Ivar Mendez

Dopamine neurons implanted into people with Parkinson's disease survive without pathology for 14 years

Postmortem analysis of five subjects with Parkinsons disease 9–14 years after transplantation of fetal midbrain cell suspensions revealed surviving grafts that included dopamine and serotonin neurons without pathology. These findings are important for the understanding of the etiopathogenesis of midbrain dopamine neuron degeneration and future use of cell replacement therapies.

Glial cell line-derived neurotrophic factor improves intrastriatal graft survival of stored dopaminergic cells

Glial cell line-derived neurotrophic factor, the newest member of the transforming growth factor-beta superfamily, has been shown to promote the survival and differentiation of dopaminergic neurons in the ventral mesencephalon. Glial cell line-derived neurotrophic factor has been implicated in both the in vitro and in vivo recovery of mesencephalic dopaminergic cells challenged with the neurotoxins 1-methyl-4-phenylpyridinium and 6-hydroxydopamine. Previous studies have shown increased survival of intrastriatally transplanted dopaminergic cells when followed by infusion of neurotrophic factors such as basic fibroblast growth factor, brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor. However, the effects of glial cell line-derived neurotrophic factor co-administered with dopaminergic cells prior to implantation in the host striatum have not been studied. In the present study, the hypothesis was that treating fetal ventral mesencephalic tissue containing the dopaminergic substantia nigra with glial cell line-derived neurotrophic factor either during storage or at the time of transplantation, would enhance grafted dopaminergic cell survival and functional reinnervation of the host striatum in the unilaterally 6-hydroxydopamine-lesioned rat. To test this hypothesis, two experiments were performed. In the first experimental group (n = 7), fetal ventral mesencephalons from embryonic day 14 rats were maintained in hibernation medium containing glial cell line-derived neurotrophic factor (1 migrogram/ml) at 4 degrees C for six days prior to dissociation and stereotactic implantation into the host striatum: the control group (n = 5) received tissue hibernated without glial cell line-derived neurotrophic factor. The second experimental group (n = 8) received fresh fetal ventral mesencephalic tissue treated with glial cell line-derived neurotrophic factor (0.2 microgram/microliter) while the control group (n = 5) received the fresh graft with no glial cell line-derived neurotrophic factor. Transplantation success was assessed by behavioural analysis (rotometry) and tyrosine hydroxylase immunohistochemistry. Cell counts of tyrosine hydoxylase-stained sections revealed a statistically significant increase in tyrosine hydroxylase-positive neurons in grafts exposed to glial cell line-derived neurotrophic factor during hibernation as compared to control grafts. In addition, there was a statistically significant enhancement of fibre density in the glial cell line-derived neurotrophic factor hibernation graft group as compared to the glial cell line-derived neurotrophic factor fresh graft group. Behavioural analysis three weeks post-grafting exhibited a statistically significant decrease in amphetamine-induced rotations in animals transplanted with glial cell line-derived neurotrophic factor grafts as compared to control grafts. These findings suggest that storing dopaminergic cells in a glial cell line-derived neurotrophic factor-containing medium prior to transplantation increases graft survival, graft derived fibre outgrowth, and behavioural recovery in the adult host. This observation has potential implications for enhancing the efficacy of neural transplantation in the treatment of Parkinsons disease.

Reducing hardware-related complications of deep brain stimulation

BACKGROUND Deep brain stimulation (DBS) is used increasingly worldwide for the treatment of Parkinsons 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. METHODS The authors undertook a prospective analysis of their patients receiving this therapy in two Canadian centres, over a four-year period. RESULTS 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. CONCLUSION 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.

Intrastriatal and intranigral grafting of hNT neurons in the 6-OHDA rat model of Parkinson's disease

The clinical findings on neural transplantation for Parkinsons disease (PD) reported thus far are promising but many issues must be addressed before neural transplantation can be considered a routine therapeutic option for PD. The future of neural transplantation for the treatment of neurological disorders may rest in the discovery of a suitable alternative cell type for fetal tissue. One such alternative may be neurons derived from a human teratocarcinoma (hNT). hNT neurons have been shown to survive and integrate within the host brain following transplantation and provide functional recovery in animal models of stroke and Huntingtons disease. In this study, we describe the transplantation of hNT neurons in the substantia nigra (SN) and striatum of the rat model for PD. Twenty-seven rats were grafted with one of three hNT neuronal products; hNT neurons, hNT-DA neurons, or lithium chloride (LiCl) pretreated hNT-DA neurons. Robust hNT grafts could be seen with anti-neural cell adhesion molecule and anti-neuron-specific enolase immunostaining. Immunostaining for tyrosine hydroxylase (TH) expression revealed no TH-immunoreactive (THir) neurons in any animals with hNT neuronal grafts. THir cells were observed in 43% of animals with hNT-DA neuronal grafts and all animals with LiCl pretreated hNT-DA neuronal grafts (100%). The number of THir neurons in these animals was low and not sufficient to produce significant functional recovery. In summary, this study has demonstrated that hNT neurons survive transplantation and express TH in the striatum and SN. Although hNT neurons are promising as an alternative to fetal tissue and may have potential clinical applications in the future, further improvements in enhancing TH expression are needed.

Bilateral Stimulation of the Globus Pallidus Internus to Treat Choreathetosis in Huntington's Disease: Technical Case Report

OBJECTIVE AND IMPORTANCE: Huntingtons disease (HD) produces debilitating motor abnormalities that are poorly responsive to medical therapy. Deep brain stimulation (DBS) may offer a treatment option for afflicted patients, but its role in the management of HD remains unclear. In the present case, DBS leads were implanted bilaterally into the posteroventral globus pallidus internus (GPi) to control disabling and medically intractable choreathetosis in a severely affected HD patient. The surgical procedure, intraoperative electrophysiological findings, and 12-month postoperative course, with patient video, are presented. CLINICAL PRESENTATION: This 41-year-old man with genetically confirmed HD developed motor symptoms at age 28. He had completed multiple medical trials without alleviation of his progressive and debilitating choreathetosis. Extensive clinical assessment, including neuropsychological testing, was performed to determine surgical candidacy. INTERVENTION: DBS leads were bilaterally implanted, under stereotactic guidance, into the posteroventral GPi. Disease progression and symptom control were assessed at regular postoperative intervals. Bilateral pallidal stimulation produced a dramatic reduction in choreathetoid movements and improvement in overall motor functioning. The patient also exhibited normalization of body weight, mood, and energy level, as well as improved performance of activities of daily living. These effects were sustained at 1 year after surgery. CONCLUSION: The clinical benefits of DBS observed in this HD patient were comparable to those reported in other hyperkinetic disorders and demonstrate that pallidal stimulation can provide long-term alleviation of HD-associated choreathetosis.

Benefits, risks and ethical considerations in translation of stem cell research to clinical applications in Parkinson’s disease

Stem cells are likely to be used as an alternate source of biological material for neural transplantation to treat Parkinson’s disease in the not too distant future. Among the several ethical criteria that must be fulfilled before proceeding with clinical research, a favourable benefit to risk ratio must be obtained. The potential benefits to the participant and to society are evaluated relative to the risks in an attempt to offer the participants a reasonable choice. Through examination of preclinical studies transplanting stem cells in animals and the transplantation of fetal tissue in patients with Parkinson’s disease, a current set of potential benefits and risks for neural transplantation of stem cells in clinical research of Parkinson’s disease are derived. The potential benefits to research participants undergoing stem cell transplantation are relief of parkinsonian symptoms and decreasing doses of parkinsonian drugs. Transplantation of stem cells as a treatment for Parkinson’s disease may benefit society by providing knowledge that can be used to help determine better treatments in the future. The risks to research participants undergoing stem cell transplantation include tumour formation, inappropriate stem cell migration, immune rejection of transplanted stem cells, haemorrhage during neurosurgery and postoperative infection. Although some of these risks are general to neurosurgical transplantation and may not be reduced for participants, the potential risk of tumour formation and inappropriate stem cell migration must be minimised before obtaining a favourable potential benefit to risk calculus and to provide participants with a reasonable choice before they enrol in clinical studies.

GDNF therapy for Parkinson’s disease

With an increase in the aging population, the incidence of Parkinson’s disease (PD), a disabling neurodegenerative disorder mainly affecting motor function, will inevitably present a challenge to an already overburdened healthcare system. Current medical and surgical therapies offer symptomatic relief but do not provide a cure. Experimental studies suggest that GDNF has the ability to protect degenerating dopamine neurons in PD as well as promote regeneration of the nigrostriatal dopamine system. However, clinical trials of GDNF infusion to date remain inconclusive. This review will examine the experimental and clinical evidence of GDNF use in PD with particular focus on its potential as an effective therapy in the treatment of PD.

Spinal GABAergic transplants attenuate mechanical allodynia in a rat model of neuropathic pain.

Injury to the spinal cord or peripheral nerves can lead to the development of allodynia due to the loss of inhibitory tone involved in spinal sensory function. The potential of intraspinal transplants of GABAergic cells to restore inhibitory tone and thus decrease pain behaviors in a rat model of neuropathic pain was investigated. Allodynia of the left hind paw was induced in rats by unilateral L5– 6 spinal nerve root ligation. Mechanical sensitivity was assessed using von Frey filaments. Postinjury, transgenic fetal green fluorescent protein mouse GABAergic cells or human neural precursor cells (HNPCs) expanded in suspension bioreactors and differentiated into a GABAergic phenotype were transplanted into the spinal cord. Control rats received undifferentiated HNPCs or cell suspension medium only. Animals that received either fetal mouse GABAergic cell or differentiated GABAergic HNPC intraspinal transplants demonstrated a significant increase in paw withdrawal thresholds at 1 week post‐transplantation that was sustained for 6 weeks. Transplanted fetal mouse GABAergic cells demonstrated immunoreactivity for glutamic acid decarboxylase and GABA that colocalized with green fluorescent protein. Intraspinally transplanted differentiated GABAergic HNPCs demonstrated immunoreactivity for GABA and β‐III tubulin. In contrast, intraspinal transplantation of undifferentiated HNPCs, which predominantly differentiated into astrocytes, or cell suspension medium did not affect any behavioral recovery. Intraspinally transplanted GABAergic cells can reduce allodynia in a rat model of neuropathic pain. In addition, HNPCs expanded in a standardized fashion in suspension bioreactors and differentiated into a GABAergic phenotype may be an alternative to fetal cells for cell‐based therapies to treat chronic pain syndromes.

Robotic long-distance telementoring in neurosurgery.

OBJECTIVE:To test the feasibility of long-distance telementoring in neurosurgery by providing subspecialized expertise in real time to another neurosurgeon performing a surgical procedure in a remote location. METHODS:A robotic telecollaboration system (Socrates; Computer Motion, Inc., Santa Barbara, CA) capable of controlling the movements of a robotic arm, of handling two-way video, and of audio communication as well as transmission of neuronavigational data from the remote operating room was used for the telementoring procedures. Four integrated services digital network lines with a total speed of transmission of 512 kilobytes per second provided telecommunications between a large academic center (Halifax, Nova Scotia) and a community-based center (Saint John, New Brunswick) located 400 km away. RESULTS:Long-distance telementoring was used in three craniotomies for brain tumors, a craniotomy for an arteriovenous malformation, a carotid endarterectomy, and a lumbar laminectomy. There were no surgical complications during the procedures, and all patients had uneventful outcomes. The neurosurgeons in the remote location believed that the input from the mentors was useful in all of the cases and was crucial in the removal of a mesial temporal lobe glioma and resection of an occipital arteriovenous malformation. CONCLUSION:Our initial experience with long-distance robotic-assisted telementoring in six cases indicates that telementoring is feasible, reliable, and safe. Although still in its infancy, telementoring has the potential to improve surgical care, to enhance neurosurgical training, and to have a major impact on the delivery of neurosurgical services throughout the world.

Sustained relief of dystonia following cessation of deep brain stimulation.

We describe the unusual clinical course of a patient with cranial dystonia (i.e., Meige syndrome) and additional upper limb involvement, who developed sustained relief of motor symptoms following cessation of a prolonged course of bilateral pallidal deep brain stimulation (DBS). Early response to therapy proved titratable and reversible; however, the patient gained independence from DBS in the fifth postoperative year and has since been more than a year without treatment or exacerbation of motor symptoms. Among the potential explanations for these neurological benefits lies the intriguing possibility that DBS therapy may have the capacity to induce plastic change that lessens or obviates the need for further treatment in susceptible patients.