Research news and notes

1. Biomechanics of bioresorbable plates for anterior cervical diskectomy and fusion 

Anterior cervical diskectomy and fusion is one of the most commonly performed neurosurgical procedures. Recently, bioresorbable plates from materials such as polylactide acids were introduced. They are less stiff and more load sharing than metal plates, radiolucent, and temporary while still aiming to provide adequate stability for bone healing [8]. In a recent study, Freeman et al [3] asked an important question—how do bioresorbable plates compare with titanium plates when subjected to various mechanical stresses? They examined 16 human cervical spine segments in their laboratory, in the intact state, after anterior cervical diskectomy with graft fusion without plate and then with either a resorbable or a titanium plate. All the segments were tested in flexion-extension, lateral bending, and axial rotation. The constructs were subjected to 500 cycles of movements each. None of the plated constructs failed, and there was no graft migration during testing. The resorbable plates limited motion, lateral bending and flexion-extension to a degree intermediate between having no plate and a titanium plate. For example, bioresorbable plates reduced segmental motion in flexion-extension by 49% compared to 69% reduction with titanium plates, both in comparison with uninstrumented anterior cervical diskectomy with graft fusion. The authors conclude that the bioresorbable plates provided some stabilization with more load sharing compared with titanium plates.

Plates that eventually disappear may seem attractive to patients. Decreasing the metal artifact on magnetic resonance imaging is also useful. Future clinical studies may show whether this new technology is indeed a valuable contribution to our armamentarium.

2. Vaccines against smoking (and other drug abuse) 

Smoking is considered to be a major public health problem. Within our field, it may contribute to the incidence of stroke and aneurysmal subarachnoid hemorrhage, as well as metastatic lung cancer. Despite the obvious health hazards, millions continue to smoke. One of the possible reasons—the addiction to nicotine is notoriously difficult to overcome. Mark Twain famously said: “Quitting smoking is the easiest thing in the world to do. I know—I've done it many times.” Over the past several years, biotechnology companies have been working on a paradigm that can take the fight against addiction beyond reliance on willpower.

Vaccines have had an important role in the prevention of infections diseases. Now several studies are underway [5] that evaluate vaccination against a different type of target—an addictive molecule. Because most drugs of abuse are small molecules, they are not immunogenic on their own. Rather, they are attached to large proteins known to trigger immune response. Some antibodies formed in response to the drug-protein complex recognize parts of the protein, and others latch on to the drug. The vaccines are designed to bind the addictive molecule, such as nicotine or cocaine, and prevent it from crossing the blood-brain barrier and attaching to its receptors. The absence of positive feedback from taking the addictive substance rapidly extinguished addictions in animal models [5]. The vaccine does not prevent the person from taking the drug or from smoking, but it takes away the pleasure associated with it. Some of these vaccines are advancing toward extensive clinical trials [7]. Cytos Biotechnology was the latest to announce plans to begin a phase IIb/III trial in 2007 [4], joining 2 other companies who are conducting clinical trials of their vaccines.

The companies that are conducting these trials must expect a large market for “vice vaccines.” Nevertheless, I cannot help feeling uneasy with the concept. Vaccination against specific behaviors has profound implications for our society. Cross-reactivity with endogenous substances and neurotransmitters is also a risk that must be considered in a long-term study in humans.

3. Long-term follow-up after transplantation for Huntington's disease 

Degenerative diseases of the brain remain a terrible burden on those who have them and their families. Although medical treatment is available for Parkinson's disease and even Alzheimer's disease, there is no cure. The situation is even grimmer with the uncommon but devastating Huntington disease. This autosomal dominant disorder strikes in middle age and results in progressive motor and cognitive symptoms that lead to the death of the victim within 10 to 15 years. There is no effective treatment. This disease affects mostly the basal ganglia and has become one of the targets for experimental cell replacement therapy [2]. A European clinical trial started several years ago, and now some longer-term follow-up is available. Six years of follow-up was available in 5 patients and was reported in Lancet Neurology [1]. The patients received fetal striatal grafts into their striatum. An increase in local metabolic activity and clinical improvement on standard assessment scales was noted initially in 3 of the patients. Improvement plateaued after 2 years, and in years 4 to 6 of clinical follow-up, especially motor deterioration was noted. Cognitive performance remained stable in the 3 initial responders. The 2 patients who did not improve, as well as patients who never received grafts, continued to deteriorate in all parameters. The study shows both the hope of cell replacement therapy and its current limitations.

Some of the temporary and limited success of cell transplantation may be related to our inadequate understanding and treatment of immunologic graft rejection. The brain has been considered a “relatively privileged” site. The local immune response remained little understood, and immune suppression in clinical neural transplantation studies was empirical, partial, and often also empirically limited in time. A recent study [6] in patients with Huntington's disease who received fetal allografts revealed evidence of immunization against the graft without what appeared to the authors as clinical evidence of rejection. Of course, because the brain could not be removed and studied, chronic rejection and cellular infiltrate around the graft could not be demonstrated. In one patient, there were also radiologic signs of rejection with loss of graft activity. This loss of activity was reversible after immune suppression was restarted. The authors propose that some of the results obtained in the past with neural transplants were biased or limited by unrecognized immune response.

This conclusion makes sense. Moreover, it is very likely that even in patients who appear not to have any “clinical or radiologic” rejection, an inflammatory or microglia infiltrate exists. It was seen in patients who died while on follow-up in the controlled Parkinson's disease fetal graft study (personal communication), and we routinely see it whenever we stain animal brains after neural transplantation with markers for inflammatory cells. Microglia and macrophages are seen even when immune suppression with cyclosporine is used. There is much to be learned about immune response in the central nervous system, and the sooner, the better for the future of clinical neural transplantation.