LENA CARLSSON'S COLUMN
Summaries of some
transplantation studies. Click here to get back to the first side of this
column.
Implantation of
retinal cells
Stover NP, Bakay RA, Subramanian T, Raiser CD,
Cornfeldt ML, Schweikert AW, Allen RC, Watts R:
Intrastriatal implantation of human retinal
pigment epithelial cells attached to
microcarriers in advanced Parkinson disease. Arch
Neurol. 2005 Dec;62(12):1833-7
In this study patients with Parkinson's disease
received implants of human retinal cells. In
other cases such patients have been transplanted
with dopamine producing fetal cells. The retinal
cells produce l-dopa, which is the precursor of
dopamine. The result was that the patients
improved their muscular function. Earlier
experiments have yielded positive results in
animal models of rodents and apes.
Retinal cells can be isolated from diseased
people and cultured in the laboratory. The cells
can then be attached to small particles,
so-called microcarriers, which are implanted into
the brain. Six patients with an advanced form of
Parkinson's disease participated in this
open-label pilot study. The patients muscular
function improved significantly, with 48 procent,
at 12 months, and the improvement was sustained
through two years after treatment. No serious
side effects and no dyskinesias (involuntary
movements) were seen. Immunosuppressive medicine
was not used.
Yearly follow-up continues. The authors comment
that the placebo effect may play a role, and a
placebo-controlled, double-blind study has been
started.
Transplantation
of cell suspension
Ivar Mendez et al: Cell type analysis of
functional fetal dopamine cell suspension
transplants in the striatum and substantia nigra
of patients with Parkinson's disease. Brain 2005
128(7): 1498-1510
For the first time, two patients with Parkinson's
disease, who were transplanted with fetal cells
in suspension, are analyzed after death. These
two patients received transplants both in the
striatum and in the substantia nigra (black
nucleus). In many other transplantations the
fetal cells are in the form of solid tissue
pieces, and the cells are introduced only into
the striatum. Animal models with rodents show
that transplants in both the stiatum and the
substantia nigra improve muscular function more
than if the transplant is only introduced into
the striatum. The fetal cells that were
transplanted to the two patients were carefully
selected dopamine producing cells of a kind which
is lost in Parkinson's disease.
The patients' muscular function got better and
none of them experienced adverse side effects, as
for instance dyskinesias (involuntary movements)
as a result of the transplantation. Both patients
were treated with immunosuppressive medicine. One
patient, a 69 year-old man, who had suffered from
Parkinson's disease for 15 years, gradually
improved a few months after the operation. The
three-year follow-up showed that the dyskinesias
not related to transplantation had decreased.
The other patient was a 59 year-old woman, who
had had of Parkinson's disease for 11 years. In
this woman, the operation could only be completed
in the right hemisphere, due to bleeding in the
left hemisphere during the procedure.
After the operation the patient's symptoms
successively improved, and the treatment with
l-dopa could be reduced by 30 procent. There was
a considerable recovery, with 50 percent, of the
muscular function and of the life quality, in
spite of the fact that this patient had a serious
kind of Parkinson's disease at the time of the
operation. The improvement of the muscular
function occurred at the left side of the body,
while there was a deterioration of the right side
after three years. (The right hemisphere controls
the left side of the body and vice versa.)
Three years after the operation the patients'
brains were investigated with PET, which is an
imaging technique. These investigations showed
that the transplanted cells survived and made new
fibers. Both patients died some years after
transplantation, from causes unrelated to the
operation.
Earlier transplantations with cellsuspension show
that 90 percent of the patients are spared from
dyskinesias. Among others, Olle Lindvall at the
University of Lund, Sweden, has made such
operations. In some of these patients, the graft
has functioned for more than 11 years. The graft
function was measured by dopamine release and
improval of the symptoms.
NIH:
Placebo-controlled study by Olanow
Olanow CW, Goetz CG, Kordower JH et al. A
double-blind controlled trial of bilateral fetal
nigral transplantation in
Parkinson's disease. Ann Neurol 2003; 54(3):
403-14
Thirty-one patients with Parkinson's disease were
transplanted with fetal cells in this
double-blind 24-month trial. No significant
treatment effect was seen. After analysis of
patients with a milder form of the disease there
was however a significant positive treatment
effect on muscular function. A serious adverse
treatment effect was that more than half of the
transplanted patients developed involuntary
movements. The authors' conclusion is that
transplantation with fetal cells cannot be
recommended at this time.
Review
by Olanow
Snyder Brian, Olanow CW: Stem cell treatment for
Parkinson's disease: an update for 2005. Curr
Opin Neurol. 2005 Aug;18(4):376-85
In this article Warren Olanow and Brian Snyder go
through studies of transplantation and research
on stem cells.
The authors establish that a number of open-label
trials reported varying but mostly good results.
Two placebo-controlled studies initiated by NIH
(National Institute of Health) failed however to
reach their primary goals. Many patients
experienced involuntary movements. Recent trials
suggest that incomplete connections between the
transplanted cells and the neurons of the
striatum may be a reason behind the dyskinesias.
The results could be improved if more dopamine
producing nerve cells are implanted, if
immunosuppression is given, and if younger
patients with less severe symptoms are treated.
Stem cells could be an alternative, the authors
continue. Stem cells, which can evolve into
dopamine cells, have been useful in animal models
of Parkinson's disease, even if the result has
been modest. The authors think that stem cells
are very promising, although many difficulties
must be overcome. A lot of questions have to be
answered before one can even consider such a
treatment. Can for example adequate numbers of
stem cell-derived dopamine neurons survive and be
incorporated into the nervous system of the
brain? If so, can stem cells provide benefits to
Parkinson's disease patients, benefits which are
superior to what has been obtained with
transplantation of fetal cells? Other questions
concern which type of stem cell that is best to
use, and which method that is the optimal for
expanding stem cells and making them to
differentiate into dopamine cells. One must also
determine the target site for implantation, the
number of cells to be transplanted, and the need
for immunosuppression. Further, the risk of tumor
formation, dyskinesias and other adverse
side-effects must be investigated before trials
in patients are initiated. One must also be aware
of the fact that symptoms not related to dopamine
deficiency may not be taken care of by stem
cells.
The authors think that unrealistic expectations
have been created in the media and lay community.
"Enthusiasm for stem cells must be tempered
by the experience with fetal nigral
transplantation", they say. The authors also
emphasize the significance of placebo-controlled
double-blind trials.
Stem cell transplantation is an important
experimental treatment, but there is no guarantee
for success, conclude Snyder and Olanow.
Review
by Lindvall and Björklund
Lindvall Olle, Björklund Anders. Cell Therapy in
Parkinson's Disease. NeuroRx 2004 Oct;1(4):
382-392
Olle Lindvall and Anders Björklund at Lund
University, Sweden, are pioneers in the
transplantations on patients with Parkinson's
disease. Both of them do research on stem cells
at the Stem Cell Center, Lund.
With this article Lindvall and
Björklund participate in a special feature issue
of cell therapy in diseases of the central
nervous system. The authors establish that the
results of transplantation studies with fetal
cells are varying. In the most successful cases
performed in Lund the patients have shown an
improvement through more than 10 years. These
patients have been able to stop medication with
l-dopa and return to a normal life. The authors
think, however, that for groups of patients
current transplantation methods have not been
superior to other treatments. Further, he authors
believe that stem cells can be an alternative,
but they point out that a lot of problems remain
to be solved.
NIH:
Placebo-controlled study with strong placebo
effect
Freed CR, Greene PE, Breeze RE, Tsai WY,
DuMouchel W, Kao R, Dillon S, Winfield H, Culver
S, Trojanowski JQ, Eidelberg D, Fahn S.
Transplantation of embryonic dopamine neurons for
severe Parkinson's disease. N Engl J Med. 2001
Mar 8;344(10):710-9
Gordon PH, YU Q, Qualis C et al. Reaction time
and movement time after embryonic cell
implantation in Parkinson's disease.
Arch Neurol 2004; 61(6): 858-61
McRae C, Cherin E, Yamazaki TG et al. Effects of
perceived treatment on quality of life and
medical outcomes in a double-
blind placebo surgery trial. Arch Gen Psychiatry
2004; 61(4): 412-20
In a study by Freed et al in 2001, 40 patients
with Parkinson's disease participated. The
patients were randomly divided into two groups.
Half of them was transplanted with dopamine
producing fetal cells, while the other half was
part of a control group, which had a sham
operation where no fetal cells were provided. No
patient had immunosuppressive medication. This
trial was double-blind for as long as one year.
During that time, neither the patients nor the
staff knew which patients that had received fetal
cells. The average length of a double-blind study
is 8 weeks. The result showed that the symptoms
of Parkinson's disease improved significantly
more in the transplanted group than in the sham
group, in patients 60 years old or younger.
In a substudy in 2004, Gordon et al made a deeper
analysis, which showed that the reaction time and
the movement time improved more in the
transplanted group.
In another substudy, McRae et al investigated the
patients' quality of life after surgery. The
result from this study was partly different from
the result of the parent study. Thirty patients
participated in his substudy. Twelve of them
received a transplant, and 18 patients underwent
sham surgery. The result was, that those patients
who believed that they had received fetal cells,
reported greater improvements than those patients
who did not believe that they had been
transplanted. The recovery comprised both the
objective and the subjective elements. The
medical staff who evaluated the patients, made
the same reports. The results had no connection
with what kind of treatment the patients really
received. The authors conclude that the placebo
effect is very strong on both subjective and
objective measures. Other controlled trials show
similar results. The more extreme the placebo
treatment is, the greater is the placebo effect.
And brain surgery is an extreme treatment,
establish the authors.
The only significant difference between the
transplanted and the sham-operated patients was,
that the sham-operated group reported more social
contact four months after surgery. The authors
speculate about the reason. Concerning the
physical function, both groups ameliorated
significantly after one year, and the improvement
was greater in the transplanted group.
The scientists also compared the quality of life
between the group who believed to have been
transplanted, and the group who believed to have
had sham operation. Several differences were
discovered. Those patients who thought they
underwent a transplantation reported a greater
physical improvement and a better social support,
than those who believed they had sham surgery,
after 8 and 12 months. The difference in physical
improvement was greater than between the group
who really received the transplant and the group
who really had a sham operation.
Quality of life comprises three factors, namely
physical, emotional and social functioning. The
physical functioning is an objective measure,
while the emotional and the social functioning
are subjective measures. The physical functioning
is evaluated by rating scales, which measure
partly how the patient copes with his or her
activities of daily living, partly how serious
his or her symptoms are. Motor performance,
muscle rigidity, tremor, and speech are
estimated. Emotional function includes degree of
stress, depression and anxiety, as well as the
disease's interference with usual life
activities. The social function, finally, is
measured by rating scales of the patient's
perceived social support, and the patient's
frequency of social contact.
June 2006
Lena Carlsson
© Lena Carlsson
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