A patient with Huntington's disease and long-surviving fetal neural transplants that developed mass lesions

Abstract

Transplantation of human fetal neural tissue into adult neostriatum is an experimental therapy for Huntington's disease (HD). Here we describe a patient with HD who received ten intrastriatal human fetal neural transplants and, at one site, an autologous sural nerve co-graft. Although initially clinically stable, she developed worsening asymmetric upper motor neuron symptoms in addition to progression of HD, and ultimately died 121 months post transplantation. Eight neural transplants, up to 2.9 cm, and three ependymal cysts, up to 2.0 cm, were identified. The autologous sural nerve co-graft was found adjacent to the largest mass lesion, which, along with the ependymal cyst, exhibited pronounced mass effect on the internal capsules bilaterally. Grafts were composed of neurons and glia embedded in disorganized neuropil; robust Y chromosome labeling was present in a subset of grafts and cysts. The graft-host border was discrete, and there was no evidence of graft rejection or HD pathologic changes within donor neurons. This report, for the first time, highlights the potential for graft overgrowth in a patient receiving fetal neural transplantation.

Figure 1. Radiographic imaging and brain sectioning reveal large left putaminal cyst and multiple masses

A) Axial T2-weighted MRI in 2003 shows a large cyst in the left putamen (right side of image, black asterisk) and a large, circumscribed mass in the right putamen (left side of image, white asterisk). B) Coronal brain section at the level of the anterior commissure shows four mass lesions (black arrows), including a large mass in the left putamen, a smaller mass in the right putamen, and mass occupying the left caudate nucleus, and a cyst encased by a mass lesion in the right caudate nucleus. C) Coronal brain section at the level of the optic chiasm demonstrating the large left putaminal cyst (black asterisk) with prominent mass effect on surrounding structures, including internal capsule, as well as the large right putaminal mass (white asterisk). D) Higher power photograph of anterior left neostriatum seen in [B]. E) Higher power photograph of right neostriatal mass seen in [C]. F) Higher magnification image of large left neostriatal cyst wall. Scale bar in B and C indicates centimeters.

Figure 2. Hematoxylin and Eosin/luxol fast blue staining delineates characteristic features of grafts, peripheral nerve, and cyst wall

A-B) 12.5X magnification of right (A) and left (B) putaminal masses. Insets of serial sections stained with MAP-2 or MBP show well demarcated transplant tissue. C) Autologous sural nerve graft is identified adjacent to the large right putaminal transplant within gliotic host putamen. D) Higher magnification view of sural nerve graft shows well circumscribed nerve fascicles associated with several adipocytes and focal lymphohistiocytic inflammatory infiltrates. E) Large left putaminal cyst wall contains patches of intact ependyma, which contain abundant cilia (inset, upper right) and are GFAP immunopositive (inset, lower left). F) Transplanted tissues contain focal microcalcifications (magnified in inset). Tx = transplant; IC = internal capsule; PN = peripheral nerve; MAP-2 = microtubule associated protein 2; MBP = myelin basic protein; GFAP = glial fibrillary acidic protein.

Figure 3. Key microscopic features of transplants and graft-host interaction

Top Half: Transplant tissue is shown in the top half of the figure, with H&E/LFB high magnification center image showing rare mature neurons surrounded by numerous small neurons and occasional glia. Surrounding pictures, from top left counterclockwise, show immunopositivity of neurons for MAP-2 (uniform), neurofilaments 2F11 and N52 (occasional), calbindin-D28K (rare), and calretinin (common). Graft axons bundles are shown with 2F11 immunostaining, and are further apparent in MBP-stained sections, which also depict occasional haphazard/chaotic tract formation not normally seen in mature brain parenchyma. GFAP immunostains highlight occasional reactive astrocytes present individually or in groups within the masses. Bottom Half: The bottom four photomicrographs show graft-host border with MBP, MAP-2, tyrosine hydroxylase, and GFAP. MBP-immunostains highlight the transverse fiber bundles coursing through host putamen, and graft tissue (outlined in white) exhibiting local mass effect without bundled myelinated axons. TH and MAP-2 immunostains further highlight abrupt graft-host border where virtually no neuronal processes appear to cross. GFAP-immunostains show less well-defined border, as local reactive gliosis blurs boundaries, but also highlights general lack of pathology within most grafted tissues.

Figure 4. XY chromosome fluorescence in situ hybridization (FISH)

A-E) Gross (A-B) and microscopic (C-E) depictions of graft chromosomal identity, wherein graft masses are labeled with XX for female and XY for male. Cysts are labeled for XX/XY signal in ependyma lining cyst walls (B,C,E). Microscopic sections (C-E) are stained with antibodies to MAP-2 in order to highlight the grafts. F-G) High magnification fluorescence photomicrographs showing astrocytic (F), oligodendroglial (G), and neuronal (H-I) differentiation of XY chromosome-positive cells. X chromosomes are stained green and Y chromosomes are stained red. Immunostains are colored pink, and are labeled accordingly. Note the stellate processes in the GFAP immunopositive astrocyte, variable nuclear immunopositivity in small round nuclei characteristic of oligodendroglia, and the immature (H) and mature (I) morphology of MAP-2 immunopositive graft neurons.