Mienke Rijsdijk

Diagnostic Threshold Values of Cerebral Perfusion Measured With Computed Tomography for Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage

Background and Purpose— Early diagnosis of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage is critical but difficult. We analyzed diagnostic threshold values of CT perfusion for use in detection of DCI in patients with subarachnoid hemorrhage. Methods— We prospectively enrolled patients with subarachnoid hemorrhage with CT perfusion on admission and at time of clinical deterioration or after 1 week if no deterioration occurred. The gold standard was the clinical diagnosis of DCI based on all clinical, laboratory, and imaging data except CT perfusion. Patients with failed imaging (n=6) and other causes of deterioration (n=45) were excluded for the current study. We measured CT perfusion values, including cerebral blood volume, blood flow, mean transit time (MTT), and time to peak in predefined regions of interest and then compared absolute perfusion and perfusion asymmetry for patients with and without DCI. Diagnostic threshold values for DCI were evaluated and sensitivity and specificity calculated for optimal thresholds. Results— Of 85 eligible patients with subarachnoid hemorrhage, 50 had DCI; 35 patients with no clinical deterioration comprised the reference group. Cerebral blood flow was significantly lower, MTT higher, and perfusion asymmetry larger in patients with DCI. We found that largest absolute MTT and the MTT difference between hemispheres were good diagnostic tests. Diagnostic threshold values with optimal sensitivity and specificity were an MTT of 5.9 seconds and an MTT difference of 1.1 second. Conclusion— Thresholds for absolute MTT values and between-hemisphere MTT differences on CT perfusion can distinguish between patients with delayed cerebral ischemia and clinically stable patients.

The effects of glucocorticoids on neuropathic pain: a review with emphasis on intrathecal methylprednisolone acetate delivery.

Methylprednisolone acetate (MPA) has a long history of use in the treatment of sciatic pain and other neuropathic pain syndromes. In several of these syndromes, MPA is administered in the epidural space. On a limited basis, MPA has also been injected intrathecally in patients suffering from postherpetic neuralgia and complex regional pain syndrome. The reports on efficacy of intrathecal administration of MPA in neuropathic pain patients are contradictory, and safety is debated. In this review, we broadly consider mechanisms whereby glucocorticoids exert their action on spinal cascades relevant to the pain arising after nerve injury and inflammation. We then focus on the characteristics of the actions of MPA in pharmacokinetics, efficacy, and safety when administered in the intrathecal space.

Safety assessment and pharmacokinetics of intrathecal methylprednisolone acetate in dogs.

Background: Intrathecal methylprednisolone acetate (MPA) has been used in patients with chronic pain syndromes. Its safety has been debated after reports of adverse events. No systematic preclinical evaluation of MPA has been reported. In the current study, the acute and long-term effects of intrathecal MPA on dog spinal tissue was studied with the injectate reformulated to include minimal adjuvants. Methods: Seventeen dogs were implanted with intrathecal catheters and randomized to three groups: vehicle (lidocaine; 4 dogs), MPA 20 mg/ml (human dose; 7 dogs), and MPA 80 mg/ml (maximum deliverable dose; 6 dogs). In parallel with the human protocols, dogs received four injections at 7-day intervals. Clinical observations and plasma methylprednisolone measurements were done before and at intervals after intrathecal delivery. One week (acute) or 6 weeks (long-term) after the last injection, animals were sacrificed and spinal tissues harvested for histopathology. Results: Other than a brief motor block, no adverse clinical event occurred in any animal. Group A (vehicle) showed minimal histologic changes (median histology-score; acute: 1.3, long-term: 1.0). Group B (MPA 20 mg/ml) had a diffuse inflammatory reaction (acute: 2.0, long-term: 3.0), group C (MPA 80 mg/ml) a severe inflammatory response, with large inflammatory masses (acute: 4.0, long-term: 7.0) The severity of the inflammatory reaction increased significantly with increasing dose at long-term sacrifice (acute P = 0.167, long-term P = 0.014). No neuronal injury, demyelination, or gliosis was seen in any animal. Conclusion: These results, showing dose-dependent intrathecal inflammatory reactions at MPA doses and injectate concentrations comparable to those used in humans, indicate that the continued use of this modality in humans is not recommended.

No beneficial effect of intrathecal methylprednisolone acetate in postherpetic neuralgia patients

High efficacy of intrathecal methylprednisolone acetate (MPA) with lidocaine has been reported in a large patient group suffering from intractable postherpetic neuralgia (PHN). Because the treatment effect was never independently confirmed and there are ongoing safety concerns, intrathecal MPA did not become standard care for intractable PHN. We report the results of a replication trial assessing pain relief and spinal cytokine/chemokine levels in PHN patients.

Analgesic properties of intrathecal glucocorticoids in three well established preclinical pain models

Abstract Background and aim Glucocorticoids, a group of anti-inflammatory agents, are frequently administered in pain medicine. Of interest is the reported activity after intrathecal delivery in patients with neuropathic pain syndromes such as postherpetic neuralgia, though its efficacy is controversial. After the publication of two randomized clinical trials in postherpetic neuralgia patients treated with similar intrathecal methylprednisolone acetate (MPA) dosing regimes with conflicting results; one showing significant pain reduction (Kotani N, Kushikata T, Hashimoto H, Kimura F, Muraoka M, Yodono M, Asai M, Matsuki A: Intrathecal methylprednisolone for intractable postherpetic neuralgia. N Engl J Med 2000;23: 1514–9), the other increased pain sensations (Rijsdijk M, van Wijck AJ, Meulenhoff PC, Kavelaars A, van der Tweel I, Kalkman CJ: No beneficial effect of intrathecal methylprednisolone acetate in postherpetic neuralgia patients. Eur J Pain 2013;38:175–200), we decided additional research was warranted. Present study sought to determine effects of intrathecally delivered methylprednisolone on pain-like behaviour and pain-associated markers in three well established rodent pain models: (1) intraplantar carrageenan, (2) intraplantar formalin, and (3) ligation of L5/L6 spinal nerves (SNL model). Methods Male rats with intrathecal catheters were examined for (1) tactile allodynia after unilateral hindpaw intraplantar carrageenan injection (2%), (2) flinching and subsequent long term tactile allodynia after unilateral hindpaw intraplantar formalin injection (2.5%) or (3) tactile allodynia after unilateral ligation of the L5 and L6 spinal nerves. Rats were treated with the maximum tolerable intrathecal dose of the soluble methylprednisolone sodium succinate (MP) or the particulate methylprednisolone acetate (MPA). Dorsal root ganglia and spinal cords were harvested for immunohistochemistry to assess markers of neuronal damage (ATF3) and glial activation (GFAP, Iba1). Results During dose finding, severe generalized allodynia was observed with high intrathecal doses of both MPA and MP in naive rats. MPA had no effect upon tactile allodynia after carrageenan. MP and MPA did not reverse tactile allodynia in the SNL model, and did not reduce flinching in the formalin model. MP and MPA prevented the delayed (7–day) tactile allodynia otherwise observed in the formalin-injected paw. Systemic MP or perineural MP or MPA did not reduce pain-like behaviour in the SNL model. No reduction of neuronal injury (ATF3) in the dorsal root ganglion or astrocyte activation (GFAP) in the spinal dorsal horn with intrathecal MP or MPA was observed. There was a decrease in microglial activation (Iba1) in the spinal dorsal horn with MPA after SNL. Conclusion Severe generalized allodynia was observed after high intrathecal doses of MP and MPA in naive rats. No acute analgesic effects with intrathecal glucocorticoids were observed in three well established pain models. Only a late antiallodynic effect was present in the formalin model, 7 days after formalin injection and drug treatment. Implications Our results do not support use of intrathecal methylprednisolone in the treatment of pain.

Effect of intrathecal glucocorticoids on the central glucocorticoid receptor in a rat nerve ligation model

Abstract Background and aims Despite widespread use, the efficacy of neuraxial glucocorticoids for neuropathic painis subject to debate. Since most glucocorticoid actions are mediated through its receptor, we explored the effects of intrathecal methylprednisolone acetate (MPA) on total glucocorticoid receptor (tGR) levels and activation of the glucocorticoid receptor (phosphorylated state = pGR) within the spinal dorsal horn (SDH) and dorsal root ganglion (DRG) in a spinal nerve ligation (SNL) model in rats. Methods Rats received unilateral ligation of the L5/L6 spinal nerves and were treated with two intrathecal doses of either 400 μg MPA or 0.9% saline with a 72-h interval. Plantar tactile thresholds were measured over time. Seven days after drug treatment, DRG and SDH were harvested to assess tGR and pGR levels using immunohistochemistry and qPCR. Results Allodynia, defined by lowered tactile withdrawal thresholds after SNL, was unaltered by intrathecal MPA. In saline controls, mRNA levels of tGR did not change after SNL in the DRGs or SDH. tGR and pGR protein levels in the SDH however, significantly increased on the ipsilateral side of SNL compared to the contralateral side and to naïve tissue. When treating rats with MPA, tGR mRNA levels were significantly reduced in the SDH compared to saline controls. tGR and pGR protein levels, however were not significantly lower compared to saline controls. Conclusions In intrathecal MPA treated rats, tGR mRNA levels decreased after SNL. However this did not result in lower tGR and pGR protein levels compared to saline controls, and did not decrease ligation-induced mechanical hypersensitivity. Implications Intrathecal MPA treatment after SNL did not result in lower tGR and pGR levels within the SDH and DRG compared to saline controls. In present study we did not differentiate between the various isoforms of the GR which might clarify this finding.

Safe use of epidural corticosteroid injections: recommendations of the WIP Benelux workgroup

Epidural corticosteroid injections are used frequently worldwide in the treatment of radicular pain. Concerns have arisen involving rare major neurologic injuries after this treatment. Recommendations to prevent these complications have been published, but local implementation is not always feasible due to local circumstances, necessitating local recommendations based on literature review.