Psychological symptoms correlate with reduced hippocampal volume in fragile X premutation carriers.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder occurring in male and occasional female carriers of a premutation expansion (55-200 CGG repeats) of the fragile X mental retardation 1 gene (FMR1). This study assessed the relationship between hippocampal volume and psychological symptoms in carriers, both with and without FXTAS, and controls. Volumetric MRI measures, clinical staging, cognitive testing, molecular analysis, and measures of psychological symptoms were performed for female premutation carriers both with FXTAS (n = 16, age: 57.50 + or - 12.46) and without FXTAS (n = 17, age: 44.94 + or - 11.23), in genetically normal female controls (n = 8, age: 50.63 + or - 11.43), male carriers with FXTAS (n = 34, age: 66.44 + or - 6.77) and without FXTAS (n = 21, age: 52.38 + or - 12.11), and genetically normal male controls (n = 30, age: 57.20 + or - 14.12). We examined the relationship between psychological symptom severity and hippocampal volume, as well as correlations with molecular data. We found a significant negative correlation between total hippocampal volume and anxiety in female carriers, with and without FXTAS. This finding was mainly driven by the significant negative correlation between right hippocampal volume and anxiety. Other anxiety-related subscales also correlated with the right hippocampus in females. In male carriers with and without FXTAS, only paranoid ideation negatively correlated with hippocampal volume. Female premutation carriers demonstrated a negative association between hippocampal volume and the severity of anxiety-related psychological symptoms. Though the presentation of FXTAS symptoms is less common in females, anxiety-related problems are common both prior to and after the onset of FXTAS, and may be related to hippocampal changes.

Neuropathology of fragile X-associated tremor/ataxia syndrome (FXTAS).

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder that affects carriers, principally males, of premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. Clinical features of FXTAS include progressive intention tremor and gait ataxia, accompanied by characteristic white matter abnormalities on MRI. The neuropathological hallmark of FXTAS is an intranuclear inclusion, present in both neurons and astrocytes throughout the CNS. Prior to the current work, the nature of the associations between inclusion loads and molecular measures (e.g. CGG repeat) was not defined. Post-mortem brain and spinal cord tissue has been examined for gross and microscopic pathology in a series of 11 FXTAS cases (males, age 67-87 years at the time of death). Quantitative counts of inclusion numbers were performed in various brain regions in both neurons and astrocytes. Inclusion counts were compared with specific molecular (CGG repeat, FMR1 mRNA level) and clinical (age of onset, age of death) parameters. In the current series, the three most prominent neuropathological characteristics are (i) significant cerebral and cerebellar white matter disease, (ii) associated astrocytic pathology with dramatically enlarged inclusion-bearing astrocytes prominent in cerebral white matter and (iii) the presence of intranuclear inclusions in both brain and spinal cord. The pattern of white matter pathology is distinct from that associated with hypertensive vascular disease and other diseases of white matter. Spongiosis was present in the middle cerebellar peduncles in seven of the eight cases in which those tissues were available for study. There is inclusion formation in cranial nerve nucleus XII and in autonomic neurons of the spinal cord. The most striking finding is the highly significant association between the number of CGG repeats and the numbers of intranuclear inclusions in both neurons and astrocytes, indicating that the CGG repeat is a powerful predictor of neurological involvement in males, both clinically (age of death) and neuropathologically (number of inclusions).

A comparison of the predictive power for survival in gliomas provided by MIB-1, bromodeoxyuridine and proliferating cell nuclear antigen with histopathologic and clinical parameters.

The purpose of this prospective study of 65 patients was to compare side-by-side the predictive power for survival of (a) MIB-1, (b) bromodeoxyuridine (BUDR), and (c) proliferating cell nuclear antigen (PCNA). They were compared (a) with each other, (b) with several clinical predictors, and (c) with histopathologic grade under actual clinical biopsy conditions in a study of 1993 World Health Organization (WHO) grade II to IV adult supratentorial gliomas. There was a strong positive relationship between MIB-1 and BUDR by Spearman Rank correlation. In univariate analysis, MIB-1 (logrank p = 0.06) was more predictive of survival than BUDR or PCNA. Longer survivors were distinguished from others by the lowest MIB-1 labeling indices (LI < or = 2.5%) better than by the lowest histopathologic grade. However, histopathologic grades were highly predictive among the entire group (logrank p < 0.0001). Young age (p < 0.0001) and high Karnofsky performance status (p < 0.0001) were the clinical factors most predictive of longer survival. Female gender correlated with longer survival (logrank p = 0.02). In multivariate Cox proportional hazards models, age, Karnofsky performance status, and histopathologic grading remained statistically significant after full reduction of the model. We conclude that Ki-67 measured by MIB-1 monoclonal antibody was superior to other markers of proliferation. When all factors are considered simultaneously over all 3 grades of malignancy, greatest predictive power resides in histopathologic grade and clinical variables. MIB-1 is expected to be most important in cases where clinical or histopathologic factors are ambiguous or where they cannot be fully assessed.

Ventricular enlargement, neuropsychological status, and premorbid function in schizophrenia.

Ventricular enlargement is one of the most consistently documented neurobiological abnormalities in schizophrenia. The timing of the development of this abnormality in the course of schizophrenic illness and its relationship to neuropsychological dysfunction and premorbid adjustment is, however, unclear. To address these questions, we examined the relationship between ventricle-brain ratio (VBR), premorbid adjustment, and neuropsychological function, in 23 acutely exacerbated chronic schizophrenic inpatients. We observed that larger ventricles were associated with better current neuropsychological test performance, better premorbid cognitive ability, greater cognitive deterioration, better childhood premorbid social function, and greater decline in social function from premorbid levels. These data suggest that at least two developmental processes may operate in the genesis of cognitive and social dysfunction in schizophrenia: (1) childhood onset associated with poor premorbid childhood function, low educational achievement, lower intelligence quotient (IQ) and variably with VBR; and (2) adolescent onset associated with relatively normal childhood social function, higher academic achievement and IQ and increased VBR. Ventricular enlargement may reflect a late developmental or degenerative pathological process in schizophrenia.

Depression in stroke rehabilitation.

Despite recent advances in understanding the pathophysiology of poststroke depression, major questions remain. They include the relative importance of lesion location and size and the confounding effects of time since stroke, age, prior history of depression, and cerebral atrophy. To evaluate these issues, we systematically assessed depressive features, functional status, and brain structure with computer tomography scans in 91 men undergoing stroke rehabilitation. Forty percent met DSM-III criteria for major depressive disorder. Mood disturbance was more severe for patients with right than with left hemisphere lesions, correlated with functional disability and lesion size, and was associated with previous history of depression. Age, time since stroke, and atrophy did not correlate with mood. Depression is common in delayed stroke recovery, regardless of lesion location. Because there are no demographic or anatomic features that predict the absence of depression, depression screening should be part of the assessment of all patients undergoing stroke rehabilitation.

Treatment of Wilson disease with ammonium tetrathiomolybdate. II. Initial therapy in 33 neurologically affected patients and follow-up with zinc therapy.

OBJECTIVE: To test the efficacy and toxic effects of ammonium tetrathiomolybdate in the initial treatment of a relatively large series of patients with neurologic symptoms and signs caused by Wilson disease. Two key aspects of efficacy are to preserve the neurologic function present at the onset of therapy and to maximize the opportunity for long-term recovery. DESIGN: An open study of 33 patients treated for 8 weeks each, including further follow-up data on the original 17 patients. Neurologic function was evaluated by frequent quantitative neurologic and speech pathology examinations. Several copper-related variables were studied to evaluate the effect of the drug on copper, and several biochemical and clinical variables were studied to evaluate potential toxic effects. Patients were then followed up at yearly intervals, with follow-up periods of 1 to 8 years reported. SETTING: A university hospital referral setting. INTERVENTION: Patients were generally treated for 8 weeks with tetrathiomolybdate, followed by zinc maintenance therapy. MAIN OUTCOME MEASURES: Neurologic function was evaluated by quantitative neurologic and motor speech examinations and magnetic resonance imaging scans of the brain. RESULTS: During the 8 weeks of tetrathiomolybdate administration, only 1 of the 33 patients showed deterioration in neurologic function. Copper status and potential further toxic effects were generally well controlled quickly. Evaluation of data from individual patients revealed evidence of a toxic side effect in only 1 patient, who exhibited reversible anemia. During the ensuing period of follow-up of 1 to 6 years, neurologic recovery in most patients was good to excellent. CONCLUSIONS: Tetrathiomolybdate appears to be an excellent form of initial treatment in patients with Wilson disease who present with neurologic symptoms and signs. In contrast to penicillamine therapy, initial treatment with tetrathiomolybdate rarely allows further, often irreversible, neurologic deterioration.

Spinal cord schistosomiasis: a pediatric case mimicking intrinsic cord neoplasm.

We present the clinical, myelographic, MRI, and histologic data on a 7-year-old girl with confirmed Schistosoma mansoni infection of the spinal cord. MRI of the granulomatous spinal lesion revealed extensive enlargement of the cord in the T11-12 area, with some intramedullary swelling extending to T-5 through T-7. The clinical manifestations of spinal schistosomiasis can be diverse, and there should be a high index of suspicion for all patients from endemic areas.

Correlation of evoked potential and MRI findings in Wilson's disease.

We recorded brainstem auditory evoked potentials (BAEPs) and somatosensory evoked potentials to median nerve stimulation (MSEPs) within 10 days of brain MRI in 20 patients with Wilson's disease (WD). MRI was abnormal in 90% of patients, demonstrating symmetric striatum and brainstem lesions with or without thalamic lesions. MSEPs were abnormal in 65% of patients, usually showing bilaterally prolonged N/P13-N20 latencies. BAEPs were abnormal in 40%, most often with bilateral prolongation of the III-V latency. The III-V and N/P13-N20 interpeak latencies correlated significantly with the severity of MRI lesions in the caudal pons, rostral pons, and caudal midbrain. Our results indicate that subclinical sensory dysfunction is common in WD, and that auditory and somatosensory pathways are most severely affected at the brainstem level. Both the localization and severity of evoked potential abnormalities correspond closely to the morphologic changes in the pons and caudal midbrain shown by MRI.

Brain structure and cognition in a community sample of elderly Latinos.

BACKGROUND: Previous studies have found that hippocampal atrophy and white matter hyperintensities (WMH) on MRI are linked to cognitive impairment and dementia. The authors measured these variables in a population-based cohort of older Mexican Americans with a wide spectrum of cognitive ability, ranging from normal cognition to dementia. OBJECTIVE: To investigate whether these structural brain changes were seen in individuals prior to the development of dementia and how these changes were related to the presence of dementia. METHODS: A sample of 122 subjects was selected from the Sacramento Area Latino Study on Aging, and subjects were categorized into four groups of increasing levels of cognitive impairment: normal, memory impaired (MI), cognitively impaired but not demented (CIND), and demented. Hippocampal volume was quantified using a region of interest approach. WMH was rated on a semiquantitative scale as the percent of total volume of white matter. RESULTS: Hippocampal volume was significantly reduced in CIND and demented individuals, and WMH were significantly increased in demented subjects. MI subjects did not have any significant changes in hippocampal volume or WMH. The risk for developing dementia was significantly and comparably increased in subjects with either hippocampal atrophy or high WMH. However, the risk for dementia increased dramatically in subjects with both hippocampal atrophy and a high degree of WMH. CONCLUSION: Reductions in hippocampal volume may be present before dementia but not until cognitive impairment is relatively severe. Because there is a synergistic effect between high WMH and hippocampal atrophy, interactions between vascular and degenerative processes may be important determinants of dementia.

In vivo cerebral metabolism and central benzodiazepine-receptor binding in temporal lobe epilepsy.

Positron emission tomography measured interictal cerebral glucose metabolism with [18F]fluorodeoxyglucose and central benzodiazepine-receptor binding with [11C]flumazenil in 10 mesial temporal lobe epilepsy (TLE) patients and in normal subjects. Eight TLE patients had mesial temporal, lateral temporal, and thalamic hypometabolism ipsilateral to EEG ictal onsets, with additional extratemporal hypometabolism in four. One had unilateral anterior mesial temporal hypometabolism only, and one had normal metabolism. Each patient had decreased benzodiazepine-receptor binding in the ipsilateral anterior mesial temporal region, without neocortical changes. Thus, interictal metabolic dysfunction is variable and usually extensive in TLE, whereas decreased central benzodiazepine-receptor density is more restricted to mesial temporal areas. Metabolic patterns in TLE may reflect diaschisis, while benzodiazepine-receptor changes may reflect localized neuronal and synaptic loss that is specific to the epileptogenic zone. [11C]Flumazenil imaging may be useful in presurgical evaluation of refractory complex partial seizures.

Magnetic resonance imaging in patients with central nervous system pathology: a comparison of OptiMARK (Gd-DTPA-BMEA) and Magnevist (Gd-DTPA).

RATIONALE AND OBJECTIVES: The objective of the two pivotal phase 3 studies was to evaluate the safety and efficacy of OptiMARK (Gd-DTPA-bis(methoxyethylamide) [Gd-DTPA-BMEA]) compared with Magnevist (Gd-DTPA) in magnetic resonance imaging of the central nervous system. METHODS: Two multicenter, randomized, double-blind, parallel group studies were conducted in 395 patients with known or suspected central nervous system pathology. Subjects were randomized to receive a single 0.1 mmol/kg intravenous injection of either Gd-DTPA-BMEA or Gd-DTPA. The safety of Gd-DTPA-BMEA and Gd-DTPA was monitored for up to 72 hours after study drug administration. Precontrast and postcontrast administration magnetic resonance scans were acquired using identical imaging planes and techniques. RESULTS: No deaths or unexpected adverse events were reported in either group. A comparison of adverse events by intensity and relation demonstrated no statistically significant differences between the two groups. Gd-DTPA-BMEA and Gd-DTPA were equivalent with respect to confidence in diagnosis, conspicuity, and border delineation. CONCLUSIONS: Gd-DTPA-BMEA and Gd-DTPA demonstrated comparable efficacy profiles, and the safety profiles were considered similar.

Prevalence of cavum septum pellucidum in schizophrenia studied with MRI.

OBJECTIVE: To study the prevalence of cavum septum pellucidum (CSP), a midline developmental anomaly, in patients with schizophrenia. METHODS: Three-millimeter coronal T1 weighted MRI images of 43 normal controls and 73 patients with schizophrenia were examined. The images were resampled into 1-mm slices and CSP was measured by the number of slices in which it appeared. RESULTS: Patients had significantly higher incidence of CSP (Fisher's exact test 0.042; one-sided). Eighteen (41.9%) of the controls and 44 (60.3%) of patients had a CSP, and one of 46 controls and three of 73 patients had a large CSP of six slices or more. There was no relationship between the presence or size of CSP and regional brain volumes or volumes of hippocampus-amygdala complex, caudate, superior temporal gyrus or ventricular CSF. CONCLUSION: Higher incidence of CSP may reflect a neurodevelopmental disturbance in schizophrenia.

Does neuroanatomy predict ECT response?

1. Structural neuropathologic abnormalities have been associated with severe psychiatric illnesses, including bipolar disorder, major depressive disorder, and schizophrenia. In the latter, ventricular enlargement has been variably associated with symptom severity and poor treatment response. In patients with severe depressive disorders, the relationship between cortical and subcortical pathology and ventricle enlargement, symptom severity, and response to treatment is far from clear. 2. The present study investigated the relationship between structural CNS pathology, symptom severity and treatment response in patients undergoing ECT. It was hypothesized that patients with greater neuroanatomic abnormalities would demonstrate greater initial symptom severity and poorer response to ECT. 3. The subjects were 57 patients with unipolar or bipolar depression admitted for ECT treatment. Symptom severity was quantified using the Hamilton Depression Rating Scale (HRSD) at baseline and post-ECT. 4. Lateral and third ventricle-brain ratio (LVBR, 3VBR) were determined from CT scans and cortical atrophy was rated by a faculty neuroradiologist. 5. Contrary to our first hypothesis, structural pathology was not associated with baseline symptom severity. In terms of treatment response, the number of treatments required to achieve benefit was correlated with larger 3VBR; CT variables were not related to total post-treatment or change in HRSD score. Third ventricle enlargement may be an index of generalized pathology or regional brainstem abnormalities that influence ECT response rate by limiting individual seizure efficacy or neurochemical responsiveness, thereby necessitating a greater number of ECT treatments, without significant impact on overall response.

Postvaricella basal ganglia infarction in children.

Two patients presented with acute neurologic deficits attributable to contralateral basal ganglia infarction 1 to 3 months after episodes of chickenpox. Both presented with hemiparesis with one patient also demonstrating ipsilateral choreoathetosis. In both patients MR revealed unilateral basal ganglia infarction. Cerebral angiography findings in one patient were normal; in the second, there was unilateral narrowing of the common carotid artery and of proximal branches of the anterior and middle cerebral artery.

Gadopentetate dimeglumine-enhanced MR of the brain: clinical utility and safety in patients younger than two years of age.

PURPOSE: To evaluate the clinical utility and safety of gadopentetate dimeglumine as a contrast agent for MR of the brain in patients younger than 2 years of age. METHODS: In 125 consecutive patients younger than 2 years of age, MR images obtained before and after gadopentetate dimeglumine administration (0.1 mmol/kg) were independently and prospectively evaluated. After interpreting the unenhanced T1- and T2-weighted images, we rated the utility of contrast administration in each patient as not helpful, helpful, or essential for formulation of the radiologic diagnosis. Ratings were categorized both on the basis of the referring clinical diagnoses and on the basis of a radiologic diagnosis that was established from the clinical history and from the findings on the precontrast and postcontrast T1- and T2-weighted images. Patients' vital signs were recorded, and general medical status was observed for 120 minutes after gadopentetate dimeglumine administration. RESULTS: In no case did gadopentetate dimeglumine permit detection of lesions when precontrast T1- and T2-weighted images were normal. In only 4 of 125 patients were postcontrast images considered essential for establishing the radiologic diagnosis. Abnormal contrast enhancement was radiologically helpful in 20 of 125 patients. Lack of enhancement was considered helpful in 22 of 125 patients. No adverse clinical events or clinically important trends in vital signs were observed after contrast administration. CONCLUSION: The indiscriminate use of contrast agents in the MR imaging of patients younger than 2 years of age is not warranted. Appropriate decisions regarding the use of gadopentetate dimeglumine can be based on the findings in unenhanced T1- and T2-weighted images and on the referring clinical diagnosis.

Venovenous extracorporeal membrane oxygenation: early CT alterations following use in management of severe respiratory failure in neonates.

PURPOSE: To describe brain CT alterations occurring after neonatal venovenous extracorporeal membrane oxygenation (V-V ECMO). METHODS: CT studies were prospectively obtained after V-V ECMO in 31 neonates with severe respiratory failure. Images were scored for cerebrospinal fluid space size, hemorrhage, and regions of decreased attenuation. RESULTS: Subarachnoid space enlargement at the interhemispheric fissure, frontal, temporal, or parietal convexity occurred in 21 of the 31 patients. When subarachnoid space enlargement was asymmetric (six of the 21), it was always isolated to or greater on the right. Ventricular enlargement was demonstrated in seven of the 31. Hemorrhage occurred in seven and regions of low brain attenuation in 11 of the 31 neonates. CONCLUSIONS: Increased sagittal sinus pressure caused by internal jugular vein ligation and cannulation of the superior vena cava may contribute to subarachnoid space enlargement by decreasing cerebrospinal fluid resorption at the arachnoid villi. Reduced incidence of cerebral hemorrhage with V-V ECMO, as compared with venoarterial (V-A) ECMO, may relate to sparing of the right common carotid artery (it is ligated with V-A ECMO), and to routing of oxygenated blood to the right atrium with V-V ECMO rather than to the arterial circuit as with V-A ECMO.

Chronic acquired hepatic failure: MR imaging of the brain at 1.5 T.

The results of MR imaging of the brain at 1.5 T in 42 adults with non-Wilsonian chronic hepatic failure are reported. T1-weighted images demonstrated increased signal in the globus pallidus in 30 patients and in the putamen in 21, while T2-weighted images demonstrated no corresponding alteration in signal intensity. Symmetric low intensity in the central portion of the globus pallidus on spin-density and T2-weighted images in two patients correlated with regions of calcification on CT scans. Increased intensity on T1-weighted images also occurred in the mesencephalon surrounding the red nucleus (17/42) and in the quadrigeminal plate (4/42). Three patients demonstrated increased intensity in the pons on T2-weighted images unassociated with clinical brainstem dysfunction. Increased intensity on T1-weighted images was seen in the anterior pituitary in 28 of 35 patients. Alterations in signal intensity were not demonstrated in the cerebral cortex or cerebellum. MR findings did not correlate with laboratory indices of hepatic or thyroid function, with histologic liver diagnosis, or with neurologic status at the time of MR evaluation. Increased signal intensity in the basal ganglia, pituitary gland, and mesencephalon surrounding the red nuclei is characteristic of chronic hepatocellular dysfunction. Deposition of an as yet unidentified paramagnetic substance or altered intracellular water relaxation associated with the proliferation of astrocyte cytoplasmic organelles is postulated as the likely mechanism for this previously undescribed MR manifestation of chronic acquired hepatic failure.

Solitary fibrous tumor of the paranasal sinuses: CT and MR appearance.

We describe the CT and MR appearance of a solitary fibrous tumor of the paranasal sinuses with intracranial invasion. The tumor was hypointense on T2-weighted MR images and had a large calcific component that proved to be reactive remodelling of native bone.

Spinal cord infection: myelitis and abscess formation.

PURPOSE: Our purpose was to describe the MR findings and evolution of spinal cord abscess and to define those MR features that allow differentiation of cord infection from other intramedullary abnormalities. METHODS: We retrospectively reviewed the MR studies of all patients in whom intramedullary spinal cord abscess was proved either by blood or cerebrospinal fluid culture or by serologic examination at our institution between January 1988 and January 1996. The study group included four adults and two children, 7 to 74 years old (mean age, 38 years). RESULTS: Initial MR studies showed intramedullary high signal on T2-weighted sequences with poorly defined marginal enhancement on T1-weighted images. On follow-up contrast-enhanced T1-weighted studies, the lesions had well-defined enhancing margins with central low signal intensity. After the initiation of therapy, T2 signal abnormalities decreased markedly and contrast-enhanced studies showed ring enhancement. These T1 findings resolved with treatment over serial studies in four patients. The organisms identified were Streptococcus milleria, S pyogenes, atypical mycobacteria, Mycobacterium tuberculosis, and Schistosoma mansoni (both children). CONCLUSION: A characteristic sequence of imaging findings aids in the differentiation of cord infection from other intramedullary lesions.