CNS Measures of Pain Responses Pre- and Post-Anesthetic Ketamine in a Patient with Complex Regional Pain Syndrome.

BACKGROUND: Previous reports have indicated that ketamine anesthesia may produce significant improvement if not complete recovery of patients with complex regional pain syndrome (CRPS). AIMS: Here we report on a patient who had CRPS affecting mainly the right side of her body who underwent functional magnetic resonance imaging (fMRI) scans prior to and in the months following apparent successful treatment with anesthetic doses of ketamine. MATERIALS AND METHODS: The patient underwent two imaging sessions: one during her pain state (CRPS+) and 1 month after her ketamine treatment in her pain-free state (CRPS-). Both spontaneous and evoked (brush, cold, and heat) pain scores decreased from 7­9/10 on a visual analog scale prior to the treatment to 0­1 immediately following and for months after the treatment. For each imaging session, the identical mechanical (brush) and thermal (cold and heat) stimuli were applied to the same location (the skin of the dorsum of the right hand). RESULTS: Comparison of CRPS+ vs CRPS- for the three stimuli showed significant changes throughout the cerebral cortex (frontal, parietal, temporal, cingulate, and hippocampus), in subcortical regions such as caudate nucleus, and in the cerebellum. In addition, resting state network analysis showed a reversal of brain network state, and the recovered state paralleled specific default networks in healthy volunteers. DISCUSSION: The observed changes in brain response to evoked stimuli provide a readout for the subjective response. CONCLUSION: Future studies of brain function in these patients may provide novel insight into brain plasticity in response to this treatment for chronic pain.

Development and validation of a sensitive LC-MS/MS method for the determination of D-serine in human plasma.

A validated LC-MS/MS method was developed for the determination of d -Serine in human plasma. The method was fully validated for use with human plasma samples and was linear from 0.19 nmol/ml to 25 nmol/ml. The coefficient of variation was ≤5% for the high QC standards and ≤8% for the low QC standards in plasma. d -Serine and l -serine were resolved by pre-column derivatization using (R)-1-Boc-2-piperidine carbonyl chloride as the derivatizating agent. The method was used to determine the concentration of d-serine in plasma samples obtained in patients receiving a continuous 5-day intravenous infusion of (R,S)-ketamine. The changes in d-Ser levels varied in the six patients, with circulating d-Ser levels increasing as much as 35% in a patient, while decreasing 20% in a patient. While only preliminary data, the results suggests the potential importance in determining the d-Ser levels in plasma and their potential role in physiological response.

Elevated blood levels of inflammatory monocytes (CD14+ CD16+ ) in patients with complex regional pain syndrome.

Complex regional pain syndrome (CRPS) is a chronic pain disorder. Although its pathophysiology is not completely understood, neurogenic inflammation is thought to play a significant role. Microglia and astrocytes are activated following tissue injury or inflammation and have been reported to be both necessary and sufficient for enhanced nociception. Blood-borne monocytes/macrophages can infiltrate the central nervous system (CNS) and differentiate into microglia resulting in hypersensitivity and chronic pain. The primary aim of this study was to evaluate the proportion of the proinflammatory CD14(+) CD16(+) monocytes as well as plasma cytokine levels in blood from CRPS patients compared to age- and gender-matched healthy control individuals. Forty-six subjects (25 CRPS, 21 controls) were recruited for this study. The percentage of monocytes, T, B or natural killer (NK) cells did not differ between CRPS and controls. However, the percentage of the CD14(+) CD16(+) monocyte/macrophage subgroup was elevated significantly (P<0·01) in CRPS compared to controls. Individuals with high percentage of CD14(+) CD16(+) demonstrated significantly lower (P<0·05) plasma levels on the anti-inflammatory cytokine interleukin (IL)-10. Our data cannot determine whether CD14(+) CD16(+) monocytes became elevated prior to or after developing CRPS. In either case, the elevation of blood proinflammatoty monocytes prior to the initiating event may predispose individuals for developing the syndrome whereas the elevation of blood proinflammatory monocytes following the development of CRPS may be relevant for its maintenance. Further evaluation of the role the immune system plays in the pathogenesis of CRPS may aid in elucidating disease mechanisms as well as the development of novel therapies for its treatment.

Migraine may be a risk factor for the development of complex regional pain syndrome.

The aim was to assess the relative frequency of migraine and the headache characteristics of complex regional pain syndrome (CRPS) sufferers. CRPS and migraine are chronic, often disabling pain syndromes. Recent studies suggest that headache is associated with the development of CRPS. Consecutive adults fulfilling International Association for the Study of Pain criteria for CRPS at a pain clinic were included. Demographics, medical history, and pain characteristics were obtained. Headache diagnoses were made using International Classification of Headache Disorders, 2nd edn criteria. Migraine and pain characteristics were compared in those with migraine with those without. anova with Tukey post hoc tests was used to determine the significance of continuous variables and Fisher's exact or χ(2) tests for categorical variables. The expected prevalence of migraine and chronic daily headache (CDH) was calculated based on age- and gender-stratified general population estimates. Standardized morbidity ratios (SMR) were calculated by dividing the observed prevalence of migraine by the expected prevalence from the general population. The sample consisted of 124 CRPS participants. The mean age was 45.5 ± 12.0 years. Age- and gender-adjusted SMRs showed that those with CRPS were 3.6 times more likely to have migraine and nearly twice as likely to have CDH as the general population. Aura was reported in 59.7% (74/124) of participants. Of those CRPS sufferers with migraine, 61.2% (41/67) reported the onset of severe headaches before the onset of CRPS symptoms Mean age of onset of CRPS was earlier in those with migraine (34.9 ± 11.1 years) and CDH (32.5 ± 13.4 years) compared with those with no headaches (46.8 ± 14.9 years) and those with tension-type headache (TTH) (39.9 ± 9.9 years), P < 0.05. More extremities were affected by CRPS in participants with migraine (median of four extremities) compared with the combined group of those CRPS sufferers with no headaches or TTH (median 2.0 extremities), P < 0.05. The presence of static, dynamic and deep joint mechano-allodynia together was reported by more CRPS participants with migraine (72.2%) than those with no headaches or TTH (46.2%), P ≤ 0.05. Migraine may be a risk factor for CRPS and the presence of migraine may be associated with a more severe form of CRPS. Specifically: (i) migraine occurs in a greater percentage of CRPS sufferers than expected in the general population; (ii) the onset of CRPS is reported earlier in those with migraine than in those without; and (iii) CRPS symptoms are present in more extremities in those CRPS sufferers with migraine compared with those without. In addition, as we also found that the presence of aura is reported in a higher percentage of those CRPS sufferers with migraine than reported in migraineurs in the general population, further evaluation of the cardiovascular risk profile of CRPS sufferers is warranted.

High-dose cyclophosphamide without stem-cell rescue for refractory CIDP.

Four patients with chronic inflammatory demyelinating polyneuropathy (CIDP) who were refractory to conventional treatment were treated with high-dose cyclophosphamide (200 mg/kg over 4 days). All improved in functional status and muscle strength. Nerve conduction studies improved in three of four. Other immunomodulatory medications have been discontinued. High-dose cyclophosphamide can be given safely to patients with CIDP and patients with disease persistence after standard therapy may have a response that lasts for over 3 years and results in long-term disease remission.

Diagnostic criteria used in studies of reflex sympathetic dystrophy.

OBJECTIVE: Assessment of the diagnostic criteria of reflex sympathetic dystrophy (RSD) and evaluation of the impact of the introduction of the diagnostic criteria of complex regional pain syndrome (CRPS) on the international application of diagnostic criteria of RSD. METHODS: Randomized controlled trials and clinical investigations, published between January 1980 and June 2000, were evaluated with regard to the applied diagnostic criteria of RSD. RESULTS: One hundred seven studies were identified. Thirty-four of these studies were excluded because of inadequate reporting of diagnostic criteria. The 73 included studies were not homogeneous with regard to the diagnostic criteria because they applied many different aspects of sensory and autonomic features. Only 12% of the studies considered the presence of motor features, mostly vaguely described, as mandatory for the diagnosis RSD. Although 10 of the 23 studies published since the introduction of CRPS have applied this term, only 3 used the exact criteria without additions or other modifications. CONCLUSION: Diagnostic criteria sets of RSD focus on many different aspects of sensory and autonomic features that generally are described vaguely. This has not changed since the introduction of the CPRS criteria. These findings question whether the current criteria adequately define RSD.

Neuropathic central pain: epidemiology, etiology, and treatment options.

BACKGROUND: Nociceptive pain is a major problem in clinical neurology. Peripheral nerve injury may change the physiology of the dorsal horn so that pain becomes progressively centralized. OBJECTIVE: To review mechanisms underlying the plasticity of dorsal root ganglia and dorsal horn neurons that lead to central pain from a peripheral nerve injury. RESULTS: Evidence is reviewed that points to molecular changes in nociceptive terminals, ectopic firing of afferent pain fibers at the level of the dorsal root ganglia, and physiologic changes of the N-methyl-D-aspartate receptor that cause chronic nociceptive pain. CONCLUSIONS: Central sensitization is the physiologic manifestation of many severe peripherally induced pain states. It is maintained by nociceptive input and a physiologic change in the N-methyl-D-aspartate receptor. It consists of: (1) hypersensitivity at the site of injury; (2) mechanoallodynia; (3) thermal hyperalgesia; (4) hyperpathia; (5) extraterritoriality in the case of complex regional pain syndrome/reflex sympathetic dystrophy; and (6) associated neurogenic inflammation, autonomic dysregulation, and motor phenomena.

Neurologic complications of the Novacor left ventricular assist device.

BACKGROUND: The left ventricular assist device (LVAD) is a bridging mechanism for patients with severe heart failure to remain viable until heart transplantation. The rate of cerebral embolism has been reported as high as 47% in some studies but the rate of other neurologic complications in patients with LVADs is not known. METHODS: Retrospective chart review of all patients who had LVADs implanted at our hospital from September 1993 until September 1997. Complications from the time of implantation until heart transplantation or death and functional outcome were assessed. RESULTS: Twenty-three patients had LVADs placed in the four-year period. Of 23 patients, 9 had neurologic complications after placement of the LVAD. These included four strokes, three seizures, and two cases of delirium. The 3 patients with seizures all died from multiorgan failure. All of the patients with strokes received a transplant. One patient with delirium died from multiorgan failure and another received a transplant. The most devastating medical complication was renal failure, which occurred in 7 patients and was associated with 100% mortality. All surviving patients with neurologic complications went on to transplant and good functional outcome. CONCLUSIONS: Neurologic complications are common in patients with LVADs, occurring in 9 out of 23 patients in our series. Seizures are a poor prognostic indicator and were associated with 100% mortality. Strokes did not have a negative impact on outcome. Patients with delirium had a mixed outcome, which reflects the multifactorial nature of delirium. Further study needs to be done to limit the neurologic complications associated with LVADs and further improve outcomes.

Increased plasma endothelin levels in angina patients with rapid coronary artery disease progression.

AIMS: To investigate the association between plasma endothelin levels and rapid coronary artery disease progression, as assessed by quantitative angiography. METHODS AND RESULTS: Changes in diameter were assessed in 224 coronary stenoses of 92 consecutive patients (62 men) with chronic stable angina pectoris who were on a waiting list for routine coronary angioplasty and underwent coronary angiography on two occasions: the first (diagnostic) angiogram was carried out at study entry and the second 5.5+/-3.0 months later, immediately prior to coronary angioplasty. A digital quantitative angiographic analysis system was used to assess differences in stenosis diameter between the first and second angiogram. Plasma immunoreactive endothelin levels were estimated by radioimmunoassay at study entry. Rapid coronary artery disease progression occurred in 29 (31.5%) patients according to pre-established criteria: 12 (41%) had a > or =10% diameter reduction of at least one pre-existing stenosis > or =50%, 10 (34%) had a > or =30% diameter reduction of a pre-existing stenosis <50%, 5 (17%) patients developed a new stenosis and 2 (7%) had progression of a lesion to total occlusion by the second angiogram. Baseline demographic, clinical and angiographic data were similar in patients with and without stenosis progression. Plasma endothelin levels were significantly higher in patients with rapid disease progression than in those without (5.7+/-2.0 pg. ml(-1)vs 3.9+/-1.6 pg. ml(-1), P<0.001). Multiple logistic regression analysis revealed that endothelin was an independent predictor of disease progression (P=0.001). Moreover, endothelin levels above 4.26 pg. ml(-1)(the median of the total endothelin concentrations) were associated with a sixfold increase in the risk of developing rapid stenosis progression. CONCLUSIONS: Plasma endothelin is raised in patients with coronary artery disease progression and may be a marker of risk of rapid stenosis progression. Endothelin may also play a pathogenic role in this process.

Embolic stroke secondary to an aortic arch tumor--a case report.

An acute stroke from an aortic arch tumor is reported. These tumors are rare and have to be differentiated from atheromas. Aortic atheromas commonly present with embolic phenomena and occasionally as masses. Aortic tumors are more likely to produce obstructive phenomena, presenting as a coarctation or dissection. Magnetic resonance imaging with gadolinium can facilitate the diagnosis. A literature review of aortic masses and their diagnosis and treatment are presented.

Quantitative sensory studies in complex regional pain syndrome type 1/RSD.

OBJECTIVE: Patients with complex regional pain syndrome type I (CRPSD1) may have thermal allodynia after application of a non-noxious thermal stimulus to the affected limb. We measured the warm, cold, heat-evoked pain threshold and the cold-evoked pain threshold in the affected area of 16 control patients and patients with complex regional pain syndrome type 1/RSD to test the hypothesis that allodynia results from an abnormality in sensory physiology. SETTING: A contact thermode was used to apply a constant 1 degrees C/second increasing (warm and heat-evoked pain) or decreasing (cold and cold-evoked pain) thermal stimulus until the patient pressed the response button to show that a temperature change was felt by the patient. Student t test was used to compare thresholds in patients and control patients. RESULTS: The cold-evoked pain threshold in patients with CRPSD1/RSD (p <0.001) was significantly decreased when compared with the thresholds in control patients (i.e., a smaller decrease in temperature was necessary to elicit cold-pain in patients with CRPSD1/RSD than in control patients). The heat-evoked pain threshold in patients with CRPS1/RSD was (p <0.05) decreased significantly when compared with thresholds in control patients. The warm- and cold-detection thresholds in patients with CRPS1/RSD were similar to the thresholds in control patients. CONCLUSIONS: This study suggests that thermal allodynia in patients with CRPS1/RSD results from decreased cold-evoked and heat-evoked pain thresholds. The thermal pain thresholds are reset (decreased) so that non-noxious thermal stimuli are perceived to be pain (allodynia).

Postinjury neuropathic pain syndromes.

Pain is clearly one of the most daunting problems of modern medicine. Posttraumatic neuropathic pain syndromes are a major component of the clinical problem. Structural lesions affecting roots, nerves, the plexi, and central structures can be imaged noninvasively. The molecular biology of the intraneural cascades that cause sensitization of the central pain-projecting neurons of the dorsal horn and subsequent allodynia, hyperalgesia, and hyperpathia is a subject of intense inquiry. The role of the clinician in identifying and eliminating the source of the pain is crucial before the effects of excitotoxicity and central sensitization permanently alter the physiology of the central pain-projecting neurons and make treatment ineffectual.

The expression pattern of thyroid hormone response genes in the tadpole tail identifies multiple resorption programs.

Expression of genes up-regulated by thyroid hormone (TH) during amphibian tail resorption was localized by in situ hybridization. The constitutive thyroid hormone receptor (TRalpha) and its heterodimeric partners (RXRalpha and RXRbeta) are expressed ubiquitously in the resorbing tail. A group of early response genes, including those encoding transcription factors, are expressed at greatest levels within tissues whose cells attempt to grow and differentiate in the tail, but eventually succumb to the resorption program. The TH-inducible TR isoform, TRbeta, is expressed ubiquitously in the tail, but especially high in fibroblasts. Similarly, a group of delayed response genes including two proteolytic enzymes that appear to execute the tail resorption program, is expressed specifically in fibroblasts that line and surround the notochord and lie beneath the epidermal lamella (subepidermal fibroblasts). During active tail resorption these fibroblasts invade their neighboring epidermal and notochord lamellae as part of the resorption process. Expression analysis implicates the single layer of invasive subepidermal fibroblasts as crucial in tail resorption. Stromelysin-3 is up-regulated by TH with early kinetics, and is expressed most actively in fibroblasts within the tail fins. None of the proteases are expressed in the tadpole epidermis, which will be replaced entirely during metamorphosis. While very few TH response genes are expressed in tadpole muscle, many are activated in fibroblasts that surround muscle and could induce muscle cell death by proteolysis of the extracellular matrix. These distinct localization patterns suggest that the common fate of all cell types within the tail is the result of multiple genetic programs.

Methylenetetrahydrofolate reductase polymorphism (C-677T) and coronary artery disease.

1. Many studies have shown that hyperhomocysteinaemia is a risk factor for atherosclerotic vascular disease. A mutation (C-677T) in the gene coding for the methylenetetrahydrofolate reductase (MTHFR) enzyme has been shown to produce a thermolabile form of the enzyme. Homozygosity for this mutation has been correlated with an elevated plasma homocysteine concentration. The present study aimed to determine whether this mutation was a risk factor for coronary artery disease (CAD). This was achieved by comparing the frequency of the C-677T mutation in patients with angiographically proven CAD against angiographically normal patients in two separate U.K. samples. The analysis was repeated with CAD patients split into those with >=99% stenosis of arteries and those without, to establish whether the C-677T mutation could be correlated with severity of CAD.2. Two patient groups were selected from London and Sheffield. The London group comprised 174 cases and 148 controls. The Sheffield group comprised 93 cases and 85 controls. The DNA samples of the patients were genotyped by polymerase chain reaction and restriction enzyme digestion.3. For London the homozygous C-677T frequencies were: 0.07 (controls), 0.09 (CAD without >=99% stenosis) and 0.10 (CAD with >=99% stenosis). For Sheffield the homozygous C-677T frequencies were: 0.08 (controls), 0.10 (CAD without >=99% stenosis) and 0.11 (CAD with >=99% stenosis). No association was found between the C-677T mutation and CAD in our sample geographical groups. Statistical comparison by genotype distribution for 0 VD (no vessel disease, i.e. 0% diameter reduction in all epicardial arteries) versus CAD without >=99% stenosis: London, P=0.19; Sheffield, P=0.53; 0 VD versus CAD with >=99% stenosis: London, P=0. 23; Sheffield, P=0.55.

Angiographic progression in patients with angina pectoris and normal or near normal coronary angiograms who are restudied due to unstable symptoms.

BACKGROUND: Syndrome X patients commonly remain symptomatic during follow-up and may be readmitted with unstable anginal symptoms. Angiographic disease progression must be considered as a possible mechanism for instability, particularly where multiple coronary risk factors are present and an interval of several years has elapsed since previous angiography. METHODS AND RESULTS: We reviewed data from 139 consecutive patients with chest pain and normal or near normal coronary angiograms (101 patients with completely normal angiograms and 38 patients with minimal lumenal irregularities). During a 5-year period, 24 patients (19 women, median age 56 years) underwent repeat angiography due to primary unstable angina (median interval between angiograms 58 months (range 8-130 months)). This group included three patients with minimal lumenal irregularities and four patients with left bundle branch block. Only two patients had progression to significant angiographic stenosis (> 30% diameter reduction); both were male patients with minimal irregularities at baseline angiography, left bundle branch block and multiple coronary risk factors. However, overall only two of 18 (11%) patients with one or more conventional coronary risk factors had angiographic progression. CONCLUSIONS: Unstable symptoms in patients with chest pain and previously normal or near normal coronary arteriograms are rarely due to angiographic disease progression. However, the presence of minimal lumenal irregularities at baseline angiography and LBBB may identify a sub-group at increased risk.

Elevated plasma lipoprotein(a) is associated with coronary artery disease in patients with chronic stable angina pectoris.

OBJECTIVES: We sought to assess the relation between plasma lipoprotein(a) [Lp(a)] levels, clinical variables and angiographic coronary artery disease (CAD) in patients with chronic stable angina. BACKGROUND: The relation between plasma Lp(a) levels and the severity and extent of angiographic CAD has not been studied in well characterized patients with stable angina pectoris. METHODS: We investigated clinical variables, lipid variables and angiographic scores in 129 consecutive white patients (43 women) undergoing coronary angiography for chronic stable angina. RESULTS: Plasma Lp(a) levels were significantly higher in patients with than in those without significant angiographic stenoses (> or =70%) (372 mg/liter [interquartile range 87 to 884] vs. 105 mg/liter [interquartile range 56 to 366], respectively, p=0.002). This difference remained significant when patients with mild or severe angiographic disease were compared with those with completely normal coronary arteries (312 mg/liter [interquartile range 64 to 864] vs. 116 mg/liter [interquartile range 63 to 366], respectively, p=0.02). However, subset analysis indicated that this difference achieved statistical significance only in women. Multiple logistic regression analysis indicated that Lp(a) concentration was independently predictive of significant angiographic stenoses (adjusted odds ratio [OR] 9.1, 95% confidence interval [CI] 2.0 to 42.1, p=0.006) and remained true even after exclusion of patients receiving lipid-lowering treatment (n=27) (OR 10.4, 95% CI 1.1 to 102.9, p=0.05). Lp(a) also had independent predictive value in a similar analysis using mild or severe angiographic disease as the outcome variable (OR 11.8, 95% CI 1.5 to 90.8, p=0.02). CONCLUSIONS: Our results indicate that elevated plasma Lp(a) is an independent risk factor for angiographic CAD in chronic stable angina and may have particular significance in women.

Personality assessment of patients with complex regional pain syndrome type I.

OBJECTIVE: There is controversy regarding the importance of psychological/psychiatric factors in the development of the Complex Regional Pain Syndrome (CRPS). Our objective was to determine whether CRPS type I patients were psychiatrically different from other chronic pain patients, with particular attention to personality pathology. DESIGN: A standardized clinical assessment of all major psychiatric categories, including personality disorders, was performed on 25 CRPS type I patients and a control group of 25 patients with chronic low back pain from disc-related radiculopathy. MEASURES: Both sections of the Structured Clinical Interview for the Diagnostic and Statistical Manual (3rd ed., rev.) and the visual analog scale. RESULTS: Both groups were similar in terms of pain intensity and duration. Statistical analysis showed both groups to have a significant amount of major psychiatric comorbidity, in particular major depressive disorder, and a high incidence of personality disorders. Therefore, intense chronic pain was associated with significant psychiatric comorbidity in both groups and in similar proportions. CONCLUSION: The high incidence of personality pathology in both groups may represent an exaggeration of maladaptive personality traits and coping styles as a result of a chronic, intense, state of pain.