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.

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.

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.

Effects of degradable Mg-Ca alloys on dendritic cell function.

Degradable magnesium alloys are new materials for implants used in orthopedic and trauma surgery. The aim of this study was to investigate the influence of degradable magnesium alloys on the function of dendritic cells (DC) as these cells represent the major antigen presenting cells of the body. MgP (pure magnesium), MgCa 0.6 (0.6% calcium), MgCa 0.8 (0.8% calcium), MgCa 1.0 (1% calcium), and MgCa 1.2 (1.2% calcium) alloys were degraded in cell culture medium. In parallel, murine bone marrow-derived DC were incubated with increasing concentrations (0.1-10 mmol/L) of magnesium chloride and calcium chloride, respectively. Incubation of DC with degradation media over 6 days had no influence on cell viability and only marginal influence on DC migration. Also, the production of TNFα and expression of CD86 was not enhanced by incubation with degraded magnesium alloys. The mixed leukocyte reaction revealed that there was also no increase of the T-cell proliferation in comparison to untreated controls. However, there was a trend toward macrophage development at the expense of DC expansion and an enhanced DC migration was induced by incubation with higher magnesium concentrations. Particularly the latter should be verified in in vivo experiments.

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.

Analysis of early biofilm formation on oral implants in man.

Biofilm formation on oral implants can cause inflammation of peri-implant tissues, which endangers the long-term success of osseointegrated implants. It has been reported previously that implants revealing signs of peri-implantitis contain subgingival microbiota similar to those of natural teeth with periodontitis. The purpose of the first part of this study was an atraumatic, quantitative investigation of biofilm formation on oral implant abutments; the objective of the second part was to investigate whether Haemophilus actinomycetemcomitans and Porphyromonas gingivalis were present in the crevicular fluid around oral implants. Biofilm formation on 14 healing abutments, inserted for 14 days in 10 patients, was analysed quantitatively by use of secondary-electron and Rutherford-backscattering-detection methods. A 16S rRNA-based polymerase chain reaction detection method was used to detect the presence of H. actinomycetemcomitans and P. gingivalis in the crevicular fluid. For this investigation, samples of sulcus fluid were collected with sterile paper points at four measurement points per abutment. The difference between biofilm coverage of supragingival surfaces (17.5 +/- 18.3%) and subgingival surfaces (0.8 +/- 1.0%) was statistically significant (P < 0.05). By use of universal primers, bacteria were found in all the samples taken, although the two periodontal pathogens were not found in any of the samples. The absence of periodontal pathogens from the sulcus fluid during initial bacterial colonization, despite massive supragingival biofilm formation, substantiates the assumption that cellular adherence of peri-implant tissue by means of hemidesmosoma, actin filaments and microvilli reduces the risk of formation of anaerobic subgingival pockets.

A double-blind, controlled study of botulinum toxin A in chronic myofascial pain.

BACKGROUND: Recent studies have reported a potential analgesic effect of botulinum toxin A (BTXA) in musculoskeletal pain. The present double-blind, randomized, placebo-controlled, parallel clinical trial studied the effect of BTXA on pain from muscle trigger points and on EMG activity at rest and during voluntary contraction. METHODS: Thirty patients with trigger points in the infraspinatus muscles received either 50 units/0.25 mL of BTXA or 0.25 mL of isotonic saline. Baseline measures were determined during a run-in period of 1 week. Outcome measures including local and referred spontaneous pain, pain detection and tolerance thresholds to mechanical pressure, and shoulder movement were assessed at 3 and 28 days after injection. The interference pattern of the EMG during maximal voluntary effort of infraspinatus muscle was recorded and a standardized search for spontaneous electrical motor endplate activity at the trigger points was performed before and 28 days after BTXA or saline injection. RESULTS: BTXA reduced motor endplate activity and the interference pattern of EMG significantly but had no effect on either pain (spontaneous or referred) or pain thresholds compared with isotonic saline. CONCLUSIONS: The results do not support a specific antinociceptive and analgesic effect of botulinum toxin A.

Patterns of experimentally induced pain in pericranial muscles.

Nociceptive mechanisms in the craniofacial muscle tissue are poorly understood. The pain pattern in individual pericranial muscles has not been described before. Experimental muscle pain was induced by standardized infusions of 0.2 ml 1 m hypertonic saline into six craniofacial muscles (masseter, anterior temporalis, posterior temporalis, trapezius, splenius capitis and sternocleidomastoid) in 20 healthy subjects. The pressure pain thresholds (PPTs) were determined before and after infusions. The subjects continuously reported intensity of saline-induced pain on an electronic visual analogue scale (VAS) and the perceived area of pain was drawn on anatomical maps. The pain areas were measured and the localization determined by a new centre-of-gravity method. The PPTs were lowest on the sternocleidomastoid muscle (anova: P<0.001), but the saline-evoked VAS pain scored highest following injection into the masseter muscle (anova: P<0.05). The centre-of-gravity measures demonstrated significantly different localization of the pain areas (anova: P<0.001). The trigeminally vs. the cervically innervated muscles had significantly different patterns of spread and referral of pain according to trigeminally vs. cervically innervated dermatomes (P<0.005). In conclusion, there appear to be characteristic pain patterns and pain sensitivity in different craniofacial muscles in healthy volunteers, which may be of importance for further research on different craniofacial pain conditions.

Therapeutic outcome in neuropathic pain: relationship to evidence of nervous system lesion.

Treatment outcome in patients with neuropathic pain (NP) is often variable and disappointing. We tested the hypothesis that patients with clear evidence of nervous system lesion respond better to pharmacological treatment with documented effect on NP than patients with poor or no evidence of nervous system lesion. Furthermore, we examined whether specific symptoms or signs were associated with treatment outcome. A total of 214 patients with suspected non-cancer NP were divided into four groups with graded evidence of nervous system lesion based on medical history, bedside sensory examination, quantitative sensory tests, electrophysiology, and neuroimaging. Patients were treated with imipramine guided by plasma-drug concentrations. Gabapentin 2400 mg/day was given in case of treatment failure or if imipramine treatment was not possible. Two hundred patients completed the study. Global pain relief was similar in the four groups. There was no association between evidence of nervous system lesion and treatment outcome. Classical NP signs: abnormal temporal summation, cold and brush allodynia, and abnormal sensibility to temperature were also unrelated to outcome. Treatment outcome was similar in peripheral and central definite NP. Neither definite evidence of nervous system lesion nor abnormal sensory phenomena seems to predict for good outcome of therapy with imipramine or gabapentin in patients with suspected neuropathic pain.

Sensory perception in complete spinal cord injury.

OBJECTIVES: To describe sensations evoked by painful or repetitive stimulation below injury level in patients with a clinically complete (American Spinal Injury Association, ASIA Grade A) spinal cord injury (SCI). MATERIAL AND METHODS: Twenty-four patients (11 with central neuropathic pain and 13 without pain) with a traumatic SCI above the tenth thoracic vertebra were examined using quantitative sensory testing, MR imaging, and somatosensory evoked potentials (SEP). RESULTS: Painful (pressure, pinch, heat or cold) or repetitive (pinprick) stimuli elicited vague localized sensations in 12 patients (50%). Pain, spasticity, and spasms were equally seen in SCI patients with or without localized sensations. SEP and MRI did not differentiate between these two groups. CONCLUSION: The present study suggests retained sensory communication across the injury in complete SCI, i.e. 'sensory discomplete' SCI.

MRI in chronic spinal cord injury patients with and without central pain.

BACKGROUND: Central pain following spinal cord injury (SCI) is common and thought to be related to lesion of the spinothalamic pathways. OBJECTIVE: To examine additional mechanisms of SCI pain. METHODS: Twenty-three SCI patients with traumatic lesions above T10 (14 with central neuropathic pain and 9 without pain) underwent MRI examination. The authors quantitatively assessed extent of cord lesion on axial T2-weighted images as percentage of 1) gray matter, 2) dorsolateral, 3) anterolateral, and 4) dorsolateral columns based on standardized drawings made by a neuroradiologist blinded to patient history. RESULTS: At the level of maximal cord injury, 21 patients had lesions involving the entire cord on axial images except for a small border of lower signal intensity, whereas 2 patients had central lesions. Rostral to the main injury, the first image with an incomplete lesion showed significantly more involvement of gray matter in pain than in pain-free patients. CONCLUSION: Consistent with animal models of SCI, spinothalamic tract lesion together with neuronal hyperexcitability due to lesion of inhibitory interneurons at the rostral end of injury are hypothesized to lead to central pain.

Sensory function above lesion level in spinal cord injury patients with and without pain.

Patients with spinal cord injury (SCI) may or may not develop central neuropathic pain despite having cord lesions of apparently the same site, extension and nature. The consequences of the cord lesion in the central nervous system and the mechanisms underlying pain are unclear. In this study, we examined sensory detection and pain thresholds above injury level in 17 SCI patients with central neuropathic pain, in 18 SCI patients without neuropathic pain, and in 20 control subjects without injury and pain. The SCI pain group had significantly higher cold and warm detection thresholds compared with the SCI pain free group and controls and higher tactile detection thresholds compared with the SCI pain free group. No difference in pain or pain tolerance thresholds was seen among pain and pain free SCI patients. These data suggest changes in somatosensory function in dermatomes rostral to the segmental injury level linked to the presence of central neuropathic pain in SCI patients. The results are discussed in relation to current concepts of pain inhibitory and facilitating systems.

Venlafaxine versus imipramine in painful polyneuropathy: a randomized, controlled trial.

BACKGROUND: Tricyclic antidepressants (TCA) are often used in the treatment of painful polyneuropathy. Venlafaxine is a serotonin and weak noradrenaline reuptake inhibitor antidepressant with a different profile of other pharmacologic actions from those of TCA. OBJECTIVE: To test if venlafaxine would relieve painful polyneuropathy and compare its possible efficacy with that of the TCA imipramine. METHODS: The study design was randomized, double blind, and placebo controlled, with a three-way crossover. Forty patients were assigned to one of the treatment sequences, and 29 completed all three study periods. The daily doses were venlafaxine 225 mg and imipramine 150 mg. During the three treatment periods, each of 4 weeks' duration, patients rated pain paroxysms, constant pain, and touch- and pressure-evoked pain by use of 0- to 10-point numeric rating scales. RESULTS: The sum of the individual pain scores during treatment week 4 was lower on venlafaxine (80% of baseline score; p = 0.006) and imipramine (77%; p = 0.001) than on placebo (100%) and did not show any statistical difference between venlafaxine and imipramine (p = 0.44). The individual pain scores for pain paroxysms, constant pain, and pressure-evoked pain showed a similar pattern, whereas touch-evoked pain was uncommon and was not altered by any of the drugs. Numbers needed to treat to obtain one patient with moderate or better pain relief were 5.2 for venlafaxine and 2.7 for imipramine. CONCLUSION: Venlafaxine relieves pain in polyneuropathy and may be as effective as imipramine.

Sensory function in spinal cord injury patients with and without central pain.

Spinal cord injury (SCI) frequently results in neuropathic pain. However, the pathophysiology underlying this pain is unclear. In this study, we compared clinical examination, quantitative sensory testing (QST) and somatosensory evoked potentials (SEPs) in SCI patients with and without pain below spinal lesion level, with a control group of 20 subjects without injury. All patients had a traumatic SCI with a lesion above T10; 20 patients presented with spontaneous central neuropathic pain below lesion level, and 20 patients had no neuropathic pain or dysaesthesia. Patients with and without pain had a similar reduction of mechanical and thermal detection and pain thresholds, and SEPs. SCI patients with central pain more frequently had sensory hypersensitivity (brush- or cold-evoked pain, dysaesthesia or pinprick hyperalgesia) in dermatomes corresponding to lesion level than SCI patients without pain. There was no difference in intensity of pain evoked by repetitive pinprick at lesion level between patient groups. There was a significant correlation between intensity of brush-evoked dysaesthesia at lesion level and spontaneous pain below lesion level of SCI. These data suggest that lesion of the spinothalamic pathway alone cannot account for central pain in SCI patients, and that neuronal hyperexcitability at injury or higher level may be an important mechanism for pain below injury level.

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.

Pain and dysesthesia in patients with spinal cord injury: A postal survey.

STUDY DESIGN: A postal survey. OBJECTIVES: To assess the prevalence and characteristics of pain and dysesthesia in a community based sample of patients with spinal cord injury (SCI) with special focus on neuropathic pain. SETTING: Community. Western half of Denmark. METHODS: We mailed a questionnaire to all outpatients (n = 436) of the Viborg rehabilitation centre for spinal cord injury. The questionnaire contained questions regarding cause and level of spinal injury and amount of sensory and motor function below this level. The words pain and unpleasant sensations were used to describe pain (P) and dysesthesia (D) respectively. Questions included location and intensity of chronic pain or dysesthesia, degree of interference with daily activity and sleep, presence of paroxysms and evoked pain or dysesthesia, temporal aspects, alleviating and aggravating factors, McGill Pain Questionnaire (MPQ) and treatment. RESULTS: Seventy-six per cent of the patients returned the questionnaire, (230 males and 100 females). The ages ranged from 19 to 80 years (median 42.6 years) and time since spinal injury ranged from 0.5 to 39 years (median 9.3 years). The majority (> 75%) of patients had traumatic spinal cord injury. Of the respondents, 77% reported having pain or unpleasant sensations, and 67% had chronic pain or unpleasant sensations at or below lesion. Forty-eight per cent reported that P/D could be evoked by non-noxious stimulation of the skin indicating that allodynia is present in almost half of the patients. Forty-three per cent of respondents took analgesics, 7% received antidepressants or anticonvulsants. CONCLUSION: This survey suggests that pain and dysesthesia are common and serious complaints in SCI patients. Unexpectedly, only 7% of the patients were treated with drugs considered to be most effective in neuropathic pain. This emphasizes the need for a continued research and education on P/D in SCI.