Vitamin B12-responsive severe leukoencephalopathy and autonomic dysfunction in a patient with "normal" serum B12 levels.

Leukoencephalopathy and autonomic dysfunction have been described in individuals with very low serum B(12) levels (<200 pg/ml), in addition to psychiatric changes, neuropathy, dementia and subacute combined degeneration. Elevated homocysteine and methylmalonic acid levels are considered more sensitive and specific for evaluating truly functional B(12) deficiency. A previously healthy 62-year-old woman developed depression and cognitive deficits with autonomic dysfunction that progressed over the course of 5 years. The patient had progressive, severe leukoencephalopathy on multiple MRI scans over 5 years. Serum B(12) levels ranged from 267 to 447 pg/ml. Homocysteine and methylmalonic acid levels were normal. Testing for antibody to intrinsic factor was positive, consistent with pernicious anaemia. After treatment with intramuscular B(12) injections (1000 µg daily for 1 week, weekly for 6 weeks, then monthly), she made a remarkable clinical recovery but remained amnesic for major events of the last 5 years. Repeat MRI showed partial resolution of white matter changes. Serum B(12), homocysteine and methylmalonic acid levels are unreliable predictors of B(12)-responsive neurologic disorders, and should be thoroughly investigated and presumptively treated in patients with unexplained leukoencephalopathy because even long-standing deficits may be reversible.

Pretreatment Dynamic Susceptibility Contrast MRI Perfusion in Glioblastoma: Prediction of EGFR Gene Amplification.

BACKGROUND AND PURPOSE: Molecular and genetic testing is becoming increasingly relevant in GBM. We sought to determine whether dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) perfusion imaging could predict EGFR-defined subtypes of GBM. MATERIALS AND METHODS: We retrospectively identified 106 consecutive glioblastoma (GBM) patients with known EGFR gene amplification, and a subset of 65 patients who also had known EGFRvIII gene mutation status. All patients underwent T2* DSC MRI perfusion. DSC perfusion maps and T2* signal intensity time curves were evaluated, and the following measures of tumor perfusion were recorded: (1) maximum relative cerebral blood volume (rCBV), (2) relative peak height (rPH), and (3) percent signal recovery (PSR). The imaging metrics were correlated to EGFR gene amplification and EGFRvIII mutation status using univariate analyses. RESULTS: EGFR amplification was present in 44 (41.5 %) subjects and absent in 62 (58.5 %). Among the 65 subjects who had undergone EGFRvIII mutation transcript analysis, 18 subjects (27.7 %) tested positive for the EGFRvIII mutation, whereas 47 (72.3 %) did not. Higher median rCBV (3.31 versus 2.62, p = 0.01) and lower PSR (0.70 versus 0.78, p = 0.03) were associated with high levels of EGFR amplification. Higher median rPH (3.68 versus 2.76, p = 0.03) was associated with EGFRvIII mutation. CONCLUSION: DSC MRI perfusion may have a role in identifying patients with EGFR gene amplification and EGFRvIII gene mutation status, potential targets for individualized treatment protocols. Our results raise the need for further investigation for imaging biomarkers of genetically unique GBM subtypes.

Potential role of preoperative conventional MRI including diffusion measurements in assessing epidermal growth factor receptor gene amplification status in patients with glioblastoma.

BACKGROUND AND PURPOSE: Epidermal growth factor receptor amplification is a common molecular event in glioblastomas. The purpose of this study was to examine the potential usefulness of morphologic and diffusion MR imaging signs in the prediction of epidermal growth factor receptor gene amplification status in patients with glioblastoma. MATERIALS AND METHODS: We analyzed pretreatment MR imaging scans from 147 consecutive patients with newly diagnosed glioblastoma and correlated MR imaging features with tumor epidermal growth factor receptor amplification status. The following morphologic tumor MR imaging features were qualitatively assessed: 1) border sharpness, 2) cystic/necrotic change, 3) hemorrhage, 4) T2-isointense signal, 5) restricted water diffusion, 6) nodular enhancement, 7) subependymal enhancement, and 8) multifocal discontinuous enhancement. A total of 142 patients had DWI available for quantitative analysis. ADC maps were calculated, and the ADCmean, ADCmin, ADCmax, ADCROI, and ADCratio were measured. RESULTS: Epidermal growth factor receptor amplification was present in 60 patients (40.8%) and absent in 87 patients (59.2%). Restricted water diffusion correlated with epidermal growth factor receptor amplification (P = .04), whereas the other 7 morphologic MR imaging signs did not (P > .12). Quantitative DWI analysis found that all ADC measurements correlated with epidermal growth factor receptor amplification, with the highest correlations found with ADCROI (P = .0003) and ADCmean (P = .0007). CONCLUSIONS: Our results suggest a role for diffusion MR imaging in the determination of epidermal growth factor receptor amplification status in glioblastoma. Additional work is necessary to confirm these results and isolate new imaging biomarkers capable of noninvasively characterizing the molecular status of these tumors.

Potential utility of conventional MRI signs in diagnosing pseudoprogression in glioblastoma.

OBJECTIVE: To examine the potential utility of conventional MRI signs in differentiating pseudoprogression (PsP) from early progression (EP). METHODS: This retrospective study reviewed initial postradiotherapy MRI scans of 321 patients with glioblastoma undergoing chemotherapy and radiotherapy. A total of 93 patients were found to have new or increased enhancing mass lesions, raising the possibility of PsP. Final diagnosis of PsP or EP was established upon review of surgical specimens from a second resection or by clinical and radiologic follow-up. A total of 11 MRI signs potentially helpful in the differentiation between PsP and EP were examined on the initial post-RT MRI and were correlated with the final diagnosis through χ(2) or Fisher exact test. RESULTS: Sixty-three (67.7%) of the 93 patients had EP, of which 22 (34.9%) were diagnosed by pathology. Thirty patients (32.3%) had PsP; 6 (16.7% of the 30) were diagnosed by pathology. Subependymal enhancement was predictive for EP (p = 0.001) with 38.1% sensitivity, 93.3% specificity, and 41.8% negative predictive value. The other 10 signs had no predictive value (p = 0.06-1.0). CONCLUSIONS: Conventional MRI signs have limited utility in diagnosing PsP in patients with recently treated glioblastomas and worsening enhancing lesions. We did not find a sign with a high negative predictive value for PsP that would have been the most useful for the clinical physician. When present, subependymal spread of the enhancing lesion is a useful MRI marker in identifying EP rather than PsP.

Overlapping and distinct mechanisms of action of multiple sclerosis therapies.

In the last two decades MS has changed from an idiopathic condition with only symptomatic treatments to a disease with better characterized pathophysiologic underpinnings and several treatments that modify its long-term course based on specific mechanisms of action. There are now several FDA approved options for therapy at the onset of disease, and discussions have begun on choosing the best treatment in individual patients and what option to choose next in patients who are failing their current treatment. Numerous studies have begun to highlight that the underlying pathology of CNS damage may be different in subsets of patients, raising the possibility that some may respond to a treatment with a mechanism of action that is targeted to 'their' MS. Trials are ongoing of numerous new agents with different mechanisms of action and some combination therapies. A better understanding of how each therapy works may guide decisions on initiating, combining or changing therapy in a more rational way to improve patient outcomes. Further knowledge of underlying mechanisms of disease in different patients with 'the same' disease may lead to more targeted therapies, as will biomarkers that predict clinical response to therapy. Studies of the effects of various agents used in MS reveal both overlapping and distinct mechanisms of actions that may be relevant to their efficacy and side effects in individual patients. However, it is important to remember that most agents are approved based on their reduction of MRI lesions and relapse rates over a short time frame. These measures only partially correlate with long-term disability, which may be the most relevant clinical outcome for people with MS. Fixed disability requires years to become apparent, and there is a lack of large studies of biomarkers for chronic outcomes. In addition, few large studies correlate response to therapy with cognitive outcomes, which are a major cause of chronic disability. This review will attempt to summarize clinically relevant knowledge of the mechanisms of action of current FDA approved therapies for MS in the context of ongoing clinical trials of combination therapy and address rational approaches to changing therapy in a patient suspected to be 'unresponsive' to their current treatment.