In November 1987, Lund neuroscientists grafted fetal dopamine neurons into the brain of a 47-year old PD patient, launching a hopeful new era of neural grafting aimed at reversing the symptoms of PD. But after some promising initial results, two negative (and highly publicized) double blind placebo controlled trials (in 2001 and 2003) brought the field to a virtual standstill. Proponents have continued to argue that the technique can work provided multiple factors — patient selection (i.e. age, type, stage), graft preparation, graft placement, immunotherapy, duration of patient follow up, appropriate study end points etc. — are properly controlled. Now Zinovia Kefalopoulou et al report striking evidence of such success, telling the dramatic stories of two graft recipients known as Patient 7 and Patient 15.
It’s quite a tale. The two British men were diagnosed nearly 30 years ago with the akinetic rigid PD subtype. Both responded well to L-dopa but developed severe motor fluctuations and dyskinesias. So, in the 1990s the two patients traveled to Sweden where surgeons transplanted dopaminergic fetal tissue into the striatum on both sides of their brains.
Ever since, Patient 7 and Patient 15 have been carefully followed up in the National Hospital for Neurology and Neurosurgery, at Queen Square in London. Kefalopoulou and colleagues report that for a long time the patients experienced little benefit. But after roughly four years, the positive effects had become unmistakable. First, both patients were able to completely drop all dopaminergic medication. Second, their motor states, as measured by the Unified Parkinson’s Disease Rating Scale part three (UPDRS 3), showed a sustained benefit. After 4 years, Patient 7 had a score of 22 and Patient 15, a score of 18. These low scores — which indicate only mild impairment — remain unchanged to this day. Third, PET scans of the patients’ brains shows clear signs of dopamine innervation of the striatum.
It is exceedingly difficult to explain away these two striking case histories as a placebo effect. Patient 7 and Patient 15 have had PD for almost 30 years. Despite living with a relentlessly progressive disease, they are walking around without L-dopa. Ockham’s razor suggests that the simplest explanation for all this is that the grafts (in these two cases, at least) worked; they reversed many (but not all) of the patients’ motor symptoms.
The authors also provide compelling video evidence. Patient 15 (taped recently) looks quite remarkable. He stands up from a chair, effortlessly walks down the corridor with good arm swing, and easily passes a balance test, where the neurologist pulls him from behind.
Patient 7 isn’t so impressive. He shows persistent graft-induced dyskinesias (GIDs). These troublesome side effects of the surgery are one reason why many neuroscientists, especially in the US, remain skittish about neural grafting.
Even if it’s just two cases, it’s exciting stuff. As the authors say, “The results from these 2 cases indicate that dopaminergic cell transplantation can offer very long-term symptomatic relief in patients with Parkinson disease and provide proof-of-concept support for future clinical trials using fetal or stem cell therapies.”
And indeed, in Europe neural transplantation is not dead. Neuroscientists are pushing ahead with the TRANSEURO project designed to give neural transplants to early stage PD cases.
