Screening for late-onset Pompe disease in western Denmark.

OBJECTIVE: Late-onset Pompe disease (LOPD) is a rare autosomal recessively inherited metabolic myopathy caused by reduced activity of the lysosomal enzyme alpha-glucosidase. In a previous screening study at two large neuromuscular university clinics in Denmark, three patients with LOPD were identified out of 103 patients screened. No systematic screening has been performed at the other neurological departments in the western part of Denmark. Thus, patients with a diagnosis of unspecified myopathy were screened for LOPD. MATERIALS AND METHODS: At seven neurological departments in the western part of Denmark, medical records were evaluated for all patients registered with myopathy diagnosis codes (ICD 10 codes: G 71.0-71.9 and G 72.0-72.9) during the period January 1, 2002, to December 31, 2012. If no specific diagnosis has been reached, patients were invited for screening. Dried blood spot (DBS) test was used to analyze the activity of the enzyme alpha-glucosidase. RESULT: A total of 654 patients were identified. From the medical records, information was obtained concerning symptoms, family history, electromyography, muscle biopsy results and creatine kinase levels. Eighty-seven patients (13.3%) (males 61%) at a mean age of 53.3 years (SD 16.5) fulfilled the criteria for screening. A DBS test was performed in 47 (54%) patients. In all patients, the enzyme activity was within reference values. CONCLUSION: None of the screened patients had a reduced activity of the enzyme alpha-glucosidase. Although the cohort studied was small, our findings do not suggest that LOPD is underdiagnosed in patients with unspecified myopathy in western Denmark.

Autoimmune encephalitis associated with voltage-gated potassium channels-complex and leucine-rich glioma-inactivated 1 antibodies - a national cohort study.

BACKGROUND AND PURPOSE: The aim of this study was to describe clinical and paraclinical characteristics of all Danish patients who tested positive for anti-voltage-gated potassium channels (VGKC)-complex, anti-leucine-rich glioma-inactivated 1 (LGI1) and anti-contactin-associated protein-2 antibodies in the serum/cerebrospinal fluid between 2009 and 2013 with follow-up interviews in 2015 and 2016. METHODS: We evaluated antibody status, symptoms leading to testing, course of disease, suspected diagnosis and time of admission as well as diagnosis and treatment. All magnetic resonance imaging, electroencephalography and 18 F-fluorodeoxyglucose positron emission tomography scans were re-evaluated by experts in the field. RESULTS: A total of 28/192 patients tested positive for VGKC-complex antibodies by radioimmunoassay and indirect immunofluorescence; 17 had antibodies to LGI1 and 6/7 of the available cerebrospinal fluids from these patients were seropositive. These 17 patients all had a clinical phenotype appropriate to LGI1 antibodies. The remaining 11 were LGI1 negative (n = 4) or not tested (n = 7). Of these, two had a phenotype consistent with limbic encephalitis. The remaining phenotypes were Guillain-Barré syndrome, Creutzfeldt-Jakob disease, neuromyotonia and anti-N-methyl-D-aspartate receptor encephalitis. Magnetic resonance imaging abnormalities were demonstrated in 69% of the LGI1-positive patients. Two patients with normal magnetic resonance imaging demonstrated temporal lobe hypermetabolism using 18 F-fluorodeoxyglucose positron emission tomography. Abnormal electroencephalography recordings were found in 86% of the patients. Upon follow-up (median 3.2 years), the median modified Rankin Scale score of anti-LGI1-positive patients was 2 and only two patients reported seizures in the past year. CONCLUSIONS: Patients diagnosed with anti-LGI1 autoimmune encephalitis increased significantly from 2009 to 2014, probably due to increased awareness. In contrast to seropositive anti-VGKC-complex patients, all anti-LGI1-positive patients presented with a classical limbic encephalitis. The majority of patients recovered well.

Pain, spasticity and quality of life in individuals with traumatic spinal cord injury in Denmark.

STUDY DESIGN: Cross-sectional survey. OBJECTIVES: To estimate the prevalence, predictors and impact of self-reported pain and spasticity and examine variables affecting quality of life in individuals with a traumatic spinal cord injury (SCI). SETTING: Nationwide, Denmark. METHODS: An anonymous questionnaire was sent out to individuals with a traumatic SCI. The questionnaire included questions about demographics and SCI characteristics, pain, spasticity and quality of life. RESULTS: In total, 537 questionnaires were completed. Seventy-three percent reported chronic pain of which 60% used descriptors suggestive of neuropathic pain. The average pain intensity and interference were 5.6 (s.d. 2.3) and 5.0 (s.d. 2.8), respectively, on a 0-10 numeric rating scale (NRS), and 28.1% reported severe pain. Seventy-one percent reported spasticity. Average interference of spasticity was 2.9 (s.d. 2.7). Quality of life scores were 6.5 (s.d. 2.5) for life and life situation, 5.5 (s.d. 2.6) for physical health and 6.7 (s.d. 2.6) for mental health on the NRS (0-10). Female gender was associated with lower mental health scores and tetraplegia with lower physical health scores, and high pain interference and shorter time since injury were associated with lower quality-of-life scores for all three parameters. Pain with descriptors suggestive of neuropathic pain was associated with lower quality-of-life scores than pain without such descriptors. CONCLUSION: Chronic pain and spasticity are common problems after SCI, and in particular, high pain interference is associated with lower quality of life.

Pregabalin in the treatment of post-traumatic peripheral neuropathic pain: a randomized double-blind trial.

BACKGROUND: Pregabalin is effective in the treatment of peripheral and central neuropathic pain. This study evaluated pregabalin in the treatment of post-traumatic peripheral neuropathic pain (including post-surgical). METHODS: Patients with a pain score >or=4 (0-10 scale) were randomized and treated with either flexible-dose pregabalin 150-600 mg/day (n = 127) or placebo (n = 127) in an 8-week double-blind treatment period preceded by a 2-week placebo run-in. RESULTS: Pregabalin was associated with a significantly greater improvement in the mean end-point pain score vs. placebo; mean treatment difference was -0.62 (95% CI -1.09 to -0.15) (P = 0.01). The average pregabalin dose at end-point was approximately 326 mg/day. Pregabalin was also associated with significant improvements from baseline in pain-related sleep interference, and the Medical Outcomes Study sleep scale sleep problems index and sleep disturbance subscale (all P < 0.001). In the all-patient group (ITT), pregabalin was associated with a statistically significant improvement in the Hospital Anxiety and Depression Scale anxiety subscale (P < 0.05). In total, 29% of patients had moderate/severe baseline anxiety; treatment with pregabalin in this subset did not significantly improve anxiety. More patients reported global improvement at end-point with pregabalin than with placebo (68% vs. 43%; overall P < 0.01). Adverse events led to discontinuation of 20% of patients from pregabalin and 7% from placebo. Mild or moderate dizziness and somnolence were the most common adverse events in the pregabalin group. CONCLUSION: Flexible-dose pregabalin 150-600 mg/day was effective in relieving neuropathic pain, improving disturbed sleep, improving overall patient status, and was generally well tolerated in patients with post-traumatic peripheral neuropathic pain.

Clinical assessment of prognostic factors for long-term pain and handicap after whiplash injury: a 1-year prospective study.

BACKGROUND AND PURPOSE: Physical mechanisms are the possible factors involved in the development and maintenance of long-term handicaps after acute whiplash injury. This study prospectively examined the role of active neck mobility, cervical and extra-cervical pains, as well as non-painful complaints after a whiplash injury as predictors for subsequent handicap. METHODS: Consecutive acute whiplash patients (n = 688) were interviewed and examined by a study nurse after the median of 5 days after injury, and divided into a high- or a low-risk group by an algorithm based on pain intensity, number of non-painful complaints and active neck mobility [active cervical range of motion (CROM)]. All 458 high-risk patients and 230 low-risk patients received mailed questionnaires after 3, 6 and 12 months. Two examiners examined all high-risk patients (n = 458) and 41 consecutive low-risk patients at median 11, 109, 380 days after injury. The main outcome measures were: handicaps, severe headaches, neck pain and neck disability. RESULTS: The relative risk for a 1-year disability increased by 3.5 with initial intense neck pain and headaches, by 4.6 times with reduced CROM and by four times with multiple non-painful complaints. CONCLUSION: Reduced active neck mobility, immediate intense neck pain and headaches and the presence of multiple non-painful complaints are the important prognostic factors for a 1-year handicap after acute whiplash.

Impact of etiology and duration of pain on pharmacological treatment effects in painful polyneuropathy.

BACKGROUND: The pharmacological treatments for painful polyneuropathy have not changed much for more than a decade, and less than half of the patients obtain adequate pain relief with first line treatments. Therefore, patient-specific factors which could predict drug response are searched for. METHODS: We analysed data from four published, randomized, controlled trials of drugs in painful polyneuropathy to see if diabetic etiology and duration of neuropathic pain had an impact on drug efficacy. The studies had a cross-over design, and had nearly similar outcome recordings as well as a thorough baseline registration of symptoms, signs and quantitative sensory testing. 244 patient records of drug effect distributed over treatments with three antidepressants (imipramine, venlafaxine, escitalopram) and two anticonvulsants (pregabalin, oxcarbazepine) were analysed. RESULTS: Diabetes as etiology of polyneuropathy had no impact on the effect of antidepressants (imipramine, venlafaxine, escitalopram), but there was a significant interaction with treatment effect on anticonvulsants with better effects in diabetics (0.86 NRS points, p = 0.021) with most pronounced interaction for oxcarbazepine (1.47 NRS points, p = 0.032). There was an interaction between duration of neuropathic pain and treatment with antidepressants with better effect with duration less than 3 years (0.62 NRS points, p = 0.036), whereas anticonvulsants tended to work best with duration of pain for more than 3 years. CONCLUSION: Despite the small sample size and limited number of drugs included this study suggests that diabetic etiology of polyneuropathy may impact on the efficacy of anticonvulsants, and duration of neuropathic pain may impact on the efficacy of antidepressants. SIGNIFICANCE: This study found that duration of pain appears to have an impact on the effect of antidepressants in neuropathic pain and that diabetes as etiology for painful polyneuropathy appears to influence pain relief obtained with anticonvulsants.

Creatine kinase BB and beta-2-microglobulin as markers of CNS metastases in patients with small-cell lung cancer.

Creatine kinase (CK) and its BB isoenzyme (CK-BB) were measured in CSF in 65 evaluable patients suspected of CNS metastases secondary to small-cell lung cancer (SCLC). In addition, CSF and plasma levels of beta-2-microglobulin (beta-2-m) were measured in a group of 73 evaluable patients. Of the 65 patients analysed for CK-BB, 17 had meningeal carcinomatosis (MC), 26 had parenchymal metastases only, and 22 had no CNS disease. Patients with MC had a significantly higher CK-BB concentration in CSF than did patients belonging to the other two groups (P less than .01). Taking 0.4 U/L (upper limit in patients without CNS disease) as a cut-off point, 15 patients (88%) with MC had elevated CSF concentrations of CK-BB. Patients without CNS metastases had no CSF levels exceeding this value, whereas five patients with multiple CNS metastases did. Receiver operating characteristic (ROC) analysis suggests that CK-BB may be useful in distinguishing MC among patients suspected of having CNS metastases, and CK-BB appears superior to total CK, CSF protein, and CSF lactic dehydrogenase (LDH). In 12 patients with MC at autopsy, CK-BB was, with the above cut-off point, elevated in six patients with a false negative cytology. Of the 73 patients examined for beta-2-m, 18 had MC, 30 had parenchymatous metastases only, and 25 patients had no CNS metastases. The CSF concentrations in the three groups were not significantly different. The median concentrations in the groups were 133 nmol/L, 125 nmol/L, and 107 nmol/L, respectively. The ratios between beta-2-m in CSF and plasma were also not significantly different between the three groups. Thus, the data on CK-BB are promising, and further studies are warranted to see if the usefulness of CK-BB can be more firmly established. By contrast, beta-2-m has no role as a marker of CNS disease secondary to SCLC.

Insulin/hypoglycemia-induced adrenocorticotropin and beta-endorphin release: involvement of hypothalamic histaminergic neurons.

We have previously found that histamine (HA) is involved in the mediation of restraint- and ether stress-induced release of the POMC-derived peptides ACTH and beta-endorphin (beta-END). In the present study we investigated the possible involvement of hypothalamic histaminergic neurons in the mediation of insulin/hypoglycemia-induced release of ACTH and beta-END in conscious male rats. To do so, hypoglycemia stress was performed during 1) inhibition of HA synthesis, 2) activation of inhibitory presynaptic HA H3-auto-receptors, or 3) blockade of postsynaptic HA H1- or H2-receptors. Hypoglycemia (plasma glucose, 2.2 +/- 0.3 nmol) induced by insulin (3 IU/kg, ip) caused a 3- to 5-fold increase in the plasma concentrations of ACTH and beta-END. A negative exponential correlation was found between the plasma glucose concentration and the ACTH and beta-END levels. Pretreatment of the animals with the HA synthesis inhibitor alpha-fluoromethylhistidine (1.0 mumol) intracerebroventricularly (icv) in a lateral ventricle, inhibited the ACTH and beta-END responses to insulin/hypoglycemia by 60%. When administered ip (100 mumol/kg), the synthesis inhibitor decreased the beta-END response 50%, but did not affect ACTH secretion significantly. Pretreatment of the rats with the H3-receptor agonist R(alpha)methylhistamine (50 mumol/kg, ip, twice) inhibited the secretory responses of ACTH and beta-END to insulin/hypoglycemia by 60-80%. This inhibitory effect of R(alpha)methylhistamine was reversed by prior administration of the specific H3-receptor antagonist thioperamide. Administration of the H1-antagonists mepyramine and cetirizine dose-dependently inhibited the ACTH and beta-END responses to insulin/hypoglycemia, with the highest dose (mepyramine, 350 nmol, icv; cetirizine, 40 mumol/kg, ip) inhibiting the response by 80-100%. The H1-antagonist SKF-93944 (226 nmol, icv) inhibited the ACTH response, but had no effect on the beta-END response. Administration of the H2-antagonists cimetidine (400 nmol, icv) and ranitidine (400 nmol, icv) inhibited the ACTH and beta-END responses to insulin/hypoglycemia by 50-80%. We conclude that histaminergic neurons are involved in the mediation of the insulin/hypoglycemia-induced release of ACTH and beta-END and that the effect is mediated via activation of primarily postsynaptic H1-receptors and, to a lesser extent, H2-receptors.

Corticotropin-releasing activity of gastrin-releasing peptide in normal men.

Gastrin-releasing peptide (GRP; mammalian bombesin) exerts several functions within the hypothalamus and is a putative regulator of pituitary hormone secretion. We investigated the effect of GRP on the secretion of pituitary hormones and cortisol in normal men. GRP was infused iv as primed infusions of 0.12 pmol/kg BW. min for 30 min (GRP I) and 1.50 pmol/kg. min for an additional 30 min (GRP II). GRP dose-dependently stimulated ACTH secretion compared with the effect of saline [net change in ACTH (delta ACTH) before and after treatment: GRP I, 3 +/- 1 (+/- SEM) vs. 0 +/- 1 pmol/L (P less than 0.05); GRP II, 5 +/- 1 vs. -3 +/- 1 pmol/L; P less than 0.01)]. A further increase in plasma ACTH concentration occurred after cessation of GRP infusion (7 +/- 2 vs. 0 +/- 1 pmol/L; P less than 0.025). GRP caused a similar dose-dependent stimulation of cortisol secretion compared with the effect of saline [delta cortisol before and after treatment: GRP I, -19 +/- 21 vs. -68 +/- 14 nmol/L (P less than 0.05); GRP II, 38 +/- 33 vs. -86 +/- 15 nmol/L (P less than 0.005)]. The serum cortisol concentration increased further after cessation of the GRP infusion (72 +/- 31 vs. -124 +/- 33 nmol/L; P less than 0.0025). GRP dose-dependently stimulated beta-endorphin immunoreactivity compared with the effect of saline [delta beta-endorphin immunoreactivity before and after treatment: GRP I, 6 +/- 1 vs. -3 +/- 1 pmol/L (P less than 0.01); GRP II, 11 +/- 4 vs. -6 +/- 2 pg/mL (P less than 0.025)]. GRP had no effect on PRL or GH secretion. We suggest that GRP participates in the neuroendocrine regulation of the secretion of proopiomelanocortin-derived peptides.

Decreased nociceptive flexion reflex threshold in chronic tension-type headache.

OBJECTIVE: To study nociceptive processing in chronic tension-type headache. DESIGN: Survey of the threshold for the nociceptive flexion reflex obtained by sural nerve stimulation in a convenience sample of 40 patients with chronic tension-type headache and in 29 sex- and age-matched healthy subjects. Muscular response was recorded from the biceps femoris muscle. For each stimulation, subjects recorded pain on a visual analogue scale. RESULTS: In seven subjects (four headache sufferers and three healthy subjects), no nociceptive flexion reflex response could be elicited. The median nociceptive flexion reflex threshold in the headache group was significantly lower (median, 10 mA) than in the control group (median, 20 mA). Pain tolerance thresholds were significantly lower in the headache group than in the control group. A high degree of correlation was found between nociceptive flexion reflex threshold and tolerated stimulus strength. The slopes of the stimulus intensity/visual analogue scale pain rating response curves were steeper in patients with headache than in control subjects. CONCLUSIONS: Chronic tension-type headache may represent a disorder of an endogenous antinociceptive system with a lowering of tone and recruitment of descending inhibitory systems.

Handicap after acute whiplash injury: a 1-year prospective study of risk factors.

BACKGROUND: Exposure to a whiplash injury implies a risk for development of chronic disability and handicap, with reported frequencies ranging from 0% to 50% in follow-up studies. The exact risk for development of chronic whiplash syndrome is not known. OBJECTIVE: To prospectively determine the sensitivity and specificity of five possible predictors for handicap following a whiplash injury. METHODS: In a 1-year prospective study of persons with acute whiplash injury (n = 141) and control subjects who had acute ankle distortion (n = 40), pain intensity, number of nonpainful neurologic complaints, cervical mobility, workload during extension and flexion of the neck, and results of psychometric assessment were recorded. The consecutively sampled injured persons were assessed with structured and semistructured questionnaires, and underwent neurologic examination after 1 week and 1, 3, 6, and 12 months. After 3 to 4 years, participants with whiplash injury were questioned about legal issues. RESULTS: After 1 year, 11 (7.8%) persons with whiplash injury had not returned to usual level of activity or work. The best single estimator of handicap was the cervical range-of-motion test, which had a sensitivity of 73% and a specificity of 91% (p < 0.01, Cox regression analysis). Accuracy and specificity increased to 94% and 99% when combined with pain intensity and other complaints. This increase was gained at the expense of a reduced sensitivity. Initiation of lawsuit within first month after injury did not influence recovery. CONCLUSION: The cervical range-of-motion test has a high sensitivity in prediction of handicap after acute whiplash injury. The value of cervical range-of-motion test is further improved by additional recording of symptoms and pain intensity.

Neurologic disease among women with breast implants.

OBJECTIVE: To investigate the risk of neurologic disease among women with silicone breast implants. BACKGROUND: Since 1992, several case series reported an association between silicone breast implants and neurologic diseases. METHODS: Between 1977 and 1992, 1,135 women received cosmetic silicone breast implants, and 7,071 women had breast reduction surgery, as identified by the Danish National Register of Patients (NRP). NRP files provided information on numbers and types of subsequent neurologic disorders at hospital discharge, which were compared with expected numbers, calculated on the basis of national hospital discharge rates. RESULTS: In the two study cohorts, hospital discharge rates for neurologic diseases were raised by some 60% to 70% compared with Danish women in general. Among women with silicone breast implants, 13 subsequently developed a neurologic disorder compared with 7.7 expected; whereas in the comparison group, 63 observed versus 39.1 expected disorders were recorded. These results indicate that relative to the comparison cohort, women with implants had no excessive levels of definite neurologic disease. Furthermore, medical record reviews revealed that the majority of women with implants discharged with a neurologic diagnosis had either symptoms before implant surgery or neurologic symptoms secondary to degenerative diseases. CONCLUSIONS: Our findings do not support the hypothesis of silicone-induced neurologic disease. The reasons for the elevated rates of neurologic disease in both the exposed and comparison cohorts remain unclear, but may reflect selection processes associated with these women seeking medical care more often than the general population.

Increased cerebrospinal fluid Met-enkephalin immunoreactivity in patients with chronic tension-type headache.

Cerebrospinal fluid (CSF) concentration of Met-enkephalin immunoreactivity (Met-enkephalin-ir) was determined by radioimmunoassay in 47 patients with chronic tension-type headache and in 47 headache-free control subjects. Thirty-nine of the controls were patients receiving spinal analgesia before surgery for diseases not associated with pain; 8 were healthy paid volunteers. Patients reporting migraine more than 1 day per month were excluded. Pericranial tenderness, nociceptive flexion reflex and thermal pain thresholds were determined in the majority of the patients. The median level of CSF Met-enkephalin-ir was significantly higher (115 pmol/l) (quartiles (107-134) pmol/l) in the headache patients than in the controls (median 79 pmol/l) (quartiles (73-87) pmol/l) (Mann-Whitney, P < 0.001). No indication of sex-difference or correlation with age with respect to CSF Met-enkephalin-ir was found. No correlation was found between CSF Met-enkephalin-ir and either pericranial tenderness, nociceptive flexion-reflex threshold, or thermal pain threshold. There was no indication of correlation between consumption of mild analgesics and CSF Met-enkephalin-ir. The higher levels of CSF Met-enkephalin-ir in the headache patients may be indicate activation of the enkephalinergic antinociceptive system at the spinal/trigeminal level, whereas the beta-endorphinergic system appears normal. This enkephalinergic activation may be caused by increased activity in the primary nociceptive afferents, or may be compensatory to decreased activity in other endogenous antinociceptive systems than the opioid.

Release of beta-endorphin immunoreactivity from brain by activation of a hypothalamic N-methyl-D-aspartate receptor.

Lateral ventricle-cisterna magna perfusion in the halothane-anesthetized rat was used as a model to study beta-endorphin release in the brain. Microinjection of N-methyl-D-aspartate into the arcuate nucleus of the hypothalamus released beta-endorphin immunoreactivity into perfusate and the release was blocked by systemic pretreatment with the N-methyl-D-aspartate antagonist dizocilpine (MK-801). N-methyl-D-aspartate microinjections did not increase beta-endorphin immunoreactivity in plasma, and pretreatment with dexamethasone did not prevent release of beta-endorphin immunoreactivity into perfusate, emphasizing that the released beta-endorphin immunoreactivity did not come from plasma. The non-N-methyl-D-aspartate glutamate receptor agonist alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid hydrobromide did not release beta-endorphin immunoreactivity. High-performance liquid chromatography characterization of perfusates collected after N-methyl-D-aspartate microinjection showed that a major part, but not all, of the beta-endorphin immunoreactivity co-eluted with authentic beta-endorphin. Microinjection of N-methyl-D-aspartate provoked an algogenic response in the anesthetized rat, and inhibited the motor and cardiovascular responses to tail immersion in 52.5 degrees C water. This block was reversed by pretreatment with MK-801, but not naloxone. Injection of alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid hydrobromide elicited the same behavioral response and blocked the nociceptive tail-dip reaction, but did not release beta-endorphin immunoreactivity.(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebrospinal fluid beta-endorphin in models of hyperalgesia in the rat.

Cerebrospinal fluid (CSF) obtained by acute percutaneous puncture of the cisternal membrane of the halothane anesthetized rat has low but measurable concentrations of beta-endorphin-like immunoreactivity (beta-EPir: 32.8 +/- 3.0 pmol/l). Chromatographic separation of beta-EPir showed that authentic beta-endorphin1-31 was the main component of beta-EPir in cisternal CSF. Subcutaneous injection of 5% formalin in the hind paws did not increase beta-EPir in cisternal CSF. Rats with tactile paw hyperalgesia evoked by unilateral ligation of the L5/6 nerve roots 2 weeks earlier had beta-EPir concentrations that did not differ from sham operated or unoperated control animals. In contrast, capsaicin injected in the hindpaws increased the mean beta-EPir concentration compared to saline injections (P = 0.006) 45 min after emerging from anesthesia following injection. These results show that acute activation of C fibers (by capsaicin) will evoke the release of beta-endorphin into the CSF, suggesting activation of the beta-endorphin terminal systems in the brain/midbrain. The failure of formalin injections to release beta-EPir to CSF may be due to specificity of the afferent stimulus evoking beta-EPir release, a lower stimulus intensity, and/or the duration of the stimulus generated by formalin. The normal concentrations of beta-EPir found in the hyperalgesic state following nerve injury suggest that the supraspinal beta-endorphin system does not display tonic changes under such conditions.

Effect of sulpiride or paroxetine on cerebrospinal fluid neuropeptide concentrations in patients with chronic tension-type headache.

In lumbar cerebrospinal fluid (CSF) obtained from patients with chronic tension-type headache (CTH), the concentrations of beta-endorphin, met-enkephalin, dynorphin, cholecystokinin (CCK), calcitonin gene-related peptide (CGRP), and somatostatin were measured before and after 8 weeks of treatment with sulpiride or paroxetine. We previously reported higher than normal met-enkephalin concentrations in CTH. The present study reveals normal basal concentrations of CCK, CGRP and somatostatin and slightly decreased dynorphin in the same patients. Treatment with sulpiride or paroxetine did not change the concentration of any of the neuropeptides measured. These data suggest central changes in opioid systems but not in other peptide systems (CCK, CGRP, somatostatin) involved in nociceptive processing at the level of the spinal cord dorsal horn/nucleus caudalis of the trigeminal nerve in CTH. Such central changes might be pathophysiologically important or merely secondary to other more important occurrences. The lack of changes in neuropeptide concentrations during drug treatment makes planning of studies involving CSF analysis easier, but also limits the probability of obtaining information on specific neuropeptide systems through CSF analysis.

Quantitative assessment of tactile allodynia in the rat paw.

We applied and validated a quantitative allodynia assessment technique, using a recently developed rat surgical neuropathy model wherein nocifensive behaviors are evoked by light touch to the paw. Employing von Frey hairs from 0.41 to 15.1 g, we first characterized the percent response at each stimulus intensity. A smooth log-linear relationship was observed, with a median 50% threshold at 1.97 g (95% confidence limits, 1.12-3.57 g). Subsequently, we applied a paradigm using stimulus oscillation around the response threshold, which allowed more rapid, efficient measurements. Median 50% threshold by this up-down method was 2.4 g (1.81-2.76). Correlation coefficient between the two methods was 0.91. In neuropathic rats, good intra- and inter-observer reproducibility was found for the up-down paradigm; some variability was seen in normal rats, attributable to extensive testing. Thresholds in a sizable group of neuropathic rats showed insignificant variability over 20 days. After 50 days, 61% still met strict neuropathy criteria, using survival analysis. Threshold measurement using the up-down paradigm, in combination with the neuropathic pain model, represents a powerful tool for analyzing the effects of manipulations of the neuropathic pain state.

Release into ventriculo-cisternal perfusate of beta-endorphin- and Met-enkephalin-immunoreactivity: effects of electrical stimulation in the arcuate nucleus and periaqueductal gray of the rat.

To examine the resting and evoked release of the endogenous opioid peptides beta-endorphin and Met-enkephalin from brain, we examined the levels of the respective immunoreactivities in the lateral ventricle-cisterna magna perfusate of the halothane-anesthetized rat. Ten Hz but not 100 Hz stimulation in the arcuate nucleus (ARC) of the hypothalamus released beta-endorphin immunoreactivity (beta-EPir) to the perfusate, whereas 100 Hz but not 10 Hz stimulation in the periaqueductal gray (PAG) of the mid brain released Met-enkephalin immunoreactivity (MEir). MEir was not released by stimulation in ARC and beta-EPir was not released by stimulation in PAG. Characterization of the released beta-EPir and MEir by high performance liquid chromatography showed that authentic beta-endorphin and Met-enkephalin were the major constituents of beta-EPir and MEir, respectively. Systemic administration of the dopaminergic antagonist haloperidol increased plasma, but not perfusate levels of beta-EPir. Both the opioid antagonist naloxone and the NMDA antagonist MK-801 failed to affect beta-EPir or MEir release. ARC and PAG stimulated inhibited a nociceptive reflex (tail-dip in 52.5 degrees C water), and naloxone did not reliably reverse this inhibition. These data support the previously suggested possibility of opioid mediation of stimulation induced analgesia, although we were unable to confirm the theory by naloxone reversibility in this study. Furthermore, the data support the assumption that measurement of opioid peptides in cerebrospinal fluid is a relevant approach in research aimed at elucidating the physiological and pathophysiological roles of endogenous opioid peptides.

Release of beta-endorphin immunoreactivity into ventriculo-cisternal perfusate by lumbar intrathecal capsaicin in the rat.

A model employing perfusion of artificial cerebrospinal fluid from the lateral ventricle to the cisterna magna in the halothane anesthetized rat was used to study beta-endorphin release in the brain. Injection of 75 micrograms capsaicin into the lumbar intrathecal space released beta-endorphin immunoreactivity into perfusate. The release was blocked by intrathecal pretreatment with 1.25 mg lidocaine and the capsaicin receptor antagonist capsazepine (92 micrograms), showing that the release is caused by binding of capsaicin to a spinal receptor. The release was also blocked by intrathecal pretreatment with the NMDA antagonist MK-801 (3 micrograms) and the NK-1 receptor antagonist CP96,345 (200 micrograms), whereas the AMPA receptor antagonist NBQX (6 micrograms) yielded no significant inhibition. Surprisingly, morphine (30 micrograms) and sufentanil (1.5 micrograms) did not prevent release of beta-endorphin immunoreactivity, although blocking the cardiovascular responses to a noxious heat stimulus. High performance liquid chromatography characterization of perfusates collected after capsaicin injection showed that all beta-endorphin immunoreactivity coeluted with authentic beta-endorphin1-31. beta-Endorphin immunoreactivity in plasma was increased 10 min, but not 25 min, after capsaicin injection. Capsaicin injection abolished the motor and cardiovascular responses to tail immersion in 52.5 degrees C water. Addition of MK-801 (10(-4) mol/l) to the lateral ventricle-cisterna magna perfusate blocked the capsaicin-induced beta-endorphin release, showing that our previous demonstration of an NMDA receptor regulating arcuate nucleus beta-endorphin neuron activity has functional significance. We conclude that in this in vivo, anesthetized preparation including three hot water tail immersions, beta-endorphin can be released into a ventriculo-cisternal perfusate, by activation of the central axons of small primary afferent neurons by capsaicin. These data support the idea that central beta-endorphin may be released in response to prolonged, intense noxious stimulation.

The clinical picture of neuropathic pain.

Neuropathic pains refer to a heterogeneous group of pain conditions characterised by lesion or dysfunction of the normal sensory pathways. Clinical characteristics include: delayed onset of pain after nervous system lesion, pain in area of sensory loss, spontaneous and different evoked types of pains. It has so far only been possible to classify these pains on basis of underlying cause or on anatomical location. The mechanisms underlying neuropathic pain are not yet clear, but neuronal hyperexcitability in those neurons that have lost their normal patterned input seems to be a common denominator for many, if not all types, of neuropathic pains. Along these lines, a mechanism-based classification has recently been proposed, which is an attractive approach because it provides a frame for a rationally based therapy of neuropathic pains. The clinical manifestations of neuronal hyperexcitability due to nervous system lesions is described.