Ruediger Hilker

Nosocomial Pneumonia After Acute Stroke. Implications for Neurological Intensive Care Medicine

Background and Purpose— Pneumonia has been estimated to occur in about one third of patients after acute stroke. Only limited data are available on stroke-associated pneumonia (SAP) in specialized neurological intensive care units (NICUs). Methods— We enrolled 124 patients with acute stroke who were treated at our university hospital NICU in a prospective observational study. Incidence rates and risk factors of SAP and long-term clinical outcome were determined. Results— SAP incidence was 21% with a spectrum of pathogens, which is comparable to previously published data on general ICU patients. Mechanical ventilation, multiple location, and vertebrobasilar stroke, as well as dysphagia and abnormal chest x-ray findings, were identified as risk factors for the disease. SAP patients showed higher mortality rates than nondiseased subjects (acute, 26.9% versus 8.2%; long-term, 35.3% versus 14.3%) and a significantly poorer long-term clinical outcome (Barthel Index, 50.5±42.4 versus 81.5±27.8; Rankin Scale, 3.5±1.7 versus 2.2±1.6). Conclusions— Our data underline the considerable epidemiological and prognostic impact of SAP for the treatment of acute stroke patients in a specialized NICU setting. They demonstrate that the occurrence of SAP deteriorates clinical outcome in these patients. Our results allow us to identify high-risk stroke patients at time of NICU admission in whom the use of preventive treatment strategies is most promising.

Positron emission tomographic analysis of the nigrostriatal dopaminergic system in familial Parkinsonism associated with mutations in the Parkin gene

A kindred from South Tyrol (northern Italy) with familial, adult‐onset parkinsonism of pseudo‐dominant inheritance and mutations in the parkin gene was recently described. To gain insight into basal ganglia dysfunction in this form of hereditary parkinsonism, positron emission tomography (PET) with 18‐fluorodopa (FDOPA) and 11C‐raclopride (RAC) was performed in 5 affected family members and 5 asymptomatic relatives with proven compound heterozygous or heterozygous parkin mutations. Results were compared to findings in healthy control subjects and patients with typical sporadic, idiopathic Parkinson‘s disease. Similar to findings in the sporadic Parkinson’s disease group, presynaptic striatal FDOPA storage was decreased in patients with compound heterozygous parkin mutations, with the most prominent reduction in the posterior part of the putamen. Along with the presynaptic lowered FDOPA uptake, we found a uniform reduction of the striatal 11C‐raclopride binding index in all affected family members as compared to asymptomatic family members carrying a heterozygous parkin mutation, sporadic Parkinsons disease, and control subjects. Our PET data provide evidence that parkinsonism in this family is associated with presynaptic dopaminergic dysfunction similar to idiopathic Parkinsons disease pathophysiology, along with alterations at the postsynaptic D2 receptor level. In asymptomatic carriers of a single parkin mutation with an apparently normal allele, we found a mild but statistically significant decrease of mean FDOPA uptake compared to control subjects in all striatal regions. These data indicate a preclinical disease process in these subjects. Ann Neurol 2001;49:367–376

DJ-1 (PARK7) mutations are less frequent than Parkin (PARK2) mutations in early-onset Parkinson disease

Background: Mutations in the Parkin gene (PARK2) are the most commonly identified cause of recessively inherited early-onset Parkinson disease (EOPD) but account for only a portion of cases. DJ-1 (PARK7) was recently reported as a second gene associated with recessively inherited PD with a homozygous exon deletion and a homozygous point mutation in two families. Methods: To investigate the frequency of DJ-1 mutations, the authors performed mutational analysis of all six coding exons of DJ-1 in 100 EOPD patients. For the detection of exon rearrangements, the authors developed a quantitative duplex PCR assay. Denaturing high performance liquid chromatography analysis was used to screen for point mutations and small deletions. Further, Parkin analysis was performed as previously described. Results: The authors identified two carriers of single heterozygous loss-of-function DJ-1 mutations, including a heterozygous deletion of exons 5 to 7 and an 11-base pair deletion, removing the invariant donor splice site in intron 5. Interestingly, both DJ-1 mutations identified in this study were found in the heterozygous state only. The authors also detected a polymorphism (R98Q) in 1.5% of the chromosomes in both the patient and control group. In the same patient sample, 17 cases were detected with mutations in the Parkin gene. Conclusions: Mutations in DJ-1 are less frequent than mutations in Parkin in EOPD patients but should be considered as a possible cause of EOPD. The effect of single heterozygous mutations in DJ-1 on the nigrostriatal system, as described for heterozygous changes in Parkin and PARK6, remains to be elucidated.

Subthalamic nucleus stimulation restores glucose metabolism in associative and limbic cortices and in cerebellum: Evidence from a FDG-PET study in advanced Parkinson's disease

Deep brain stimulation of the subthalamic nucleus (STN-DBS) is a highly effective surgical treatment in patients with advanced Parkinsons disease (PD). Because the STN has been shown to represent an important relay station not only in motor basal ganglia circuits, the modification of brain areas also involved in nonmotor functioning can be expected by this intervention. To determine the impact of STN-DBS upon the regional cerebral metabolic rate of glucose (rCMRGlc), we performed positron emission tomography (PET) with 18-fluorodeoxyglucose (FDG) in eight patients with advanced PD before surgery as well as in the DBS on- and off-conditions 4 months after electrode implantation and in ten age-matched healthy controls. Before surgery, PD patients showed widespread bilateral reductions of cortical rCMRGlc versus controls but a hypermetabolic state in the left rostral cerebellum. In the STN-DBS on-condition, clusters of significantly increased rCMRGlc were found in both lower thalami reaching down to the midbrain area and remote from the stimulation site in the right frontal cortex, temporal cortex, and parietal cortex, whereas rCMRGlc significantly decreased in the left rostral cerebellum. Therefore, STN-DBS was found to suppress cerebellar hypermetabolism and to partly restore physiologic glucose consumption in limbic and associative projection territories of the basal ganglia. These data suggest an activating effect of DBS upon its target structures and confirm a central role of the STN in motor as well as associative, limbic, and cerebellar basal ganglia circuits.

Brain parenchyma sonography detects preclinical parkinsonism

Substantia nigra (SN) hyperechogenicity on brain parenchyma sonography (BPS) is highly characteristic for idiopathic PD. We studied 7 symptomatic and 7 asymptomatic parkin mutation carriers (PMC) from a large kindred with adult‐onset parkinsonism. BPS revealed larger SN echogenic sizes in PMC with parkin mutations on both alleles (homozygous, compound‐heterozygous), compared to PMC with only one mutated allele (Mann–Whitney U test, P = 0.007). In symptomatic PMC, larger SN echogenic size was correlated with younger age at onset of the disease (Spearman rank correlation, Rho = −0.937, P = 0.002) but not with age, disease duration, or disease severity. BPS demonstrated SN hyperechogenicity, in concordance with abnormal nigrostriatal 18F‐dopa positron emission tomography (PET), in all symptomatic and 3 asymptomatic PMC. In 2 asymptomatic PMC, PET and BPS were normal. However, in another 2 asymptomatic PET‐normal PMC, SN hyperechogenicity could be detected. Data suggest SN hyperechogenicity as an early marker to detect preclinical parkinsonism.

[18F]fluorodopa uptake in the upper brainstem measured with positron emission tomography correlates with decreased REM sleep duration in early Parkinson's disease

Sleep disturbances are common in patients with Parkinsons disease (PD). Previous studies have shown alterations of polysomnographic sleep parameters in PD, such as overall diminution of slow-wave and REM sleep duration, absence of muscle atonia during REM and increased occurrence of periodic leg movements during sleep. The pathogenesis of sleep dysregulation in PD is unknown. The aim of this study was to determine relations of abnormal polysomnographic sleep parameters and the dopaminergic function of the striatum and the upper brainstem measured with the use of positron emission and magnetic resonance tomography in 10 early-stage PD patients with a history of sleep disturbances. Our data demonstrated a significant inverse correlation of absolute and percentage REM sleep duration with the mesopontine [18F]6-fluorodopa (FDOPA) uptake in PD patients. Therefore, the results point to a REM inhibiting effect of increased monaminergic transmission within the upper brainstem in early-stage PD. This finding emphasises the pathophysiological significance of a disturbed neurotransmitter equilibrium in the rostral brainstem for REM sleep alterations in PD.

Molecular and functional imaging technology for the development of efficient treatment strategies for gliomas.

Gliomas are the most common types of brain tumors, which invariably lead to death over months or years. Before new and potentially more effective treatment strategies, such as gene therapy, can be effectively introduced into clinical application the following goals must be reached: (1) the determination of localization, extent and metabolic activity of the glioma; (2) the assessment of functional changes within the surrounding brain tissue; (3) the identification of genetic changes on the molecular level leading to disease; and in addition (4) a detailed non-invasive analysis of both endogenous and exogenous gene expression in animal models and in the clinical setting. Non-invasive imaging of endogenous gene expression by means of positron emission tomography (PET) may reveal insight into the molecular basis of pathogenesis and metabolic activity of the glioma and the extent of treatment response. When exogenous genes are introduced to serve for a therapeutic function, PET imaging techniques may reveal the assessment of the location, magnitude and duration of therapeutic gene expression and its relation to the therapeutic effect. Here, we review the main principles of PET imaging and its key roles in neurooncology research.

Functional brain imaging in combined motor and sleep disorders

The pathophysiology of sleep-related motor diseases and sleep dysfunction in movement disorders is widely unknown as yet. Functional brain imaging, in particular radioisotope and magnetic resonance techniques, are powerful tools to investigate possible pathomechanisms of combined sleep and motor dysregulation. In patients with Restless legs syndrome (RLS), only a subtle striatal dopamine deficit was found in PET and SPECT despite a good treatment effect of dopaminergic drugs. Functional MRI suggested a central generator of periodic limb movements during sleep (PLMs) in RLS. In contrast, a marked striatal dopamine depletion was demonstrated in patients with REM sleep behaviour disorder (RBD) as the base for the clinical and nosological overlap of RBD with parkinsonian disorders. PET and SPECT also suggested that sleep abnormalities in Parkinsons disease (PD), such as REM sleep diminution or increased PLMs, are indirect manifestations of the primary striatal dopamine deficiency.

Belly dancer's syndrome following central pontine and extrapontine myelinolysis

We report on a woman with delayed‐onset of belly dancers syndrome 5 months after central pontine and extrapontine myelinolysis (CPM/EPM) and severe hyponatriemia. This case demonstrates that basal ganglia lesions in EPM can be the underlying pathoanatomic substrate for the rarely observed belly dancers syndrome. The sequential appearance of extrapyramidal symptoms might reflect an ongoing but ineffective or deficient remyelination process. The presence of CPM/EPM should be considered in patients with involuntary dyskinesias of the abdominal wall.

Relative sparing of the parietal cortex in cerebellar ataxia documented by positron emission tomography

With the intention to assess remote effects of cerebellar dysfunction, 23 patients with inherited or idiopathic cerebellar ataxia were studied with positron emission tomography (PET) and 2[18F]fluoro-2-deoxy-D-glucose (FDG). Eight patients (group 1) suffered from early onset cerebellar ataxia (EOCA, age of symptom onset <20 years), nine patients (group 2) from late onset cerebellar ataxia (LOCA, symptom onset between the ages of 20 and 50), and six patients (group 3) experienced symptom onset beyond the age of 50 years. The pattern of cerebral glucose metabolism in cerebellar ataxia was compared to the results in a control group of 16 healthy subjects. In all patients, a reduction in relative (EOCA, group 1) or absolute (LOCA, groups 2 and 3) values of regional cerebral glucose metabolism (rCMR(glu)) occurred in both cerebellar hemispheres as well as the vermis and both dentate nuclei. In patients from all groups presenting with a clinical syndrome of pure cerebellar ataxia, impairment of regional glucose metabolism also extended to the pontine and brainstem regions. In contrast to this infratentorial reduction of rCMR(glu) in all patients, in those with LOCA, a significant relative increase in rCMR(glu) was present in distinct supratentorial cortical regions, namely the cuneus, the pre-cuneus and the gyrus supramarginalis in the patients of group 2. In group 3, this significant relative increase in rCMR(glu) was restricted to the cuneus. Thus, FDG-PET in patients suffering from cerebellar ataxia shows distinct patterns of altered glucose metabolism which exceed pure cerebellar impairment. Most importantly, FDG-PET yields insight into the influence of cerebellar disease on supratentorial glucose metabolism and documents impairment of supratentorial neuronal function with relative sparing of the parietal cortex.