Neurodegenerative Disease Huntington’s Disease
progressively declined. In patients who improveed, individual improvements in motor function continued for two years after transplantation and then remained stable for several years before deteriorating four to six years postgrafting. While the transplant had no effect on dystonia, which deteriorated consistently, chorea remained at a stable level for between four and six years after surgery. The authors attribute this to the lower number of tracts in the posterior putamen compared with the caudate nucleus and anterior putamen. This is in contrast to Rosser et al.11
(see below), where
dystonia varied between grafted patients and chorea progressively increased (unpublished data).
Further investigation of graft integration in these patients was performed using electrophysiological recording of the N20 wave produced in the somatosensory cortex upon median nerve stimulation. While reappearance of this wave, once lost, was never observed in the cohort of non-grafted HD patients, bilateral recovery of the N20 wave did reappear in three of the transplanted patients (though it was lost in one patient after the second transplant).
For six years after transplantation there was a slower decline in striatal metabolic activity compared with non-transplanted patients. Furthermore, normal metabolic activity was restored and maintained in frontal and prefrontal cortices for six years post-operatively, showing that cortical hypometabolism is reversible, at least in early HD.10,12
This effect was only seen in the three patients who showed clinical improvement.
Antibody assays in patients from this series of transplants showed evidence of alloimmunisation to donor antigens, which in one case lead to graft rejection.13
Hauser et al., Florida14
In this study seven moderately-advanced HD patients were transplanted bilaterally with tissue derived from the lateral parts of two to eight foetal lateral ganglionic eminences. This selective dissection was done to try and enhance the yield of striatal tissue relative to the other tissue that takes its origin from the developing striatal eminences, though there were limited experimental data to support such a dissection. Three patients suffered subdural haemorrhages perioperatively and two actually required further surgeries for this.
When all seven patients were considered there was no significant difference in Unified Huntington’s Disease Rating Scale (UHDRS) scores before and 12 months after surgery. A post hoc analysis, excluding the patient who suffered the worst subdural haemorrhage, showed significantly lower UHDRS scores 12 months after transplantation. Positron emission tomography (PET) imaging one year after transplantation showed no significant change in striatal metabolism or in D1 or D2 receptor binding compared with normative data.15
Post-mortem studies of these patients have shown surviving grafted cells 18 months after transplantation in one deceased patient (although not in the caudate) and in only two out of three patients 10 years post-grafting.16,17
Where survival of cells was seen, the grafted
striatal tissue appeared unhealthy and the medium spiny neurons of the graft had degenerated more than interneurons, mirroring to a degree that seen in the striatum of patients dying with HD. This led the authors to conclude that the striatal transplant may have followed
42 EUROPEAN NEUROLOGICAL REVIEW
Table 1: Summary of the Main Transplant Trials Carried Out to Date Study
Number of Age of Kopyov et al., 19985 3 8–10 weeks Amount and
5–8 foetuses per side (LGE)
Immunosuppression of Patients Foetal Implant Area Implanted Treatment
Bachoud-Lévi 5 et al., 20009,10
Hauser et al., 200214 Rosser et al., 200211 Reuter et al., 200919
Gallina et al., 4 200820,21,22
9–12 weeks 2 9–10 weeks 4 7 7.5–9.5 weeks Equivalent to
None reported in original paper, though cyclosporine had been used in the two autopsy patients for 18 and 35 months7 Cyclosporine
1 foetus (WGE) prednisolone (1 year), azothiprine (1 year)
8–9 weeks 2–8 striatum 8.5–12 weeks 1–2 foetuses 2–3 foetuses Cyclosporine
per side (Lateral (6 months) part of LGE)
Cyclosporine A, azathioprine 6 months
per side (WGE) and prednisolone until 1 year post-transplant Prednisolone (1 month),
per side (WGE) cyclosporine (1 year) 2 foetuses Methylprednisolone (2 weeks), Mean
per side (WGE) cyclosporine A (1 year), azathioprine (continuing)
24.7 months 60 months 12 months
Length of Clinical Efficacy Follow-up
12 months
No detailed follow-up carried out
Imaging MRI
Tracks/graft targets seen6
PET Not reported
2 patients at 74 and 79 months after grafting: some striatal tissue survival, little integration.7
post-grafting: cysts present though probably due to sural nerve co-graft8
72 months
Clinical improvement in 3 of 5 patients Hypo-intense FDG PET: restored and None reported 2 years after transplant, maintained
signal at graft maintained metabolic
for 4–6 years after surgery (compared sites for 6 years activity for 6 years, only with non-grafted patients) No overall difference in UHDRS scores before and 1 year after transplant
in improved patients10,12
None Reported D1R: no change. D2R: no 4 patients: Graft survival at 18 but change in rate of decline, only 2/3 at 10 years. Grafts show
as normally seen in HD15
No significant difference in UHDRS scores 6 months after transplant compared with non-grafted patients Radically improved UHDRS score in 1 of 2 patients at 5 years after transplant
UHDRS score stabilisation or
slight improvement at 2 years (no comparison with non-grafted patients)
of decline, as normally seen in HD
HD-like pathology at 10 years16,17
Tracks/graft D2R: no change in rate None reported targets seen
None Reported D2R : increased binding None reported at 2.5 years post
transplant (last PET scan)
Tracks/graft D2R : Increased targets seen
None reported in 3 out of 4 patients
D1R = D1 receptor binding; D2R = D2 receptor binding; FDG = (18F)-fludeoxyglucose; HD = Huntington’s disease; LGE = lateral ganglionic eminence; MRI = magnetic resonance imaging; PET = positron emission tomography; UHDRS = Unified Huntington's Disease Rating Scale; WGE = whole ganglionic eminence.
1 patient at 121 months
Post-mortem
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72 |
Page 73 |
Page 74 |
Page 75 |
Page 76 |
Page 77 |
Page 78 |
Page 79 |
Page 80 |
Page 81 |
Page 82 |
Page 83 |
Page 84 |
Page 85 |
Page 86 |
Page 87 |
Page 88 |
Page 89 |
Page 90 |
Page 91 |
Page 92 |
Page 93 |
Page 94 |
Page 95 |
Page 96 |
Page 97 |
Page 98 |
Page 99 |
Page 100 |
Page 101 |
Page 102 |
Page 103 |
Page 104 |
Page 105 |
Page 106 |
Page 107 |
Page 108