Kai Kallenberg

Updated clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease

Several molecular subtypes of sporadic Creutzfeldt–Jakob disease have been identified and electroencephalogram and cerebrospinal fluid biomarkers have been reported to support clinical diagnosis but with variable utility according to subtype. In recent years, a series of publications have demonstrated a potentially important role for magnetic resonance imaging in the pre-mortem diagnosis of sporadic Creutzfeldt–Jakob disease. Magnetic resonance imaging signal alterations correlate with distinct sporadic Creutzfeldt–Jakob disease molecular subtypes and thus might contribute to the earlier identification of the whole spectrum of sporadic Creutzfeldt–Jakob disease cases. This multi-centre international study aimed to provide a rationale for the amendment of the clinical diagnostic criteria for sporadic Creutzfeldt–Jakob disease. Patients with sporadic Creutzfeldt–Jakob disease and fluid attenuated inversion recovery or diffusion-weight imaging were recruited from 12 countries. Patients referred as ‘suspected sporadic Creutzfeldt–Jakob disease’ but with an alternative diagnosis after thorough follow up, were analysed as controls. All magnetic resonance imaging scans were assessed for signal changes according to a standard protocol encompassing seven cortical regions, basal ganglia, thalamus and cerebellum. Magnetic resonance imaging scans were evaluated in 436 sporadic Creutzfeldt–Jakob disease patients and 141 controls. The pattern of high signal intensity with the best sensitivity and specificity in the differential diagnosis of sporadic Creutzfeldt–Jakob disease was identified. The optimum diagnostic accuracy in the differential diagnosis of rapid progressive dementia was obtained when either at least two cortical regions (temporal, parietal or occipital) or both caudate nucleus and putamen displayed a high signal in fluid attenuated inversion recovery or diffusion-weight imaging magnetic resonance imaging. Based on our analyses, magnetic resonance imaging was positive in 83% of cases. In all definite cases, the amended criteria would cover the vast majority of suspected cases, being positive in 98%. Cerebral cortical signal increase and high signal in caudate nucleus and putamen on fluid attenuated inversion recovery or diffusion-weight imaging magnetic resonance imaging are useful in the diagnosis of sporadic Creutzfeldt–Jakob disease. We propose an amendment to the clinical diagnostic criteria for sporadic Creutzfeldt–Jakob disease to include findings from magnetic resonance imaging scans.

Comparison of Perfusion Computed Tomography and Computed Tomography Angiography Source Images With Perfusion-Weighted Imaging and Diffusion-Weighted Imaging in Patients With Acute Stroke of Less Than 6 Hours’ Duration

Background and Purpose— We aimed to determine the diagnostic value of perfusion computed tomography (PCT) and CT angiography (CTA) including CTA source images (CTA-SI) in comparison with perfusion-weighted magnetic resonance imaging (MRI) (PWI) and diffusion-weighted MRI (DWI) in acute stroke <6 hours. Methods— Noncontrast-enhanced CT, PCT, CTA, stroke MRI, including PWI and DWI, and MR angiography (MRA), were performed in patients with symptoms of acute stroke lasting <6 hours. We analyzed ischemic lesion volumes on patients’ arrival as shown on NECT, PCT, CTA-SI, DWI, and PWI (Wilcoxon, Spearman, Bland–Altman) and compared them to the infarct extent as shown on day 5 NECT. Results— Twenty-two stroke patients underwent CT and MRI scanning within 6 hours. PCT time to peak (PCT-TTP) volumes did not differ from PWI-TTP (P =0.686 for patients who did not undergo thrombolysis/ P =0.328 for patients who underwent thrombolysis), nor did PCT cerebral blood volume (PCT-CBV) differ from PWI-CBV (P =0.893/ P =0.169). CTA-SI volumes did not differ from DWI volumes (P =0.465/ P =0.086). Lesion volumes measured in PCT maps significantly correlated with lesion volumes on PWI (P =0.0047, r =1.0/ P =0.0019, r =0.897 for TTP; P =0.0054, r =0.983/ P =0.0026, r =0.871 for CBV). Also, PCT-CBV lesion volumes significantly correlated with follow-up CT lesion volumes (P =0.0047, r =1.0/ P =0.0046, r =0.819). Conclusions— In hyperacute stroke, the combination of PCT and CTA can render important diagnostic information regarding the infarct extent and the perfusion deficit. Lesions on PCT-TTP and PCT-CBV do not differ from lesions on PWI-TTP and PWI-CBV; lesions on CTA source images do not differ from lesions on DWI. The combination of noncontrast-enhanced CT (NECT), perfusion CT (PCT), and CT angiography (CTA) can render additional information within <15 minutes and may help in therapeutic decision-making if PWI and DWI are not available or cannot be performed on specific patients.

Magnetic resonance imaging evidence of cytotoxic cerebral edema in acute mountain sickness.

The present study applied T2- and diffusion-weighted magnetic resonance imaging to examine if mild cerebral edema and subsequent brain swelling are implicated in the pathophysiology of acute mountain sickness (AMS). Twenty-two subjects were examined in normoxia (21% O2), after 16 hours passive exposure to normobaric hypoxia (12% O2) corresponding to a simulated altitude of 4,500 m and after 6 hours recovery in normoxia. Clinical AMS was diagnosed in 50% of subjects during hypoxia and corresponding headache scores were markedly elevated (P < 0.05 versus non-AMS). Hypoxia was associated with a mild increase in brain volume (+ 7.0 ± 4.8 ml, P < 0.05 versus preexposure baseline) that resolved during normoxic recovery. Hypoxia was also associated with an increased T2 relaxation time (T2rt) and a general trend toward an increased apparent diffusion coefficient (ADC). During the normoxic recovery, brain volume and T2rt recovered to pre-exposure baseline values, whereas a more marked reduction in ADC in the splenium of the corpus callosum (SCC) was observed (P < 0.05). While changes in brain volume and T2rt were not selectively different in AMS, ADC values were consistently lower (P < 0.05 versus non-AMS) and associated with the severity of neurologic symptoms. Acute mountain sickness was also characterized by an increased brain to intracranial volume ratio (P < 0.05 versus non-AMS). These findings indicate that mild extracellular vasogenic edema contributes to the generalized brain swelling observed at high altitude, independent of AMS. In contrast, intracellular cytotoxic edema combined with an anatomic predisposition to a ‘tight-fit’ brain may prove of pathophysiologic significance, although the increase in brain volume in hypoxia was only about 0.5% of total brain volume.

MRI lesion profiles in sporadic Creutzfeldt–Jakob disease

Background: With respect to sporadic Creutzfeldt–Jakob disease (sCJD), six molecular subtypes (MM1, MM2, MV1, MV2, VV1, and VV2) have been described, which vary with respect to age at disease onset, disease duration, early symptoms, and neuropathology. MRI signal alterations were reported to correlate with distinct Creutzfeldt–Jakob disease (CJD) subtypes. This multicenter, international study aimed to describe the brain MRI findings associated with each of the sCJD molecular subtypes. Methods: Pathologically confirmed sCJD cases with codon 129 genotype (MM, MV, and VV), PrPSc type, and fluid-attenuated inversion recovery (FLAIR) or diffusion-weighted imaging (DWI) were collected in seven countries. All MRI scans were assessed for signal changes according to a standard protocol encompassing seven cortical regions, basal ganglia, thalamus, and cerebellum. Results: MRI scans were evaluated in 211 CJD patients (98 MM1, 23 MM2, 19 MV1, 30 MV2, 9 VV1, and 32 VV2). Basal ganglia hyperintensities occurred most frequently in MV2, VV2, and MM1 subtypes (79, 77, and 70%). Wide cerebral cortical signal increase was most common in VV1, MM2, and MV1 subtypes (86, 77, and 77%). Thalamic hyperintensities occurred most often in VV2 (45%) and MV2 (43%). The most consistent finding across most subtypes was high signal in basal ganglia, with these abnormalities found in 63% (FLAIR) and 71% (DWI). Conclusion: Cortical signal increase and hyperintensities in the basal ganglia and thalamus are detected by MRI across all molecular sporadic Creutzfeldt–Jakob disease subtypes. Our findings argue that characteristic MRI lesion patterns may occur for each molecular subtype.

Free Radical-Mediated Damage to Barrier Function is not Associated with Altered Brain Morphology in High-Altitude Headache:

The present study combined molecular and neuroimaging techniques to examine if free radical-mediated damage to barrier function in hypoxia would result in extracellular edema, raise intracranial pressure (ICP) and account for the neurological symptoms typical of high-altitude headache (HAH) also known as acute mountain sickness (AMS). Twenty-two subjects were randomly exposed for 18 h to 12% (hypoxia) and 21% oxygen (O2 (normoxia)) for collection of venous blood (0 h, 8 h, 15 h, 18 h) and CSF (18 h) after lumbar puncture (LP). Electron paramagnetic resonance (EPR) spectroscopy identified a clear increase in the blood and CSF concentration of O2 and carbon-centered free radicals (P > 0.05 versus normoxia) subsequently identified as lipid-derived alkoxyl (LO•) and alkyl (LC•) species. Magnetic resonance imaging (MRI) demonstrated a mild increase in brain volume (7.0 ± 4.8mL or 0.6% ± 0.4%, P > 0.05 versus normoxia) that resolved within 6 h of normoxic recovery. However, there was no detectable evidence for gross barrier dysfunction, elevated lumbar pressures, T2 prolongation or associated neuronal and astroglial damage. Clinical AMS was diagnosed in 50% of subjects during the hypoxic trial and corresponding headache scores were markedly elevated (P > 0.05 versus non-AMS). A greater increase in brain volume was observed, though this was slight, independent of oxidative stress, barrier dysfunction, raised lumbar pressure, vascular damage and measurable evidence of cerebral edema and only apparent in the most severe of cases. These findings suggest that free-radical-mediated vasogenic edema is not an important pathophysiological event that contributes to the mild brain swelling observed in HAH.

High-resolution maps of magnetization transfer with inherent correction for RF inhomogeneity and T1 relaxation obtained from 3D FLASH MRI

An empirical equation for the magnetization transfer (MT) FLASH signal is derived by analogy to dual‐excitation FLASH, introducing a novel semiquantitative parameter for MT, the percentage saturation imposed by one MT pulse during TR. This parameter is obtained by a linear transformation of the inverse signal, using two reference experiments of proton density and T1 weighting. The influence of sequence parameters on the MT saturation was studied. An 8.5‐min protocol for brain imaging at 3 T was based on nonselective sagittal 3D‐FLASH at 1.25 mm isotropic resolution using partial acquisition techniques (TR/TE/α = 25ms/4.9ms/5° or 11ms/4.9ms/15° for the T1 reference). A 12.8 ms Gaussian MT pulse was applied 2.2 kHz off‐resonance with 540° flip angle. The MT saturation maps showed an excellent contrast in the brain due to clearly separated distributions for white and gray matter and cerebrospinal fluid. Within the limits of the approximation (excitation <15°, TR/T1 ≪ 1) the MT term depends mainly on TR, the energy and offset of the MT pulse, but hardly on excitation and T1 relaxation. It is inherently compensated for inhomogeneities of receive and transmit RF fields. The MT saturation appeared to be a sensitive parameter to depict MS lesions and alterations of normal‐appearing white matter. Magn Reson Med 60:1396–1407, 2008.

Voluntary pelvic floor muscle control--an fMRI study.

Storage and periodic expulsion of urine by the bladder are controlled by central pathways and organized as simple on-off switching circuits. Several reports concerning aspects of micturition control have identified distinct regions in the brainstem, like the pontine micturition center (PMC) and the periaqueductal gray (PAG), as well as the cerebellum, basal ganglia, limbic system, and cortical areas that are organized in a widespread network. The present study focused on the involvement of these specific brain regions in pelvic floor muscle control. Functional magnetic resonance imaging (fMRI) was performed at 3T in 11 healthy women with urge to void due to a filled bladder, who were instructed to either imitate voiding by releasing or to imitate interruption of voiding by contracting pelvic floor muscles. None of the subjects was able to start voiding during the experiments, presumably due to subconscious restraint resulting from the inconvenient situation. Relaxation and contraction of pelvic floor muscles induced strong and similar activation patterns including frontal cortex, sensory-motor cortex, cerebellum, and basal ganglia. Furthermore, well-localized activations in the PMC and the PAG were identified. To our knowledge, this is the first study using fMRI to demonstrate micturition-related activity in these brainstem structures. The presented approach proved to characterize the widespread central network in pelvic floor muscle control. Thus, in patients with voiding dysfunction, fMRI will be useful to elucidate the individual disturbance level.

Diagnosing cerebral aneurysms by computed tomographic angiography: Meta‐analysis

Cerebral aneurysms can cause substantial morbidity and mortality, specifically if they rupture, leading to nontraumatic subarachnoid hemorrhage (SAH). This meta‐analysis summarizes evidence about the accuracy of noninvasive computed tomographic (CT) angiography for diagnosing intracranial aneurysms in symptomatic patients.

Sporadic Creutzfeldt–Jakob disease Clinical and diagnostic characteristics of the rare VV1 type

Background: Recently, six molecular subtypes of sporadic CJD (sCJD) have been identified showing differences regarding the disease course, neuropathologic lesion patterns, and sensitivity to diagnostic tools. Only isolated cases of the rare VV1 type have been reported so far. Objective: To describe the clinical characteristics and neuropathologic lesion profiles in nine cases. Methods: In the years 1993 until late 2003, 571 definite neuropathologically confirmed cases of sporadic CJD were identified in Germany. Of these, nine were homozygous for valine and displayed type 1 of the pathologic PrPSc in the brain (VV1 type). Results: The authors describe eight men and one woman belonging to the VV1 type. All patients were relatively young at disease onset (median 44 years vs 65 years in all sCJD) with prolonged disease duration (median 21 months vs 6 months in all sCJD). During the initial stages, their main clinical signs were personality changes and slowly progressive dementia as well as focal neurologic deficits. None of the nine VV1 patients had periodic sharp-wave complexes (PSWCs) in the EEG. Only two out of seven displayed the typical signal increase of the basal ganglia on MRI, whereas signal increase of the cortex was seen in all patients. The 14-3-3 protein levels were elevated in CSF in all cases tested. Conclusions: The clinical diagnosis of the VV1 type of sCJD can be best supported by the 14-3-3 test and cortical signal increase on MRI. Because of the young age at onset vCJD is sometimes suspected as a differential diagnosis. MRI plays an important role in differentiating these two disease types and should be performed early during the disease course.

Untreated Glioblastoma Multiforme: Increased Myo-inositol and Glutamine Levels in the Contralateral Cerebral Hemisphere at Proton MR Spectroscopy

PURPOSE To use localized in vivo proton magnetic resonance (MR) spectroscopy of the contralateral hemisphere in patients with glioblastoma multiforme (GBM) to detect alterations in cerebral metabolites as potential markers of infiltrating GBM cells. MATERIALS AND METHODS The study was approved by the ethics committee, and written informed consent was obtained. Twenty-two patients with newly diagnosed and untreated GBM underwent in vivo single-voxel short echo time proton MR spectroscopy with a 3-T MR imaging system. Absolute metabolite concentrations in the hemisphere contralateral to the tumor were compared with data from five patients with low-grade gliomas (LGGs) and from a group of 14 age-matched control subjects by using analysis of variance and subsequent t tests or corresponding nonparametric tests. RESULTS In the contralateral hemisphere, MR spectroscopy revealed increased concentrations of myo-inositol and glutamine. Mean myo-inositol levels were significantly increased in patients with GBM (3.6 mmol/L +/- 0.8 [standard deviation]) relative to levels in control subjects (3.1 mmol/L +/- 0.6; P = .03) and tended to be higher relative to levels in patients with LGG (2.7 mmol/L +/- 0.8; P = .09). Mean glutamine concentrations in patients with GBM (3.4 mmol/L +/- 0.9) differed significantly from those in control subjects (2.7 mmol/L +/- 0.7; P = .01); mean concentrations in patients with GBM differed from those in patients with LGG (2.4 mmol/L +/- 0.5; P = .01). There were no significant differences between data in patients with LGG and in control subjects. CONCLUSION Increased concentrations of myo-inositol and glutamine in the contralateral normal-appearing white matter of GBM patients are consistent with mild astrocytosis and suggest the detectability of early neoplastic infiltration by using proton MR spectroscopy in vivo.