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Therapeutic approaches in neurodegeneration
Ole Isacson, Udall Parkinson's Disease Research Center of Excellence, Belmont, MA, USA,
Kwang-Soo Kim, Udall Parkinson's Disease Research Center of Excellence, Belmont, MA, USA,
Ivar Mendez, Division of Neurosurgery, Dalhousie University, Halifax, NS, Canada,
Craig van Horne, Udall Parkinson's Disease Research Center of Excellence, Belmont, MA, USA,
Lars M. Bjorklund, Udall Parkinson's Disease Research Center of Excellence, Belmont, MA, USA,
Rosario Sanchez-Pernaute, Udall Parkinson's Disease Research Center of Excellence, Belmont, MA, USA
New therapeutic non-pharmacological methodology involves cell and synaptic renewal or replacement in the living brain to restore function of neuronal systems, including the dopaminergic (DA) system in Parkinson's disease. Understanding the cell biological principles for generating functional DA neurons in lieu of the diseased can provide many new avenues for better treatment of patients with PD. Recent laboratory work has focused on using stem cells as a starting point for exogenous or endogenous derivation of the optimal DA cells for repair (Fig. 24.1). Using fetal DA cell therapy in PD patients (Piccini et al., 1999, 2000; Freed et al., 2001; Isacson et al., 2001; Mendez et al., 2002a) and stem cell-derived DA neurons in animal models (Bjorklund et al., 2002; Kim et al., 2002), it has been demonstrated that functional motor deficits associated with PD can be reduced after application of this new technology. Evidence shows that the underlying disease process does not destroy the transplanted fetal DA cells, although the patient's original DA system degeneration progresses (Piccini et al., 1999, 2000). The optimal DA cell regeneration system would reconstitute a normal network capable of restoring feedback-controlled release of DA in the nigro-striatal system (Bjorklund & Isacson, 2002). The success of cell therapy for neurological diseases is limited by access to preparation and development of highly specialized dopaminergic neurons found in the A9 and A10 region of the substantia nigra (SN) in the ventral mesencephalon, as well as technical and surgical steps associated with transplantation.
Deep brain stimulation (DBS) is used increasingly worldwide for the treatment of Parkinson's disease, dystonia, tremor and pain. As with any implanted system, however, DBS introduces a new series of problems related to its hardware. Infection, malfunction and lead migration or fracture may increase patient morbidity and should be considered when evaluating the risk/benefit ratio of this therapy. This work highlights several factors felt to increase DBS hardware complications.
The authors undertook a prospective analysis of their patients receiving this therapy in two Canadian centres, over a four-year period.
One hundred and forty-four patients received 204 permanent electrode implants. The average follow-up duration was 24 months. Complications related to the DBS hardware were seen in 11 patients (7.6%). There were two lead fractures (1.4%) and nine infections (6.2%) including two erosions (1.4%). There was a significantly greater risk of infection in patients who underwent staged procedures with externalization. In patients with straight scalp incisions, the rate of infection was higher than that seen with curved incisions.
Hardware complications were not common. A period of externalization of the electrodes for a stimulation trial was associated with an increased infection rate. It is also possible that a straight scalp incision instead of curvilinear incision may lead to an increase in the rate of infection. With a clear understanding of the accepted DBS device indications and their potential complications, patients may make a truly informed decision about DBS technology.
Six hundred and fifty-two patients with histologically proven primary malignant melanoma have been followed by the London Regional Cancer Centre from 1960 to 1985. Neurological signs and symptoms secondary to metastases to the brain developed in fifty-five patients (8.4%). The median age was 49 years; 71% were male and 29% female. Multiple lesions were found in 61% and a single metastasis in 39%. The most common site for the primary lesion was the trunk in males (44%) and the lower limb in females (37%). Six month survival for patients with a single metastasis was 58% if surgical excision was possible and 25% of these patients survived greater than two years. In patients with multiple metastases that received radiotherapy, survival times of greater than six months were found in 12% of the patients. Patients with a single metastasis appear to benefit by being managed by surgical removal of the lesion.
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