Transdermal dopaminergic stimulation with rotigotine in Parkinsonian akinetic crisis.

Akinetic crisis (AC) is a much-feared complication of Parkinson's disease (PD) which may appear upon abrupt cessation or malabsorption of dopaminergic medication due to gastrointestinal tract disorders or acute surgery. Intravenous infusion of amantadine sulphate or subcutaneous administration of apomorphine are established treatment strategies for AC. We speculate whether the use of a non-invasive transdermal application form (patch) of a dopaminergic drug (rotigotine) may represent a useful alternative treatment option. We describe the successful treatment of severe AC using rotigotine in a PD patient with gastro-oesophageal ulcers which precluded administration of any oral medication. This case demonstrates that a rotigotine patch might be effective in the treatment of AC. We suggest that rotigotine may represent a useful treatment option due to its favourable receptor profile and unique application form. In particular, it may be helpful in situations that might provoke AC, such as acute surgery. However, experience of the use of the rotigotine patch in this clinical setting is rather sparse and the patch is currently not approved for this indication.

High rate of restenosis after carotid artery stenting in patients with high-grade internal carotid artery stenosis. Medium-term follow-up.

OBJECTIVE: Carotid endarterectomy (CEA) is the gold-standard procedure for the majority of patients with high-grade symptomatic internal carotid artery stenosis and also for specified high-grade asymptomatic stenoses; however, a proportion of patients are treated with carotid endovascular therapy. We aimed to document medium-term clinical and neurosonographical outcome after carotid artery stenting (CAS). METHODS: 53 patients (mean age: 65 +/- 8 years) with high-grade (> or = 70 % by means of duplex sonography) carotid artery stenosis were enrolled into the study. Nineteen patients had asymptomatic, 34 patients had symptomatic stenoses. All patients had a pre-interventional CT, Doppler and duplex sonography, and digital subtraction angiography (DSA) or magnetic resonance angiography (MRA) prior to the procedural DSA. All patients were offered CEA as the gold-standard procedure and as an alternative to CAS. Both clinical and Duplex sonographical follow-up was obtained at day 1 and 7, month 1, month 3, month 6, month 12, and every subsequent 6 months after the procedure. Mean follow-up time was 22 +/- 1.6 months (+/- SEM). RESULTS: 2/53 patients suffered from stroke. A further 2 patients suffered from carotid artery occlusion shortly after CAS. The cumulative rate of restenosis during follow-up was 24.5 % (13/53). Four of these (7.5 %) were of high-grade and led to further interventional or surgical therapy. CONCLUSIONS: A high rate of restenosis was found during follow-up after CAS. Our analysis of non-selected patients emphasizes that CEA remains the gold-standard procedure for the treatment of symptomatic internal carotid artery stenosis. The frequently performed endovascular treatment of carotid stenosis outside the setting of a randomized controlled trial is not supported by our data.

Comparison of intravenous and intraperitoneal [123I]IBZM injection for dopamine D2 receptor imaging in mice.

INTRODUCTION: Intraperitoneal (IP) injection represents an attractive alternative route of radiotracer administration for small animal imaging, e.g., for longitudinal studies in transgenic mouse models. We explored the cerebral kinetics of the reversible dopamine D2 receptor ligand [(123)I]IBZM after IP injection in mice. METHODS: Cerebral [(123)I]IBZM kinetics were assessed by ex vivo autoradiography in mice sacrificed between 30 and 200 min after IP or intravenous (IV) injection. The striatum-to-cerebellum (S/C) uptake ratio at 140 min was evaluated in wild-type mice and R6/2 transgenic mice (a Huntington's disease model) in comparison with in vitro autoradiography using [(3)H]raclopride. RESULTS: [(123)I]IBZM uptake was slower and lower after IP injection [maximum uptake in striatum 5.6% injected dose per gram (ID/g) at 60 min] than IV injection (10.5%ID/g at 30 min). Between 60 and 120 min, striatal (cerebellar) uptake after IP injection reached 63% (91%) of the uptake after IV injection. The S/C uptake ratio increased to 15.5 at 200 min after IP injection, which corresponds to 87% of the IV injection value (17.8). Consistent with in vitro [(3)H]raclopride autoradiography, the S/C ratio given by ex vivo [(123)I]IBZM autoradiography (140 min after IP injection) was significantly reduced in R6/2 mice. CONCLUSIONS: Although IP injection resulted in slower kinetics, relevant measures of dopamine D2 receptor availability were comparable. Thus, IP injection represents a promising route of tracer administration for small animal [(123)I]IBZM SPECT. This should considerably simplify the implementation of longitudinal small animal neuroimaging studies, e.g., in transgenic mouse models.

Cerebral kinetics of the dopamine D(2) receptor ligand [(123)I]IBZM in mice.

INTRODUCTION: In vivo small animal imaging of the dopaminergic system is of great interest for basic and applied neurosciences, especially in transgenic mice. Small animal SPECT is particularly attractive because of its superior spatial resolution and tracer availability. We investigated the kinetics of the commercial dopamine D(2) receptor (DZR) ligand [(123)I]IBZM in mice as a prerequisite for an appropriate design of translational SPECT imaging between mice and humans. METHODS: Cerebral kinetics of [(123)I]IBZM under isoflurane anaesthesia were assessed by autoradiography in mice sacrificed at 30, 60, 120 and 200 min after iv injection. To explore the possible effects of isoflurane anaesthesia, an additional mice group was only anaesthetized for 20 min before being sacrificed at 140 min (putative time of single-scan SPECT analysis). RESULTS: Maximum [(123)I]IBZM uptake in the striatum (D(2)R-rich; 10.5+/-2.7 %ID/g) and cerebellum (D(2)R-devoid; 2.4+/-0.7 %ID/g) was observed at 30 min after injection. Thereafter, [(123)I]IBZM uptake decreased slowly in striatum and rapidly in the cerebellum (200 min: 5.3+/-1.9 and 0.4+/-0.2 %ID/g, respectively). The striatum-to-cerebellum (S/C) [(123)I]IBZM uptake ratio increased from 4.6+/-1.2 at 30 min to 11.6+/-2.6 at 120 min. The S/C ratio at 200 min was highly variable (17.8+/-10.1), possibly indicating pseudo-equilibration in some animals. In mice, which were only anaesthetized between 120 and 140 min, a higher S/C ratio of 17.0+/-5.1 was observed. CONCLUSIONS: The present study suggests that [(123)I]IBZM is a suitable ligand for D(2)R-SPECT in mice. Although a single-scan analysis may be a pragmatic semi-quantitative approach, tracer kinetic analyses on dynamic SPECT data should be pursued. The interfering effects of isoflurane anaesthesia need to be considered.

Inducing huntingtin inclusion formation in primary neuronal cell culture and in vivo by high-capacity adenoviral vectors expressing truncated and full-length huntingtin with polyglutamine expansion.

BACKGROUND: Huntington's disease (HD) is an inherited autosomal dominant neurodegenerative disease caused by the expansion of a CAG trinucleotide repeat in exon 1 of the huntingtin (htt) gene. Vector-mediated delivery of N-terminal fragments of mutant htt has been used to study htt function in vitro and to establish HD models in rats. Due to the large size of the htt cDNA vector-mediated delivery of full-length htt has not been achieved so far. METHODS: High-capacity adenoviral (HC-Ad) vectors were generated expressing mutant and wild-type versions of N-terminal truncated and full-length htt either in vitro in primary neuronal cells or in the striatum of mice. RESULTS: In vitro these vectors were used for transduction of primary neuronal cells isolated from E17 mouse embryos. Expression of mutant htt resulted in the formation of htt inclusions, a surrogate marker of the HD pathology. Kinetics of generation and localization of htt inclusions differed between truncated and full-length htt carrying identical mutations. Following injection into the striatum vector-mediated expression of mutant truncated htt led to prominent accumulation of htt inclusions in cell nuclei, while inclusions formed upon expression of mutant full-length htt localized to the cytoplasm. CONCLUSIONS: These results indicate that HC-Ad vector-mediated in vitro and in vivo delivery of truncated and full-length mutant htt results in prominent inclusion formation in neuronal cells but in different cell compartments. These vectors will be useful tools for studying HD and may be used to generate large animal HD models.

Myopathy as a first symptom of Huntington's disease in a Marathon runner.

A semi professional marathon runner at risk for Huntington's disease (HD) (43 CAG repeats) developed signs of a slowly progressive myopathy with exercise-induced muscle fatigue, pain, elevated creatine kinase level, and worsening of his running performance many years before first signs of chorea were detected. Muscle biopsy displayed a mild myopathy with mitochondrial pathology including a complex IV deficiency and analysis of the patient's fibroblast culture demonstrated deficits in mitochondrial function. Challenging skeletal muscle by excessive training might have disclosed myopathy in HD even years before the appearance of other neurological symptoms.

High-capacity adenoviral vector-mediated reduction of huntingtin aggregate load in vitro and in vivo.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by the expansion of a CAG trinucleotide repeat in exon 1 of the huntingtin (htt) gene. Emergence and progression of HD depend on continuous expression of mutant Huntingtin protein (Htt). Therefore, blocking expression of mutant Htt might be a promising therapeutic strategy. We generated a high-capacity adenoviral (HC-Ad) vector expressing a short hairpin RNA (shRNA) targeted to exon 1 of the htt gene. In vitro, this vector efficiently inhibited Htt expression in neuronal and nonneuronal cell lines. In addition, the number of Htt-immunoreactive (IR) aggregates, a hallmark of HD pathology, was significantly reduced after gene transfer with this vector. Importantly, the attenuation of aggregate formation by shRNA was observed in vivo after stereotaxic injection into the striatum of mouse models of HD. The vector was tested in two models: the R6/2 transgenic mouse model and a mouse model based on the local injection of an adenoviral vector expressing a truncated version of mutant Htt. In both models an efficient reduction in mutant Htt aggregate load measured by decreased Htt-IR aggregate formation was observed. Our results support the further development of shRNA for HD therapy.

Rapid geographical clustering of wound botulism in Germany after subcutaneous and intramuscular injection of heroin.

BACKGROUND: Wound infections due to Clostridium botulinum in Germany are rare and occur predominantly in heroin injectors, especially after subcutaneous or intramuscular injection of heroin ("skin popping"), which is contaminated with spores of C. botulinum. We report a rapid geographical clustering of cases in Germany in a region between Cologne, Bonn, and Aachen with wound botulism and consecutive systemic C. botulinum intoxication in intravenous drug users (IDUs) within 6 weeks in October and November 2005. PATIENTS: A group of 12 IDUs with wound botulism after "skin popping." RESULTS: Clinical data were available in 11 (92%) of 12 patients; in 7 (58%) of the 12 cases, there was cranial nerve involvement including mydriasis, diplopia, dysarthria, and dysphagia, followed by progressing symmetric and flaccid paralysis of proximal muscles of the neck, arms, trunk, and respiratory muscles. Mechanical respiratory support was necessary. Five of the IDUs were treated with antitoxin, but mechanical respiratory support could not be avoided. The mean ventilation duration was 27.4 days (range 6-77 days). In 4 patients (33%), mechanical ventilation could be avoided; two were treated with antitoxin. CONCLUSIONS: This report describes rapid geographical clustering of wound botulism with severe respiratory complications in IDUs after "skin popping," which has not previously been reported either in Germany or any other European country. Based on these observations and those in other European countries, we conclude that there is a trend towards "skin popping," suggesting a change in injection practices in IDUs. Secondly, we conclude that the total number of cases with wound botulism is likely to increase because "skin popping" is the main risk factor.

Time of transplantation and cell preparation determine neural stem cell survival in a mouse model of Huntington's disease.

Cell replacement therapies for neurodegenerative diseases, using multipotent neural stem cells (NSCs), require above all, a good survival of the graft. In this study, we unilaterally injected quinolinic acid (QA) into the striatum of adult mice and transplanted syngeneic NSCs of enhanced green fluorescent protein-transgenic mice into the lesioned striatum. The injection of QA leads to an excitotoxic lesion with selective cell death of the medium sized spiny neurons, the same cells that are affected in Huntington's disease. In order to investigate the best timing of transplantation for the survival of donor cells, we transplanted the stem cells at 2, 7 and 14 days after injury. In addition, the influence of graft preparation prior to transplantation, i.e., intact neurospheres versus dissociated cell suspension on graft survival was investigated. By far the best survival was found with the combination of early transplantation (i.e., 2 days after QA-lesion) with the use of neurospheres instead of dissociated cell suspension. This might be due to the different states of host's astrocytic and microglia activation which we found to be moderate at 2, but pronounced at 7 and 14 days after QA-lesion. We also investigated brain derived neurotrophic factor (BDNF)-expression in the striatum after QA-lesion and found no significant change in BDNF protein-level. We conclude that already the method of graft preparation of NSCs for transplantation, as well as the timing of the transplantation procedure strongly affects the survival of the donor cells when grafted into the QA-lesioned striatum of adult mice.

Neural cell adhesion molecule L1-transfected embryonic stem cells promote functional recovery after excitotoxic lesion of the mouse striatum.

We have generated a murine embryonic stem cell line constitutively expressing L1 at all stages of neural differentiation to investigate the effects of L1 overexpression on stem cell proliferation, migration, differentiation, cell death, and ability to influence drug-induced rotation behavior in an animal model of Huntington's disease. L1-transfected cells showed decreased cell proliferation in vitro, enhanced neuronal differentiation in vitro and in vivo, and decreased astrocytic differentiation in vivo without influencing cell death compared with nontransfected cells. L1 overexpression also resulted in an increased yield of GABAergic neurons and enhanced migration of embryonic stem cell-derived neural precursor cells into the lesioned striatum. Mice grafted with L1-transfected cells showed recovery in rotation behavior 1 and 4 weeks, but not 8 weeks, after transplantation compared with mice that had received nontransfected cells, thus demonstrating for the first time that a recognition molecule is capable of improving functional recovery during the initial phase in a syngeneic transplantation paradigm.

Low stability of Huntington muscle mitochondria against Ca2+ in R6/2 mice.

OBJECTIVE: The aim of the present work was the detection of Mitochondrial dysfunction of Huntington's disease (HD). METHODS: We investigated muscle and muscle mitochondria of 14- to 16-week-old R6/2 mice in comparison with wild-type mice. RESULTS: Atrophic fibers, increased fuchsinophilic aggregates, and reduced cytochrome c oxidase (15%) were found in HD muscle. With swelling measurements and Ca2+ accumulation experiments, a decreased stability of HD mitochondria against Ca2+-induced permeability transition was detected. Complex I-dependent respiration of HD mitochondria was more sensitive to inhibition by adding 10 microm Ca2+ than wild-type mitochondria. INTERPRETATION: Data suggest that the decreased stability of HD mitochondria against Ca2+ contributes to energetic depression and cell atrophy.

Do normal D-dimer levels reliably exclude cerebral sinus thrombosis?

BACKGROUND AND PURPOSE: Cerebral sinus thrombosis (CST) needs to be considered in the differential diagnosis of all patients with acute headache. Early diagnosis is essential because early treatment may prevent morbidity and may even be life-saving. Definite exclusion, however, needs advanced neuroradiologic diagnostics, which are not readily available in many hospitals. Because measurement of D-dimers has been demonstrated to be helpful in excluding thromboembolic disease, our aim was to investigate whether D-dimers would be also sensitive enough to exclude CST. METHODS: We undertook a prospective multicenter study over a 2.5-year period including all patients who came to the emergency departments with symptoms suggestive of CST. All patients were diagnosed either by magnetic resonance venography, spiral computed tomography scan venography, or intra-arterial digital subtraction angiography. D-dimer levels were measured at admission and analyzed by the same method in all patients. RESULTS: A total of 343 patients were included. CST was diagnosed in 35 patients, of whom 34 had D-dimers above the cutoff value (>500 microg/L). From the 308 patients not having CST, D-dimers were elevated in 27. Sensitivity of D-dimers was 97.1%, with a negative predictive value of 99.6%. Specificity was 91.2%, with a positive predictive value of 55.7%. D-dimers were positively correlated with the extent of the thrombosis and negatively correlated with the duration of symptoms (Spearman rank correlation coefficients 0.76, -0.58, respectively). CONCLUSIONS: D-dimer measurement is useful in patients with suspected CST. Normal D-dimers make the presence of CST very unlikely.

The metabotropic glutamate receptor 5 antagonist MPEP and the mGluR2 agonist LY379268 modify disease progression in a transgenic mouse model of Huntington's disease.

Chronic glutamate mediated excitotoxicity has been suggested to contribute to the pathogenesis of Huntington's disease (HD). Both, inhibition of glutamate release through stimulation of presynaptic metabotropic glutamate receptor (mGluR) 2 and blockade of postsynaptic mGluR5 have been demonstrated to be neuroprotective against excitotoxicity. R6/2 HD transgenic mice which express an expanded CAG triplet repeat serve as a well-characterized mouse model for HD with progressing neurological abnormalities and limited survival. We treated R6/2 HD transgenic mice with either the mGluR2 agonist LY379268 (1.2 mg/kg) or with the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) (100 mg/kg) orally from a presymptomatic stage until death to investigate their potential disease modifying effects. We found that survival time in both the MPEP treated mice and the LY379268 treated mice was significantly increased in comparison to placebo treated transgenic controls (14.87+/-0.14 and 14.22+/-0.11 weeks versus 12.87+/-0.11 weeks, respectively). Additionally, the progressive decline in motor coordination of HD transgenic mice as tested with the rotarod test was significantly attenuated in MPEP- but not in LY379268-treated mice. Early pathological hyperactivity, which can be found in placebo treated HD transgenic mice, was significantly attenuated by both MPEP and LY379268 treatment. Immunohistologial examination of HD characteristic neuronal intranuclear inclusion (NII), however, demonstrated no effect on NII formation by either of the treatments applied. These data suggest that inhibition of glutamate neurotransmission via specific interaction with mGluRs might be interesting for both inhibition of disease progression as well as early symptomatic treatment in HD.

[Fulminant meningoencephalitis associated with Mycoplasma pneumoniae infection in adults. Aggressive treatment enabled a good outcome]. / Fulminante Mycoplasma-pneumoniae-assoziierte Meningoenzephalitis des Erwachsenen. Aggressive Therapie ermöglicht gutes Outcome.

Mycoplasma pneumoniae (M. pn.) commonly causes respiratory tract infections in humans. In a certain percentage of cases it may also be associated with various peripheral and central nervous system manifestations. We report a case of a 38-year-old previously healthy man who presented with hemiplegia and somnolence after he had suffered from a febrile respiratory infection 10 days earlier. Clinical features and laboratory investigations supported the diagnosis of an acute M. pneumoniae-associated meningoencephalitis. He was treated by an aggressive antibiotic and immunomodulatory regimen over the course of several weeks in the neurocritical care unit. Decompressive hemicraniectomy was performed due to life-threatening raised intracranial pressure. However, the patient recovered almost completely and presented with a mild neurological deficit after 3 months. Based on this case we give a review of the literature and discuss potential pathomechanisms and diagnostic approaches.

Akathisia as a side effect of antipsychotic treatment with quetiapine in a patient with Parkinson's disease.

Due to its low profile for extrapyramidal side-effects, quetiapine has become an alternative to clozapine in the treatment of dopamimetic psychosis in patients with Parkinson's disease (PD). We describe the case of a patient with PD who developed severe akathisia, a common complication with classical antipsychotics, with quetiapine.

Huntington's disease transgenic mice are resistant to global cerebral ischemia.

Excitotoxicity plays a key role in ischemic neuronal death and is also one of the candidate mechanisms contributing to neurodegeneration in Huntington's disease (HD). Unexpectedly we have now found that transgenic mice expressing exon 1 of a mutant human HD gene (R6/1) are protected against global cerebral ischemia (GCI), installed by temporary bilateral occlusion of the carotid arteries. Whereas wild type mice showed a substantial neuronal damage in the hippocampus following 15, 20 and 60 min of GCI, transgenic mice were partially protected after 15 and 20 minutes of hypoxemia. This tolerance to ischemia is not blocked by pretreatment of mice with cycloheximide, an unspecific protein synthesis inhibitor. We conclude that this form of tolerance to ischemia in HD transgenic mice--although somewhat reminiscent of ischemic tolerance after ischemic preconditioning--is therefore independent of short term expression of endogenous neuroprotective proteins.

Riluzole prolongs survival time and alters nuclear inclusion formation in a transgenic mouse model of Huntington's disease.

Glutamate excitotoxicity has been suggested to contribute to the pathogenesis of Huntington's disease (HD). Riluzole is a substance with glutamate antagonistic properties that is used for neuroprotective treatment in amyotrophic lateral sclerosis and which is currently tested in clinical trials for treatment of HD. R6/2 transgenic mice, which express exon 1 of the human HD gene with an expanded CAG triplet repeat, serve as a well-characterized mouse model for HD with progressing neurological abnormalities and limited survival. We treated R6/2 HD transgenic mice with riluzole orally beginning at a presymptomatic stage until death to investigate its potential neuroprotective effects in this mouse model and found that survival time in the riluzole group was significantly increased in comparison to placebo-treated transgenic controls. Additionally, the progressive weight loss was delayed and significantly reduced by riluzole treatment; behavioral testing of motor coordination and spontaneous locomotor activity, however, showed no statistically significant differences. We also examined the formation of the HD characteristic neuronal intranuclear inclusions (NII) immunohistologically. At a late disease stage, striatal NII from riluzole-treated transgenic mice showed profound changes in ubiquitination, i.e., NII were less ubiquitinated and surrounded by ubiquitinated micro-aggregates. Staining with antibodies directed against the mutated huntingtin revealed no significant difference in this component of NII. Taken together, these data suggest that riluzole is a promising candidate for neuroprotective treatment in human HD.