Thomas Liebscher

Small-molecule-induced Rho-inhibition: NSAIDs after spinal cord injury

Limited axonal plasticity within the central nervous system (CNS) is a major restriction for functional recovery after CNS injury. The small GTPase RhoA is a key molecule of the converging downstream cascade that leads to the inhibition of axonal re-growth. The Rho-pathway integrates growth inhibitory signals derived from extracellular cues, such as chondroitin sulfate proteoglycans, Nogo-A, myelin-associated glycoprotein, oligodendrocyte-myelin glycoprotein, Ephrins and repulsive guidance molecule-A, into the damaged axon. Consequently, the activation of RhoA results in growth cone collapse and finally outgrowth failure. In turn, the inhibition of RhoA-activation blinds the injured axon to its growth inhibitory environment resulting in enhanced axonal sprouting and plasticity. This has been demonstrated in various CNS-injury models for direct RhoA-inhibition and for downstream/upstream blockade of the RhoA-associated pathway. In addition, RhoA-inhibition reduces apoptotic cell death and secondary damage and improves locomotor recovery in clinically relevant models after experimental spinal cord injury (SCI). Unexpectedly, a subset of “small molecules” from the group of non-steroid anti-inflammatory drugs, particularly the FDA-approved ibuprofen, has recently been identified as (1) inhibiting RhoA-activation, (2) enhancing axonal sprouting/regeneration, (3) protecting “tissue at risk” (neuroprotection) and (4) improving motor recovery confined to realistic therapeutical time-frames in clinically relevant SCI models. Here, we survey the effect of small-molecule-induced RhoA-inhibition on axonal plasticity and neurofunctional outcome in CNS injury paradigms. Furthermore, we discuss the body of preclinical evidence for a possible clinical translation with a focus on ibuprofen and illustrate putative risks and benefits for the treatment of acute SCI.

Spinal cord injury-induced immunodeficiency is mediated by a sympathetic-neuroendocrine adrenal reflex

Acute spinal cord injury (SCI) causes systemic immunosuppression and life-threatening infections, thought to result from noradrenergic overactivation and excess glucocorticoid release via hypothalamus–pituitary–adrenal axis stimulation. Instead of consecutive hypothalamus–pituitary–adrenal axis activation, we report that acute SCI in mice induced suppression of serum norepinephrine and concomitant increase in cortisol, despite suppressed adrenocorticotropic hormone, indicating primary (adrenal) hypercortisolism. This neurogenic effect was more pronounced after high-thoracic level (Th1) SCI disconnecting adrenal gland innervation, compared with low-thoracic level (Th9) SCI. Prophylactic adrenalectomy completely prevented SCI-induced glucocorticoid excess and lymphocyte depletion but did not prevent pneumonia. When adrenalectomized mice were transplanted with denervated adrenal glands to restore physiologic glucocorticoid levels, the animals were completely protected from pneumonia. These findings identify a maladaptive sympathetic-neuroendocrine adrenal reflex mediating immunosuppression after SCI, implying that therapeutic normalization of the glucocorticoid and catecholamine imbalance in SCI patients could be a strategy to prevent detrimental infections.

Airway complications in traumatic lower cervical spinal cord injury: A retrospective study

Abstract Objective To investigate risk factors for pneumonia in patients with traumatic lower cervical spinal cord injury. Design Observational study, retrospective study. Setting Spinal cord unit in a maximum care hospital. Methods Thirty-seven patients with acute isolated traumatic spinal cord injury at levels C4–C8 and complete motor function injury (AIS A, B) treated from 2004 to 2010 met the criteria for inclusion in our retrospective analysis. The following parameters were considered: ventilation-specific parameters, re-intubation, creation of a tracheostomy, pneumonia, antibiotic treatment, and length of intensive care unit (ICU) stay and total hospitalization. Results Among the patients, 81% had primary invasive ventilation. In 78% of cases a tracheostomy was created; 3% of these cases were discharged with invasive ventilation and 28% with a tracheostomy without ventilation. Pneumonia according to Centers for Disease Control criteria occurred in 51% of cases within 21 ± 32 days of injury, and in 3% at a later date. The number of pre-existing conditions was significantly associated with pneumonia. Length of ICU stay was 25 ± 34 days, and average total hospital duration was 230 ± 144 days. Significant factors affecting the duration of ventilation were the number of pre-existing conditions and tetraplegia-specific complications. Conclusions Our results confirm that patients with traumatic lower cervical spinal cord injuries defined by lesion level and AIS constitute a homogeneous group. This group is characterized by a high rate of pneumonia during the first 4 weeks after injury. The number of pre-existing general conditions and spinal injury-specific comorbidities are the only risk factors identified for the development of pneumonia and/or duration of ventilation.

Outcome analyses of a multimodal treatment approach for deep pressure ulcers in spinal cord injuries: a retrospective cohort study

Study designRetrospective observational cohort study.ObjectivesTo describe outcomes, risk factors for complications, and relapse rates associated with the multimodal treatment approach for deep pressure ulcers (PUs) grade IV for the ischium, trochanter major, and sacral regions of patients with traumatic and non-traumatic spinal cord injury (SCI).SettingThe settings comprised two spinal cord units within a maximum care hospital. The treatment of all patients followed the modified interdisciplinary “Basler treatment concept”.MethodsWe included all individuals with SCI with a first occurrence of PU grade IV in the buttocks area between August 2008 and December 2012 inclusive, with a maximum follow-up of 3 years. Descriptive, univariate, and bivariate analyses were undertaken, as were group comparisons.ResultsIn 47 patients aged 18–87 years (mean age: 51 years) a total of 63 fasciocutaneous and myocutaneous flaps were performed. Wound healing was complete after a mean of 34 days (SD = 21). Postoperative mobilisation in a wheelchair was performed after a mean of 46 days (SD = 24). Delayed healing was reported in 18 patients (38%), and revision surgery was necessary in five patients (11%). ASIA impairment scale (AIS) A (p = .001), and male gender (p = .001) were identified as risk factors for delayed wound healing and prolonged inpatient stay.Treatment-associated pneumonia occurred in four cases (11% of all patients, 25% of patients with tetraplegia). Patients were discharged when the time spent sitting in a wheelchair was 2 × 2 h per day; this occurred after a mean of 100 days (SD = 36). PU recurrence was observed in six cases (18%).ConclusionsOur multimodal treatment concept was found to have complication rates comparable to those in the literature; additionally, this approach might be associated with lower recurrence rates with respect to the literature. To reduce high rates of pneumonia occurrence among patients with tetraplegia, preventive measures need to be established. Further evidence of the efficiency of this complex treatment approach for PU in individuals with SCI is needed.

Breathing-synchronised electrical stimulation of the abdominal muscles in patients with acute tetraplegia: A prospective proof-of-concept study

Objective: To examine whether, by enhancing breathing depth and expectoration, early use of breathing-synchronised electrical stimulation of the abdominal muscles (abdominal functional electrical stimulation, AFES) is able to reduce pulmonary complications during the acute phase of tetraplegia. Design: Prospective proof-of-concept study. Setting: Spinal cord unit at a level 1 trauma center. Method: Following cardiovascular stabilisation, in addition to standard treatments, patients with acute traumatic tetraplegia (ASIA Impairment Scale A or B) underwent breathing-synchronised electrical stimulation of the abdominal muscles to aid expiration and expectoration. The treatment was delivered in 30-minute sessions, twice a day for 90 days. The target was for nine of 15 patients to remain free of pneumonia meeting Centers for Disease Control and Prevention (CDC) diagnostic criteria. Results: Eleven patients were recruited to the study between October 2011 and November 2012. Two patients left the study before completion. None of the patients contracted pneumonia during the study period. No complications from electrical stimulation were observed. AFES led to a statistically significant increase in peak inspiratory and expiratory flows and a non-statistically significant increase in tidal volume and inspiratory and expiratory flow. When surveyed, 6 out of 9 patients (67%) reported that the stimulation procedure led to a significant improvement in breathing and coughing. Conclusion: AFES appears to be able to improve breathing and expectoration and prevent pneumonia in the acute phase of tetraplegia (up to 90 days post-trauma). This result is being validated in a prospective multicentre comparative study.

SCISSOR—Spinal Cord Injury Study on Small molecule-derived Rho inhibition: a clinical study protocol

Introduction The approved analgesic and anti-inflammatory drugs ibuprofen and indometacin block the small GTPase RhoA, a key enzyme that impedes axonal sprouting after axonal damage. Inhibition of the Rho pathway in a central nervous system-effective manner requires higher dosages compared with orthodox cyclooxygenase-blocking effects. Preclinical studies on spinal cord injury (SCI) imply improved motor recovery after ibuprofen/indometacin-mediated Rho inhibition. This has been reassessed by a meta-analysis of the underlying experimental evidence, which indicates an overall effect size of 20.2% regarding motor outcome achieved after ibuprofen/indometacin treatment compared with vehicle controls. In addition, ibuprofen/indometacin may also limit sickness behaviour, non-neurogenic systemic inflammatory response syndrome (SIRS), neuropathic pain and heterotopic ossifications after SCI. Consequently, ‘small molecule’-mediated Rho inhibition after acute SCI warrants clinical investigation. Methods and analysis Protocol of an investigator-initiated clinical open-label pilot trial on high-dose ibuprofen treatment after acute traumatic, motor-complete SCI. A sample of n=12 patients will be enrolled in two cohorts treated with 2400 mg/day ibuprofen for 4 or 12 weeks, respectively. The primary safety end point is an occurrence of serious adverse events, primarily gastroduodenal bleedings. Secondary end points are pharmacokinetics, feasibility and preliminary effects on neurological recovery, neuropathic pain and heterotopic ossifications. The primary safety analysis is based on the incidence of severe gastrointestinal bleedings. Additional analyses will be mainly descriptive and casuistic. Ethics and dissemination The clinical trial protocol was approved by the responsible German state Ethics Board, and the Federal Institute for Drugs and Medical Devices. The study complies with the Declaration of Helsinki, the principles of Good Clinical Practice and all further applicable regulations. This safety and pharmacokinetics trial informs the planning of a subsequent randomised controlled trial. Regardless of the result of the primary and secondary outcome assessments, the clinical trial will be reported as a publication in a peer-reviewed journal. Trial registration number NCT02096913; Pre-results.