Peter Raab

Multimodality Assessment of Brain Tumors and Tumor Recurrence

Neuroimaging plays a significant role in the diagnosis of intracranial tumors, especially brain gliomas, and must consist of an assessment of location and extent of the tumor and of its biologic activity. Therefore, morphologic imaging modalities and functional, metabolic, or molecular imaging modalities should be combined for primary diagnosis and for following the course and evaluating therapeutic effects. MRI is the gold standard for providing detailed morphologic information and can supply some additional insights into metabolism (MR spectroscopy) and perfusion (perfusion-weighted imaging) but still has limitations in identifying tumor grade, invasive growth into neighboring tissue, and treatment-induced changes, as well as recurrences. These insights can be obtained by various PET modalities, including imaging of glucose metabolism, amino acid uptake, nucleoside uptake, and hypoxia. Diagnostic accuracy can benefit from coregistration of PET results and MRI, combining the high-resolution morphologic images with the biologic information. These procedures are optimized by the newly developed combination of PET and MRI modalities, permitting the simultaneous assessment of morphologic, functional, metabolic, and molecular information on the human brain.

Longitudinal extensive transverse myelitis—it's not all neuromyelitis optica

Longitudinal extensive transverse myelitis (LETM) is defined as a spinal cord lesion that extends over three or more vertebrae, as seen on MRI of the spine. The clinical presentation of a patient with LETM is often dramatic and can consist of paraparesis or tetraparesis, sensory disturbances, and gait, bladder, bowel and/or sexual dysfunction. LETM is a characteristic feature of neuromyelitis optica, but such spinal lesions can also occur in various other autoimmune and inflammatory diseases that involve the CNS—such as multiple sclerosis, sarcoidosis or Sjögren syndrome—or in infectious diseases with CNS involvement. Patients with a neoplastic disorder or traumatic spinal cord injury can also present with longitudinal spinal lesions. In this Review, the signs and symptoms that suggest various etiologies and differential diagnoses of LETM are described, and illustrated by educational case studies. The best therapeutic options for patients with each diagnosis are also discussed.

Evidence for neuroinflammation and neuroprotection in HCV infection-associated encephalopathy

Objective Fatigue, mood disturbances and cognitive dysfunction are frequent in patients infected with hepatitis C virus (HCV) who have mild liver disease. The reason is still unclear. The present study aims to gain more insight into the pathomechanism by combining an extensive neuropsychological examination with magnetic resonance spectroscopy in four different brain regions in a patient group covering the whole spectrum of neuropsychiatric findings in patients afflicted with HCV who have only mild liver disease. Methods 53 HCV-positive patients with only mild liver disease and differing degrees of neuropsychiatric symptoms were studied with single-voxel MRS of the parietal white matter, occipital grey matter, basal ganglia and pons. Brain metabolite concentrations were quantitatively analysed by using LCmodel. MRS data were compared to those of 23 healthy controls adjusted for age, and analysed for relationships with the extent of neuropsychiatric symptoms. Results Choline (p=0.02), creatine (p=0.047) and N-acetyl-aspartate plus N-acetyl-aspartyl-glutamate (NN, p=0.02) concentrations in the basal ganglia and choline concentrations in the white matter (p=0.045) were significantly higher in the patients than in controls. Interestingly, the difference was most evident for the patients with low fatigue scores (eg, white matter: choline: p=0.001, creatine: p=0.003, NN: p=0.031). Myo-inositol differed significantly between groups in the white (p=0.001) and grey matter (p=0.003). Fatigue correlated negatively with white matter NN, choline and creatine and myo-inositol levels in white and grey matter and basal ganglia (p<0.01). Conclusion As the increase of choline, creatine and myo-inositol are usually interpreted to indicate glial activation and macrophage infiltration in chronic inflammation and slow virus infections of the brain the present data endorse the hypothesis, that HCV infection may induce neuroinflammation and brain dysfunction. The concomitant increase of NN and the negative correlation to the extent of fatigue suggest a cerebral compensatory process after HCV infection.

Anti-leucine rich glioma inactivated 1 protein and anti-N-methyl-D-aspartate receptor encephalitis show distinct patterns of brain glucose metabolism in 18F-fluoro-2-deoxy-d-glucose positron emission tomography.

BackgroundPathogenic autoantibodies targeting the recently identified leucine rich glioma inactivated 1 protein and the subunit 1 of the N-methyl-D-aspartate receptor induce autoimmune encephalitis. A comparison of brain metabolic patterns in 18F-fluoro-2-deoxy-d-glucose positron emission tomography of anti-leucine rich glioma inactivated 1 protein and anti-N-methyl-D-aspartate receptor encephalitis patients has not been performed yet and shall be helpful in differentiating these two most common forms of autoimmune encephalitis.MethodsThe brain 18F-fluoro-2-deoxy-d-glucose uptake from whole-body positron emission tomography of six anti-N-methyl-D-aspartate receptor encephalitis patients and four patients with anti-leucine rich glioma inactivated 1 protein encephalitis admitted to Hannover Medical School between 2008 and 2012 was retrospectively analyzed and compared to matched controls.ResultsGroup analysis of anti-N-methyl-D-aspartate encephalitis patients demonstrated regionally limited hypermetabolism in frontotemporal areas contrasting an extensive hypometabolism in parietal lobes, whereas the anti-leucine rich glioma inactivated 1 protein syndrome was characterized by hypermetabolism in cerebellar, basal ganglia, occipital and precentral areas and minor frontomesial hypometabolism.ConclusionsThis retrospective 18F-fluoro-2-deoxy-d-glucose positron emission tomography study provides novel evidence for distinct brain metabolic patterns in patients with anti-leucine rich glioma inactivated 1 protein and anti-N-methyl-D-aspartate receptor encephalitis.

Association of Molecular Markers With Perihematomal Edema and Clinical Outcome in Intracerebral Hemorrhage

Background and Purpose— Perihematomal edema contributes to secondary brain injury in intracerebral hemorrhage (ICH). Increase of matrix metalloproteinases (MMPs) and growth factors is considerably involved in blood–brain barrier disruption and neuronal cell death in ICH models. We therefore hypothesized that increased levels of these molecular markers are associated with perihematomal edema and clinical outcome in ICH patients. Methods— Fifty-nine patients with spontaneous ICH admitted within 24 hours of symptom onset were prospectively investigated. Noncontrast CT was performed on admission for diagnosis of ICH and quantification of initial hematoma volume. MRI was performed on day 3 to evaluate perihematomal edema. Concentrations of MMP-3, MMP-9, as well as vascular endothelial growth factor and angiopoietin-1 on admission were determined by enzyme-linked immunosorbent assays. Clinical outcome was assessed by modified Rankin Scale at 90 days. Results— Increased MMP-3 levels were independently associated with perihematomal edema volume (P<0.05). Cytotoxic edema surrounding the hematoma was seen in 36 (61%) cases on 3-day MRI. Cytotoxic edema did not correlate with the level of any of the biomarkers studied. Levels of MMP-3 ≥12.4 ng/mL and MMP-9 ≥192.4 ng/mL but not vascular endothelial growth factor and angiopoietin-1 predicted poor clinical outcome at 90 days (modified Rankin Scale >3) independent of stroke severity and hematoma volume at baseline (odds ratio, 25.3, P=0.035; odds ratio, 68.9, P=0.023; respectively). Conclusions— MMPs 3 and 9 seem to be significantly involved in secondary brain injury and outcome after primary ICH in humans, and thus should be further evaluated as targets for therapeutic strategies in this devastating disorder.

Clinical approach to optic neuritis: pitfalls, red flags and differential diagnosis

Demyelinating optic neuritis (ON) is the most common cause of optic neuropathy typically presenting with a subacute painful visual loss. In 20% of patients with multiple sclerosis (MS), ON is the presenting symptom and half of the patients with isolated ON develop MS within 15 years. The diagnosis of ON plays an important role in neurological practice. A correct and early diagnosis is necessary to ensure optimal further investigations and treatment. Other causes of optic neuropathies such as connective tissue disorders, infectious diseases, tumours or ischaemic neuropathies are less frequent but clinical and therapeutic management can differ dramatically. We present five patients admitted to our hospital with suspected demyelinating ON, but the clinical work up revealed different causes of optic neuropathy. We discuss the differential diagnosis of ON and clinical red flags that require careful diagnostic assessment of other diseases. A workflow for the diagnosis of optic neuropathies is presented.

Neurologic manifestations of E coli infection–induced hemolytic-uremic syndrome in adults

Objective: To describe the neurologic and neuroradiologic complications of Shiga toxin producing Escherichia coli infection (STEC)–associated hemolytic-uremic syndrome (HUS) in adults. Methods: All 52 adult patients with STEC O104:H4 infection cared for at Hannover Medical School during the outbreak in Germany through May–July 2011 are considered in this observational study. Forty-three of the 52 patients underwent a standard neurologic diagnostic procedure including clinical examination, Mini-Mental State Examination, and Glasgow Coma Scale Score. Thirty-six patients underwent EEG, and 26 had cerebral MRI, 9 of them repeatedly. Case records of 9 patients who had not been seen by a neurologist were analyzed retrospectively. Results: Forty-eight of the 52 patients had HUS. All but 1 of these showed neurologic symptoms. Focal neurologic signs like double vision, difficulties in finding words, or hyperreflexia were present in 23, additional deficits in orientation, attention, memory, or constructive abilities in 9, and marked impairment of consciousness in 15. MRI showed brainstem, midbrain, thalamus, corpus callosum, and white matter lesions in half of the patients, predominantly in diffusion-weighted images. The extent of MRI lesions did not correlate with clinical symptoms. General slowing but no focal alteration was found in half of the patients examined by EEG. Conclusion: Our findings suggest a toxic-metabolic pathology behind the neurologic impairment instead of multiple infarction due to microthrombosis. Future studies should aim to clarify if early antibiotic therapy or bowel cleansing might help to decrease the rate of neurologic complications in STEC-HUS.

Cerebral microglia activation in hepatitis C virus infection correlates to cognitive dysfunction.

Hepatitis C virus (HCV) infection may induce chronic fatigue and cognitive dysfunction. Virus replication was proven within the brain and HCV‐positive cells were identified as microglia and astrocytes. We hypothesized that cerebral dysfunction in HCV‐afflicted patients is associated with microglia activation. Microglia activation was assessed in vivo in 22 patients with chronic HCV infection compared to six healthy controls using [11C]‐PK11195 Positron Emission Tomography (PET) combined with magnetic resonance tomography for anatomical localization. Patients were subdivided with regard to their PCR status, Fatigue Impact Scale score (FIS) and attention test sum score (ATS). A total of 12 patients (54.5%) were HCV PCR positive [of which 7 (58.3%) had an abnormal FIS and 7 (58.3%) an abnormal ATS], 10 patients (45.5%) were HCV PCR negative (5 (50%) each with an abnormal FIS or ATS). Patients without attention deficits showed a significantly higher accumulation of [11C]‐PK11195 in the putamen (P = 0.05), caudate nucleus (P = 0.03) and thalamus (P = 0.04) compared to controls. Patients with and without fatigue did not differ significantly with regard to their specific tracer binding in positron emission tomography. Preserved cognitive function was associated with significantly increased microglia activation with predominance in the basal ganglia. This indicates a probably neuroprotective effect of microglia activation in HCV‐infected patients.

Hepatic encephalopathy after treatment with temozolomide.

Temozolomide in combination with radiation has been in use for more than 5xa0years for the therapy of glioblastoma. Known adverse effects concerning the gastrointestinal system are elevation of liver enzymes. We present the case of a patient treated with temozolomide who developed severe cholestatic liver damage and consecutive hepatic encephalopathy. Neurological symptoms were mistaken as being caused by focal brain damage for more than 9xa0months. After the correct diagnosis had been made and the treatment had been started, the patient’s condition ameliorated. In conclusion, neurological deficits in patients with known brain lesion should not be attributed automatically to the pre-existing damage even if it is progressive but should be examined carefully, also including toxic and metabolic encephalopathies into the differential diagnosis. Furthermore, new side effects of drugs have to be considered. At least this case might lead to a closer monitoring of liver enzymes during temozolomide therapy.

McDonald Criteria 2010 and 2005 Compared: Persistence of High Oligoclonal Band Prevalence Despite Almost Doubled Diagnostic Sensitivity

The 2010 McDonald criteria were developed to allow a more rapid diagnosis of relapsing-remitting multiple sclerosis (MS) by only one MRI of the brain. Although cerebrospinal fluid (CSF) is not a mandatory part of the latest criteria, the evidence of an intrathecal humoral immunoreaction in the form of oligoclonal bands (OCB) is crucial in the diagnostic workup. To date, the impact of the 2010 McDonald criteria on the prevalence of OCB has not been investigated. We retrospectively evaluated data of 325 patients with a clinical relapse suggestive of demyelination that were treated in a German university hospital between 2010 and 2015. One hundred thirty-six patients (42%) were diagnosed with MS and 189 patients with CIS when the criteria of 2010 were applied. The criteria of 2005 allowed only 70 patients (22%) to be designated as MS. In contrast, the prevalence of OCB was marginal affected in MS patients with 96% for the criteria of 2010 and 98.5% for the criteria of 2005. In conclusion, OCB are prevalent in most MS patients and reflect the chronic inflammatory nature of the disease. We recommend CSF examination to exclude alternative diagnoses and reevaluation of the diagnosis MS in patients with negative OCB.