Neurology February 2009 Volume 72 Issue 7

Objective: To determine the potential of directional diffusivities from diffusion tensor imaging (DTI) to predict clinical outcome of optic neuritis (ON), and correlate with vision, optical coherence tomography (OCT), and visual evoked potentials (VEP).Methods: Twelve cases of acute and isolated ON were imaged within 30 days of onset and followed prospectively. Twenty-eight subjects with a remote clinical history of ON were studied cross-sectionally. Twelve healthy controls were imaged for comparison. DTI data were acquired at 3T with a surface coil and 1.3 x 1.3 x 1.3 mm3 isotropic voxels.Results: Normal DTI parameters (mean +/- SD, [mu]m2/ms) were axial diffusivity = 1.66 +/- 0.18, radial diffusivity = 0.81 +/- 0.26, apparent diffusion coefficient (ADC) = 1.09 +/- 0.21, and fractional anisotropy (FA) = 0.43 +/- 0.15. Axial diffusivity decreased up to 2.5 SD in acute ON. The decrease in axial diffusivity at onset correlated with visual contrast sensitivity 1 month (r = 0.59) and 3 months later (r = 0.65). In three subjects followed from the acute through the remote stage, radial diffusivity subsequently increased to >2.5 SD above normal, as did axial diffusivity and ADC. In remote ON, radial diffusivity correlated with OCT (r = 0.81), contrast sensitivity (r = 0.68), visual acuity (r = 0.56), and VEP (r = 0.54).Conclusion: In acute and isolated demyelination, axial diffusivity merits further investigation as a predictor of future clinical outcome. Diffusion parameters are dynamic in acute and isolated optic neuritis, with an initial acute decrease in axial diffusivity. In remote disease, radial diffusivity correlates with functional, structural, and physiologic tests of vision.(C)2009AAN Enterprises, Inc.

Background: It is unclear whether the severity of and recovery from the initial demyelinating event (IDE) are recapitulated in subsequent multiple sclerosis (MS) relapses. We sought to identify the factors associated with relapse severity and recovery and to evaluate whether events have inherent severity or recovery.Methods: Patients seen at the UCSF MS Clinic within 1 year of disease onset were identified from a prospective database. Ordinal logistic regression was used to analyze predictors of three-level categorizations of event severity and recovery.Results: We identified 330 patients with MS or clinically isolated syndrome; 152 had a second event and 63 had a third event. Nonwhite and younger patients were at an increased risk of more severe demyelinating events. A severe prior event predicted a substantial increase in the odds of being above any given severity cutoff for a severe subsequent event (for second event severity, odds ratio [OR] = 5.62, 95% confidence interval [CI] [2.39, 13.26], p < 0.0001; for third event severity, OR = 6.74, 95% CI [1.67, 27.18], p = 0.007). Similarly, poor recovery of the IDE predicted poor second event recovery (OR = 5.28, 95% CI [1.95, 14.25], p = 0.001), while fair or poor second event recovery predicted about a 5- or 13-fold increase in the odds of poor third event recovery. A more severe event also predicted a substantial increase in the odds of poor recovery.Conclusions: Patients with severe presentation and poor recovery at disease onset continue on a similar trajectory with subsequent demyelinating events. Whether genetic or other biologic factors are responsible for this pattern remains to be determined.(C)2009AAN Enterprises, Inc.

Background: Charcot Marie Tooth (CMT) disease is a heterogeneous group of inherited peripheral motor and sensory neuropathies. CMT4H is an early onset autosomal recessive demyelinating neuropathy. The locus responsible for CMT4H was assigned to chromosome 12p11.21-q13.11 by homozygosity mapping and mutations in the Frabin gene (FGD4 Rho GDP/GTP exchange factor) were subsequently identified in six families.Methods: We sequenced the Frabin gene in a cohort of 12 UK CMT families with clinically defined autosomal recessive demyelinating neuropathy.Results: We identified a novel homozygous Frabin p.R275X mutation in a family from Northern Ireland. The two affected cases in this family had a very slowly progressive neuropathy with both cases remaining ambulant into middle age. Examination of mRNA from lymphoblasts showed that this stop mutation caused very little nonsense mediated mRNA decay and the predominant mRNA species was the mutant form that is likely to be translated into a truncated protein.Conclusions: This work extends the understanding of the pathogenesis of Frabin mutation-associated Charcot Marie Tooth (CMT) 4H and suggests that mutations in Frabin should also be considered in ambulant adults with CMT1.(C)2009AAN Enterprises, Inc.

Background: Conventional arterial imaging focuses on the vessel lumen but lacks specificity because different pathologies produce similar luminal defects. Wall imaging can characterize extracranial arterial pathology, but imaging intracranial walls has been limited by resolution and signal constraints. Higher-field scanners may improve visualization of these smaller vessels.Methods: Three-tesla contrast-enhanced MRI was used to study the intracranial arteries from a consecutive series of patients at a tertiary stroke center.Results: Multiplanar T2-weighted fast spin echo and multiplanar T1 fluid-attenuated inversion recovery precontrast and postcontrast images were acquired in 37 patients with focal neurologic deficits. Clinical diagnoses included atherosclerotic disease (13), CNS inflammatory disease (3), dissections (3), aneurysms (3), moyamoya syndrome (2), cavernous angioma (1), extracranial source of stroke (5), and no definitive clinical diagnosis (7). Twelve of 13 with atherosclerotic disease had focal, eccentric vessel wall enhancement, 10 of whom had enhancement only in the vessel supplying the area of ischemic injury. Two of 3 with inflammatory diseases had diffuse, concentric vessel wall enhancement. Three of 3 with dissection showed bright signal on T1, and 2 had irregular wall enhancement with a flap and dual lumen.Conclusions: Three-tesla contrast-enhanced MRI can be used to study the wall of intracranial blood vessels. T2 and precontrast and postcontrast T1 fluid-attenuated inversion recovery images at 3 tesla may be able to differentiate enhancement patterns of intracranial atherosclerotic plaques (eccentric), inflammation (concentric), and other wall pathologies. Prospective studies are required to determine the sensitivity and specificity of arterial wall imaging for distinguishing the range of pathologic conditions affecting cerebral vasculature.(C)2009AAN Enterprises, Inc.

Objective: It is unknown if impaired cerebral vasoreactivity recovers after ischemic stroke, and whether it compromises perfusion in regions surrounding infarct and other vascular territories. We investigated the regional differences in CO2 vasoreactivity (CO2VR) and their relationships to peri-infarct T2 hyperintensities (PIHs), chronic infarct volumes, and clinical outcomes.Methods: We studied 39 subjects with chronic large middle cerebral artery territory infarcts and 48 matched controls. Anatomic and three-dimensional continuous arterial spin labeling imaging at 3-Tesla MRI were used to measure regional cerebral blood flow (CBF) and CO2VR during normocapnia, hypercapnia, and hypocapnia in main arteries distributions.Results: Stroke patients showed a significantly lower augmentation of blood flow at increased CO2 but greater reduction of blood flow with decreased CO2 than the control group. This altered vasoregulatory response was observed both ipsilateral and contralateral to the stroke. Lower CO2VR on the stroke side was associated with PIHs, greater infarct volume, and worse outcomes. The cases with PIHs (n = 27) had lower CBF during all conditions bilaterally (p < 0.0001) compared to cases with infarct only.Conclusions: Perfusion augmentation is inadequate in multiple vascular territories in patients with large artery ischemic infarcts, but vasoconstriction is preserved. Peri-infarct T2 hyperintensities are associated with lower blood flow. Strategies aimed to preserve vasoreactivity after an ischemic stroke should be tested for their effect on long-term outcomes.(C)2009AAN Enterprises, Inc.

Educators of the next generation of neurologists will face several challenges, including changes in academic medical centers and hospitals, changes in the scope and practice of neurology itself, and changes in trainees, related to both access to information technology and professional goals. This article, which originated as a lecture given at the A.B. Baker Education Symposium at the 60th annual meeting of the American Academy of Neurology in April 2008, arose out of an attempt to enumerate these challenges and to suggest ways to address them. First, approaches to overcoming challenges will likely require reinvigorating the commitment to teaching in fundamental and concrete ways, including, for example, establishing communities of educators and taking seriously the teaching role provided by clinicians. Second, it is expected that changes in the scope of educational content will be needed. Learning the role of the neurologist in a broader societal context will become an increasingly important part of training. It should be emphasized, as well, that trainees should play an important role in the redesign of neurology training and practice; in fact, their participation in this hidden curriculum constitutes an important part of their education. Third, new information technologies, such as Google, Wikipedias, and podcasting, will likely play an increasingly important role in neurology education. Finally, generational differences in familiarity with these new technologies, and differences in professional and personal goals, may lead to different career opportunities and plans for future neurologists than have been considered the norm in the past.(C)2009AAN Enterprises, Inc.