Intra-arterial thrombectomy versus standard intravenous thrombolysis in patients with anterior circulation stroke caused by intracranial arterial occlusions: a single-center experience.

BACKGROUND: Severely impaired patients with persisting intracranial occlusion despite standard treatment with intravenous (IV) administration of recombinant tissue plasminogen activator (rtPA) or presenting beyond the therapeutic window for IV rtPA may be candidates for interventional neurothrombectomy (NT). The safety and efficacy of NT by the Penumbra System (PS) were compared with standard IV rtPA treatment in patients with severe acute ischemic stroke (AIS) caused by large intracranial vessel occlusion in the anterior circulation. METHODS: Consecutive AIS patients underwent a predefined treatment algorithm based on arrival time, stroke severity as measured by the National Institutes of Health Stroke Scale (NIHSS) score, and site of arterial occlusion on computed tomographic angiography (CTA). NT was performed either after a standard dose of IV rtPA (bridging therapy [BT]) or as single treatment (stand-alone NT [SAT]). Rates of recanalization, symptomatic intracranial bleeding (SIB), mortality, and functional outcome in NT patients were compared with a historical cohort of IV rtPA treated patients (i.e., controls). Three-month favourable outcome was defined as a modified Rankin Scale (mRS) score ≤2. RESULTS: Forty-six AIS patients were treated with NT and 51 with IV rtPA. The 2 groups did not differ with regard to demographics, onset NIHSS score (18.5±4 v 17±5; P=.06), or site of intracranial occlusion. Onset-to-treatment time in the NT and IV rtPA groups was 230 minutes (±78) and 176.5 (±44) minutes, respectively (P=.001). NT patients had significantly higher percentages of major improvement (≥8 points NIHSS score change at 24 hours; 26% v 10%; P=.03) and partial/complete recanalization (93.5% v 45%; P<.0001) compared to controls. Treatment by either SAT or BT similarly improved the chance of early recanalization and early clinical improvement. No significant differences were observed in the rate of SIB (11% v 6%), 3-month mortality (24% v 25%), or favorable outcome (40% v 35%) between NT and IV rtPA patients. CONCLUSIONS: Despite significantly delayed time of intervention, NT patients had higher rates of recanalization and early major improvement, with no differences in symptomatic intracranial hemorrhages. Early NIHSS score improvement did not translate into better 3-month mortality or outcome. NT seems a safe and effective adjuvant treatment strategy for selected patients with severe AIS secondary to large intracranial vessel occlusion in the anterior circulation.

Drugs and clinical trials in neurodegenerative diseases.

Neurodegenerative diseases are disabling conditions continuously increasing due to aging of population. A disease modifying therapy that slows or stops disease progression is therefore a major unmet medical need. Unfortunately, research for effective treatments is hampered by lack of knowledge on the pathologic processes underpinning these diseases and of reliable biomarkers. Clinical trials are difficult, as they require large populations that need to be followed for very long periods to capture possible effects on disease progression. These difficulties produce frequent failures and waste of human and economic resources. Since research has to continue in this area, until comprehensive knowledge of basic pathologic processes is obtained, alternative study designs can be considered to identify disease modifiers and to reduce costs of clinical studies.

Correlation between changes in CSF dopamine turnover and development of dyskinesia in Parkinson's disease.

To assess possible differences in dopamine metabolism that could parallel disease progression in Parkinson's disease (PD), we measured dopamine (DA) and its metabolites in the cerebrospinal fluid (CSF) in PD patients at different stages of disease: de novo (DEN), advanced not showing dyskinesias (ADV), and advanced with dyskinesias (DYS). DA, homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC) were significantly higher in DEN patients compared with other groups. A negative exponential correlation related DA level and disease duration. The HVA/DA ratio was significantly higher in the ADV and DYS group than that found in DEN group. Our data show that disease progression produces an early large decay of DA levels, followed by a stabilization. On the contrary, a late change in DA turnover (increased HVA/DA ratio) is documented in patients with longer disease duration. Our results suggest that the appearance of dyskinesia may not be related to a further loss of DA terminals but to a different, abnormal, DA turnover.

Pedunculopontine nucleus deep brain stimulation changes spinal cord excitability in Parkinson's disease patients.

Bilateral peduncolopontine nucleus (PPN) and subthalamic nucleus (STN) deep brain stimulation (DBS) was performed in six-advanced Parkinson's disease (PD) patients. We report the effect of both PPN-DBS (25 Hz) and STN-DBS (185 Hz) on patient spinal reflex excitability by utilizing the soleus-Hoffman reflex (HR) threshold. Compared to controls (n = 9), patients showed an increase of HR-threshold, which was scarcely affected by levodopa, but significantly reduced by DBS. In particular, we found that PPN-DBS alone, or plus STN-DBS induced a complete recovery of HR-threshold up to control values. The HR-threshold changes, although do not allow to investigate the contribution of specific intraspinal pathways, suggest that PPN may play a key-role in modulating spinal excitability in PD possibly by improving the basal ganglia-brainstem descending system activity.

Bilateral deep brain stimulation of the pedunculopontine and subthalamic nuclei in severe Parkinson's disease.

Gait disturbances and akinesia are extremely disabling in advanced Parkinson's disease. It has been suggested that modulation of the activity of the pedunculopontine nucleus (PPN) may be beneficial in the treatment of these symptoms. We report the clinical affects of deep brain stimulation (DBS) in the PPN and subthalamic nucleus (STN). Six patients with unsatisfactory pharmacological control of axial signs such as gait and postural stability underwent bilateral implantation of DBS electrodes in the STN and PPN. Clinical effects were evaluated 2-6 months after surgery in the OFF- and ON-medication state, with both STN and PPN stimulation ON or OFF, or with only one target being stimulated. Bilateral PPN-DBS at 25 Hz in OFF-medication produced an immediate 45% amelioration of the motor Unified Parkinson's Disease Rating Scale (UPDRS) subscale score, followed by a decline to give a final improvement of 32% in the score after 3-6 months. In contrast, bilateral STN-DBS at 130-185 Hz led to about 54% improvement. PPN-DBS was particularly effective on gait and postural items. In ON-medication state, the association of STN and PPN-DBS provided a significant further improvement when compared to the specific benefit mediated by the activation of either single target. Moreover, the combined DBS of both targets promoted a substantial amelioration in the performance of daily living activities. These findings indicate that, in patients with advanced Parkinson's disease, PPN-DBS associated with standard STN-DBS may be useful in improving gait and in optimizing the dopamine-mediated ON-state, particularly in those whose response to STN only DBS has deteriorated over time. This combination of targets may also prove useful in extra-pyramidal disorders, such as progressive supranuclear palsy, for which treatments are currently elusive.

Biochemical and electrophysiological changes of substantia nigra pars reticulata driven by subthalamic stimulation in patients with Parkinson's disease.

To understand the events underlying the clinical efficacy of deep brain stimulation (DBS) of the subthalamic nucleus (STN), electrophysiological recordings and microdialysis evaluations were carried out in the substantia nigra pars reticulata (SNr), one of the two basal ganglia (BG) nuclei targeted by STN output, in patients with Parkinson's disease (PD). Clinically effective STN-DBS caused a significant increase of the SNr firing rate. The poststimulus histogram (PSTH) showed an excitation peak at 1.92-3.85 ms after the STN stimulus. The spontaneous discharge of SNr neurons was driven at the frequency of the stimulation (130 Hz), as shown in the autocorrelograms (AutoCrl). The fast Fourier transform (FFT) analysis showed a peak at 130 Hz, and a less pronounced second one at 260 Hz. Accordingly, in the distribution of the interspike intervals (ISIs), the mode was earlier, and skewness more asymmetric. Biochemically, the increased excitatory driving from the STN was reflected by a clear-cut increase in cyclic guanosine 3',5'-monophosphate (cGMP) levels in the SNr. These results indicate that the beneficial effect of DBS in PD patients is paralleled with a stimulus-synchronized activation of the STN target, SNr. Our findings suggest that, during STN-DBS, a critical change towards a high-frequency oscillatory discharge occurs.

Bilateral Implantation of Centromedian-Parafascicularis Complex and GPi: A New Combination of Unconventional Targets for Deep Brain Stimulation in Severe Parkinson Disease.

Objectives. Traditional deep brain stimulation (DBS) at the subthalamic nucleus (STN) has proved to be efficacious on core Parkinsonian symptoms. However, very disabling l-dopa-induced abnormal involuntary movements (AIMs) and axial signs are slightly affected, suggesting that we target less conventional targets. Our candidates for DBS were the globus pallidus internus (GPi) plus the intralaminar thalamic complex (Pf or CM), given its extensive functional links with basal ganglia nuclei. Materials and Methods. The routine utilization of our innovative stereotactic apparatus allows us to implant, at the same time, both the CM-Pf complex together with the GPi in six Parkinson disease patients. Both intraoperative and postoperative neurophysiologic assessments helped us recognize functional subregions while optimizing implantation of electrodes. Unified Parkinson disease rating scale (UPDRS) motor scores, AIMs, and freezing were carefully blindly evaluated for each condition. Results. A significant amelioration of UPDRS scores was achieved by simultaneous activation of both targets. CM-Pf activation was only slightly effective in reducing rigidity and akinesia, but more efficacious on freezing. Not surprisingly, AIMs were peculiarly decreased by the activation of the permanent electro-catheter in the posteroventral GPi. Conclusions. These findings confirm that, in selected patients, it is conceivable to target structures other than the conventional STN in order to maximize clinical benefit.

Kyphoplasty: a new opportunity for rehabilitation of neurologic disabilities.

Using percutaneous kyphoplasty, we treated a patient with a diagnosis of Guillain-Barré syndrome who complained of an unremitting pain in the spine, refractory to the conventional medical therapy, elicited by pressure over the spinous process, and in absence of neurologic deficits. The method provided swift midline back pain relief associated with an evident augmentation in the stability and in the vertebral body's height. The injection of polymethylmethacrylate was effective and safe, no cement leakages were observed, and no complications such as pulmonary embolism, toxicity, or infection were observed. Due to the rapid pain relief, a rehabilitation program was promptly undertaken with a good improvement of the disability score (FIM scale score). Kyphoplasty is a new method for treatment of vertebral collapses consequent to osteoporosis, aggressive hemangiomas, myelomas, and metastases, and it may aid in rehabilitation of the underlying systemic neurologic disorder if the pain is interfering with those therapies.

Induction of corticostriatal LTP by 3-nitropropionic acid requires the activation of mGluR1/PKC pathway.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder typically affecting individuals in midlife. HD is characterized by the selective loss of striatal spiny neurons, while large cholinergic interneurons are spared. An impaired mitochondrial complex II (succinate dehydrogenase, SD) activity is known as a prominent metabolic alteration in HD. Accordingly, chronic treatment with 3-nitropropionic acid (3-NP), an irreversible SD inhibitor, mimics motor abnormalities and pathology of HD in several animal models. We have previously shown that in vitro application of 3-NP induces a long-term potentiation (LTP) of corticostriatal synaptic transmission through NMDA glutamate receptor. Since this 3-NP-induced LTP (3-NP-LTP) is shown by striatal spiny neurons, but not by cholinergic interneurons, it might play a role in the regional and cell type-specific neuronal death observed in HD. Here we investigate the role of group I metabotropic glutamate receptors (mGluRs) in the induction of 3-NP-LTP. We report that selectively blocking mGluR1, but not mGluR5, suppresses 3-NP-LTP induction. Moreover, we show that a PKC-mediated mechanism is involved in the formation of 3-NP-LTP. Characterizing the cellular mechanisms underlying 3-NP-LTP may provide new insights to better understand the processes leading to the selective neuronal loss observed in HD.

Neuronal vulnerability following inhibition of mitochondrial complex II: a possible ionic mechanism for Huntington's disease.

An impaired complex II (succinate dehydrogenase, SD) striatal mitochondrial activity is one of the prominent metabolic alterations in Huntington's disease (HD), and intoxication with 3-nitropropionic acid (3-NP), an inhibitor of mitochondrial complex II, mimics the motor abnormalities and the pathology of HD. We found that striatal spiny neurons responded to this toxin with an irreversible membrane depolarization/inward current, while cholinergic interneurons showed a hyperpolarization/outward current. Both these currents were sensitive to intracellular concentration of ATP. The 3-NP-induced depolarization was associated with an increased release of endogenous GABA, while acetylcholine levels were reduced. Moreover, 3-NP induced a higher depolarization in presymptomatic R6/2 HD transgenic mice compared to wild-type (WT) mice, showing an increased susceptibility to SD inhibition. Conversely, the hyperpolarization did not significantly differ from the one recorded in WT mice. The diverse membrane changes induced by SD inhibition may contribute to the cell-type-specific neuronal death in HD.

Tissue plasminogen activator is required for striatal post-ischemic synaptic potentiation.

Recent experimental observations indicate that tPA plays a key role in the development of neuronal damage that follows cerebral ischemia and excitotoxicity. In an attempt to clarify how tPA favors ischemia-induced neuronal damage, we performed in vitro electrophysiological experiments in striatal slices by using mice selectively lacking this serine protease.We found that tPA ablation did not affect the membrane depolarization of striatal neurons exposed to combined oxygen and glucose deprivation but fully prevented the induction of NMDA-dependent post-ischemic long-term synaptic potentiation. The absence of striatal post-ischemic pote ntiat ion observed in tPA-lacking mice may account for the significant neuroprotection observed in these animals after the occlusion of middle cerebral artery.