgesia the MAPK pathway is activated in the peripheral neurone and the spinal cord. This hyperalgesia can be attenuated by specific inhibitors of this pathway with no effect on nociceptive processing.
DEMYELINATING NEUROPATHY AND NEUROPATHIC PAIN IN PERIAXIN-DEFICIENT MICE.
Brophy P.J., Gillespie C.S., Griffiths I.R.(1), Ure J.(2), Cottrell D.F., Fleetwood-Walker S.M., Sherman D.L., Smith A.(2) University of Edinburgh, Edinburgh EH9 lQH, UK, (1)University of Glasgow, Glasgow G61 IQH, UK, (2)University of Edinburgh EH9 3JQ, UK.
The Periaxin gene is specifically expressed in myelinating
Schwann cells. Mice lacking a functional Periaxin gene
develop a neuropathy characterized by focal hypermyelination and
segmental demyelination in the peripheral nervous system (PNS).
The mice display allodynia, a painful response to normally innocuous
stimuli, at an early age and by six to eight months they exhibit
severe functional impairment. All peripheral myelinated nerves
examined are severely affected. We conclude that the periaxins
play an essential a role in stabilizing the interaction of the
axon with myelin-forming Schwann cells. We also suggest that these
animals will be useful models for studying late-onset forms of
demyelinating neuropathy, particularly where neuropathic pain
is associated with demyelination.
PROSAPTIDE TX14(A) PREVENTS ABNORMAL NOCICEPTION IN DIABETIC RATS
Calcutt N.A.(1), O'Brien J.S.(2) Departments of Pathology (1) and Neuroscience (2), University of California San Diego, La Jolla, CA 92093, USA.
We have recently demonstrated that prosaptide TX14(A), a peptide derived from the N terminal region of the saposin C domain of prosaposin, protects diabetic rats from electrophysiologic and structural disorders of large myelinated fibers. TX14(A) also acutely alleviates hyperalgesia in an animal model of neuropathic pain. As diabetes induces a number of sensory disorders in rats including tactile allodynia, thermal hypoalgesia and hyperalgesia during the formalin test. We investigated whether TX14(A) has effects on these sensory disorders. All studies were performed on adult female Sprague Dawley rats in which insulin-deficient diabetes was induced by streptozotocin. After 4 weeks of diabetes, rats displayed tactile allodynia, as assessed using von Frey filaments. Tactile allodynia was alleviated (p<0.01 vs pre-injection values) in a dose-dependent (0.2-5.0 mg/kg ip) manner by a single injection of TX14(A), with maximal effect 6 hr following injection while a return to allodynia occurred between 24-48 hr post injection. A single injection of TX14(A) delivered 30 min prior to testing (0.2 mg/kg ip) also prevented hyperalgesia during the 0.5% formalin test (p<0.05 vs saline-treated diabetics). TX14(A) (0.2 or 1.0 mg/kg ip) was without effect on thermal response latencies of either control or diabetic rats for up to 48 hr following a single injection. However, thrice weekly injections (0.2 or 1.0 mg/kg ip) of TX14(A) for 4 weeks reversed the established thermal hypoalgesia in diabetic rats (p<0.05 vs untreated diabetics), while having no effect on the thermal responses of control rats. TX14(A) appears to have multiple mechanisms of action on sensory disorders in diabetic rats, with rapid acting anti-hyperalgesic and anti-allodynic effects and an ability to reverse thermal hypoalgesia that requires chronic treatment. Supported by Myelos Corporation and the UC BioSTAR program.
A TRIAL OF IGF-1 IN THE TREATMENT OF IDIOPATHIC SMALL FIBER PAINFUL NEUROPATHY (ISFPN).
Campion J.K., Sorenson E.J., Windebank A.J. Mayo Molecular Neuroscience Program, Rochester, MN 55905.
Patients with ISFPN typically present with burning pain in the feet. Examination is normal except for distal symmetric loss of pain and temperature sensation. Reflexes, strength, and standard electrophysiological studies are usually normal. A neuropathic cause for the pain may be inferred from quantitative autonomic testing or skin biopsy from a distal site (Holland et al Ann Neurol 44:47-59, 1998). Sural nerve biopsy may be normal suggesting that the process involves distal axonal degeneration. The condition is indolently progressive but patients are disabled by severe pain. We have identified this condition as an ideal disorder for empirical treatment by a growth factor which promotes axonal growth. Nerve growth factor (NGF) would be a candidate for use in therapeutic trials but is potentially limited because it has been shown to cause hyperalgesia (Dyck et al Neurology 48:501-505, 1997). We have therefore initiated a trial using recombinant human IGF-1 (0.1 mg/kg/day) by subcutaneous injection in a prospective placebo controlled double blind study. A total of forty patients will be randomized to treatment or placebo for 6 months. The primary end-point is the subjective estimate of pain using the analog pain scale. Secondary end points include Neuropathy impairment score, nerve conduction studies, computer assisted sensory examination, quantitative autonomic evaluation and quality of life scores. Twenty-six patients have been randomized into this study and twenty have completed the treatment phase. Four patients have had significant improvement in symptoms, but their assignment to placebo or active drug is unknown. No patients have experienced significant worsening of symptoms; no serious adverse events have been encountered. We conclude that IGF-I is safe and well tolerated by patients with small fiber painful neuropathy. Study supported by funds from Cephalon Inc and Mayo Foundation
UP-REGULATION OF a2d CALCIUM CHANNEL SUBUNIT IN DORSAL ROOT GANGLIA AND SPINAL CORD OF RATS WITH TACTILE ALLODYNIA
Luo Z.D., Higuera E.S., Stauderman K.A(1)., Williams M.E.(1), Chaplan S.R. UC San Diego, La Jolla, CA USA. (1)SIBIA Neurosciences, Inc., La Jolla, CA USA
After peripheral nerve injury, sensation may be pathologically altered such that light touch is intensely painful. Gabapentin selectively reduces this tactile allodynia by an unknown mechanism. In vitro, gabapentin binds to a2d voltage-dependent calcium channel subunits, suggesting a functional role of the a2d subunit in neuropathic pain processing. We investigated a2d subunit expression in dorsolumbar spinal cord and in the dorsal root ganglia (DRG) in a rat nerve injury model. After unilateral L5/6 spinal nerve ligation (SNL), rats developed tactile allodynia within four days as measured by paw withdrawal to von Frey hairs. At 1 week, Western blots using a2d monoclonal antibody showed over 10 fold increases in a2d protein in ipsilateral L5/6 DRG compared to contralateral. L5/6 DRG a2d mRNA levels, measured by RNase protection assay, were increased 6-7 fold two days after SNL and remained up-regulated for at least one week. Spinal cord a2d mRNA and protein levels were also mildly increased one week after SNL. Spinal cord a2d subunits were of lower apparent molecular mass than DRG a2d subunits in denaturing gels. Nerve injury results in up-regulation of the a2d calcium channel subunit in DRG and spinal cord, preceding allodynia onset. Differential isoform expression or post-translational modification of the a2d subunit may occur in specific neuronal tissues. Thus, a2d subunit regulation may play a role in the development of allodynia, and gabapentin binding to this subunit may have pharmacologic significance. Support: NIH, HHMI
SWELLING DISTAL IN THE FOREARM AND PAINFUL MEDIAN NERVE COMPRESSION
Dammers J., Veering M.M. Department of Neurology, Medical Centre Alkmaar, The Netherlands
In Cambridge ('97) we presented the results of our double blind
placebo controlled study on corticosteroid injection in carpal
tunnel syndrome. 1) Our results (50% responders after one year)
were better than generally met. We think that our good result
is due to the fact that we give an injection 4 cm proximal to
the carpal tunnel. In 66% of the cases we observe a swelling on
the volar side of the forearm, proximal to the carpal tunnel.
After one or two injections we see this swelling diminish. This
is due to the fact that corticosteroids have lipolytic properties.
Echography and MRI-imaging of these swellings do not show any
other structures than subcutaneus fat and muscle. Local swelling
after Colles fracture, ganglion, arthritis and tendinitis are
well known causes of CTS. Apart from these, two other types of
local swelling (fat and muscle) do exist, but no mention of these
is made in literature. We studied 200 persons, patients and accompanying
persons visiting our out-patient department, on the incidence
of these local swellings. This can be an fatty structure subcutaneous,
on the volar side of the distal forearm. More often we see a swelling
which is predominantly caused by pronator quadratus muscle. We
consider this a swelling when it protrudes above the level of
the tendons of the flexor muscles. This swelling disappears by
forcefully closing of the fist, by pressure of the tendons, becoming
a swelling again when the person pronates the fist against resistance.
We asked 200 persons between 20 and 90 years (mean age 53, 82
male, 118 female) to have their forearm inspected. We tried to
discover by history and neurological examination if they suffered
CTS. This was the case in 33 women, 11 men. (p<0.015). Pronator
quadratus muscle hypertrophia was seen in 70.29%. 54 Female and
16 male (p<0.001). Correlation of pronator muscle hypertrophia
and CTS was highly significant. Fatty swellings subcutaneous were
met in 12 cases, correlation with CTS was high, (p<0.09). Women
do have more often than man local swelling. This often leads to
CTS, especially in women because of their smaller canals and menopausal
accumulation of fat. A narrow carpal tunnel and subcutaneous fat
and muscle cause distal median nerve compression. In 95% of the
cases it positively reacts on an injection of corticosteroids,
the way we inject it and gives long-lasting results of about 50%
after a year. Conclusion: painful distal median nerve compression
is not only caused by a narrow tunnel. Beside well known local
swellings, pronator quadratus muscle hypertrophia and/or local
fat are pathogenic as well. Lipolysis by locally applied steroids
is probably the reason injections give longstanding results in
about 50% of "CTS" patients
1. Dammers J, Prins J, Veering MM, Vermeulen M. Corticosteroids
close to the carpal tunnel. A double blind study with encouraging
outcome. Abstract Peripheral Nerve Society Meeting. Cambridge,
UK, 1997.
NEUROPATHIC PAIN AFTER CCI IS PERMANENTLY REVERSED BY GABA THERAPY
Eaton M.J., Karmally S., Martinez M.A., Plunkett J.A., Cejas P., Lopez T. The Miami Project to Cure Paralysis, University of Miami School of Medicine, Miami, FL 33136
Little is known about the endogenous spinal mechanisms of the altered sensory behaviors related to unilateral chronic constriction injury (CCI) of the sciatic nerve and the development of neuropathic pain. Cellular therapy that is able to reverse chronic pain after CCI, also reverses the loss of GABA in the endogenous GABA interneurons of the dorsal horn. The neuronal cell line, 33G120.17, transfected with rat GAD67 cDNA (glutamate decarboxylase for GABA synthesis) was used as a subarachnoid graft in a model of chronic neuropathic pain induced by CCI. When 33G10.17 cells were transplanted one week after CCI, they survived greater than seven weeks on the pia matter around the spinal cord and synthesized GABA. Furthermore, the tactile and cold allodynia and tactile and thermal hyperalgesia induced by CCI was significantly reduced during the two to seven week period after grafts of 33G10.17 cells. The maximal effect on chronic pain behaviors with the GABAergic grafts occurred two to three weeks after transplantation. To investigate whether the induction of chronic neuropathic pain is sensitive to GABA levels, a single dose of intrathecal (IT) GABA was substituted for cells grafts, one week after CCI. Both thermal and tactile sensory behaviors were potently reversed for at least 4-5 weeks after IT GABA. These data suggest that altered spinal GABA levels contribute to the induction and maintenance of chronic neuropathic pain and that cell therapy can prevent or relieve that pain. This work was supported by the Miami Project; NIH #36438-02; and The State of Florida.
EFFECTS OF 4030W92, A NEW ANTI-HYPERALGESIC AGENT, ON HUMAN SURAL NERVE COMPOUND ACTION POTENTIALS IN VITRO
Grosskreutz J., Quasthoff S. Department of Neurology, TU Munich, Germany
The aim of the study was to compare the effects of known antihyperalgesic agents (Carbamazepine and Phenytoin) with a new sodium channel blocker 4030W92 and an unspecific ion channel blocker Riluzole on human sural nerve A and C fibre compound action potentials (CAP) max. amplitudes and latenties. In total we investigated 43 nerve fascicles from 12 specimens of human sural nerve biopsies in a in vitro registration chamber. All four agent reduced the max. A fibre amplitude in a dose dependent manner (1-10-100 µM). 4030W92 and carbamazepine (100 µM) showed the most significant effects by reducing 70 % of the initial A fibre CAT amplitude. Riluzole compared to Carbamazepine and 4030W92 (100 µM) was more selective in reducing C fibre max. CAP. However the drugs induced latency increase in human C fibres was greatest under 4030W92 and carbamazepine (100 µM) indicating a similar ion channel blocking mechanism. 4030W92 also showed a use dependent block of A and C fibre CAP amplitude thereby increasing its pharmacological potency. In conclusion, our studies demonstrated the potency of 4030W92 to reduce nerve conduction in A and C fibres of human sensory axons which was greater compared to the known drugs carbamazepine and phenytoin. This might indicate the possible role of 4030W92 as a new antihyperalgesic agent.
COLD HYPERALGESIA IN FABRY PATIENTS
Hilz M.J. (1,2) , Stemper B.1, Kolodny E.H.
(2)
Depts. of Neurology, University Erlangen-Nuremberg, Erlangen,
Germany (1), and New York University, New York, NY, USA (2)
In Fabry disease, peripheral small nerve fibers are particularly susceptible to the a-galactosidase A deficiency induced storage of glycosphingolipids. Patients suffer from painful crises and limb paresthesias possibly linked to thermal exposure. Small fiber function has not yet been tested after temperature challenge. To study whether small fiber function deteriorates with cold exposure, we assessed thermal thresholds before and after cold challenge in two Fabry patients (15 and 17 years old), their 19-year-old healthy sister, their 45-year-old mother, a disease carrier, and eight healthy controls (27.4±10.3 years). Using the method of limits and a Somedic-Thermo-test™, we determined cold and warm perception thresholds at the dorsal foot and lower medial calf, before and 1, 5, 10 and 15 min after 30 s cold exposure. The tested leg was immersed into 5C water, up to the mid-thigh. Discomfort was rated on a 0-10 analog scale. Before cold stimulation, all participants had normal thermal thresholds. The patients tolerated the cold stimulation only with, interruptions after 15 and 20 s. The mother tolerated cold for 6 s only. After cold challenge, the patients had paradoxical thermal sensations and highly elevated thresholds which normalized after 20 min and 80 min, respectively. The thermal thresholds of the controls were slightly elevated after cold exposure but normalized within 10.0± 4.6 min. Discomfort was rated 8-10 by the patients and their mother, but 3-5 by the controls. We speculate that the cold intolerance and small fiber dysfunction in the Fabry patients is due to hypothermia induced hypoxia which might originate from glycolipid accumulation in small nerve vessel walls.
VENIPUNCTURE INDUCED CAUSALGIA: ANATOMIC CORRELATIONS OF SUPERFICIAL VEINS AND NERVES
Horowitz S.H. University of Missouri-Columbia, MO 65212 USA
In 1994 this author reported 11 patients with injury to upper extremity (UE) cutaneous nerves following routine venipuncture. All developed symptoms of causalgia. According to standard anatomy texts--with elbow extension--at the volar surface of the cubital fossa, forearm and wrist, and at the dorsum of the hand, veins commonly employed in venipuncture are superficial to cutaneous nerves. Thus, nerve injury appeared to result from direct trauma due to 'inappropriate' needle or bolused material entry into the plane of the nerves deep to the veins. This theory was supported by rapid hematoma formation, Subsequently, 12 more patients have been examined, 10 fitting the aforementioned pattern. However, in 2, venipunctures were properly performed and atraumatic. Their development of causalgia prompted an anatomical reevaluation of UE superficial veins and cutaneous nerves. The 14 UEs of 7 randomly chosen cadavers were dissected. The following nerve-vein relationships were seen: 1. Major branches of cutaneous nerves were superficial to and overlay veins in 6 extremities; 2. In multiple instances, nerves and veins were intertwined requiring detailed dissection to separate them; 3. In the classical situation, with veins superficial to nerves, the nerves were in close proximity, immediately deep to veins, often with no fascial separation. It is concluded that anatomical relationships between UE superficial veins and cutaneous nerves are so intimate that nerve contact during venipuncture must be common. Since venipuncture-induced nerve injuries are rare, factors other than direct nerve contact are necessary for the causalgic pain syndrome to occur in this context.
EFFECTS OF MID-AXONAL TNFa ON MECHANICAL ALLODYNIA AND C NOCICEPTOR ACTIVITY IN THE RAT
Junger H., Doom C., Sorkin L.S. University of California San Diego, La Jolla, CA. USA
TNFa (TNF) is a pleiotropic cytokine, which is involved in the immune response, inflammation and nociception. We investigated the effects of TNF applied to the nerve trunk on mechanical allodynia in awake rats and generation of ectopic discharge in the pentobarbital anesthetized rat. In male Holtzmann rats, mechanical paw withdrawal thresholds to a series of calibrated von Frey hairs were measured before and for 3 hrs after drug application through a catheter lying over the midthigh portion of the sciatic nerve. At the end of the experiment, bupivacaine was administered through the catheter to confirm placement. When the local anesthetic test was positive, TNF (0.9 ng in 90 ml, followed by a 20 ml saline flush) reduced the mechanical withdrawal threshold of the ipsi-lateral foot at time points 45 and 90 min after injection. In parallel, we observed in single fiber recordings the development of ectopic discharge of C nociceptors of the sural nerve after application of TNF (2 pg in 100 ml in a bathing chamber along a 5 min length of the nerve trunk. Duration of the TNF-associated activation lasted up to 2 hours. An i.v. infusion of lidocaine, at plasma concentrations well below that necessary for conduction blockade, inhibited the ongoing activity. This implicates Na2+ channels in the TNF-elicited C fiber response. Following replacement of TNF with vehicle and cessation of ongoing activity, the nerve trunk became mechanosensitive. These data suggest that TNF evoked nerve activity after application along the nerve and that this level of evoked activity was sufficient to sensitize the spinal cord to produce a behavioral allodynia. Thus, our data further support the role of TNF in the generation and/or maintenance of neuropathic pain. Supported by NS35630
ROLE OF SPINAL PROTEIN KINASE C (PKC) IN NERVE INJURY-INDUCED TACTILE ALLODYNIA IN CHUNG NEUROPATHIC RATS
Kalcheva I., Hua X-Y, Chen P., Butler M.1, Newton A., Yaksh T.L. University of California San Diego, La Jolla, CA, USA, 1ISIS Pharmaceuticals, Carlsbad, CA, USA
The activation of protein kinase C (PKC) leading to the phosphorylation of membrane channels and receptors has been implicated in persistent pain states. In the present study, we have examined: (1) the effects of a number of PKC inhibitors by intrathecal delivery on tactile allodynia in a rat model with chronic nerve ligation (Chung model); and (2) the changes of Ca2+ -dependent PKC activity and expression of PKC isozymes, PKCa and PKCg in the spinal cord and lumbar DRG upon the nerve lesion. Male Sprague Dawley rats (120-140 g) were used in the study, and drugs were administered via chronic intrathecal catheters. Tactile allodynia developed 2-5 days after the left L5 and L6 spinal nerves were ligated. Intrathecal PKC inhibitors (GF109203X > PKC19-31 > chelerythrine) displayed an anti-allodynic effect in the Chung neuropathic pain model. The effect was dose-dependent, and stereospecific (Bisindoly-maleimide V was inactive). Chronic changes in PKC activity and differential spinal PKC isoform expression were noted in response to nerve ligation. The changes were time-dependent: no change was observed on day 1, but were apparent by day 12 post-surgery. In contrast, no significant alteration was observed in DRG as regards either the PKC activity or the PKC protein expression. There is a unique increase in PKCg expression in neurons at a restricted location, i.e., the medial lamina II. These data suggest that the increase in expression of PKC, probably PKCg, and a subsequent increase in its activity in the specific population of the neurons in the spinal cord may play a critical role in developing and maintaining tactile allodynia induced by nerve injury. Supported by NIH HL 50403, NS 0747, and NS 16541
ASSESSMENT OF THERMAL SENSORY THRESHOLDS IN REFLEX SYMPATHETIC DYSTROPHY
Kemler M.A., Reulen J.P.H., van Kleef M., Barendse G.A.M., van den Wildenberg F.A.J.M., Spaans F. Maastricht University Hospital, Maastricht, the Netherlands
Reflex sympathetic dystrophy (RSD) may affect small calibre fibre function, which can be assessed with the quantitative somatosensory thermotest. There is no clarity on whether the method of limits (MLI) or the method of levels (MLE) is preferable. In the present study perception thresholds for warmth and cold sensation were assessed twice, at a one month interval, both on the unaffected and the affected wrist (n=33) or foot (n=20) of patients with RSD of one extremity. Warm and cold hypoesthesia were found in about one third of patients. The sensitivity in detection of pathology of both methods was similar. Concerning the threshold, the MLE showed significantly better coefficients of repeatability (CR) on both the unaffected and affected wrist, but on the foot CR's of both methods were bad. The thresholds measured with the MLI agreed poorly with those of the MLE, and because of the reaction time artefact of the NMI this is in favour of the MLE. The more accurate thresholds and the better CR's in the wrist make the MLE the preferable method to assess thermal sensory thresholds.
PROBE SIZE INFLUENCES THE DETECTION OF PAIN SENSATION FOLLOWING TOPICAL CAPSAICIN INDUCED EPIDERMAL DENERVATION
Kennedy W.R. (1), Khalili N.(1), Wendelschafer-Crabb G.(1), Simone D.A.(2) Departments of Neurology(1) and Psychiatry(2) , University of Minnesota, Minneapolis, MN, USA.
Topical application of capsaicin (CAP) cream causes disappearance of epidermal nerve fibers (ENFs). Cessation of treatment results in partial reinnervation (Nolano et al. In Press, PAIN). The detection of the sensory deficiency to hot pain varied depending on the type of stimuli applied. We decided to determine if detection was dependent upon the size of the stimulating probe. METHODS: Five human subjects applied 0.075% CAP cream q.i.d. for 1 week to a 4 by 5 cm area of the forearm. Before treatment, daily for 1 week and at selected times thereafter heat pain sensation was assessed with a small (7.1 mm(exp2)) and large (900 mm(exp2)) heat probe and skin biopsies were processed for assessment of ENFs. RESULTS: Within 24 hours of CAP treatment the number of ENFs had decreased dramatically. Changes in the subepidermal neural plexus were not apparent. A pronounced sensory loss to heat stimuli was detected using the small heat probe but not with a larger probe. CONCLUSIONS: The rapid CAP-induced degeneration of nerve fibers in skin may contribute to the analgesia accredited to CAP. The importance of probe size for detecting the functional deficit suggests that large probes stimulate a larger number of surviving ENFs and that the stimulus penetrates deeper into the dermis exciting proximal stumps of degenerated ENFs thereby masking ENF loss.
CORRELATION BETWEEN FUNCTIONS OF PERIPHERAL NERVE FIBERS AND PAIN IN DIABETIC NEUROPATHY
Lang E., Birklein F., Handwerker H.O., Neundörfer B. Neurological Clinic, University of Erlangen, D-91054 Erlangen, Germany.
In the present study we investigated whether neuropathic pain in patients suffering from diabetic neuropathy (DN) depends predominantly on lesion of thin nerve fibers. In 21 patients suffering from DN (50 ± 14 y) we correlated intensity of neuropathic pain on visual analogue scale (%VAS) with functions of thick and thin nerve fibers (motor nerve conduction velocity of the tibial nerve, sensation threshold of vibration on the big toe, sensation threshold of warmth, cold and heat pain on the foot dorsum and the histamine induced vasodilatation [laser Doppler flowmetry] on the foot dorsum). To examine possible covariation between natural changes of pain and function of nerve fibers we measured the time course of parameters within 1 year (0, 1.5, 3, 6 and 12 months). Control data were obtained from 24 healthy subjects (55 ± 9 y). Parameters of thick and thin nerve fibers were significantly reduced in patients but did not change significantly within 1 year. Intensity of neuropathic pain (%VAS) correlated significantly with the functional deficit of both the thin and the thick nerve fibers (means of repeated measurements): sensation threshold of heat pain (r=0.72), cold (r=0.63) and warmth (r=0.66); histamine induced vasodilation (r=-0.42); sensation threshold of vibration (r=0.51), motor nerve conduction velocity (r=-0.49). Conclusion: since in DN all classes of nerve fibers are damaged to similar degree, the correlations between intensity of neuropathic pain and functions of thick and thin nerve fibers do not indicate a specific class of nerve fibers, which may cause the neuropathic activity.
UP-REGULATION OF NEURONAL NITRIC OXIDE SYNTHASE IN DORSAL ROOT GANGLION AND ITS DISSOCIATION FROM DEVELOPMENT OF ALLODYNIA IN RATS WITH TIGHT NERVE LIGATION
Luo Z.D., Chaplan S.R., Scott B.P., Cizkova D., Yaksh T.L. University of California San Diego, La Jolla, CA 92093, USA
Pharmacological evidence suggests a functional role for spinal nitric oxide (NO) in modulation of thermal/inflammatory hyperalgesia. To assess the role of NO in nerve injury induced tactile allodynia, we examined neuronal NO synthase (nNOS) expression in the spinal cord and dorsal root ganglia (DRG) of rats with allodynia due to tight ligation of the left fifth and sixth lumbar spinal nerves (Chung model). RNase protection assays indicated that nNOS mRNA levels were increased in DRG, but not spinal cord, neurons on the injury side one day after nerve ligation, peaked (about 9 fold increase) in two days and remained elevated for at least 2 weeks. A corresponding increase of nNOS protein (over 20 fold) was also evident in DRG as indicated by Western blots and localized mainly to small sensory neurons by immunohistological studies. The increased expression of nNOS preceded substantially the onset of allodynia. However, similar increases in DRG nNOS mRNA were observed in nerve-injured Holtzman rats, a strain that does not develop allodynia following nerve ligation, and in Harlan rats fully recovered from allodynia three months after the nerve ligation. These data indicate that upregulation of DRG nNOS is not associated with the development of allodynia. In addition, systemic treatment with a nNOS-specific inhibitor failed to reverse allodynia in nerve injured rats. Thus, regulation of nNOS at the mRNA level may contribute to the development of neuronal plasticity after peripheral nerve injury. However, up-regulation of nNOS is not responsible for the development/maintenance of allodynia following nerve injury. Support: HHMI institutional grant to ZDL, SRC and NIH F32HLO9848 to ZDL and NS01769 to SRC
CUTANEOUS BRANCHING STRUCTURE OF PHYSIOLOGICALLY IDENTIFIED NOCICEPTORS
Meyer R.A., Peng Y.B., Ringkamp M., Campbell J.N. Johns Hopkins School of Medicine, Baltimore, MD, USA
Little is known about the branching structure of physiologically identified cutaneous nociceptors. We used electrophysiological. techniques to locate the position of the branch point where daughter fibers innervating two separate locations in the receptive field join the parent axon. Single-fiber recording techniques were used to investigate 32 Ad and 10 C-fiber nociceptors innervating the hairy skin of the monkey. Electrodes for transcutaneous stimulation were fixed at two separate locations inside the receptive field. Distinct steps in latency of the recorded action potential (AP) were observed as the electrical stimulus intensity increased in the receptive field indicating discrete sites for AP initiation. The number of discrete latencies at each stimulation location ranged from 1 to 9 for the Ad fibers and 2 to 6 for the C fibers. The mean size of the latency step was larger in the Ad fibers (9.9 ± 1.0 ms) than in the C fibers (4.0 ± 1.0 ms). Collision experiments were performed to determine the connectivity between one AP initiation site from each location in the receptive field. To correct for changes in electrical excitability following AP propagation, collision experiments between the two skin locations and between each skin location and a nerve trunk electrode were necessary. For nine branch points from 7 Ad fibers, the mean distance between the skin and the branch point was 54 ± 10 mm. For one C-fiber, the branch point was 94 mm from the skin. These results indicate that some nociceptive afferents branch quite proximal to their peripheral receptive field. Furthermore, these results demonstrate that collision techniques can be used to study the functional anatomy of identified nociceptive afferent terminals.
ONGOING ACTIVITY IN AXOTOMIZED DRG NEURONS
Michaelis M., Liu X-G, Jänig W. Physiologisches Institut, Kiel University, Germany.
Prior studies have shown that transection of the sciatic nerve gives rise to ongoing action potential activity in axotomized afferent neurons originating within dorsal root ganglia (DRGs) which may underlie pain and other neuropathic symptoms. We investigated which functional types of DRG neurons are affected. In anaesthetized rats, the left sural nerve supplying hairy skin and gastrocnemius-soleus (GS) nerve supplying skeletal muscle were ligated and cut. In other experiments, additionally the left common peroneal and tibial nerves were transected. Six-12 days later, centrally connected nerve strands were teased from the sural nerve or GS nerve for recording. In case of a small nerve lesion (solely sural and GS nerves cut), spontaneous activity was found in DRG neurons projecting into the GS nerve (29/141 A-neurons with myelinated axons, 0/41 C-neurons with unmyelinated axons) but not in DRG neurons projecting into the sural nerve (0/126 A-neurons, 0/140 C-neurons). After a large nerve lesion (additionally peroneal and tibial nerves cut), a similar number of DRG neurons with spontaneous activity was found (GS nerve: 30/135 A-neurons, 4/55 C-neurons; sural nerve: 0/152 A-neurons, 0/487 C-neurons). The mean firing rate in ectopically discharging GS neurons was 2.6±3.2 imp/s after a small lesion, but significantly higher (6.1±3.8 imp/s, p<0.001, t-test) when a large nerve lesion preceded. Moreover, in case of a large but not after a small nerve lesion most neurons showed a bursting discharge pattern. We demonstrated that exclusively DRG neurons projecting into skeletal muscle exhibited ectopic spontaneous discharges following peripheral nerve lesion. The rate of their ectopic discharge increased with the total number of lesioned nerve fibers. Supported by the DFG, Mi 457/2-1 and Ja 240/15-1
PAINFUL PERIPHERAL NEUROPATHY IN ASSOCIATION WITH CHRONIC HEPATITIS C
Neundörfer B. (1), Heckmann J.G.(1), Kayser C.(1), Heuss D.(1), Blum H.E.(2) (1)Dept. of Neurology, University Erlangen-Nuremberg, (2)Dept. of Internal Medicine (Gastroenterology), University of Freiburg, Germany
BACKGROUND: Hepatitis C virus (HCV) infection is often associated with abnormal immunological responses. We describe three patients with vasculitic peripheral neurological signs and symptoms following HCV infection. CASE REPORTS: A 56-year-old woman with HCV infection developed peripheral neuropathy characterized by asymmetric distal painful hypesthesia, dysesthesia and moderate motor weakness of the lower limbs. Serological examinations revealed cryoglobulinemia and low levels of complement C4. A biopsy of the sural nerve demonstrated vasculitic neuropathy. HCV infection-associated immunemediated vasculitis was diagnosed. While steroid therapy was ineffective, treatment with IFN-alpha improved the neuropathy considerably without, however, eliminating HCV infection. A 62-year-old man with HCV infection developed peripheral sensory neuropathy. Complement C3 was slightly diminished. Nerve biopsy showed vasculitic neuropathy. A 71-year-old woman developed chronic symmetric sensomotor polyneuropathy. HCV hepatitis followed blood transfusions. Cryoglobulins tested positive, consistent with type 11 cryoglobulinemia. Complement C3 and C4 were diminished. Inflammatory infiltrates in the sural nerve biopsy specimen led to the diagnosis of chronic vasculitic disorder. CONCLUSION: When caring for patients with peripheral neuropathy a hepatitis C-associated vasculitis and/or combined with cryoglobulinemia should be considered in the differential diagnosis. The present therapeutic options are immunosuppressive agents such as corticosteroids or immunemodulating interferon alpha.
SINGLE CELL RT-PCR ANALYSIS OF SODIUM CHANNEL a-SUBUNIT NaN EXPRESSION IN ADULT SENSORY NEURONS
Oddiah D., Koltzenburg M. Department of Neurology, University of Würzburg, Germany.
In adult mice, dorsal root ganglion (DRG) neurons consist of a heterogenous mix of sensory neurons exhibiting varied electrical characteristics and functional properties. In accordance, voltage-gated sodium channel a-subunits show a differential expression between populations of DRG neurons. Thus, large DRG neurons express a TTX sensitive (TTX-S) sodium current mediated by various a-subunits, whereas small diameter nociceptors coexpress a TTX-S, as well as two different TTX resistant (TTX-R) currents, attributed to SNS/PN3 and NaN/SNS2 a-subunits respectively. In this study the expression of NaN mRNA has been investigated in small to medium sized DRG neurons in dissociated culture, using the technique of single cell reverse transcription polymerase chain reaction (RT-PCR). Cells were classified by their ability to bind the lectin IB4 that provides a vital stain of non-peptidergic nociceptive neurons. Individual cells were harvested using glass micropipettes and the house-keeping gene, b-actin, was used as a positive control of harvested cells. Of 39 cells from which actin could be amplified, no IB4-positive cells of any size expressed NaN mRNA (n = 18, mean diameter = 21.3 +/- 3.6mm). NaN mRNA was however associated with a wide range of cell sizes in IB4-negative cells (n = 21, mean diameter = 24.6 +/- 8.6mm). Both small cells of <30mm diameter classified as nociceptors, as well as larger cells, >35mm, showed a robust expression of NaN mRNA. In conclusion, single cell RT-PCR can be used to characterise sodium channel gene expression in DRG neurons in association with classical biochemical markers.
AUTOMATED BEHAVIOR ANALYSIS: ASSESSMENT OF PAIN IN RATS EXPOSED TO EXPERIMENTAL DISC HERNIATION
Olmarker K., Størksson R(1). Dept
Orthopaedics, Göteborg University, Gothenburg, Sweden,
(1)Dept Physiology, Bergen University, Bergen, Norway
Although extensive work has been performed lately regarding the basic pathophysiologic events leading to sciatica, there has been apparent difficulties to interpret the clinical importance of observed changes due to the lack of facilities to assess pain in experimental animals. Just recently, a method was developed to assess general behavior of rats using various parameters. Forty rats were anaesthetized and the left 4th lumbar nerve root and DRG were exposed by a unilateral facetectomy. The rats were divided into 4 groups; Sham (n=10), Displacement (n=10) - the 4th lumbar DRG was permanently displaced medially by a 0.6 mm needle, Nucleus pulposus (n=10) - the adjacent intervertebral disc was punctured, Combination (n=10) - both disc puncture and displacement were induced. The rats were assessed; 1, 3, 7, 14, and 21 days postoperatively. The rats were placed in a wood cage with a transparent floor and were video-recorded from below for 30 minutes. The video-tapes were evaluated by a specially designed computer program. During the first 3 postoperative days the rats of the combination group showed increased locomotion, "bending to the affected side" and "lifting of the affected limb", and reduced grooming and rearing, indicating acute pain. However, after 7 days, locomotion was decreased and immobility increased, with continued reduction of rearing and grooming, indicating chronic pain. All these changes were statistically different to the sham group. The changes in the displacement group was similar to the combination group but not at all as pronounced. In the nucleus pulposus group, however, the changes mainly comprised increased locomotion and rearing and thus a picture of atypical or irritative pain. Using the described method for automated behavior analysis in rats we now have a powerful tool to assess changes that may closely relate to pain and therefore a unique possibility to study pathophysiologic mechanisms and therapies for sciatica induced by disc herniation.
ICAM AND TNF: ICAM REGULATION IN MICE WITH PAINFUL MONONEUROPATHY
Schäfers M., Sommer C. Neurologische Klinik der Universität, Würzburg, Germany
Intercellular adhesion molecule-1 (ICAM-1) is supposed to be involved in macrophage recruitment as well as in the proliferative and phagocytotic response of Schwann cells after peripheral nerve lesions. Tumornecrosis- factor-a (TNF) induces ICAM-1 in most experimental settings. Mostly, TNF-receptor 1 (R1) is supposed to be responsible for ICAM induction, however, a dependence on TNF-receptor 2 (R2) has also been described. Here we investigated whether delayed Wallerian degeneration in C57BL/Wld mice is associated with reduced ICAM-1 expression. Furthermore, we analyzed the influence of inhibition of TNF and TNF receptors by administering neutralizing antibodies (AB) to the injured nerves. Moreover, we investigated the expression of ICAM-1 in TNF-R1, -R2 and R1/R2-deficient mice. A chronic constriction injury (CCI) was induced in 75 mice. Cryostat sections were immunstained and morphometric analysis was performed using NIH-Image 6.0 software. ICAM-immuno-reactivity (IR) increased with time after surgery and was maximal on day 28, with a delayed time course in C57BL/Wld mice. ICAM-1 positive cells could be identified as fibroblasts, macrophages, and endothelial cells. Surprisingly, treatment with anti TNF-R1-AB increased ICAM-1-IR, whereas the other AB-treatments produced no difference in ICAM-1-IR compared to sham-treated CCI- animals. TNF-receptor knock-outs had moderately reduced ICAM-1-IR. In conclusion, TNF seems to regulate ICAM-1 expression in lesioned peripheral nerve in a differential way through both TNF-receptors.
CAPSAICIN SENSITIVTY OF PEPTIDERGIC AND NON-PEPTIDERGIC ADULT SENSORY NEURONS
Schmidt K.H, Koltzenburg M.. Department of Neurology University of Würzburg, Germany
In adult mice there are two large non-overlapping subpopulations of nociceptive sensory neurons that either contain CGRP and express receptors for NGF or non-peptidergic neurons that can be labeled with the lectin IB4 and respond to GDNF. Here we asked whether these two populations also differ in their functional properties, as assessed by their response to capsaicin. Sensory neurons from dissociated dorsal root ganglia of adult mice were grown in culture in serum containing medium. Cells were grown in the absence of exogenous growth factors or with addition of 50 ng/ml of NGF or GDNF for 1 or 6 days. Chemical sensitivity was assessed by uptake of cobalt ions induced by stimulation with capsaicin (1 mM, 8 min) and neurons were also identified by double labeling for CGRP and IB4. After 24 hours in culture 29 % of the neurons (n=484) were positive for IB4, 30% for CGRP and 34% for capsaicin. Less than 1% of the capsaicin sensitive cells (n=165) were IB4-positive, 68% were CGRP-positive and the remainder was negative for both markers. After 6 days in culture (n=614), the percentage of CGRP-positive neurons dropped to 18% and cobalt uptake to 8%. NGF (538 cells) prevented this drop in CGRP-(30%) and capsaicin-sensitive neurons (39%) whereas GDNF (626 cells) only prevented the drop in capsaicin sensitivity (34%), but not that of CGRP (19%). The percentage of IB4 positive neurons was neither affected by NGF (34%) nor GDNF (32%). We conclude that in adult mice the majority of CGRP-, but none of the IB4-positive neurons show capsaicin-induced cobalt uptake. Capsaicin-sensitivity and CGRP synthesis are differentially regulated by NGF and GDNF.
MATRIX METALLOPROTEINASES AND TNFa: RELATIONSHIPS IN NERVE INJURY PRODUCING WALLERIAN DEGENERATION
Shubayev V.I., Heckman H., Dolkas J., Myers R.R. University of California, San Diego and the VA Healthcare Center, San Diego, La Jolla, CA, USA
Chronic constriction injury (CCI) to nerve causes Wallerian degeneration (WD) via a process involving local increases in tumor necrosis factor alpha (TNFa), macrophage infiltration, and activation of degenerative biochemical cascades. Cell surface activation of TNFa from its transmembrane precursor is performed by the zinc-dependent enzyme family of Matrix Metalloproteinases (MMPs). We analyzed the role of MMPs in TNFa activation following CCI to rat sciatic nerve by determining temporal changes in gelatin zymography of MMPs (a SDS-PAGE-based MMP activity assay), and immunohistochemistry and western blots of TNFa protein. We report that MMPs, particularly gelatinase A (MMP-2) and gelatinase B (MMP-9), are expressed within hours of CCI and precede TNFa upregulation at the injury site. MMPs are important markers for TNFa activity, and may be one of the key initial factors in the pathogenesis of the painful neuropathies associated with WD, as indicated by recent work with a MMP inhibitor (Sommer et al., Neurosci Lett 237: 45, 1997) and our demonstration of early, specific MMP association with TNF up-regulation in nerve. We suggest that MMP-2 and MMP-9 are critical matrix (interstitial) metalloproteinases instrumental in controlling the privileged endoneurial environment and the initiation of the macrophage-dependent processes of Wallerian degeneration.
DRUGS FOR PAIN IN POLYNEUROPATHY. HOW EFFECTIVE ARE THEY?
Sindrup S.H., Jensen T.S. Depts. of Neurology, Odense and Aarhus University Hospitals, Denmark.
Drugs from several different classes have been shown to relieve pain in polyneuropathy. We performed a systematic review to identify placebo-controlled clinical trials on oral drugs in painful polyneuropathy and calculated for each drug class the numbers needed to treat (NNT) to obtain one patient with >/=50% pain relief (1/[>/=50% reliefactive/totalactive - >/=50% reliefactive/ totalplacebo]).
Drug NNT(95 % CI)
Antidepressants
Tricyclic 3(2.4-4.0)
Tricyclic, optimal dose 1.4(1.1-1.9)
Sel. serotonin reuptake inhibit. 6.7 (3.4-435)
NMDA-antagonist
Dextromethorphan 1.9 (1.1-3.7)
Sodium channel blockers
Phenytoin 2.1(1.5-3.6)
Carbamazepine 3.3(2-9.4)
Mexiletine 10 (3-infinity)
Calcium channel blocker
Gabapentin 3.7 (2.4-8.3)
Tramadol (atypical opioid) 3.4 (2.3-6.4)
L-dopa 3.4 (1.5-infiniti)
Tricyclic antidepressants appear to be the most effective drugs.
Selective serotonin reuptake inhibitors and mexiletine are clearly
less efficacious, whereas the response on dextromethorphan, gaba-pentin,
and tramadol is in the same range as the tricyclics.
RESTLESS LEGS SYNDROME AND PERIPHERAL NEUROPATHY
Smith A.G., Jones C.R., Meekins G.D., Taher K. Singleton J.R. University of Utah, Salt Lake City, Utah
Restless leg syndrome (RLS) is characterized by creeping and aching leg discomfort associated with an irresistible urge to move the limbs. Symptoms are worse at night. The relationship between RLS and peripheral neuropathy (PN) is unclear. Because pain symptoms associated with PN may be worse at night and may provoke movement, recognizing and confirming RLS in PN is problematic. 372 patients with PN seen at the University of Utah and Salt Lake City VA neuromuscular clinics were mailed a questionnaire regarding symptoms of RLS and PN. The patients' spouses completed identical surveys. An RLS score of 0-8, based on the international RLS study group diagnostic criteria, was calculated based on the answers. A score of 4 was considered highly suggestive of RLS. A neuropathy symptom inventory pertaining to sensory, motor and pain symptoms was also obtained. Patient results were compared to age matched spouses using student T tests and correlation coefficients. To date, 200 surveys have been returned. Among PN patients, 30% had a RLS score >4, 16% >5, and 5.3% >6 Among controls 8.6% had a score >4 and 1.7% >6. The mean RLS score for the PN group (2.7+/-1.6) was significantly higher than that of the control group (1.0+/-1.5), (p<.0001). Pain, but not sensory or motor PN symptoms significantly correlated with RLS (p<.009). Our findings suggest RLS is commonly associated with PN. Painful PN may predispose to RLS. These findings may have implications for the treatment of painful neuropathy. Further study is underway to validate the diagnosis of RLS in these patients and to further characterize the PN.
THE PERINEURIAL WINDOW - AN EXPERIMENTAL STUDY AND A REPORT OF SIX CLINICAL CASES.
Takayama S., Sugimoto Y., Horiuchi Y.
Department of Orthopaedic Surgery, School of Medicine, Keio University,
Tokyo Japan
To investigate the pathomechanism of the perineurial window, we designed the following two different sized models of perineurial windows using tibial nerves of Wistar rats: a 1mm length window as a small perineurial window model and a 5mm length window as a large window. Evaluation consisted of visual assessment of the herniation, histological examination and analysis of neuromuscular function using the rats foot prints using the tibial functional index (TFI). In the 1mm window model, the TFI was decreased to -20 at one week after the operation and it was sustained until the eighth week. Remarkable herniation of the endoneurial contents and severe damage of the nerve fibers was observed at one week after operation. The perineurium and nerve fibers did not show complete recovery at 12 weeks. On the contrary, in the 5mm window model the TFI was obviously decreased to -40 at one week, but it recovered to the normal range within four weeks. The herniation and damage of the nerve fibers were not so severe and the degree of herniation decreased consequently over time. The damage in the small window was sustained and the nerve fiber was more slowly compared with that of the large window, suggesting that the main pathomechanism of the perineurial window is entrapment of the nerve fibers at the edge of the window rather than a disruption of endoneurial homeostasis. We also report six clinical cases of the perineurial window. Limited protrusions on the peripheral nerves were observed in the patient with continuous pain and numbness after the minor trauma or surgery. Enlargement of the window by longitudinal incision of the perineurium relieved the pain and numbness soon after the surgery.
PAINFUL MULTIPLEX NEUROPATHY AFTER ANTIBIOTIC TREATMENT OF A BANNWARTH'S SYNDROME: CASE REPORT
Urbanits S. (1), Wanschitz J. (2), Stanek G.(3), Grisold W(1). (1)Dept. of Neurology KFJ - LBI for Neurooncology , (2)Dept. of Neuropathology - AKH, (3)Dept. of Hygiene Univ. Vienna/Austria - Europe
Bannwarth's Syndrome, the 2nd most common nervous system involvement of borelliosis in Europe, usually remits completely after appropriate antibiotic treatment. A 55-year-old patient presented with an acute swelling of the right forearm: no tick bite and no erythema chronicum migrans in patient's history. He developed a left sided facial palsy, dysphagia, asymmetric bilateral radicular pain C7/C8, numbness in the ulnar distribution to both hands, spreading also into the C8 dermatome. Muscle power of the ulnar muscles of both hands was reduced. CSF was pleocytotic (60 ml) and specific antibody titers were positive in serum and CSF. With antibiotic therapy symptoms nearly regressed. Insidiously over 4 months he complained of increasing aching sensory sensations and numbness in both hands with weakness and atrophy in the ulnar hand muscles. Electrophysiology showed absent sensory conduction velocities and demyelinating changes on upper extremities only. Nerve biopsy demonstrated an axonal neuropathy with secondary changes pointing to a vasculitis. Borrelia specific IgG remained high in CSF and moderately remitted in serum. CSF cytology was normal. Repetition of therapy with ceftriaxone, pulsed steroids added, induced a prompt amelioration of symptoms. This borelliosis induced Bannwarth's syndrome, remitted after successful antibiotic therapy, and a painful multiplex neuropathy developed. Electrophysiology differed from radiculitis with absent sensory NCVs and demyelination in motor nerves.
NO EVIDENCE FOR AN INFECTIOUS CAUSE OF REFLEX SYMPATHETIC DYSTROPHY
van de Vusse A.C., Kemler M.A., Goossens V., Weber W.E.J. University Hospital Maastricht, Maastricht, Netherlands
In 52 patients (37 females and 15 men) with reflex sympathetic dystrophy (RSD) of one extremity, serological screening on antibodies against neurotropic micro-organisms was performed to investigate a linkage to RSD. The selection is a list of possible neurotropic infections in the North-Western Europe or pathogens ever associated with reflex sympathetic dystrophy or neurologic diseases. For epidemiological reasons pathogens as rabies, JC virus, poliovirus, mumps and HIV were not screened. None of the 52 patients had antibodies against Treponema pallidum, Borrelia burgdorferi or HTLV-1. Only four patients were positive for Campylobacter. For herpes simplex, varicella zoster, Epstein Barr and Parvovirus B19 the seroprevalences were between 76 and 100 percent but not different from the literature and also almost the same as found in an independent control group. For cytomegalovirus and Toxoplasma gondii, the prevalences were 40 and 23 percent respectively, equal to control values. No correlation was found between RSD and any of the investigated neurotropic microorganisms. Reflex sympathetic dystrophy is probably not caused by an acute, latent or chronic infection. Inflammation caused by neurogenic mediators, tissue damage or ischaemia is still theoretically possible.
CHANGES IN DORSAL ROOT GANGLIA BLOOD FLOW AND ENDONEURIAL FLUID PRESSURE FOLLOWING APPLICATION OF NUCLEUS PULPOSUS
Yabuki S., Kikuchi S., Igarashi T., Myers R.R.(1) Department of Orthopaedic Surgery, Fukushima Medical University, Fukushima, Japan, (1)Department of Anesthesiology and Pathology (Neuropathology), University of California, San Diego, La Jolla, CA
Nucleus pulposus (NP) is a TNF-rich component of intervertebral
discs that can be released from herniated and degenerative discs
into the epidural spaces of nerve roots and dorsal root ganglia
(DRG). To explore the pathophysiology of nucleus pulposus-induced
changes in DRG and related effects on the corresponding hindpaw,
we applied autologous NP to nerve roots and measured DRG blood
flow and endoneurial fluid pressure (EFP). Blood flow in the corresponding
hindpaw blood flow was also measured. Autologous NP was applied
to the rat L5 nerve root just proximal to the DRG (NP group).
For control, the same volume of autologous muscle was applied
to the nerve roots (control group). DRG and hindpaw blood flow
was continuously monitored for three hours after application of
these materials, using a laser Doppler flowprobe. EFP was recorded
with a servonull micropipette system. In the control group, blood
flow in the DRG and the corresponding hindpaw was not reduced
after application of muscle. However, blood flow was significantly
reduced in these tissues two hours after application of NP. EFP
in the NP group increased significantly compared with the control
group. Edema was the principal pathological finding seen consistently
in the nerve roots from NP animals and in many of the associated
DRGs. It was concluded that application of NP to nerve root increased
EFP and decreased blood flow in the DRG and the corresponding
hindpaw. These acute physiological changes may be important initial
factors in the pathogenesis of sciatica due to disc herniation.