A magnetization transfer imaging study of normal-appearing white matter in multiple sclerosis.

We attempted to define the role of subtle changes in the normal-appearing white matter (NAWM) in the development of disability in multiple sclerosis (MS). Twenty-seven clinically definite MS patients with either relapsing-remitting or chronic-progressive courses and 10 sex- and age-matched controls entered the study. For each patient and control, we studied two NAWM areas in the frontal lobe with magnetization transfer imaging (MTI). For patients, we also calculated the MT ratios (MTRs) for three contiguous areas of NAWM progressively further from "isolated" lesions visible on conventional MRI. Frontal NAWM in MS patients had lower mean MTRs than the frontal white matter of the controls (p = 0.02). MTRs in the NAWM adjacent to isolated lesions increased with distance from them to the cortical gray matter (p = 0.04). This pattern was typical for patients with chronic-progressive MS whose MTRs in the first two regions of NAWM adjacent to lesions were lower than those of the same regions of patients with relapsing-remitting MS. This study confirms that there are alterations in the NAWM of MS patients and suggests that such changes might be relevant to the disability in MS.

Comparison of triple dose versus standard dose gadolinium-DTPA for detection of MRI enhancing lesions in patients with MS.

We studied whether a triple dose of gadolinium-DTPA alone or in combination with delayed scanning increases the sensitivity of brain MRI for detecting enhancing lesions in patients with MS. We obtained T1-weighted brain MRI scans in two sessions for 22 patients with clinically definite MS. In the first session, we obtained one scan 5 to 7 minutes after the injection of 0.1 mmol/kg gadolinium-DTPA (standard dose). In the second session, 6 to 24 hours later, we obtained one scan before the two scans 5 to 7 minutes (for all patients) and one hour (for 11 patients) after the injection of 0.3 mmol/kg gadolinium-DTPA (triple dose). We detected 83 enhancing lesions in 14 patients when the standard dose of gadolinium-DTPA was used. The numbers of enhancing lesions increased to 138 (average increase 66%; p = 0.001) and the numbers of patients with such lesions to 18 (increase 28%) when we used the triple dose of gadolinium-DTPA. In addition, the total area per patient occupied by such lesions was greater (p < 0.0001) and lesion signal intensity higher (p = 0.0001) on the triple-dose scans than the standard-dose scans. There was an increase in the number of large enhancing lesions (p = 0.03) in the scans obtained 1 hour after the injection of the triple dose of gadolinium-DTPA. These data indicate that in patients with MS, a triple dose of gadolinium-DTPA can reveal many more enhancing lesions, which also appear larger. This suggests that the pathologic nature of "active" lesions in MS is heterogeneous, which might have impact on planning clinical trials.

Antihypertensives. N-1H-Pyrrol-1-yl-3-pyridazinamines.

The hypothesis that the side effects of hydralazine, such as mutagenicity and lupus erythematosus like syndrome, might be due to the NHNH2 group prompted us to incorporate part of this moiety into a pyrrole ring. Therefore, we prepared a series of N-1H-pyrrol-1-yl-3-pyridazinamines and a limited number of N-1H-pyrrol-1-yl-1-phthalazinamines by reaction of 3-hydrazinopyridazines and 1-hydrazinophthalazines with gamma-diketones. Most of these compounds, especially in the pyridazine series, showed moderate to strong antihypertensive activity in spontaneously hypertensive rats. The decrease in blood pressure generally had a slow onset after either oral or intravenous administration. N-(2,5-Dimethyl-1H-pyrrol-1-yl)-6-(4-morpholinyl)-3-pyridazinamine hydrochloride (30) (MDL 899) showed no mutagenic activity in several tests and is now in clinical trials in patients.

Effects of urokinase and heparin on minimal cross-sectional area of the culprit narrowing in unstable angina pectoris.

The immediate and delayed effects of urokinase and heparin on minimal cross-sectional area of a patent ischemia-producing coronary artery were prospectively investigated in 43 patients with unstable angina. After baseline angiography, patients were randomized to 3 different treatment groups: group I--urokinase (1,000,000 U intravenous bolus dose), followed by heparin infusion 3 hours later; group II--heparin (10,000 U intravenous bolus, followed by continuous infusion); and group III--conventional therapy only (intravenous nitroglycerin, beta blockers and calcium antagonists). Angiography was repeated at 1 hour and at 8 days of treatment and minimal cross-sectional area was determined in the 35 patients who completed the study. In group I, minimal cross-sectional area increased from 0.84 +/- 0.48 mm2 at baseline to 0.94 +/- 0.49 mm2 at 1 hour (p less than 0.05), and to 1.00 +/- 0.51 mm2 at 8 days (p less than 0.01 vs baseline). In group II, a significant increase in minimal cross-sectional area was observed only at the 8-day angiography (0.64 +/- 0.39 mm2 at baseline; 0.67 +/- 0.37 mm2 at 1 hour [p = not significant]; and 0.79 +/- 0.48 mm2 at 8 days [p less than 0.01] vs baseline). In group III, no significant changes in minimal cross-sectional area occurred either at 1 hour or at 8 days. Thus, both urokinase and heparin improved lesion geometry in patients with unstable angina, although a large individual variation was noticed. The effect occurred earlier with urokinase than with heparin.

Early assessment of coronary artery bypass graft patency by high-dose dipyridamole echocardiography.

To assess the role of high-dose (up to 0.84 mg/kg during 10 minutes) dipyridamole echocardiographic testing in the evaluation of coronary artery bypass graft patency early after surgery, 18 consecutive patients with angina underwent dipyridamole echocardiography and coronary angiography before and 7 to 10 days after bypass surgery. Coronary angiography showed 2- or 3-vessel disease in 7 and 11 patients, respectively. A total of 53 bypass grafts were performed. Before bypass surgery 14 patients had a positive and 4 a negative test result. No complication occurred during the test performed early after surgery. Of the 14 patients with positive dipyridamole echocardiographic results before surgery, 10 had negative and 4 had positive results after surgery. All 4 patients had negative results before and after surgery. In the 4 patients with positive results after dipyridamole echocardiographic testing before and after bypass surgery, dipyridamole time increased from 5.8 +/- 5 to 9.3 +/- 0.9 minutes (p = 0.3) after the procedure and wall motion score index at peak dipyridamole changed from 1.55 +/- 0.2 to 1.28 +/- 0.3 (p = 0.05). Forty-nine of 53 grafts were patent as seen on angiography. Dipyridamole echocardiographic results were positive in 4 of 5 patients who had at least 1 obstructed graft or native vessel obstructed distal to bypass graft insertion. The remaining patient had diagnostic electrocardiographic changes during dipyridamole infusion without wall motion abnormalities. Dipyridamole echocardiographic results were negative in all 13 patients who had complete revascularization. In the 4 patients with positive test results, the procedure correctly identified the localization of the diseased bypass graft.(ABSTRACT TRUNCATED AT 250 WORDS)

CSF T-cell subsets in multiple sclerosis: relationship to cerebrospinal fluid myelin basic protein and clinical activity.

Cerebrospinal fluid myelin basic protein and cerebrospinal fluid and peripheral blood T-cell subsets have been studied in patients with multiple sclerosis and other inflammatory and non-inflammatory nervous system diseases. These biological parameters have been correlated with clinical disease activity. No changes in peripheral blood T-cell subsets were seen in multiple sclerosis patients. Low cerebrospinal fluid T8+ cells occurred only in multiple sclerosis, while high cerebrospinal fluid T4+ cells were detected both in clinically active multiple sclerosis and in inflammatory nervous system diseases. A close relationship was found between cerebrospinal fluid T4/T8 ratio and myelin basic protein in relapsing multiple sclerosis patients.

A spinal cord MRI study of benign and secondary progressive multiple sclerosis.

This study was performed to achieve a better definition of the nature of the disability in multiple sclerosis (MS). Axial spinal cord magnetic resonance imaging (MRI) at C5 was obtained in 15 patients with benign MS, 17 patients with secondary progressive MS and 10 healthy controls. Patients with secondary progressive MS had smaller spinal cord cross-sectional area (P = 0.01) and transverse diameter (P = 0.006) than patients with benign MS. The degree of disability was inversely correlated with both the cross-sectional area (r = -0.6, P = 0.0018) and transverse diameter (r = -0.5, P = 0.0032) of the cord. Spinal cord atrophy was found in 7 (41%) patients with secondary progressive MS and in 2 (13%) with benign MS. These findings suggest that destructive pathology within MS lesions might play a relevant role in the development of disability in MS.

Intra-observer reproducibility in measuring new putative MR markers of demyelination and axonal loss in multiple sclerosis: a comparison with conventional T2-weighted images.

New magnetic resonance (MR) measures considered to be putative workers of demyelination and axonal loss were found to be more closely related to clinical disability than T2-weighted MR imaging (MRI) findings in patients with multiple sclerosis (MS). In this study, we evaluated the reproducibility of such measurements in order to assess their reliability for longitudinal studies in MS. The intra-observer coefficients of variation for repeated measurements did not significantly differ among the MR techniques studied [2.6% for T2-weighted MR, 4.38% for unenhanced T1-weighted MRI, 3.65% for magnetisation transfer imaging (MTI) and 2.28% for spinal cord cross-sectional area at C5]. Our findings suggest that non-conventional MR techniques may be reliable outcome measures for clinical trials in MS.

Acute myelopathy of unknown aetiology: a clinical, neurophysiological and MRI study of short- and long-term prognostic factors.

Brain and spinal cord magnetic resonance imaging (MRI), multimodal evoked potentials (EPs) and cerebrospinal fluid (CSF) analysis were performed in 27 patients with acute myelopathy of unknown aetiology (AMUA), to detect the diagnostic and prognostic values of paraclinical tests at presentation. Spinal cord MRI was abnormal in 56% and brain MRI in 33% of the patients. Visual EPs were abnormal in 7%, median somatosensory EPs in 17%, tibial somatosensory EPs in 56% and motor EPs in 35% of the cases examined. Brain-stem acoustic EPs were normal in all the patients. CSF oligoclonal bands (OBs) were detected in 30% of cases. The patients were divided into subgroups according to the short-term clinical outcome (complete, partial or absent recovery). There were no significant differences among the three groups as regards MRI findings. Patients with complete recovery showed a significantly lower frequency of tibial somatosensory EP and motor EP abnormalities. According to the paraclinical findings at onset and on the basis of a long-term clinical follow-up (mean duration 24 months), 6 patients were diagnosed as having clinically definite multiple sclerosis, while 21 did not develop further neurological disturbances. Only the presence of CSF OBs was significantly more frequent in patients with definite multiple sclerosis. Our study indicates that EPs exploring spinal cord function are more powerful than spinal MRI for predicting the short-term outcome of AMUA, while the combined use of brain MRI and CSF OBs has the highest negative predictive value for the subsequent development of clinically definite multiple sclerosis.

RMI 12330A, an inhibitor of adenylate cyclase and cyclic AMP-phosphodiesterase activities in the segmental ganglia of the leech Hirudo medicinalis.

The effect of RMI 12330A, an inhibitor of basal as well as serotonin-stimulated adenylate cyclase in the segmental ganglia of the leech Hirudo medicinalis, has been tested on cyclic AMP-phosphodiesterase activity in the same tissue. The drug dose-dependently inhibits high and low affinity enzyme, an effect first evident at an RMI 12330A concentration of 0.5 mM. For both enzyme activities the drug reduces Vmax without substantially influencing Km values. Both basal and serotonin-stimulated adenylate cyclase as well as cyclic AMP-phosphodiesterase activities are inhibited by RMI 12330A in a non-competitive manner.

Recurrent acute transverse myelopathy associated with anticardiolipin antibodies.

In three patients with recurrent episodes of acute transverse myelopathy, spinal MR imaging during each episode showed areas of hyperintensity on proton density- and T2-weighted images with inconsistent contrast enhancement. Cranial MR imaging, laboratory screenings, and CSF analysis showed only increased titers of anticardiolipin antibodies. Although a causative role in neurologic conditions has not been established conclusively, an association between these antibodies and acute transverse myelopathy and its recurrences cannot be ignored.

Spinal cord involvement in primary angiitis of the central nervous system: a report of two cases.

SUMMARY: We report two patients with suspected primary angiitis of the CNS who underwent serial contrast-enhanced MR imaging of the spinal cord. MR abnormalities were multiple and enhancing, and located within the cervical and thoracic cord. Brain MR findings and brain biopsy specimens were positive for primary angiitis of the CNS. On follow-up MR studies, obtained after steroid and immunosuppressive therapy, a significant decrease in the number and size of the enhancing and nonenhancing abnormalities was observed, along with clinical improvement. Numerous small and enhancing abnormalities with a primarily posterior location, seen at the onset of the disease and resolved on follow-up studies, may be considered suggestive of a diagnosis of primary angiitis of the CNS.

Treatment of a ruptured dissecting vertebral artery aneurysm with double stent placement: case report.

A ruptured dissecting right vertebral artery aneurysm was treated by means of double stent placement with two overlapping stents. Control angiography performed 3 d after stent placement revealed beginning aneurysmal thrombosis. Substantial reduction in aneurysmal size was observed after 4 wk, whereas total occlusion was observed after 3 mo. The reduced stent porosity caused by the overlapping stents, which result in significant hemodynamic changes inside the aneurysmal sac, may accelerate intraaneurysmal thrombosis and may be helpful in achieving a more rapid complete occlusion compared with that achieved by single stent placement.

Acute transverse myelopathy: spinal and cranial MR study with clinical follow-up.

PURPOSE: To evaluate the contribution of MR in determining the cause of acute transverse myelopathy, to determine the frequency and types of the intracranial lesions detectable on MR at the onset of the disease, and to monitor clinical and MR evolution of the disease. METHODS: Spinal and cranial MR images were obtained for 30 patients with acute transverse myelopathy. Gadopentetate dimeglumine was administered in 10 patients. Mean follow-up time was 18 months. RESULTS: Spinal cord MR findings were abnormal in 14 of 30 patients. The abnormal MR can be divided into group A, in which one segment was involved (8 patients), and group B, in which more than one segment was involved (6 patients). In both groups there were 2 patients with enhancing lesions. Enhancement was less homogeneous in the group B patients. Enhancement did not change with increased length of lesion. At follow-up, the diagnostic categories of the patients were multiple sclerosis (8 patients), encephalomyelitis (1 patient), viral myelitis (3 patients), and myelopathy of unknown cause (18 patients). After the episode of acute transverse myelopathy, in 4 of 8 patients in group A and in 4 of 5 patients with normal spinal MR but abnormal brain MR findings clinical signs of multiple sclerosis developed. In no patients in group B did multiple sclerosis develop. The final diagnoses for the 4 patients with gadolinium-enhancing spinal lesions were myelopathy of unknown cause (2 patients), multiple sclerosis (1 patient), and viral myelitis (1 patient). CONCLUSION: MR contributed to establishing the diagnosis in 40% of our cases.

Serial contrast-enhanced MR in patients with multiple sclerosis and varying levels of disability.

PURPOSE: To compare the rates of enhancement and changes in lesion burden in patients with multiple sclerosis (MS) and varying levels of disability. METHODS: Monthly enhanced MR images of the brain were obtained for 6 months from seven patients with mildly disabling relapsing-remitting MS and from seven patients with secondary progressive MS and severe disability. At entry and 1 year later, two unenhanced T2-weighted images of the brain were also obtained. RESULTS: Despite the fact that both groups had clinically active disease and had similar increases in unenhanced MR lesion load, the total number of enhancing lesions was 239 in patients with relapsing-remitting MS (42 on the baseline images, 151 new and 46 persistent during follow-up) (average number of lesions per patient per year was 68) and 21 in those with secondary progressive MS (five on the baseline images, 13 new, and three persistent during follow-up) (average number of lesions per patients per year was seven). CONCLUSION: Our data indicate that the rate of enhancement significantly decreases in the more advanced phases of MS. This is important when planning clinical trials, and suggests that mechanisms underlying lesion formation might be dissimilar in different MS patient groups.

Endovascular management of a bleeding mandibular arteriovenous malformation by transfemoral venous embolization with NBCA.

A 13-year-old boy presented with an arteriovenous malformation (AVM) involving the left mandible that bled after intraoral biopsy. The AVM was treated on an emergency basis by primary intravenous delivery of n-butyl cyanoacrylate after transfemoral catheterization, resulting in complete anatomic and clinical cure.

A magnetization transfer study of white matter in siblings of multiple sclerosis patients.

In this study, we evaluated magnetization transfer ratio values in the brain white matter of siblings of multiple sclerosis (MS) patients and compared them to those obtained in sex- and age-matched normal controls. No statistically significant difference was found between the two groups for all the white matter areas studied (frontal and occipital lobes, centrum semiovale, periventricular white matter, internal capsule, genu and splenium of the corpus callosum).

Brain MRI correlates of cognitive impairment in primary and secondary progressive multiple sclerosis.

Brain magnetic resonance imaging (MRI) and an extensive battery of neuropsychological tests exploring frontal functions, short and long-term memory, visuo-spatial skills, attention and language were applied to 14 patients with primary progressive multiple sclerosis (PPMS) and 17 patients with secondary progressive MS (SPMS). Patients with PPMS and SPMS did not differ in degree of physical disability, but cognitive deficits were found in 9/17 (53%) patients with SPMS and in only 1/14 (7%) of those with PPMS (p = 0.01). Patients with SPMS had higher total (p = 0.004), periventricular (p = 0.008) and non-periventricular (p = 0.04) MRI lesion loads than patients with PPMS. In detail, patients with SPMS had greater involvement of frontal (p = 0.05) and occipital (p = 0.02) horns, trigones (p = 0.04), third ventricle (p = 0.03), basal ganglia (p = 0.02), parietal (p = 0.02), temporal (p = 0.004) and occipital (p = 0.03) lobes. Patients with SPMS and neuropsychological deficits had higher non-periventricular lesion loads than patients with SPMS who did not have such deficits (p = 0.005). Our results indicate that both neuropsychological and brain MRI abnormalities are more extensive in patients with SPMS. Since physical disability was similar for both groups, disability in PPMS may be predominantly due to spinal cord involvement.

Brain and spinal cord MR in benign multiple sclerosis: a follow-up study.

We performed a clinical and magnetic resonance (MR) longitudinal study in 19 patients with benign multiple sclerosis (MS) to achieve a better definition of the nature of disability in MS. Patients with higher lesion volumes on conventional T2-weighted images at entry were those with more frequent relapses (p = 0.0004) and more new MR lesions (p = 0.003) during the follow up. However, 1/3 of these new lesions were located periventricularly and about 2/3 were small or intermediate in size. Two of the 11 patients (18%) with higher lesion volumes at entry developed progressive neurological deficits: in these two patients the new lesions seen on conventional T2 images had lower magnetization transfer ratios (p = 0.005) than those present in patients who remained clinically stable and a marked increase in hypointense lesion volumes on T1-weighted images was also found. Spinal cord cross-sectional area at C5 and MTR values for the seemingly normal white matter were similar to those found in normal controls. This study suggests that patients with benign MS have two different patterns of disease evolution, one characterized by very low clinical and MR activities, the other in which the lack of disabling symptomatology might be related to factors like site, size and nature of lesions. It also indicates that in patients with benign MS and high MR lesion loads the risk of developing a secondary progressive form of the disease is still present even after many years after onset.

Brain magnetic resonance imaging correlates of cognitive impairment in multiple sclerosis.

We evaluated the correlations between cognitive impairment, clinical and brain magnetic resonance imaging (MRI) findings in 100 patients with multiple sclerosis (MS). The performance on one or more neuropsychological tests was abnormal in 47% of the 64 patients who completed the entire neuropsychological battery; the cognitive impairment was mild in 14 (22%) and severe in 16 (25%). Performance on any single neuropsychological test was unrelated to clinical parameters (age, duration of the disease, disability). The neuropsychological performance of relapsing-remitting patients was better than in patients with a chronic-progressive disease. The mean scores for almost all the neuropsychological tests were significantly lower in patients with severe ventricular dilatation and corpus callosum atrophy than in patients in whom these structures were little affected. Mean scores for WMS, performance Intelligence Quotient (IQ), total IQ and Token Test (TT) were also significantly correlated with the widening of cortical sulci and total lesional scores. Our data support the contention that the involvement of pathways that are critical for a given cognitive process as well as the progression of the axonal degeneration and sclerosis seem to play important roles in the pathophysiology of cognitive dysfunction in MS.