Anton A. van der Plas

Efficacy and safety of a single intrathecal methylprednisolone bolus in chronic complex regional pain syndrome.

Activated immune cells in the spinal cord may play an important role in the development and maintenance of neuropathic pain, such as occurs in response to peripheral inflammation or tissue injury. Immune activation may therefore serve as a therapeutic target for immune modulating drugs like corticosteroids. This double‐blind randomized placebo‐controlled parallel‐group trial aimed to investigate the efficacy and safety of a single intrathecal administration of 60 mg methylprednisolone (ITM) in chronic patients with complex regional pain syndrome (CRPS). The primary outcome measure was change in pain (pain intensity numeric rating scale; range 0–10) after 6 weeks. With 21 subjects per group the study had a 90% power to detect a clinically relevant difference (≥2 points). After 21 patients (10 on ITM) were included, the trial was stopped prematurely after the interim analysis had shown that ITM had no effect on pain (difference in mean pain intensity numeric rating scale at 6 weeks 0.3, 95% confidence interval −0.7 to 1.3) or any other outcome measure. We did not find any difference in treatment‐emergent adverse events between the ITM and placebo group. We conclude that a single bolus administration of ITM is not efficacious in chronic CRPS patients, which may indicate that spinal immune activation does not play an important role in this phase of the syndrome.

Intrathecal glycine for pain and dystonia in complex regional pain syndrome

ABSTRACT Since glycinergic neurotransmission plays an important inhibitory role in the processing of sensory and motor information, intrathecal glycine (ITG) administration may be a potential therapy for both pain and movement disorders in patients with complex regional pain syndrome (CRPS). Aims of the current study, which is the first report on ITG in humans, were to evaluate its safety and efficacy. ITG treatment during 4 weeks was studied in CRPS patients with dystonia in the period before they received intrathecal baclofen treatment. Twenty patients were assessed and after exclusion of one patient, the remaining 19 patients were randomized in a double‐blind placebo‐controlled crossover study. Safety was assessed by clinical evaluation, blood examinations and electrocardiograms. Efficacy measures involved pain (numeric rating scale, McGill pain questionnaire), movement disorders (Burke–Fahn–Marsden dystonia rating scale, unified myoclonus rating scale, tremor research group rating scale), activity (Radboud skills questionnaire, walking ability questionnaire), and a clinical global impression (CGI) and patients global impression score (PGI). Treatment‐emergent adverse events were generally mild to moderate and not different from placebo treatment. During ITG treatment growth hormone levels were slightly increased. Although there was a trend to worsening on the CGI and PGI during ITG treatment, there were no significant differences between ITG and placebo treatment in any of the outcomes. ITG given over 4 weeks was ineffective for pain or dystonia in CRPS. Although no serious adverse events occurred, further studies are required to rule out potential neurotoxicity of ITG.

Explorative analysis of urine by capillary electrophoresis-mass spectrometry in chronic patients with complex regional pain syndrome.

Complex Regional Pain Syndrome (CRPS) is characterized by various combinations of sensory, autonomic and motor disturbances. Pain disproportionate to the severity and duration of the inciting event is the most devastating symptom. Diagnosis of CRPS is difficult as the underlying mechanisms remain unclear. To try to derive metabolic indicators potentially characteristic for CRPS, we applied capillary electrophoresis time-of-flight mass spectrometry (CE-ToF-MS) to the explorative analysis of urine. The CE-ToF-MS method provided fast and stable metabolic profiles of urine samples. The mean intraday and interday CVs were <2% and <9% for migration times and peak areas, respectively, demonstrating robustness of the method. With the use of multivariate chemometric analysis, discrimination between urine samples from CRPS patients and controls was obtained, emphasizing differences in metabolic signatures between CRPS-diseased patients and controls. Several compounds, such as 3-methylhistidine, were responsible for discriminating the samples. The biological relevance of these compounds with regard to CRPS is discussed. Thus, CE-ToF-MS-based metabolic profiling of urine from CRPS patients and controls revealed metabolites that differentiate between diseased and control, illustrating the usefulness of this approach to get more insight into the pathology underlying CRPS.

The Lack of Efficacy of Different Infusion Rates of Intrathecal Baclofen in Complex Regional Pain Syndrome: A Randomized, Double-Blind, Crossover Study

OBJECTIVE Intrathecal baclofen (ITB) is effective in the treatment of dystonia related to complex regional pain syndrome (CRPS). In a previous study, we noted that the responsiveness to ITB declined in 30% of patients once drug delivery was switched from an external to an implanted device associated with a reduction of the infusion rate (IR). DESIGN In a double-blind study, we investigated the effect of varying the IR at a fixed daily dose on the efficacy and safety of ITB in patients with CRPS-related dystonia. Patients were randomized to either slower infusion rate delivery (SIRD) or four-times faster infusion rate delivery (FIRD) for 2 weeks and were crossed over after a 1-week washout period. PATIENTS Patients were eligible if they experienced no beneficial response to ITB on dystonia despite a minimum dose of 600 µg/day, or because side effects limited dose escalation. OUTCOME MEASURES Primary outcome measures were changes in global dystonia and pain severity. RESULTS There were no significant differences between the FIRD and the SIRD groups for the median change of numeric rating scale dystonia (-0.3 [interquartile range {IQR} -1.1-0.5]), pain (0.1 [IQR -0.8-1.3]), and secondary outcomes, except for the frequency of adverse events, which was significantly higher during FIRD (12 vs 2). FIRD was preferred only by patients who were included because side effects to ITB prevented dose escalation. CONCLUSIONS Increasing the IR at a fixed daily dose is not associated with improvement of dystonia or pain but warrants further investigation in patients in whom side effects prevent further dose escalation.

Efficacy of Intrathecal Baclofen on Different Pain Qualities in Complex Regional Pain Syndrome

BACKGROUND:Complex regional pain syndrome (CRPS) is characterized by severe debilitating chronic pain. Patients with CRPS may experience various pain sensations, which likely embody different pathophysiologic mechanisms. In this study, we evaluated the differential effects of central &ggr;-aminobutyric acid (B) receptor stimulation on the different pain qualities in CRPS patients with dystonia. METHODS:The 10 pain qualities of the neuropathic pain scale, dystonia severity, and changes in use of antinociceptive drugs were evaluated every 3 months for a period of 1 year in 42 CRPS patients with dystonia receiving titrated doses of intrathecal baclofen (ITB) treatment in an open design. RESULTS:Using a linear mixed model analysis and controlling for global dystonia severity and the use of supplemental analgesics, we found a significant improvement in global intense pain, sharp pain, dull pain, and deep pain during the first 6 months. After this period, the scores leveled off despite further improvement of dystonia and continued ITB dose escalation. CONCLUSIONS:&ggr;-Aminobutyric acid (B) receptor stimulation by ITB exerts differential antinociceptive effects on specific pain qualities in CRPS patients with dystonia.

1H-NMR metabolic profiling of cerebrospinal fluid in patients with complex regional pain syndrome–related dystonia

Summary 1H‐NMR spectroscopy‐based, exploratory metabolomics analysis of cerebrospinal fluid of patients with complex regional pain syndrome–related dystonia suggests a link between dystonia and aberrant inflammation. ABSTRACT In complex regional pain syndrome (CRPS)‐related dystonia, compelling evidence points to the involvement of the central nervous system, but the underpinning pathobiology is still unclear. Thus, to enable a hypothesis‐free, unbiased view of the problem and to obtain new insight into the pathobiology of dystonia in CRPS, we applied an exploratory metabolomics analysis of cerebrospinal fluid (CSF) of patients with CRPS‐related dystonia. 1H‐NMR spectroscopy in combination with multivariate modeling were used to investigate metabolic profiles of a total of 105 CSF samples collected from patients with CRPS‐related dystonia and controls. We found a significantly different metabolic profile of CSF in CRPS patients compared to controls. The differences were already reflected in the first two principal components of the principal component analysis model, which is an indication that the variance associated with CRPS is stronger than variance caused by such classical confounders as gender, age, or individual differences. A supervised analysis generated a strong model pinpointing the most important metabolites contributed to the metabolic signature of patients with CRPS‐related dystonia. From the set of identified discriminators, the most relevant metabolites were 2‐keto‐isovalerate, glucose, glutamine, and lactate, which all showed increased concentrations, and urea, which showed decreased concentration in CRPS subjects. Our findings point at a catabolic state in chronic CRPS patients with dystonia that is likely associated with inflammation.

An Explanatory Study Evaluating the Muscle Relaxant Effects of Intramuscular Magnesium Sulphate for Dystonia in Complex Regional Pain Syndrome

UNLABELLED The treatment of dystonia related to complex regional pain syndrome (CRPS) remains unsatisfactory, raising the need of alternative targets for intervention. In dystonia, pathologic muscle changes may occur, which contributes to stiffness. Because magnesium sulphate may act as a muscle relaxant through its actions on the neuromuscular junction and muscle, we performed an explanatory study of the muscle relaxant effect and safety of intramuscular magnesium sulphate (IMMG) in CRPS patients with dystonia. In a double-blind randomized placebo-controlled crossover study, 30 patients were assigned to 3-week treatments of IMMG and placebo. Treatments were separated by a 1-week washout period. The daily dose of IMMG was 1,000 mg in week 1, 1,500 mg in week 2, and 2,000 mg in week 3. The primary outcome measure was the difference in change in Burke-Fahn-Marsden scores after 3 weeks of treatment between both interventions. Secondary outcomes involved severity of dystonia, myoclonus, tremor, and pain, and functional activity. Data of 22 patients available for the explanatory analysis revealed no significant differences between IMMG and placebo treatment in any of the outcomes. In conclusion, we found no indication of efficacy of IMMG in a daily dose of 2,000 mg as a muscle relaxant in CRPS-related dystonia. PERSPECTIVE In this double-blind placebo-controlled crossover study there was no evidence found of a muscle relaxant effect of intramuscular magnesium sulphate in dystonia related to CRPS. Consequently, there is insufficient support for new studies evaluating the efficacy of other routes of MG administration in CRPS-related dystonia.

Discussing sexuality with patients with Parkinson’s disease: a survey among Dutch neurologists

Sexual functioning is often impaired in patients with Parkinson’s disease (PD) and may affect quality of life of patients and their spouse. However, little is known about the practice patterns of neurologists with regard to discussing sexuality in this field. The aim of this cross-sectional study was to evaluate to what extent neurologists discuss sexuality with PD patients. A 22-item questionnaire was sent to 139 neurologists specializing in PD. The survey contained questions about their attitudes, knowledge, and practice patterns with respect to sexual dysfunction (SD) in patients with PD. The response rate of the survey was 66.9%. Most participants (56.8%) stated that they address sexuality in less than half of their PD patients. High age of patients (42.0%), insufficient consultation time (37.5%), and a lack of patients’ initiative to raise the topic themselves (36.4%) were frequently reported barriers towards discussing sexuality. The majority of participants considered that discussing sexuality is a responsibility that lay with neurologists (85.2%), nurses (73.9%), and patients (72.7%). One quarter of the neurologists reported to have insufficient or no knowledge on SD. The majority of participants regarded screening for SD important or slightly important (85.2%). A large proportion of Dutch neurologists specializing in PD do not routinely discuss sexuality with their PD patients. Sexual healthcare in PD patients may benefit from time-efficient tools and agreements on who is responsible for discussing SD. Furthermore, recommendations in PD guidelines on screening and managing SD should be adapted to fit everyday practice.

Reliability and Validity of the Range of Motion Scale (ROMS) in Patients with Abnormal Postures

OBJECTIVE Sustained abnormal postures (i.e., fixed dystonia) are the most frequently reported motor abnormalities in complex regional pain syndrome (CRPS), but these symptoms may also develop after peripheral trauma without CRPS. Currently, there is no valid and reliable measurement instrument available to measure the severity and distribution of these postures. The range of motion scale (ROMS) was therefore developed to assess the severity based on the possible active range of motion of all joints (arms, legs, trunk, and neck), and the present study evaluates its reliability and validity. METHODS Inter- and intra-rater reliability of the ROMS was determined in 16 patients with abnormal sustained postures, who were videotaped following a standard video protocol in a university hospital. The recordings were rated by a panel of international experts. In addition, 30 patients were clinically tested with both the Burke-Fahn-Marsden (BFM) scale as well as the ROMS to assess construct validity. RESULTS Inter-rater reliability for total ROMS scores showed an intra-class correlation coefficient (ICC) of 0.85. The majority of the scores for the separate joints (13 out of 18) demonstrated an almost perfect agreement with ICCs ranging from 0.81 to 0.94; of the other items, one showed fair, one moderate, and three substantial agreement. The ICCs for the intra-rater reliability ranged from moderate to almost perfect (0.68-0.98). Spearmans correlation coefficients between corresponding body areas as measured with the ROMS or BFM were all above 0.82. CONCLUSION The ROMS is a reliable and valid instrument to evaluate the severity and distribution of sustained abnormal postures.