Satoshi Mizobuchi

Nonimmersive Virtual Reality Mirror Visual Feedback Therapy and Its Application for the Treatment of Complex Regional Pain Syndrome: An Open‐Label Pilot Study

OBJECTIVE Chronic pain conditions such as phantom limb pain and complex regional pain syndrome are difficult to treat, and traditional pharmacological treatment and invasive neural block are not always effective. Plasticity in the central nervous system occurs in these conditions and may be associated with pain. Mirror visual feedback therapy aims to restore normal cortical organization and is applied in the treatment of chronic pain conditions. However, not all patients benefit from this treatment. Virtual reality technology is increasingly attracting attention for medical application, including as an analgesic modality. An advanced mirror visual feedback system with virtual reality technology may have increased analgesic efficacy and benefit a wider patient population. In this preliminary work, we developed a virtual reality mirror visual feedback system and applied it to the treatment of complex regional pain syndrome. DESIGN A small open-label case series. Five patients with complex regional pain syndrome received virtual reality mirror visual feedback therapy once a week for five to eight sessions on an outpatient basis. Patients were monitored for continued medication use and pain intensity. RESULTS Four of the five patients showed >50% reduction in pain intensity. Two of these patients ended their visits to our pain clinic after five sessions. CONCLUSION Our results indicate that virtual reality mirror visual feedback therapy is a promising alternative treatment for complex regional pain syndrome. Further studies are necessary before concluding that analgesia provided from virtual reality mirror visual feedback therapy is the result of reversing maladaptive changes in pain perception.

Correlation between the Distribution of Contrast Medium and the Extent of Blockade during Epidural Anesthesia

Background: If the epidural spread of contrast medium can be well correlated with the spread of local anesthetics, epidurography can predict the dermatomal distribution of the anesthetic block. The authors evaluated the relation between radiographic and analgesic spread. Methods: An epidural catheter was inserted in 90 patients, and predicted catheter tip position was recorded. The analgesic area was determined by pinprick after a 5-ml injection of 1.5% lidocaine, and epidurography was performed after a 5-ml injection of 240 mg I/ml iotrolan. Patients were assigned to three groups according to catheter tip position (group C: C–T4; group T: T5–T10; group L: T11–L), and patterns of spread were compared. In 16 of 90 subjects, radiographic and analgesic spread was further investigated after an additional 5-ml injection of iotrolan and lidocaine. Results: The total radiographic spread correlated well with analgesic spread (right side: Y = 0.84 X + 0.16, r = 0.92, P < 0.01; left side: Y = 0.78 X + 0.45, r = 0.91, P < 0.01). The mean radiographic spread in the cephalad and caudal directions from the catheter tip also correlated well with mean analgesic spread (r = 0.97, P < 0.01, each direction). The mean distance between the predicted catheter tip and radiographically determined positions was 1.0 ± 0.8 segments: the value in group T was significantly larger than that in groups C (P < 0.05) and L (P < 0.01). Although the correlation of radiographic spread with age was statistically significantly (r = 0.39, P < 0.01), great individual variation in spreading pattern was seen. In 16 subjects, mean radiographic spread correlated well with analgesic spread after 5- and 10-ml injections of iotrolan and lidocaine. Conclusions: Epidurography is useful to indicate epidural catheter position and can help to predict the exact dermatomal distribution of analgesic block.

Comparison of Percutaneous Electrical Nerve Stimulation with Transcutaneous Electrical Nerve Stimulation for Long- Term Pain Relief in Patients with Chronic Low Back Pain

The long-term effect of percutaneous electrical nerve stimulation (PENS) on chronic low back pain (LBP) is unclear. We evaluated the number of sessions for which PENS should be performed to alleviate chronic LBP and how long analgesia is sustained. Patients underwent treatment on a twice-weekly schedule for 8 wk. Group A (n = 18) received PENS for 8 wk, group B (n = 17) received PENS for the first 4 wk and transcutaneous electrical nerve stimulation (TENS) for the second 4 wk, and group C (n = 18) received TENS for 8 wk. Pain level, degree of physical impairment, and the daily intake of nonsteroidal antiinflammatory drugs (NSAIDs) were assessed before the first treatment, 3 days after Week 2, Week 4, and Week 8 treatments, and at 1 and 2 mo after the sessions. During PENS therapy, the pain level decreased significantly from Week 2 in Groups A and B (P < 0.05 or 0.01), and physical impairment and required NSAIDs decreased significantly from Week 4 (P < 0.05 or 0.01) in Group A but only at Week 4 in Group B (P < 0.05 or 0.01). These effects were sustained until 1-mo follow-up (P < 0.01) in Group A but not in Group B; these effects were not observed at 2-mo follow-up even in Group A. In Group C, pain level decreased significantly only at Week 8 (P < 0.05). Our results indicate that repeated PENS is more effective than TENS for chronic LBP but must be continued to sustain the analgesic effect.

Tin chloride pretreatment prevents renal injury in rats with ischemic acute renal failure.

Objective To investigate whether tin chloride pretreatment ameliorates renal injury in rats with ischemic acute renal failure (IARF) by virtue of its kidney-specific heme oxygenase-1 induction. Design Randomized, masked, controlled animal study. Setting University-based animal research facility. Subjects Sprague-Dawley male rats, weighing 200–230 g (n = 359). Interventions Rats were injected with tin chloride subcutaneously, because subcutaneous administration of tin chloride is known to specifically and potently induce renal heme oxygenase activity in the rat. Anesthetized rats were subjected to bilateral flank incisions, and the right kidney was removed. Renal ischemia for 40 mins was performed by left renal microvascular clamping, followed by reflow of the blood. Measurements and Main Results Tin chloride treatment specifically induced heme oxygenase-1 mRNA and protein in the proximal tubular epithelial cells of the kidney without apparent cell injury in the rat. Tin chloride treatment before renal ischemia augmented the induction of heme oxygenase-1 in IARF rats at both transcriptional and protein concentrations in the renal epithelial cells compared with IARF animals. Tin chloride pretreatment, which decreased microsomal heme concentration, ameliorated the ischemic renal injury as judged by the significant decrease in serum creatinine and blood urea nitrogen concentrations and the lesser tubular epithelial cell injuries. In contrast, inhibition of heme oxygenase activity by treatment with tin mesoporphyrin, which increased microsomal heme concentration, abolished the beneficial effect of tin chloride pretreatment. Conclusion These findings indicate that tin chloride pretreatment significantly ameliorates renal injury in rats with IARF by virtue of its specific heme oxygenase-1 induction in renal epithelial cells. These findings also suggest that heme oxygenase-1 induction plays an important role in protecting renal cells from oxidative damage caused by heme.

The effects of epidural block on the distribution of lymphocyte subsets and natural-killer cell activity in patients with and without pain.

Although epidural anesthesia prevents immune suppression during surgery, no reports have elucidated how epidural block affects immune response in nonsurgical patients. We examined changes in proportion of lymphocyte subsets and in natural-killer (NK) cell activity in patients with and without pain. Fifteen patients with pain (Pain group) and 15 preoperative patients without pain (Preoperative group) received three different treatments in random order: epidural block with 7 mL 1% lidocaine, epidural injection of an identical volume of normal saline, and IV injection of 1 mg/kg lidocaine. Blood samples were drawn before and after 30, 60, and 120 min of treatment. During epidural block at 30 and 60 min, both groups showed significantly decreased epinephrine, norepinephrine, and cortisol levels, and the proportion of NK cells decreased, whereas the CD4+/CD8+ ratio increased significantly. NK cell activity in both groups decreased significantly at 30 and 60 min. At 120 min, the variables had all returned to preblock values. During treatments with saline and IV lidocaine, neither group showed significant changes in any of the above variables. We conclude that epidural block causes a transient and significant alteration of lymphocyte subsets and NK cell activity regardless of pain status.

Increased Carbon Monoxide Concentration in Exhaled Air After Surgery and Anesthesia

Heme oxygenase-1 (HO-1) is induced by oxidative stress and is thought to confer protection against oxidative tissue injuries. HO-1 catalyzes the conversion of the heme moiety of hemeproteins, such as hemoglobin, myoglobin, and cytochrome P450, to biliverdin, liberating carbon monoxide (CO) in the process. CO reacts with hemoglobin to form carboxyhemoglobin. In this study, to examine the effect of anesthesia and/or surgery on endogenous CO production, we measured the amount of exhaled CO and the arterial carboxyhemoglobin concentration of patients who underwent surgery under general or spinal anesthesia. Both CO and carboxyhemoglobin concentrations were significantly larger on the day after surgery than during the preoperative period (P <0.05) and in the recovery room (P < 0.05), regardless of anesthesia. However, neither index differed between general and spinal anesthesia. These results suggest that oxidative stress caused by anesthesia and/or surgery may induce HO-1, which catalyzes heme to produce CO, leading to increased exhaled CO concentration.

Calcineurin inhibitor-induced irreversible neuropathic pain after allogeneic hematopoietic stem cell transplantation.

The calcineurin inhibitors (CIs) cyclosporine A and tacrolimus are essential for graft-versus-host disease prophylaxis but are associated with adverse effects, including neurotoxicity. We report a case of irreversible CI-induced neuropathic pain following allogeneic hematopoietic stem cell transplantation. The patient developed dysesthesia, electric shock-like pain, and severe itching followed by intractable analgesic-resistant pain in the lower extremities. There were no abnormal radiographic findings, and there was no improvement with a reduction of CI dosage or with administration of a calcium channel blocker. These clinical findings are similar to but inconsistent with CI-induced musculoskeletal pain syndromes previously reported in organ transplantation.

Decoy strategy targeting the brain-derived neurotrophic factor exon I to attenuate tactile allodynia in the neuropathic pain model of rats.

The mechanism underlying neuropathic pain is still largely unclear. Recently, much attention has been focused on the role of brain-derived neurotrophic factor (BDNF) as a neuromodulator in the spinal cord. We previously reported that the expression of Bdnf exon I mRNA was remarkably up-regulated in the dorsal root ganglion (DRG) neurons with the rat L5 spinal nerve ligation (SNL) model. In the present study, we investigated whether neuropathic pain response would be reduced by the inhibition of the Bdnf exon I in the rat SNL model. We identified the promoter region of exon I and synthesized the decoy ODNs targeting the region. Reverse transcription-polymerase chain reaction analysis confirmed that the decoy ODN treatment reduced SNL-induced Bdnf exon I mRNA up-regulation in ipsilateral L4 and L5 DRGs. Furthermore, post-treatment with the decoy ODNs significantly attenuated SNL-induced tactile allodynia. This study suggested that decoy ODNs targeting the Bdnf exon I might provide a novel analgesic strategy for the treatment of neuropathic pain.

Epidural Blood Patch Therapy for Chronic Whiplash-Associated Disorder

BACKGROUNDDespite the absence of objective neurological deficits, patients with chronic whiplash-associated disorder (WAD) complain of symptoms such as headache, dizziness, and nausea. These symptoms are also often experienced by patients with cerebrospinal fluid (CSF) leak. It was recently reported that radioisotope (RI) cisternography is useful in the diagnosis of intracranial hypotension due to CSF leak. We investigated the relation between chronic WAD and CSF leak by RI cisternography and evaluated whether epidural blood patch (EBP) administration is effective in the treatment of chronic WAD. METHODSWe studied 66 patients with chronic WAD with symptoms lasting longer than 3 mo. All patients underwent RI cisternography to determine the presence of CSF leak. In patients in whom CSF leak was identified, EBP was administered. Symptoms were assessed before, 1 wk after, and 6 mo after EBP. Work status was also assessed and follow-up RI cisternography was performed. RESULTSOf the 66 patients, 37 showed CSF leak, and 36 of these patients received EBP 2.2 ± 0.7 times. The mean duration of symptoms was 33 mo. One week after EBP, the percentage of patients with symptoms was decreased significantly compared with that before EBP; headache: 100% vs 17%, respectively, memory loss: 94% vs 28%, dizziness: 83% vs 47%, visual impairment: 81% vs 25%, nausea: 78% vs 42% (P < 0.01). These effects were also observed at the 6 month follow-up examination (P < 0.01). Work status was also significantly improved at follow-up. CONCLUSIONSWe conclude that CSF leak should be considered in some cases of chronic WAD and that EBP is an effective therapy for chronic WAD.

Expression changes of the neuregulin 1 isoforms in neuropathic pain model rats.

The neuregulin1 (Nrg1) gene that is expressed in the dorsal root ganglion (DRG) contains an EGF-like domain, which is known to be a direct ligand for ErbB3 and ErbB4. Multiple splice variants of the Nrg1 gene are broadly classified into 3 groups by structural features (type I, type II and type III) and their functions differ in various tissues. The Nrg1 gene has emerged as a key mediator of axon-Schwann cell interactions and as a regulator of Schwann cell development. The Nrg1 gene is indicated as a promising growth factor for neuronal development. However, the function of the Nrg1 in pain has not been clarified. We therefore, examined the expression profiles of each type of the Nrg1 transcript in the bilateral L4/L5 DRGs using L5 spinal nerve ligation (SNL) model rats and complete Freunds adjuvant (CFA) model rats. Behavior tests have shown typical mechanical hyperalgesia in both the L5SNL model and the CFA model. In the L5SNL model, expression of the Nrg1 type I and type II were significantly increased in the L5 DRG. On the other hand, the expression of the Nrg1 type III was decreased in the L5 DRG. We demonstrated that the expression changes of the Nrg1 isoforms in the ipsilateral DRGs were preferentially related to the response to nerve injury. Our findings suggest that the aberrant expression may play an important role in nerve injury, regeneration and subsequent neuropathic pain on the L5SNL.