Acute vs. Chronic: Which projects should be supported?


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Time after time, a debate comes up on which type of stage of injury - acute or chronic – fundamental and clinical research should focus on. The general impression, especially in the patients’ community, is that research projects at the acute stage are systematically supported, while projects at the chronic stage get very little support despite the several million chronic patients. Is this true? We wanted to find out and investigated.

Definition

First let’s try to understand what the different steps of a lesion are. As defined by Rowland et al. there are four main stages:

1. Immediate Phase (0-2 hours): This phase is dominated by the immediate results of the injurious event itself.

2. Acute Phase, which is subdivided in two stages:

  • Early Acute Phase (2-48 hours). This phase is characterized by continuing hemorrhage, increasing edema and inflammation, and marks the onset of additional secondary injury processes.
  • Subacute Phase (2 days to 2 weeks). The repair mechanisms are starting and the injury is “resolving”.


3. Intermediate Phase (2 weeks to 6 months): The intermediate phase is characterized by the continued maturation of the glial scar and by regenerative axonal sprouting.

4. Chronic Phase (more than 6 months): The chronic phase begins at 6 months following injury and continues throughout the lifetime of the patient. It is characterized by the maturation/stabilization of the lesion including continued scar formation and the development of cysts and/or syrinxes, and is accompanied by alterations in neural circuitries.

Inherent difficulties of acute and chronic research

It is widely admitted that it is easier to save cells from dying than regenerating them altogether. Saving cells, whether they are neurons or glia, is a step that can be achieved only in the acute or sub acute phase, in which by definition the cells are degenerating. Of course, research focusing on neuroprotection is done in models of acute SCI, however, in cases of successful protection of nerve cells it will have a greater impact on the patient’s functions and his quality of life as chronic patient.

Research projects on acute vs. chronic SCI face different challenges. Regeneration during the acute (and subacute) phase must be done in an environment that is flooded with blood and cellular debris, which might have a detrimental effect on any applied treatment. When the injury is somehow “resolved” then a so called “glial scar” appears at the chronic stage. Formation of the glial scar has been shown to have both beneficial and detrimental effects. The glial scar is both a physical (dense wall of cells) and a molecular (inhibitory molecules) barrier to regrowth.

Over time, the damage in the spinal cord causes a rearrangement of neural circuits. The restoration of correct functional connections at the chronic stage is also considered to be more difficult as opposed to when the “functional memory” is still intact.

The following illustration, adapted from an article of McDonald and Sadowsky (Lancet 2002), gives a classification of the difficulties inherent to each task. The ultimate goal, the hardest, is achieving long tract re-growth with appropriate re-connectivity, thus fully restoring any lost function.



Acute vs. Chronic: An unequal support?

Before going through the numbers it is important to explain a fact that is widely ignored: Unless clearly specified as either acute or chronic, a project will have potential to benefit both such injuries. Even on later phases, testing a treatment on acute injuries just means running a fast analysis to assess the benefits and eventual secondary complications. This will in no way preclude an application on chronic injuries.

Wings for Life:
Throughout the years Wings for Life has equally supported projects on both acute and chronic injuries. Since 2004, 20% of projects focused on acute injuries, 19% on chronic injuries and 61% had the potential to be applied to both acute and chronic spinal cord injuries.

General:
A PubMed search (specialized search engine for scientific and medical journals) revealed that the same amount of scientific publications (approximately 6000 each) are focusing on acute and chronic SCI. This general analysis is confirming that there is no general consensus or preference to work on acute SCI.
An analysis on the ClinicalTrials.gov homepage (database of worldwide supported clinical trials) revealed that a majority of clinical trials are focusing on chronic spinal cord injuries, supporting again the idea that there is no particular will to support only work focusing on acute injuries. One reason is the fact that the injury itself is already stabilized, meaning that the functions will not improve or deteriorate, as opposed to more acute stages where a spontaneous “natural” recovery of functions is taking place. This means that any benefit monitored in a chronic patient will be attributed entirely to the treatment itself. Additionally, it is easier to obtain a conscious consent ("informed consent") from subacute/chronic patients than from acutely injured patients, who are much more affected by fears and uncertainties.

Should the financial support focus on projects for acute or chronic patients?

Unfortunately, acute injuries happen every day. These patients need an early specific and targeted treatment to limit the expansion of the injury while preserving as many functions as possible. Acute projects are essential, considering also the fact that a) any positive finding in this specific field has a dramatic effect on the functionality in the later chronic stage and b) results for a treatment option could also be applied to a more chronic stage. It is important to keep in mind that many treatments that are being studied today on chronic models were initially developed on acute injuries

Wings for Life strategy:
Following the concept discussed above, the Wings for Life foundation gives a high priority (during the grant selection process) to projects that focus on chronic injuries but also funds promising projects that focus uniquely on acute injuries. There is also a strong drive to “push” a promising concept that was discovered in acute injuries into more chronic stages. For example: Nogo was found to be an extrinsic inhibitor of axon regeneration in acute SCI. The effect of the Nogo decoy receptor protein in chronic SCI was shown by S. Strittmatter. Whenever possible, Wings for Life also gives high priority to projects which can benefit both acute and chronic injuries. Among those are:

  • projects that explore the fundamental mechanisms of cellular regeneration (Example 1, Example 2)  
  • projects that explore the potential of cellular treatments (Example)
  • bioinformatics tools to help the scientists and the clinicians to better “translate” findings into the clinical phase (Example)

The goal of Wings for Life is finding a cure for spinal cord injury. We want acute patients to keep more functions after their injury and we want chronic patients get functions back. For us it is important to take research to the next step: clinical trials.

References:
1.    McDonald JW, Sadowsky C. Spinal-cord injury. Lancet. 2002 Feb 2;359(9304):417-25. Review.
2.    Rowland JW, Hawryluk GW, Kwon B, Fehlings MG. Current status of acute spinal cord injury pathophysiology and emerging therapies: promise on the horizon. Neurosurg Focus. 2008;25(5).