Cerebral palsy prevention and cure: Vision or mirage? A personal view
- Conflict of interest: HKG is a consultant for Merz Pharmaceuticals and receives research support from Allergan, Inc. and OrthoPediatrics Corp.
‘When I use a word’, Humpty Dumpty said in rather a scornful tone, ‘it means just what I choose it to mean – neither more nor less’.
‘The question is’, said Alice, ‘whether you can make words mean so many different things’.
(Through the Looking Glass, Chapter 6)
As a clinician researcher, I read with interest the Viewpoint ‘Causal pathways in cerebral palsy’ by Badawi and Keogh. The article is a fitting tribute to the pioneering work of Fiona Stanley. However, I have concerns about the author's views on prevention and cure of cerebral palsy (CP). The statement that ‘prevention and cure no longer seems an unattainable goal’ and the time line suggested is overly optimistic. Does loose language and speculation matter? Is there any harm in being positive and upbeat? I think there is, both in the dilemmas faced by parents of children with CP and the clinicians who manage these children. There is also a risk that the CP research agenda and funding may be distorted.
‘Prevention’ and ‘cure’ are simple, commonly used words which have straightforward meanings when applied to disease and health conditions. I asked colleagues and parents in the clinic what they thought these terms meant when applied to CP. To many, preventing CP meant that either there would be no CP or very much less CP than there is now. Curing CP meant that individuals with CP would no longer have CP. Curing CP means CP as a disease entity is gone.
This seems to be the standard medical usage. Poliomyelitis has a viral cause. Vaccination prevents clinical cases in individuals and in populations. Ergo, polio has been prevented. Staphylococcus aureus causes osteomyelitis. Administration of appropriate antibiotics cures bone infections. In cancer therapy, the oncology team first decides if the aims of treatment are cure or palliation. Cure of cancer means no more cancer, not now, not ever. How can these terms reasonably be applied to CP?
Prevention and Cure of CP
The aphorism states, ‘An ounce of prevention is better than a pound of cure.’ If CP has been prevented, there is no need for any treatment, never mind a cure. So at a guess, the authors must mean a reduction in the prevalence of CP. So how will that be accomplished? How much and how soon?
We agree that most CP is present at birth, is rarely caused by events during birth and is a congenital condition. When specific causes of brain injury are identified (e.g. kernicterus), they can usually be prevented and/or treated. However, most CP results from complex causal pathways, which the authors understand much better than I do. It is very difficult to prevent premature birth and low birthweight. CP in premature and very-low-birthweight babies may be trending down, but total CP rates in most states in Australia and in many other countries are static. In recent studies, it can be difficult to distinguish the signal from the noise in long-term prevalence trends.
Causal pathways are like the many-headed Hydra. As soon as one head is chopped off, another two appear. Given that maternal health, nutrition, smoking, fertility treatments, alcohol and drug ingestion are important factors in causal pathways, prevention will in part rest on the most difficult proposition of all: changing human behaviour. Prevention is the best way forward and Australia is well placed by the investment in statewide and national CP registers. However, let's be realistic. It is likely to be a long, hard slog to get a meaningful reduction in CP rates. The law of diminishing returns will apply in that it may be easier to get an initial reduction and harder to get the rest. Low-hanging fruit. Some causal pathways will recede and new pathways will develop. We look forward to the publication of downward- trending total CP prevalence rates, state by state. Remember the old business adage, ‘promise long and deliver short.’
When parents were asked in a questionnaire to prioritise research in CP, prevention and cure were popular choices. This is much the same as asking me if I would prefer Krug and caviar over beer and sausages for dinner. If they are all on the menu (and someone else is paying), I will go for the Krug and caviar. Neither prevention nor cure, as the average parent would understand these terms, was ever on the menu. When a flawed question is asked, the study outcome is not very meaningful.
Cure does not mean palliation, improvement or mitigation. It means the brain lesion is healed and the CP has gone. The author's pessimism about current treatments is overstated and is not a logical platform for aiming at unattainable cure.[5, 6] Given the severity and heterogeneous nature of the brain lesions that cause CP, I believe that there is no place for using the term ‘cure.’ Neurological rehabilitation may encompass many disparate elements including biological reparative therapies such as stem cells. New combinations of neurotrophic agents and stem cells have been reported as resulting in modest improvements in gross motor function at the risk of immunosuppression, morbidity and mortality. This is par for the course and what might reasonably be expected from new therapeutics in severely compromised children with severe brain injuries. This is not what most parents and most doctors would consider curing CP. Trials like these are worth supporting, but in the interests of both science and humanity, expectations should be realistic.
The myocardium can be partially repaired by stem cells, but tissue engineering to replace a significant part of an organ, for example a heart valve, usually requires a scaffold or matrix. I have seen no description of a suitable scaffold for the brain in CP, although prototypes exist for the spinal cord. When asked by concerned parents in the clinic whether they should mortgage their house and travel overseas for stem cell treatments, it can be useful to discuss the much simpler proposition of spinal cord injury. When most patients with spinal cord injuries are walking after stem cell treatments, we can expect small improvements in the biological neuro-rehabilitation of CP brain injuries. The preferred term will be neuro-rehabilitation, not cure. Small improvements in brain function from biological reparative therapies may augment existing and new approaches to overall rehabilitation but will not replace them in any foreseeable time frame.
Australian parents are currently taking their children to overseas destinations for stem cell infusions at great expense and personal stress. In our clinic, we usually receive no information about these treatments, and it is fair to say the results to date are underwhelming. Stem cell trials are needed in Australia along with a healthy dose of realism about expected outcomes. Many parents delay or refuse conventional treatments because of unrealistic expectations of the potential outcomes of stem cell infusions. Now that we have efficient hip surveillance in Victoria, the most common cause for a dislocated hip in a child with CP is delayed intervention because parents expect stem cell treatments to cure their child of CP.[8, 9] We must avoid parents' hopes being dashed. A good start would be not using the term ‘cure’ in the context of CP in both the peer-reviewed literature and the popular press.[1, 10]