Joseph C. Masdeu

Practice Guidelines for the Use of Imaging in Transient Ischemic Attacks and Acute Stroke A Report of the Stroke Council, American Heart Association

In the modern clinical setting the practitioner can order a variety of imaging procedures for the evaluation of stroke patients or patients at risk of stroke. New procedures have improved accuracy and lessened invasiveness but increased the complexity of decision making. When all of the standard imaging techniques are available, a sequential choice must be made to optimize diagnostic yield, reduce the risk of harm to the patient, and minimize cost. Difficulties may arise when the practitioner is limited by the choice of diagnostic methods available or cost-containment policies. These guidelines are intended to update clinicians in the use of diagnostic imaging procedures in patients with acute stroke or at high risk of stroke and to provide insight for their sequential use in a hierarchical order of specificity and practicality. The target audience is physicians who care for patients with stroke, including specialists in neurology, neurosurgery, vascular surgery, internal medicine, emergency medicine, critical care medicine, and family medicine. The panel has endeavored to strike a balance between the tertiary care setting and the community hospital, offering practical recommendations that can be implemented in these settings, where most patients with acute stroke are treated. Advanced technology methods, unproved techniques, and clinical research strategies may be mentioned but are not recommended. The first section discusses the diagnostic imaging evaluation of the patient with transient ischemia at high risk of stroke. The second section explains the approach to the patient with acute stroke. The third and fourth sections are complementary, dealing with special conditions such as subarachnoid hemorrhage, arteritis, dural sinus and venous thrombosis, arterial dissection, and spinal cord stroke. Recommendations for procedures in women of child-bearing age and patients intolerant of contrast solutions are also made. These guidelines should be supplemented by consulting the literature citations provided in the reference section. Ultrasonography …

Open-ring imaging sign Highly specific for atypical brain demyelination

Objective: To test the specificity for demyelination of a new neuroimaging sign: contrast enhancement shaped as an open ring or a crescent circumscribed to the white matter. Background: Brain demyelination can cause ring enhancement mimicking neoplasm or infection on CT or MRI. Methods: A MEDLINE search of pathology-proved demyelination yielded 32 illustrated cases of ring-enhancing lesions published between 1981 and 1995. Controls consisted of the same number of published images of neoplasms and infections, pathology proved, and matched by year of publication, and age and gender of the patient. Two neuroradiologists read the images twice independently 1 year apart. Results: Interrater agreement was good (κ = 0.64 and 0.66 for either reading). Test-retest reliability was high (κ = 0.75 and 0.74 for either rater). The open-ring sign clearly distinguished demyelinating lesions from neoplasms and infections. For demyelination versus neoplasm or infection, the specificity of the reading by the first neuroradiologist was 93.8 (95% CI, 86 to 98), and that of the second was 84.4 (95% CI, 74 to 92). The likelihood ratio of demyelination versus neoplasm averaged 5.2, and versus infection, 17.2. That is, if the lesions had the same incidence in the population, in the presence of an open-ring sign demyelination would be five times more likely than neoplasm and 17 times more likely than infection. However, given the much higher incidence of neoplasms and infections, these lesions are still frequently responsible for open-ring enhancement. Conclusions: The open-ring sign is often present in large, contrast-enhancing demyelinating lesions and helps to differentiate them from neoplasms and infections.

Fatigue in multiple sclerosis is associated with the disruption of frontal and parietal pathways

Background Fatigue is one of the most frequent and disturbing symptoms in multiple sclerosis (MS), directly affecting the patient’s quality of life. However, many questions remain unclear regarding the anatomic brain correlate of MS-related fatigue. Objective To assess the relationship between fatigue and white matter lesion location and gray matter atrophy. Methods In this study, 60 patients with MS were evaluated with the Modified Fatigue Impact Scale and magnetic resonance imaging. Location of white matter lesion was analyzed using a voxel-by-voxel lesion probability mapping approach and gray matter atrophy degree and location using an optimized voxel-based morphometry method. Results We found a correlation between lesion load and fatigue score (T2 lesion load: r = 0.415, P = 0.001; T1 lesion load r = 0.328, P = 0.011). Moreover, fatigue correlated with lesions in the right parietotemporal (periatrial area, juxtaventricular white matter deep in the parietal lobe and callosal forceps) and left frontal (middle-anterior corpus callosum, anterior cingulum and centrum semiovale of the superior and middle frontal gyri) white matter regions (P < 0.001 in all cases). Finally, fatigue score significantly correlated with gray matter atrophy in frontal regions, specifically, the left superior frontal gyrus and bilateral middle frontal gyri (P < 0.001 in all cases). Conclusion Our results suggest that the symptom of fatigue is associated with a disruption of brain networks involved in cognitive/attentional processes.

Contribution of white matter lesions to gray matter atrophy in multiple sclerosis: evidence from voxel-based analysis of T1 lesions in the visual pathway.

BACKGROUND The biological basis of gray matter (GM) atrophy in multiple sclerosis is not well understood, but GM damage seems to be the most critical factor leading to permanent disability. OBJECTIVE To assess to what extent white matter (WM) lesions contribute to regional GM atrophy in multiple sclerosis. DESIGN Because optic pathway GM atrophy and optic radiation lesions, rather than being related to each other, could be independent results of the disease, we applied a nonaprioristic WM method to analyze the interrelationships of both phenomena. On a voxel-by-voxel basis, we correlated T1 magnetic resonance imaging-derived lesion probability maps of the entire brain with atrophy of the lateral geniculate nuclei and calcarine/pericalcarine cortices. SETTING Multiple sclerosis center, University of Navarra, Pamplona, Spain. PATIENTS Sixty-one patients with multiple sclerosis. MAIN OUTCOME MEASURE Mapping of WM regions contributing to GM atrophy in the optic pathway. RESULTS Patients with multiple sclerosis had lateral geniculate nucleus atrophy, which correlated with the presence of lesions specifically in the optic radiations but not in the rest of the brain. Optic pathway lesions explained up to 28% of the change of variance in lateral geniculate nucleus atrophy. Patients also had occipital cortex atrophy, which did not correlate with lesions in the optic radiations or any other WM region. CONCLUSIONS Focal WM damage is associated with upstream GM atrophy, suggesting that retrograde damage of the perikarya from axonal injury in multiple sclerosis plaques is one of the significant factors in the genesis of GM atrophy, although other neurodegenerative processes are probably at work as well.

Serum IgG Antibodies Against the NR1 Subunit of the NMDA Receptor Not Detected in Schizophrenia

To the Editor: A consensus exists that schizophrenia is not a single disease, but the final pathway of a variety of still unknown neurobiological derangements. Recently, several treatable autoimmune brain disorders have been identified presenting with psychotic symptoms that, in some cases, resemble those found in schizophrenia (1). Antibodies target synaptic proteins, interrupting synaptic transmission in brain networks supporting cognition and emotion. Particularly relevant are auto-antibodies against the NR1 subunit of the N-acetyl methyl D-aspartate receptor (NMDAR), which result in diminished NMDAR activity, now considered a hallmark of schizophrenia (2). In patients harboring these antibodies, initial psychiatric symptoms are usually followed by dyskinetic movements or seizures and decreased respiratory drive, with a reduced level of consciousness, often requiring intensive care (1). However, it could be postulated that a limited form of the disease may result in a milder syndrome, akin to schizophrenia. We tested this hypothesis using sera from patients with their first psychotic episode referred to the regional psychiatric center of the province of Alava, Spain, and from healthy controls. All were enrolled after written informed consent according to protocols approved by the local IRB. Blood was drawn and sera were frozen for subsequent study, blinded to patient-control status. After a one-year follow up, sera of patients who then met DSM-IV-TR criteria for schizophrenia-spectrum disorders were tested for antibodies to NR1 and other cell surface antigens using three criteria (immunohistochemistry on rat brain slices and dissociated rodent hippocampal neurons, and a cell-based assay in which HEK cells recombinantly express NMDAR), as previously reported (1). Patients (n=80) and healthy controls (n=40) did not differ statistically in age (29.4±9.9 and 30.7±9.4 years), or sex (28 and 38 percent women). Anti-NR1 IgG antibodies were not detected in either group. Both had four cases with sera reactive to other, still unidentified, neuronal surface antigens. Our findings and a study of seven patients with schizophrenia (3) fail to support the hypothesis that NMDAR IgG antibodies are present in the sera of patients with schizophrenia. Although another study (4) did report NMDAR antibodies in the sera of some schizophrenia patients, it was performed without a control group and test specificity was lower (only one of the above criteria was applied); differences in the clinical diagnosis could also explain the discrepant findings. It should be noted, however, that our study does not rule out that some patients could have antibodies only in cerebrospinal fluid, but not in serum (1). Additionally, antibodies could be present in patients with acute psychosis not meeting DSM-IV diagnostic criteria at one-year.

The open ring. A new imaging sign in demyelinating disease.

Because demyelinating disease of the brain occasionally presents with large ring‐enhancing lesions on computed tomography (CT) scans and magnetic resonance images (MRis), the authors sought to determine whether the ring pattern differed from that found in other common brain lesions with ring enhancement. Published MRI and CT scans of patients with adrenoleukodystrophy (23), and multiple sclerosis or similar demyelinating disorders (21), as well as a variety of tumors (44) and infections (44) matched to the demyelinating lesions by year of publication, in which ring enhancement was evident, were photographed. Photographs without diagnostic identification were presented randomly to two independent observers. The observers rated the contrast enhancement pattern as (1) open ring, with enhancement in the border of the lesion abutting the white matter; (2) closed ring; or (3) uncertain. For all diagnostically certain cases (n = 112), interrater agreement was excellent (κ = 0.75). As an average of the two reviewers, scans for 11 of 132 cases were read as uncertain; 89% of adrenoleukodystrophy cases, 41% of the multiple sclerosis cases, 3% of tumors, and 9% of infections were classified as having the open‐ring pattern. Overall, 66% of demyelinating lesions had an open‐ring pattern compared with 7% of the nondemyelinating lesions (χ2 = 41.2, p < 0.0001 ). An open‐ring pattern of enhancement is more likely to be associated with demyelinating lesions than with nondemyelinating lesions .

Fractal dimension and white matter changes in multiple sclerosis

The brain white matter (WM) in multiple sclerosis (MS) suffers visible and non-visible (normal-appearing WM (NAWM)) changes in conventional magnetic resonance (MR) images. The fractal dimension (FD) is a quantitative parameter that characterizes the morphometric variability of a complex object. Our aim was to assess the usefulness of FD analysis in the measurement of WM abnormalities in conventional MR images in patients with MS, particularly to detect NAWM changes. First, we took on a voxel-based morphometry approach optimized for MS to obtain the segmented brain. Then, the FD of the whole grey-white matter interface (WM border) and skeletonized WM was calculated in patients with MS and healthy controls. To assess the FD of the NAWM, we focused our analysis on single sections without lesions at the centrum semiovale level. We found that patients with MS had a significant decrease in the FD of the entire brain WM compared with healthy controls. Such a decrease of the FD was detected not only on MR image sections with MS lesions but also on single sections with NAWM. Taken together, the results showed that FD identifies changes in the brain of patients with MS, including in NAWM, even at an early phase of the disease. Thus, FD might become a useful marker of diffuse damage of the central nervous system in MS.

Incidence of seizures with phenytoin toxicity

Among 50 patients with phenytoin intoxication, 14 had seizures during the episode. Seizures in 9 of these 14 patients probably resulted from poor seizure control despite high phenytoin levels, but in 5 cases, attacks were attributed to phenytoin toxicity. The only factor that seemed to correlate with seizures was a serum phenytoin level over 30 μg/ml. No demographic, metabolic, neuropsychiatric, or therapeutic variables were predictive; nor were any other symptoms of toxicity particularly likely to be found in association with seizures. Seizures are an occasional manifestation of phenytoin toxicity, particularly when levels are high.

Mapping the brain pathways of declarative verbal memory: Evidence from white matter lesions in the living human brain.

Understanding the contribution of the brain white matter pathways to declarative verbal memory processes has been hindered by the lack of an adequate model in humans. An attractive and underexplored approach to study white matter region functionality in the living human brain is through the use of non-aprioristic models which specifically search disrupted white matter pathways. For this purpose, we employed voxel-based lesion-function mapping to correlate white matter lesions on the magnetic resonance images of 46 multiple sclerosis patients with their performance on declarative verbal memory storage and retrieval. White matter correlating with storage was in the temporal lobe-particularly lateral to the hippocampus and in the anterior temporal stem-, in the thalamic region and in the anterior limb of the internal capsule, all on the left hemisphere, and also in the right anterior temporal stem. The same volumes were relevant for retrieval, but to them were added temporo-parieto-frontal paramedian bundles, particularly the cingulum and the fronto-occipital fasciculus. These 3D maps indicate the white matter regions most critically involved in declarative verbal memory in humans.

The neurobiology of glucocerebrosidase-associated parkinsonism: a positron emission tomography study of dopamine synthesis and regional cerebral blood flow.

Mutations in GBA, the gene encoding glucocerebrosidase, the enzyme deficient in Gaucher disease, are common risk factors for Parkinson disease, as patients with Parkinson disease are over five times more likely to carry GBA mutations than healthy controls. Patients with GBA mutations generally have an earlier onset of Parkinson disease and more cognitive impairment than those without GBA mutations. We investigated whether GBA mutations alter the neurobiology of Parkinson disease, studying brain dopamine synthesis and resting regional cerebral blood flow in 107 subjects (38 women, 69 men). We measured dopamine synthesis with (18)F-fluorodopa positron emission tomography, and resting regional cerebral blood flow with H(2)(15)O positron emission tomography in the wakeful, resting state in four study groups: (i) patients with Parkinson disease and Gaucher disease (n = 7, average age = 56.6 ± 9.2 years); (ii) patients with Parkinson disease without GBA mutations (n = 11, 62.1 ± 7.1 years); (iii) patients with Gaucher disease without parkinsonism, but with a family history of Parkinson disease (n = 14, 52.6 ± 12.4 years); and (iv) healthy GBA-mutation carriers with a family history of Parkinson disease (n = 7, 50.1 ± 18 years). We compared each study group with a matched control group. Data were analysed with region of interest and voxel-based methods. Disease duration and Parkinson disease functional and staging scores were similar in the two groups with parkinsonism, as was striatal dopamine synthesis: both had greatest loss in the caudal striatum (putamen Ki loss: 44 and 42%, respectively), with less reduction in the caudate (20 and 18% loss). However, the group with both Parkinson and Gaucher diseases showed decreased resting regional cerebral blood flow in the lateral parieto-occipital association cortex and precuneus bilaterally. Furthermore, two subjects with Gaucher disease without parkinsonian manifestations showed diminished striatal dopamine. In conclusion, the pattern of dopamine loss in patients with both Parkinson and Gaucher disease was similar to sporadic Parkinson disease, indicating comparable damage in midbrain neurons. However, H(2)(15)O positron emission tomography studies indicated that these subjects have decreased resting activity in a pattern characteristic of diffuse Lewy body disease. These findings provide insight into the pathophysiology of GBA-associated parkinsonism.