Brian C. Bowen

A pilot study of cidofovir for progressive multifocal leukoencephalopathy in AIDS

ObjectiveTo assess the safety, tolerability and effect of cidofovir for HIV-1 associated progressive multifocal leukoencephalopathy. DesignProspective, open-label study in nine AIDS Clinical Trials Units. Patients and methodsTwenty-four HIV-1-infected individuals, with neuroimaging and clinical findings consistent with PML, and symptoms for 90 days or less, whose diagnosis was confirmed by the detection of JC virus DNA in the cerebrospinal fluid or brain biopsy, received cidofovir 5 mg/kg intravenously at baseline and 1 week, followed by infusions every 2 weeks with the dose adjusted for renal function. Follow-up continued to 24 weeks. The safety of cidofovir and changes in neurological examination scores between baseline and week 8 were assessed. ResultsSeventeen subjects were receiving potent antiretroviral agents. Survival at 12 weeks was 54%. The CD4 cell count at entry was significantly associated with survival (P = 0.02). Five subjects discontinued treatment because of toxicity: a 50% or greater decrease in intraocular pressure in either eye in four, and proteinuria in one. Overall, magnetic resonance imaging abnormalities and neurological examination scores worsened. Only two subjects experienced a 25% or greater improvement in neurological examination scores at week 8, which were significantly better in subjects with HIV-1-RNA levels of 500 copies/ml or less at entry compared with those with HIV-1-RNA levels over 500 copies/ml (P = 0.05). ConclusionCidofovir did not improve neurological examination scores at week 8. However, such scores were significantly better in subjects who entered with suppressed plasma HIV-1-RNA levels, which could be the result of control of HIV-1 infection itself or cidofovir.

Contrast-Enhanced MR Imaging of Brain Lesions: A Large-Scale Intraindividual Crossover Comparison of Gadobenate Dimeglumine versus Gadodiamide

BACKGROUND AND PURPOSE: The higher relaxivity of gadobenate dimeglumine compared with gadodiamide is potentially advantageous for contrast-enhanced brain MR imaging. This study intraindividually compared 0.1-mmol/kg doses of these agents for qualitative and quantitative lesion enhancement. MATERIALS AND METHODS: Adult patients with suggested or known brain lesions underwent 2 identical MR imaging examinations at 1.5T, one with gadobenate dimeglumine and the other with gadodiamide. The agents were administered in randomized order separated by 3–14 days. Imaging sequences and postinjection acquisition timing were identical for the 2 examinations. Three blinded readers evaluated images qualitatively for diagnostic information (lesion extent, delineation, morphology, enhancement, and global preference) and quantitatively for contrast-to-noise ratio (CNR). RESULTS: One hundred thirteen of 138 enrolled patients successfully underwent both examinations. Final diagnoses were intra-axial tumor, metastasis, extra-axial tumor, or other (47, 27, 18, and 21 subjects, respectively). Readers 1, 2, and 3 demonstrated global preference for gadobenate dimeglumine in 63 (55.8%), 77 (68.1%), and 73 (64.6%) patients, respectively, compared with 3, 2, and 3 patients for gadodiamide (P < .0001, all readers). Highly significant (P < .0001, all readers) preference for gadobenate dimeglumine was demonstrated for all qualitative end points and for CNR (increases of 23.3%–34.7% and 42.4%–48.9% [spin-echo and gradient-refocused echo sequences, respectively] for gadobenate dimeglumine compared with gadodiamide). Inter-reader agreement was good for all evaluations (κ = 0.47–0.69). Significant preference for gadobenate dimeglumine was demonstrated for all lesion subgroup analyses. CONCLUSION: Significantly greater diagnostic information and lesion enhancement are achieved on brain MR imaging with 0.1-mmol/kg gadobenate dimeglumine compared with gadodiamide at an equivalent dose.

MR angiography of the spine and spinal cord.

Objectives This review has three objectives: 1) to describe spinal vascular anatomy, focusing on thoracolumbar intradural vessels detectable by both magnetic resonance angiography (MRA) and digital subtraction x-ray angiography (DSA), 2) to compare the MRA techniques that have been used to detect the major intradural vessels, and 3) to illustrate the clinical application of these MRA techniques, especially their efficacy in characterizing spinal dural arteriovenous fistulae (AVF). Methods MRA is an adjunct to conventional magnetic resonance imaging. MRA is usually implemented as a three-dimensional (3D) contrast-enhanced (CE) gradient-echo technique, with two approaches to data acquisition: 1) “standard” 3D CE MRA, requiring ∼10 minutes per 3D volume, and 2) “fast” (bolus/dynamic) 3D CE MRA, requiring ∼0.5 to 2 minutes per 3D volume depending on k-space sampling schemes. Vessels are displayed on targeted maximum intensity projection images. Results Normal intradural vessels detected on standard CE MRA are primarily veins (medullary and median), whereas both arteries and veins are detected on fast CE MRA. Identification of arteries (artery of Adamkiewicz, anterior spinal artery) is limited, and their differentiation from veins can be incomplete. Intradural vessels in patients with dural fistulae have abnormal features on MRI (length of flow voids and postcontrast serpentine enhancement) and standard 3D CE MRA (length, tortuosity, and qualitative size of dominant perimedullary vessel), which differ significantly from those of normal vessels. Standard MRA added to a conventional MRI study significantly (P = 0.016) increased the rate of detection of the spinal level of a dural fistula. The correct level ± one vertebral segment was identified in 73% of true-positive patients. Conclusions Application of spinal MRA requires knowledge of vascular anatomy, specifically the major intradural vessels, and careful implementation of 3D CE MRA techniques. The standard technique allows for more effective noninvasive screening for vascular lesions, particularly dural AVF, than magnetic resonance imaging alone. Preliminary results indicate that the fast technique may further improve characterization of normal and abnormal intradural vessels, especially if continued technical advances yield greater temporal resolution while maintaining adequate spatial resolution.

Vascular dementia in patients with immune thrombocytopenic purpura

INTRODUCTION Platelets have been implicated in memory disorders but this has not been investigated in patients with immune or idiopathic thrombocytopenia (ITP). ITP is an autoimmune disorder in which autoantibodies bring about platelet destruction. We previously reported a group of ITP patients who manifested TIA-like syndrome and gradual memory loss leading to dementia: platelet microparticles (PMP), a marker of platelet activation, were often elevated, suggesting that procoagulant PMP released from stimulated platelets contributed to thrombosis in small vessels. We have expanded on those studies to better define the clinical, laboratory, and radiologic characteristics of this syndrome. MATERIALS AND METHODS Twenty ITP patients with this syndrome were studied in comparison to twenty-three ITP patients without it (patient controls). Clinical and laboratory features were compared and radiologic images were analyzed. Factors influencing the rate of progression to advanced dementia were also investigated. RESULTS AND CONCLUSION Recurring dizzy or weak spells, TIA-like syndrome, recent memory loss, and cognitive impairment were common initial complaints. In some, these symptoms progressed rapidly to dementia but was indolent in others. Progression was faster in those with splenectomy and higher platelet counts. MRI showed enhanced signal in subcortical, periventricular areas, consistent with ischemic small vessel disease. Compared to patient controls, bleeding was less frequent and platelet activation (increased PMP, CD62p) was more frequent in the study group. Thrombotic complications may occur in ITP, manifested as TIA-like syndrome or memory loss due to ischemic small vessel disease, progressing to vascular dementia. Memory disturbances associated with platelet disorders warrants further investigation.

Pseudotumor cerebri from cranial venous obstruction.

Dural sinus hypertension from cerebral venous outflow impairment is a cause of pseudotumor cerebri. The authors documented six such patients: two with unilateral neck dissection, one with surgical ligation of the dominant sigmoid sinus, two with thrombosed central intravenous catheterization, and one with dural sinus thrombosis. The site of cerebral venous outflow obstruction was variable and identified in three patients with computed tomography, conventional magnetic resonance imaging, magnetic resonance angiography, and/or angiography. Magnetic resonance angiography used in two patients characterized the venous flow pattern and identified the site of obstruction, confirming magnetic resonance angiography as an effective noninvasive blood flow technique in diagnosing and following these patients. Three patients were treated successfully with medical therapy and one patient with optic nerve fenestration. The two patients with thrombosed central venous catheters had serious systemic illnesses and suffered permanent visual loss.

1H-magnetic resonance spectroscopy in amyotrophic lateral sclerosis

1H-magnetic resonance spectroscopy (MRS) is potentially a powerful tool for the investigation of the chemicals of the brain in vivo in health and disease. Levels of N-acetyl-aspartate (NAA) in the motor cortex and brainstem of patients with amyotrophic lateral sclerosis (ALS) have been reported to be reduced by up to 68%, and in one report the level of glutamate in the brainstem was increased by 58%. We studied levels of metabolites in the cerebral cortex and brainstem of 20 ALS patients and 14 age-matched controls with a 1.5 Tesla Picker magnet using MRS. We used the same spectra for determining both the area of the metabolite peaks expressed as a ratio of the area of the creatine (Cr) peak, and the absolute concentrations using the Provencher LC model. These produced different results. With the LC model, the NAA content of the motor cortex of ALS patients was reduced by 7.7% (P=0.015), and that of the brainstem was reduced by 21.5% (P=0.035), compared with controls. The degree of reduction of NAA was related to the severity of upper motor neuron abnormalities. No effect of treatment with anti-glutamate agents on NAA concentration could be detected. Concentrations of other metabolites were not affected in ALS. It appears that MRS is a technique that is still in development, and that further refinement is required before it can be used to understand disease mechanisms and investigate treatment in ALS.

Application of volumetric MR spectroscopic imaging for localization of neocortical epilepsy.

PURPOSE The aim of this study was to evaluate volumetric proton magnetic resonance spectroscopic imaging (MRSI) for localization of epileptogenic foci in neocortical epilepsy. METHODS Twenty-five subjects reporting seizures considered to be of neocortical origin were recruited to take part in a 3-T MR study that included high-resolution structural MRI and a whole-brain MRSI acquisition. Using a fully automated MRSI processing protocol, maps for signal intensity normalized N-acetylaspartate (NAA), creatine, and choline were created, together with the relative volume fraction of grey-matter, white-matter, and CSF within each MRSI voxel. Analyses were performed using visual observation of the metabolite and metabolite ratio maps; voxel-based calculation of differences in these metabolite maps relative to normal controls; comparison of average grey-matter and white-matter metabolite values over each lobar volume; and examination of relative left-right asymmetry factors by brain region. RESULTS Data from 14 subjects were suitable for inclusion in the analysis. Eight subjects had MRI-visible pathologies that were associated with decreases in NAA/creatine, which extended beyond the volume indicated by the MRI. Five subjects demonstrated no significant metabolic alterations using any of the analysis methods, and one subject had no findings on MRI or MRSI. CONCLUSIONS This proof of principle study supports previous evidence that alterations of MR-detected brain metabolites can be detected in tissue areas affected by neocortical seizure activity, while additionally demonstrating advantages of the volumetric MRSI approach.

Magnetic resonance spectroscopy in childhood brainstem tumors

Five children with brainstem tumors and two control patients had magnetic resonance spectroscopy studies of the brainstem. Two of the malignant tumor patients had magnetic resonance spectroscopy studies before and after radiation therapy. The third was irradiated 14 years earlier but developed new symptoms and a new brainstem lesion on MRI. Magnetic resonance spectroscopy demonstrated a different degree of malignancy between the old and new lesion. The fourth patient had magnetic resonance spectroscopy of a chronic, large pontine lesion 6 years after diagnosis and radiation. The spectral pattern suggested a low degree of malignancy. The fifth patient had neurofibromatosis type 1 with brainstem lesions. Magnetic resonance spectroscopy suggested neoplastic tissue of low malignancy. These results suggest that magnetic resonance spectroscopy offers additional information for anticipating the degree of anaplasia in children with brainstem tumors.

Lyme neuroborreliosis masquerading as a brainstem tumor in a 15-year-old

A 15-year-old boy had onset of unilateral facial weakness. A few days later, he experienced mild vertigo, double vision, and headache. Examination confirmed a peripheral right seventh nerve weakness in addition to an internuclear ophthalmoplegia. The neurologic features suggested a pontine glioma. A T2-weighted MRI scan revealed demyelinating lesions in the pons and in several areas of the cerebrum, including the periventricular region. Subsequent history revealed that he had been diagnosed with Lyme arthritis 7 years earlier while living in Connecticut. The radiographic studies favored a diagnosis of multiple sclerosis. However, studies of blood and cerebrospinal fluid established a diagnosis of Lyme neuroborreliosis.

Case of maternally transmitted juvenile Huntington's disease with a very large trinucleotide repeat

We describe and present a video of a patient with maternally inherited juvenile Huntingtons disease (HD) caused by a very large (108‐repeat) expansion. Maternally transmitted very large trinucleotide repeats (>100) are extremely rare in juvenile HD and may represent instability during female gametogenesis.