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dystonia varied between grafted patients and chorea progressively increased (unpublished data).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