Refined sensory measures of neural repair in human spinal cord injury: bridging preclinical findings to clinical value

Sensory input from the periphery to the brain can be severely compromised or completely abolished after an injury to the spinal cord. Evidence from animal models suggests that endogenous repair processes in the spinal cord mediate extensive sprouting and that this might be further attenuated by targeted therapeutic interventions. However, the extent to which sprouting can contribute to spontaneous recovery after human spinal cord injury (SCI) remains largely unknown, in part because few measurement tools are available in order to non-invasively detect subtle changes in neurophysiology. The proposed application of segmental sensory evoked potentials (e.g., dermatomal contact heat evoked potentials and somatosensory evoked potentials) to assess conduction in ascending pathways (i.e., spinothalamic and dorsal column, respectively) differs from conventional approaches in that individual spinal segments adjacent to the level of lesion are examined. The adoption of these approaches into clinical research might provide improved resolution for measuring changes in sensory impairments and might determine the extent by which spontaneous recovery after SCI is mediated by similar endogenous repair mechanisms in humans as in animal model

Abstracts from the 8th International Conference on cGMP Generators, Effectors and Therapeutic Implications

This work was supported by a restricted research grant of Bayer AG

Assessment of spinothalamic tract function beyond pinprick in spinal cord lesions: a contact heat evoked potential study

BACKGROUND: Although a mainstay of clinical sensory examination after damage in the spinal cord, pinprick sensation represents only one afferent modality conveyed in the spinothalamic tract. As an objective outcome, complementary information regarding spinothalamic tract conduction may be elucidated by measuring contact heat evoked potentials (CHEPs). OBJECTIVE: To assess the value of CHEPs to measure spinothalamic tract function in spinal cord disorders compared with pinprick scoring. METHODS: CHEPs were examined using a standard (35°C) and increased baseline (42°C) contact heat temperature. Pinprick sensation was rated as absent, impaired, or normal according to the International Standards for the Neurological Classification of Spinal Cord Injury. RESULTS: Fifty-nine dermatomes above, at, and below the sensory level of impairment were analyzed in 37 patients with defined spinal cord disorder. In dermatomes with absent or impaired pinprick sensation, CHEPs using a standard baseline temperature were mainly abolished (3/16 and 8/35, respectively). However, when applying an increased baseline temperature, CHEPs became recordable (absent: 11/16; impaired: 31/35). Furthermore, CHEPs with increased baseline temperature allowed discerning between dermatomes with absent, impaired, and normal pinprick sensation when using an objective measure (ie, N2P2 amplitude). In contrast, the pain perception to contact heat stimulation was independent of pinprick scores. CONCLUSION: Applying pinprick testing is of limited sensitivity to assess spinothalamic tract function in spinal cord disorders. The application of CHEPs (using standard and increased baseline temperatures) as an objective readout provides complementary information of spinothalamic tract functional integrity beyond pinprick testing

Contact Heat Evoked Potentials Are Responsive to Peripheral Sensitization: Requisite Stimulation Parameters.

The sensitizing effect of capsaicin has been previously characterized using laser and contact heat evoked potentials (LEPs and CHEPs) by stimulating in the primary area of hyperalgesia. Interestingly, only CHEPs reveal changes consistent with notion of peripheral sensitization (i.e., reduced latencies). The aim of this study was to investigate contact heat stimulation parameters necessary to detect peripheral sensitization related to the topical application of capsaicin, and therefore significantly improve the current method of measuring peripheral sensitization via CHEPs. Rapid contact heat stimulation (70°C/s) was applied from three different baseline temperatures (35, 38.5, and 42°C) to a 52°C peak temperature, before and after the topical application of capsaicin on the hand dorsum. Increased pain ratings in the primary area of hyperalgesia were accompanied by reduced N2 latency. Changes in N2 latency were, however, only significant following stimulation from 35 and 38.5°C baseline temperatures. These findings suggest that earlier recruitment of capsaicin-sensitized afferents occurs between 35 and 42°C, as stimulations from 42°C baseline were unchanged by capsaicin. This is in line with reduced thresholds of type II A-delta mechanoheat (AMH) nociceptors following sensitization. Conventional CHEP stimulation, with a baseline temperature below 42°C, is well suited to objectively detect evidence of peripheral sensitization

Improved diagnosis of spinal cord disorders with contact heat evoked potentials

OBJECTIVE: To evaluate the sensitivity of contact heat evoked potentials (CHEPs) compared with dermatomal somatosensory evoked potentials (dSSEPs) and clinical sensory testing in myelopathic spinal cord disorders (SCDs). METHODS: In a prospective cohort study, light-touch (LT) and pinprick (PP) testing was complemented by dermatomal CHEPs and dSSEPs in patients with a confirmed SCD as defined by MRI. Patients with different etiologies (i.e., traumatic and nontraumatic) and varying degrees of spinal cord damage (i.e., completeness) were included. SCD was distinguished into 3 categories according to MRI pattern and neurologic examination: a) complete, b) incomplete-diffuse, and c) central or anterior cord damage. RESULTS: Seventy-five patients were included (complete n = 7, incomplete-diffuse n = 33, central/anterior n = 35). In total, 319 dermatomes were tested with combined CHEPs and dSSEPs. CHEPs, dSSEPs, and clinical sensory testing were comparably sensitive to detect the myelopathy in complete (CHEPs 100%, dSSEPs 91%, PP and LT 82%) and incomplete-diffuse (CHEPs 92%, dSSEPs and PP 86%, LT 81%, p > 0.05 for all comparisons) cord damage. In central/anterior cord damage, CHEPs showed a significantly higher sensitivity than dSSEPs (89% compared with 24%, p < 0.001) and clinical sensory testing (PP 62%, LT 57%, p < 0.05). A subclinical sensory impairment was detected more frequently by CHEPs than dSSEPs (60% compared with 29%, p = 0.001). CONCLUSIONS: Assessment of spinothalamic pathways with CHEPs is reliable and revealed the highest sensitivity in all SCDs. Specifically in incomplete lesions that spare dorsal pathways, CHEPs are sensitive to complement the clinical diagnosis

Assessments of sensory plasticity after spinal cord injury across species

Spinal cord injury (SCI) is a multifaceted phenomenon associated with alterations in both motor function and sensory function. A majority of patients with SCI report sensory disturbances, including not only loss of sensation, but in many cases enhanced abnormal sensation, dysesthesia and pain. Development of therapeutics to treat these abnormal sensory changes require common measurement tools that can enable cross-species translation from animal models to human patients. We review the current literature on translational nociception/pain measurement in SCI and discuss areas for further development. Although a number of tools exist for measuring both segmental and affective sensory changes, we conclude that there is a pressing need for better, integrative measurement of nociception/pain outcomes across species to enhance precise therapeutic innovation for sensory dysfunction in SCI

Swiss experience of atezolizumab for platinum-pretreated urinary tract carcinoma: the SAUL study in real-world practice.

AIMS OF THE STUDY Atezolizumab is an approved therapy for urothelial carcinoma based on results from the IMvigor 210 and IMvigor211 phase II and III trials. The global SAUL study evaluated atezolizumab in a broader patient population more representative of real-world populations. Among approximately 1000 patients treated in SAUL, 25 were treated in Swiss oncology centres. We evaluated outcomes in these patients to provide a better understanding of atezolizumab treatment for urinary tract carcinoma in Swiss clinical practice. METHODS Eligible patients had locally advanced or metastatic urothelial or non-urothelial urinary tract carcinoma that had progressed during or after one to three prior therapies for inoperable, locally advanced or metastatic disease. Patient populations typically excluded from clinical trials (e.g., patients with renal impairment, treated central nervous system [CNS] metastases, stable controlled autoimmune disease or Eastern Cooperative Oncology Group performance status 2) were also eligible. All patients received atezolizumab 1200 mg every 3 weeks until loss of clinical benefit or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included overall survival (OS), overall response rate (ORR) and disease control rate (DCR). RESULTS All 25 Swiss patients had previously received a gemcitabine/platinum doublet. Disease had progressed within 12 months of platinum-based therapy in all but one patient, and 19 (76%) had received one prior line of therapy for metastatic disease. The median duration of atezolizumab therapy was six cycles (range 1&ndash;27) corresponding to 3.6 months. Five patients (20%) had received &gt;20 cycles and four (16%) remained on treatment at the data cut-off. Grade 3 adverse events (AEs) occurred in 13 patients (52%) and were considered to be treatment-related in four patients (16%; liver enzyme increases, musculoskeletal pain, diverticulitis and autoimmune hepatitis). There was one grade 4 AE (hypercalcaemia) and no grade 5 AEs. After median follow-up of 17.3 months, median OS was 7.9 months (95% confidence interval [CI] 5.3&ndash;not evaluable), the 1-year OS rate was 47% (95% CI 27&ndash;65%), the ORR was 12% (95% CI 3&ndash;31%) and the DCR was 40% (95% CI 21&ndash;61%). Durable clinical benefit (&gt;1 year on treatment) was observed in seven patients (28%), including one with CNS metastases and one with small-cell carcinoma. CONCLUSIONS Atezolizumab is an active treatment option for platinum-pretreated urinary tract carcinoma, including patients with conditions that typically exclude them from clinical trials. (Trial registration no.: NCT02928406)