Methylprednisolone, early decompression, macrophage therapy and robotics

Release date: 09-Nov-2012

Organisation: Yale University Medical School, University of Toronto, University of Colorado, University of Zurich, Department of Veterans Affairs USA

Professor Alan Mackay Sim describes three clinical papers and two futuristic experimental papers that caught his eye in 2012.

Clinical papers

Bracken MB (2012) Steroids for acute spinal cord injury. Cochrane Database Syst Rev. Jan 18;1:CD001046, Yale University Medical School, CT, United States of Amercia.

This is a Cochrane systematic review of the efficacy of all randomised controlled clinical trials of steroids for treatment of acute spinal cord injury. This review is important because of the widespread belief that methylprednisolone treatment is ineffective. In contrast to that view there is evidence that methylprednisolone does improve neurologic recovery, even if the effect is small. The difference between “belief” and “evidence” may be due to the treatment regimes chosen by clinicians. This review emphasises a high dose applied early as being the most effective:

“Methylprednisolone sodium succinate has been shown to enhance sustained neurologic recovery in a phase three randomised trial, and to have been replicated in a second trial. Therapy must be started within eight hours of injury using an initial bolus of 30mg/ kg by IV for 15 minutes followed 45 minutes later by a continuous infusion of 5.4mg/kg/hour for 24 hours. Further improvement in motor function recovery has been shown to occur when the maintenance therapy is extended for 48 hours. This is particularly evident when the initial bolus dose could only be administered three to eight hours after injury.”

Fehlings MG et al (2012) Early versus delayed decompression for traumatic cervical spinal cord injury: results of the Surgical Timing in Acute Spinal Cord Injury Study (STASCIS). PLoS One. 2012;7(2):e32037, University of Toronto, Toronto, Ontario, Canada.

This paper investigates the time-window for decompression surgery and the differences in outcomes of patients receiving surgery before or after 24 hrs. The study is important because although animal experiments indicate that early decompression surgery should improve outcomes, there are no systematic clinical studies and hence no evidence to extend from animal studies into the clinic.

The study is a prospective, multicentre, cohort design that assigned patients into groups according to the timeliness of decompression surgery. The timing of the surgery was dependent on factors outside the control of the experimenters and the patients were assigned to groups according to these factors, rather than by randomisation. 470 subjects were screened for enrolment and 313 satisfied the inclusion and exclusion criteria, with 181 in the early surgery group and 131 in the later surgery group. More patients in the early surgery group had more serious injuries (ie more were in the AIS A and B grades). Despite this the early surgery group were significantly more likely to have improved two or more AIS grades after 6 months. The conclusion was that early decompression was safe and effective in improving neurologic outcome.

Lammertse DP et al (2012) Autologous incubated macrophage therapy in acute, complete spinal cord injury: results of the phase 2 randomised controlled multicenter trial. Nat Med. 18:1142-7, University of Colorado, CO, United States of America.

This is a report of the trial sponsored by Proneuron. It follows on from animal studies that showed that stimulating the immune system could improve recovery after spinal cord injury in rodents. The concept is that the macrophage immune response to spinal cord injury is blunted compared to the response after peripheral nerve injury. The animal studies showed that activating the macrophages improved recovery after spinal cord injury. This present Phase 2 trial followed on from an open-label Phase 1 trial showing that the procedure was safe and 37% of patients improved their AIS grade from A to C.

This study is a Phase 2, multicentre, randomized, parallel group controlled trial comparing autologous incubated macrophage treatment with standard care and single-blinded outcome assessments. Blood and skin were harvested. From the blood an enriched white cell fraction was extracted and was incubated with decontaminated skin fragments for one day. The cells were identified as mostly (more than 60%) macrophages. Within 38 hours after blood extraction and two weeks after spinal cord injury, the patients had 1.5 million cells injected into their spinal cords at the caudal end of their lesion. The surgery involved exposing the spinal cord and injecting the cells in six sites with a hand held syringe. Patients were assessed at 6, 9 and 12 months with the assessors blinded to treatment. Fifty patients were included in the trial and 43 completed it (26 treatment, 17 control). Ultimately, there was no significant effect of treatment on AIS grade nor on any other neurologic assessment. Of note was the high rate of conversion from AIS A to B or C in the control group (10/17 converted at 6 months) which was higher than for the treatment group (7/26 at 6 months). The treatment effect was not statistically significant.

Although the study failed to support the hypothesis that the treatment would be effective, this is major achievement to take a cell therapy into a Phase 2 clinical trial, a very important step for the field.

Experimental papers

Dominici N et al (2012) Versatile robotic interface to evaluate, enable and train locomotion and balance after neuromotor disorders. Nat Med. 18:1142-7, University of Zurich, Zurich, Switzerland.

This paper describes a new robotic device for rats that provides body weight support and allows free movement. The support is dynamically controlled and has low inertia so that it does not interfere with normal functions. They show this by first attaching it to uninjured animals and recording muscle activity and kinematic joint movements with the animals walking on a treadmill and up stairs. When paraplegic animals are electrically and pharmacologically stimulated they can show rhythmic walking with weight bearing steps. When these animals are trained for nine weeks using the robotic system they regain postural control and balance and can walk along a curved runway maintaining balance and posture. The big advance of this system is its dynamic control and freedom of movement. Current rodent and human robotic support systems for rehabilitation are limited by treadmill stepping with high inertia and unidirectional trunk support. The evidence suggests that gait rehabilitation requires overground walking in multiple contexts (flat ground, steps, curves straights, corners etc). This device claims to be able “to evaluate, enable and train motor pattern generation and balance across a variety of natural walking behaviours in rats with neuromotor impairments.” If similar principles can be applied in a human robotic interface it has the potential to be a significant advance for locomotor rehabilitation after spinal cord injury.

Hochberg LR et al (2012) Reach and grasp by people with tetraplegia using a neurally controlled robotic arm. Nature. 485:372-5, Department of Veterans Affairs, Providence, RI, United States of America.

This paper places a robot arm under direct control of the brain of the person with tetraplegia. Two patients were surgically implanted with arrays of electrodes in the hand area of the motor cortex. Recordings from electrical activity at these 96 electrodes were decoded and used as inputs to drive the robotic arm. The electrical activity was shaped by the person thinking about moving their hand and both patients were able to grasp and reach with the robot arm without explicit training. One patient used the robotic arm to drink coffee from a bottle. The bionic future is already here.

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