Transduction profiles in minipig following MRI guided delivery of AAV-5 into thalamic and corona radiata areas.

BACKGROUND: As a step towards clinical use of AAV-mediated gene therapy, brains of large animals are used to settle delivery parameters as most brain connections, and relative sizes in large animals and primates, are reasonably common. Prior to application in the clinic, approaches that have shown to be successful in rodent models are tested in larger animal species, such as dogs, non-human primates, and in this case, minipigs. NEW METHOD: We evaluated alternate delivery routes to target the basal ganglia by injections into the more superficial corona radiata, and, deeper into the brain, the thalamus. Anatomically known connections can be used to predict the expression of the transgene following infusion of AAV5. For optimal control over delivery of the vector with regards to anatomical location in the brain and spread in the tissue, we have used magnetic resonance image-guided convection-enhanced diffusion delivery. RESULTS: While the transduction of the cortex was observed, only partial transduction of the basal ganglia was achieved via the corona radiata. Thalamic administration, on the other hand, resulted in widespread transduction from the midbrain to the frontal cortex COMPARISON WITH EXISTING METHODS: Compared to other methods, such as delivery directly to the striatum, thalamic injection may provide an alternative when for instance, injection into the basal ganglia directly is not feasible. CONCLUSIONS: The study results suggest that thalamic administration of AAV5 has significant potential for indications where the transduction of specific areas of the brain is required.

Atypical presentations of DYT1 dystonia with acute craniocervical onset.

DYT1 gene mutations lead to early-onset dystonia that begins with focal limb onset and spreads to other body regions within 5 years, with typical sparing of the oromandibular muscles. In the present study, we describe two patients with an unusual presentation of the disease.

Deep brain stimulation of the subthalamic nucleus and cognitive functions in Parkinson's disease.

Deep brain stimulation of the subthalamic nucleus (DBS/STN) is an effective treatment for motor symptoms in advanced Parkinson's disease (PD). However, it is less clear how DBS/STN affects cognitive functions. We investigated 19 PD patients (13 male, 6 female, mean age 57 +/- 6, mean PD duration 15 +/- 4 years) who received bilateral DBS/STN. Neuropsychological assessment was done before the surgery and at least 12 months after DBS implantation. The patients were examined in their optimal motor status. Global cognitive performance measured by Mattis Dementia Rating Scale was not significantly changed after DBS STN. The performance in Wechsler Memory Scale III decreased in the subtest Logical Memory, in delayed recall (p < 0.05) and in recognition (p < 0.05). In Stroop Test, the performance worsened in the second (p < 0.05), and third condition (p < 0.01) measuring interference and ability to suppress automatic reactions. In conclusion, patients treated by DBS/STN tend to worsen in executive functions and in logical memory.

Functional magnetic resonance imaging during deep brain stimulation: a pilot study in four patients with Parkinson's disease.

Functional magnetic resonance imaging (fMRI) was performed in patients with Parkinson's disease during deep brain stimulation of the subthalamic nucleus (three patients) and during deep brain stimulation of the ventral intermedius nucleus of the thalamus (one patient). All showed an increase in blood oxygenation level-dependent signal in the subcortical regions ipsilateral to the stimulated nucleus. This effect cannot be simply explained by a mechanism of depolarization blockade; rather, it is caused by overstimulation of the target nucleus, resulting in the suppression of its spontaneous activity. We confirm that fMRI during deep brain stimulation is a safe method with considerable potential for elucidating the functional connectivity of the stimulated nuclei.

Differentiation between hemosiderin- and ferritin-bound brain iron using nuclear magnetic resonance and magnetic resonance imaging.

MRI is an optimal clinical (research) tool to provide information on brain morphology and pathology and to detect metal ions that possess intrinsic magnetic properties. Non-heme iron is abundantly present in the brain in three different forms: "low molecular weight" complexes, iron bound to "medium molecular weight complexes" metalloproteins such as transferrin, and "high molecular weight" complexes as ferritin and hemosiderin. The total amount and form of iron may differ in health and disease, and MRI can possibly quantify and monitor such changes. Ferritin-bound iron is the main storage form of iron and is present predominantly in the extrapyramidal nuclei where its amounts normally increase as a function of age. Ferritin is water soluble and shortens both, T1 and T2 relaxation, with as result a signal change on the MR images. Hemosiderin, a degradation product of ferritin, is water-insoluble with a stronger T2 shortening effect than ferritin. The larger cluster size of hemosiderin and its water-insolubility also explain a lack of significant T1-shortening effect on T1-weighted images. Using both in vitro specimens and intact brain tissue in vivo we demonstrate here that MRI may be able to distinguish between ferritin- and hemosiderin-bound iron.

Treatment of postherpetic trigeminal neuralgia with the gamma knife.

OBJECT: Postherpetic neuralgia is a syndrome characterized by intractable pain. Treatment of this pain has not yet been successful. Patients with postherpetic neuralgia will therefore benefit from any progress in the treatment strategy. The authors performed gamma knife radiosurgery (GKS) as a noninvasive treatment for postherpetic trigeminal neuralgia (TN) and evaluated the success rate for pain relief. METHODS: Between 1995 and February 1999, six men and 10 women were treated for postherpetic TN; conservative treatment failed in all of them. The median follow up was 33 months (range 8-34 months). The radiation was focused on the root of the trigeminal nerve in the vicinity of the brainstem (maximal dose 70-80 Gy in one fraction, 4-mm collimator). The patients were divided into five groups according to degree of pain relief after treatment. A successful result (excellent, very good, and good) was reached in seven (44%) patients and radiosurgery failed in nine (56%). Pain relief occurred after a median interval of 1 month (range 10 days-6 months). No radiation-related side effects have been observed in these patients. CONCLUSIONS: These results suggest that GKS for postherpetic TN is a relatively successful and safe method that can be used in patients even if they are in poor condition. In case this method fails, other treatment options including other neurosurgical procedures are not excluded.

First auditory brainstem implant in the Czech Republic.

In the Czech Republic, the first implantation of a stimulation electrode into the brainstem was performed on 11 January 1999 in the Department of ORL, Head and Neck Surgery, The First Medical Faculty, Charles University in Prague, University Hospital Motol. The selected patient was a 40-year-old woman with neurofibromatosis type 2 (NF2) who had previously undergone bilateral vestibular schwannoma surgery. Both tumours had been radically removed, the left-sided tumour in 1987, the right-sided one in 1988. She had been completely deaf since the last operation, i.e., for 11 years. The surgery was realized by the international cooperation of three teams. Placement of the electrode pad of the Nucleus CI21 + 1M system on the ventral and dorsal cochlear nuclei was performed. Electrically evoked auditory brainstem responses (EABRs) proved the correct position of the electrode array. The post-operative course was uneventful. Six weeks after the surgery the patient received her speech processor. Since that time, the patient already absolved several sessions of a speech processor tune-up. She uses the device as an aid in lip-reading. No adverse or pathological side effects have been observed. The patient was the 45th person in Europe to receive an ABI and the first in the Czech Republic.

Gamma knife treatment of trigeminal neuralgia: clinical and electrophysiological study.

Between October 1995 and October 1996, we treated 49 patients suffering from trigeminal neuralgia with Gamma Knife radiosurgery. There were 23 males and 26 females. The mean age was 68 (range 38-94 years) The root of the trigeminal nerve close to brain stem was chosen as the target. The maximum dose was 70 Gy in 24 cases and 80 Gy in 25 cases. A single shot with the 4-mm collimator was used. 13 patients underwent Gamma Knife treatment of trigeminal nerve root without any previous surgical procedures. 31 patients suffered from an essential neuralgia (EN), while 7 had neuralgia related to multiple sclerosis (MS). Three had atypical neuralgia (AN) and 8 patients had postherpetic neuralgia (PN). Patients were divided into five groups according to pain reduction. The success rate of pain relief (excellent, very good and good responses) in these patients was: EN 77% of patients, MS 43%, AN 33% and PN 38% of patients. Pain relief occurred after latent intervals of between 1 day and 8 months (median 2 months and mean 2.8 months). Clinically detected complications after radiosurgery occurred only in the form of tactile hypesthesia in 6%. In a selected group of 18 patients, we observed slight electrophysiological changes in 2 patients (11%) after Gamma Knife treatment.