Robert E. Breeze

Transplantation of Embryonic Dopamine Neurons for Severe Parkinson's Disease

BACKGROUND Transplantation of human embryonic dopamine neurons into the brains of patients with Parkinsons disease has proved beneficial in open clinical trials. However, whether this intervention would be more effective than sham surgery in a controlled trial is not known. METHODS We randomly assigned 40 patients who were 34 to 75 years of age and had severe Parkinsons disease (mean duration, 14 years) to receive a transplant of nerve cells or sham surgery; all were to be followed in a double-blind manner for one year. In the transplant recipients, cultured mesencephalic tissue from four embryos was implanted into the putamen bilaterally. In the patients who received sham surgery, holes were drilled in the skull but the dura was not penetrated. The primary outcome was a subjective global rating of the change in the severity of disease, scored on a scale of -3.0 to 3.0 at one year, with negative scores indicating a worsening of symptoms and positive scores an improvement. RESULTS The mean (+/-SD) scores on the global rating scale for improvement or deterioration at one year were 0.0+/-2.1 in the transplantation group and -0.4+/-1.7 in the sham-surgery group. Among younger patients (60 years old or younger), standardized tests of Parkinsons disease revealed significant improvement in the transplantation group as compared with the sham-surgery group when patients were tested in the morning before receiving medication (P=0.01 for scores on the Unified Parkinsons Disease Rating Scale; P=0.006 for the Schwab and England score). There was no significant improvement in older patients in the transplantation group. Fiber outgrowth from the transplanted neurons was detected in 17 of the 20 patients in the transplantation group, as indicated by an increase in 18F-fluorodopa uptake on positron-emission tomography or postmortem examination. After improvement in the first year, dystonia and dyskinesias recurred in 15 percent of the patients who received transplants, even after reduction or discontinuation of the dose of levodopa. CONCLUSIONS Human embryonic dopamine-neuron transplants survive in patients with severe Parkinsons disease and result in some clinical benefit in younger but not in older patients.

Neural transplantation for the treatment of Parkinson's disease

trials showed unequivocally that human fetal dopaminergicneurons can survive and function for more than 10 years inthe striatum of patients with PD and show no signs of beingaffected by the ongoing disease process. These studies have also provided a clear indication that grafted fetaldopaminergic neurons can be therapeutically effective. On thebasis of the limited, but encouraging, observations in theseearly open-label trials,

Dyskinesia after fetal cell transplantation for parkinsonism: A PET study

Persistent dyskinesias in the absence of or with only minimal amounts of dopaminergic medication have been reported after dopamine cell implantation for Parkinsons disease. In this study, we used [18F]fluorodopa (FDOPA) and positron emission tomography to determine whether this complication resulted from specific alterations in dopamine function after transplantation. Caudate and putamen FDOPA uptake values in these patients (DYS+, n = 5) were compared with those obtained in a cohort of age‐ and disease duration‐matched transplant recipients who did not develop this complication (DYS−, n = 12). PET signal for both groups was compared at baseline and at 12 and 24 months after transplantation. We found that putamen FDOPA uptake was significantly increased (p < 0.005) in DYS+ transplant recipients. These increases were predominantly localized to two zones within the left putamen. In addition to the posterodorsal zone in which a prominent reduction in FDOPA uptake was present at baseline, the DYS+ group also displayed a relative increase ventrally, in which preoperative dopaminergic input was relatively preserved. Postoperative FDOPA uptake did not reach supranormal values over the 24‐month follow‐up period. These findings suggest that unbalanced increases in dopaminergic function can complicate the outcome of neuronal transplantation for parkinsonism.

Dopamine Cell Implantation in Parkinson's Disease: Long-Term Clinical and 18F-FDOPA PET Outcomes

We have previously reported the results of a 1-y double-blind, placebo-controlled study of embryonic dopamine cell implantation for Parkinsons disease. At the end of the blinded phase, we found a significant increase in putamen uptake on 18F-fluorodopa (18F-FDOPA) PET reflecting the viability of the grafts. Nonetheless, clinical improvement was significant only in younger (age ≤ 60 y) transplant recipients, as indicated by a reduction in Unified Parkinsons Disease Rating Scale (UPDRS) motor scores. Methods: We now report long-term clinical and PET outcomes from 33 of the original trial participants who were followed for 2 y after transplantation and 15 of these subjects who were followed for 2 additional years. Longitudinal changes in UPDRS motor ratings and caudate and putamen 18F-FDOPA uptake were assessed with repeated-measures ANOVA. Relationships between these changes over time were evaluated by the analysis of within-subject correlations. Results: We found that UPDRS motor ratings declined over time after transplantation (P < 0.001). Clinical improvement at 1 y was relatively better for the younger transplant recipients and for men, but these age and sex differences were not evident at longer-term follow-up. Significant increases in putamen 18F-FDOPA uptake were evident at all posttransplantation time points (P < 0.001) and were not influenced by either age or sex. Posttransplantation changes in putamen PET signal and clinical outcome were significantly intercorrelated (P < 0.02) over the course of the study. Image analysis at the voxel level revealed significant bilateral increases in 18F-FDOPA uptake at 1 y (P < 0.001) in the posterior putamen engraftment sites. PET signal in this region increased further at 2 and 4 y after engraftment. Concurrently, this analysis disclosed progressive declines in radiotracer uptake in the nonengrafted caudate and ventrorostral putamen. Clinical improvement after transplantation correlated with the retention of PET signal in this region at the preoperative baseline. Conclusion: These results suggest that clinical benefit and graft viability are sustained up to 4 y after transplantation. Moreover, the dependence of clinical (but not imaging) outcomes on subject age and sex at 1 y may not persist over the long term. Last, the imaging changes reliably correlate with clinical outcome over the entire posttransplantation time course.

Unusual dural and skull-based mesenchymal neoplasms: A report of four cases

Dural and skull-base mesenchymal neoplasms other than meningiomas are rare. We report four such tumors, some of which are uncommon even in nonintracranial sites, in three adults and one child. The adult tumors consisted of a synovial sarcoma of the third ventricle region in a 19-year-old woman, a leiomyoma of the suprasellar region in a 57-year-old woman, and an Epstein-Barr virus (EBV)-associated smooth muscle tumor of the cavernous sinus in a 35-year-old woman with acquired immunodeficiency syndrome (AIDS). The pediatric tumor was an EBV-associated leiomyosarcoma of the left dural transverse sinus in a 14-year-old girl with common variable immunodeficiency syndrome. All tumors were thought to be primary in their dural or skull-base locations. The two EBV-associated smooth muscle tumors in immunocompromised patients expand the locations for EBV-associated smooth muscle tumors to dural and skull-base sites, the synovial sarcoma is unique to the intracranial space, and the sellar leiomyoma represents the third reported sellar smooth muscle tumor.

Differential Gene Expression in Human Cerebrovascular Malformations

OBJECTIVEWe sought to identify genes with differential expression in cerebral cavernous malformations (CCMs), arteriovenous malformations (AVMs), and control superficial temporal arteries (STAs) and to confirm differential expression of genes previously implicated in the pathobiology of these lesions. METHODSTotal ribonucleic acid was isolated from four CCM, four AVM, and three STA surgical specimens and used to quantify lesion-specific messenger ribonucleic acid expression levels on human gene arrays. Data were analyzed with the use of two separate methodologies: gene discovery and confirmation analysis. RESULTSThe gene discovery method identified 42 genes that were significantly up-regulated and 36 genes that were significantly down-regulated in CCMs as compared with AVMs and STAs (P = 0.006). Similarly, 48 genes were significantly up-regulated and 59 genes were significantly down-regulated in AVMs as compared with CCMs and STAs (P = 0.006). The confirmation analysis showed significant differential expression (P < 0.05) in 11 of 15 genes (angiogenesis factors, receptors, and structural proteins) that previously had been reported to be expressed differentially in CCMs and AVMs in immunohistochemical analysis. CONCLUSIONWe identify numerous genes that are differentially expressed in CCMs and AVMs and correlate expression with the immunohistochemistry of genes implicated in cerebrovascular malformations. In future efforts, we will aim to confirm candidate genes specifically related to the pathobiology of cerebrovascular malformations and determine their biological systems and mechanistic relevance.

Do patients with Parkinson’s disease benefit from embryonic dopamine cell transplantation?

Abstract.Embryonic dopamine cell transplants survive in nearly all patients regardless of age and without immunosuppression. Transplants can improve Parkinson “off” symptoms up to the best effects of L-dopa observed preoperatively. They cannot improve the “best on” state. Transplants appear to survive indefinitely. In 10 to 15% of patients, transplants can reproduce the dyskinetic effects of L-dopa even after discontinuing all L-dopa. Neurotransplantation should be tried earlier in the clinical course of Parkinson’s to see if earlier intervention can prevent progression of the disease, particularly the dyskinetic responses seen after longterm L-dopa treatment.

Therapeutic effects of human fetal dopamine cells transplanted in a patient with Parkinson's disease.

Publisher Summary This chapter examines the therapeutic effects of human fetal dopamine cells transplanted in a patient with Parkinsons disease. The patient was a 52 years old male with a 20 year history of Parkinsons disease that presented with left-sided symptoms. The left side remained the more impaired. The patient suffered from the on-off phenomenon and freezing spells. The patient underwent clinical evaluation by a neurologist using the Hoehn and Yahr scale and the Unified Parkinsons Disease Rating Scale (UPDRS) for motor performance and activities of daily living. The patient received broad-spectrum antibiotics at the time of surgery and for 10 days thereafter. Prophylactic phenytoin was also used. Beginning about 30 days and peaking at 60 days after surgery, the patient demonstrated bilateral increases in finger speed both before and after the first morning dose of drugs. There was a greater improvement in his response to drugs than in his basal performance. Data were analyzed in 2 month intervals and compared to pre-operative. Results of the two-way analysis of variance showed highly significant improvement in drug response after surgery for all periods.

Cerebral Cavernous Malformations: Somatic Mutations in Vascular Endothelial Cells

OBJECTIVEGermline mutations in 3 genes have been found in familial cases of cerebral cavernous malformations (CCMs). We previously discovered somatic and germline truncating mutations in the KRIT1 gene, supporting the “2-hit” mechanism of CCM lesion formation in a single lesion. The purpose of this study was to screen for somatic, nonheritable mutations in 3 more lesions from different patients and identify the cell type(s) in which somatic mutations occur. METHODSSomatic mutations were sought in DNA from 3 surgically excised, fresh-frozen CCM lesions by cloning and screening polymerase chain reaction products generated from KRIT1 or PDCD10 coding regions. Laser capture microdissection was used on isolated endothelial and nonendothelial cells to determine whether somatic mutations were found in endothelial cells. RESULTSCCM lesions harbor somatic and germline KRIT1 mutations on different chromosomes and are therefore biallelic. Both mutations are predicted to truncate the protein. The KRIT1 somatic mutations (novel c.1800delG mutation and previously identified 34 nucleotide deletion) in CCMs from 2 different patients were found only in the vascular endothelial cells lining caverns. No obvious somatic mutations were identified in the 2 other lesions; however, the results were inconclusive, possibly owing to the technical limitations or the fact that these specimens had a small proportion of vascular endothelial cells lining pristine caverns. CONCLUSIONThe “2-hit” mechanism occurs in vascular endothelial cells lining CCM caverns from 2 patients with somatic and Hispanic-American KRIT1 germline mutations. Methods for somatic mutation detection should focus on vascular endothelial cells lining pristine caverns.

Posterior fossa swelling and hydrocephalus resulting from hypertensive encephalopathy: case report and review of the literature

OBJECTIVE AND IMPORTANCE: Brain stem and cerebellar edema rarely have been described as the principal manifestation of hypertensive encephalopathy. In addition, secondary hydrocephalus has been described in only a few cases in the literature. We present an unusual case of posterior fossa swelling and hydrocephalus resulting from hypertensive encephalopathy. CLINICAL PRESENTATION: A 53-year-old man presented with increased shortness of breath, headache, and visual changes, which had been worsening for several months. Blood pressure on presentation was 253/140 mm Hg. Neuroradiological studies revealed brain stem swelling predominantly affecting the pons, with compression of the adjacent cisterns and fourth ventricle and resultant hydrocephalus. The diagnosis of brain stem glioma was briefly entertained. INTERVENTION: The patients blood pressure was brought under control with medical management, and he was treated with dexamethasone for 48 hours. Subsequent neuroradiological studies revealed decreased posterior fossa edema as well as marked improvement in the hydrocephalus. CONCLUSION: Hypertensive encephalopathy can present principally in the posterior fossa and can give rise to obstructive hydrocephalus. Invasive treatment of the hydrocephalus is not necessarily required in this clinical setting because reduction of the blood pressure may result in rapid improvement of the hydrocephalus.