Neurology August 2012 Volume 79 Issue 8

Objective: To determine the time of acceleration in white matter hyperintensity (WMH) burden, a common indicator of cerebrovascular pathology, in relation to conversion to mild cognitive impairment (MCI) in the elderly.Methods: A total of 181 cognitively intact elderly volunteers from the longitudinal, prospective, Oregon Brain Aging Study underwent yearly evaluations, including brain MRI, and cognitive testing. MRIs were analyzed for imaging markers of neurodegeneration: WMH and ventricular CSF (vCSF) volumes. The time before MCI, when the changes in WMH and vCSF burden accelerate, was assessed using a mixed-effects model with a change point for subjects who developed MCI during follow-up.Results: During a follow-up duration of up to 19.6 years, 134 subjects converted to MCI. Acceleration in %WMH volume increase occurred 10.6 years before MCI onset. On average, the annual rate of change in %WMH increased an additional 3.3% after the change point. Acceleration in %vCSF volume increase occurred 3.7 years before the onset of MCI. Out of 63 subjects who converted to MCI and had autopsy, only 28.5% had Alzheimer disease (AD) as the sole etiology of their dementia, while almost just as many (24%) had both AD and significant ischemic cerebrovascular disease present.Conclusions: Acceleration in WMH burden, a common indicator of cerebrovascular disease in the elderly, is a pathologic change that emerges early in the presymptomatic phase leading to MCI. Longitudinal changes in WMH may thus be useful in determining those at risk for cognitive impairment and for planning strategies for introducing disease-modifying therapies prior to dementia onset.GLOSSARY: AD: Alzheimer diseaseCDR: Clinical Dementia RatingCI: confidence intervalFLAIR: fluid-attenuated inversion recoveryHTN: hypertensionICV: intracranial volumeLBD: Lewy body diseaseMCI: mild cognitive impairmentMMSE: Mini-Mental State ExaminationOBAS: Oregon Brain Aging StudyTE: echo timeTR: repetition timeVaD: vascular dementiavCSF: ventricular CSFWMH: white matter hyperintensity.(C)2012 American Academy of Neurology

Objective: To examine the association of body mass index (BMI) and metabolic status with cognitive function and decline.Methods: A total of 6,401 adults (71.2% men), aged 39-63 years in 1991-1993, provided data on BMI (normal weight 18.5-24.9 kg/m2, overweight 25-29.9 kg/m2; and obese >=30 kg/m2) and metabolic status (abnormality defined as 2 or more of 1) triglycerides >=1.69 mmol/L or lipid-lowering drugs, 2) systolic blood pressure >=130 mm Hg, diastolic blood pressure >=85 mm Hg, or antihypertensive drugs, 3) glucose >=5.6 mmol/L or medications for diabetes, and 4) high-density lipoprotein cholesterol <1.04 mmol/L for men and <1.29 mmol/L for women). Four cognitive tests (memory, reasoning, semantic, and phonemic fluency) were administered in 1997-1999, 2002-2004, and 2007-2009, standardized to z scores, and averaged to yield a global score.Results: Of the participants, 31.0% had metabolic abnormalities, 52.7% were normal weight, 38.2% were overweight, and 9.1% were obese. Among the obese, the global cognitive score at baseline (p = 0.82) and decline (p = 0.19) over 10 years was similar in the metabolically normal and abnormal groups. In the metabolically normal group, the 10-year decline in the global cognitive score was similar (p for trend = 0.36) in the normal weight (-0.40; 95% confidence interval [CI] -0.42 to -0.38), overweight (-0.42; 95% CI -0.45 to -0.39), and obese (-0.42; 95% CI -0.50 to -0.34) groups. However, in the metabolically abnormal group, the decline on the global score was faster among obese (-0.49; 95% CI -0.55 to -0.42) than among normal weight individuals (-0.42; 95% CI -0.50 to -0.34), (p = 0.03).Conclusions: In these analyses the fastest cognitive decline was observed in those with both obesity and metabolic abnormality.GLOSSARY: BMI: body mass indexHDL: high-density lipoproteinMHO: metabolically healthy obesity(C)2012 American Academy of Neurology

Objective: To identify the rate of successful antiepileptic drug (AED) withdrawal after resective surgery and the predictors of postwithdrawal seizure recurrence in patients with extratemporal epilepsy.Methods: We retrospectively analyzed the postoperative AED profile of 106 consecutive patients who had completed 2 or more years after resections involving frontal, parietal, and occipital lobes for AED-resistant epilepsy. To identify the potential predictors of seizure recurrence, we compared the attributes of recurred and nonrecurred groups by univariate and multivariate analyses.Results: We attempted AED withdrawal in 94 (88.7%) patients. Forty-four (41.5%) patients had seizure recurrence while reducing AED, of which 14 (31.8%) did not become seizure-free subsequently. On multivariate analysis, an abnormal postoperative EEG and longer preoperative duration of epilepsy predicted seizure recurrence, while early postoperative seizures and presence of gliosis or dysplasia were additional predictors on univariate analysis. At mean follow-up duration of 4.6 years, 63 (59.4%) patients were seizure-free. The cumulative probability of achieving complete AED-free status was 20% at fourth year, 34% at sixth year, 40% at eighth year, and 52% at 10th year after surgery.Conclusions: Following resective extratemporal epilepsy surgery, AED can be successfully discontinued in only in a minority of patients. One-third of patients who recur fail to regain seizure control upon AED reintroduction. Longer duration of epilepsy prior to surgery, abnormal postoperative EEG, early postoperative seizures, and focal gliosis or dysplasia as substrate predispose to seizure recurrence. This information will be helpful in making rational decisions on AED withdrawal following extratemporal resective epilepsy surgery.GLOSSARY: AED: antiepileptic drugCI: confidence intervalECoG: electrocorticographyFCD: focal cortical dysplasiaIED: interictal epileptiform discharges(C)2012 American Academy of Neurology

Objectives: To evaluate the efficacy and safety of 18 months of tafamidis treatment in patients with early-stage V30M transthyretin familial amyloid polyneuropathy (TTR-FAP).Methods: In this randomized, double-blind trial, patients received tafamidis 20 mg QD or placebo. Coprimary endpoints were the Neuropathy Impairment Score-Lower Limbs (NIS-LL) responder analysis (<2-point worsening) and treatment-group difference in the mean change from baseline in Norfolk Quality of Life-Diabetic Neuropathy total score (TQOL) in the intent-to-treat (ITT) population (n = 125). These endpoints were also evaluated in the efficacy-evaluable (EE; n = 87) population. Secondary endpoints, including changes in neurologic function, nutritional status, and TTR stabilization, were analyzed in the ITT population.Results: There was a higher-than-anticipated liver transplantation dropout rate. No differences were observed between the tafamidis and placebo groups for the coprimary endpoints, NIS-LL responder analysis (45.3% vs 29.5% responders; p = 0.068) and change in TQOL (2.0 vs 7.2; p = 0.116) in the ITT population. In the EE population, significantly more tafamidis patients than placebo patients were NIS-LL responders (60.0% vs 38.1%; p = 0.041), and tafamidis patients had better-preserved TQOL (0.1 vs 8.9; p = 0.045). Significant differences in most secondary endpoints favored tafamidis. TTR was stabilized in 98% of tafamidis and 0% of placebo patients (p < 0.0001). Adverse events were similar between groups.Conclusions: Although the coprimary endpoints were not met in the ITT population, tafamidis was associated with no trend toward more NIS-LL responders and a significant reduction in worsening of most neurologic variables, supporting the hypothesis that preventing TTR dissociation can delay peripheral neurologic impairment.Classification of evidence: This study provides Class II evidence that 20 mg tafamidis QD was associated with no difference in clinical progression in patients with TTR-FAP, as measured by the NIS-LL and the Norfolk QOL-DN score. Secondary outcomes demonstrated a significant delay in peripheral neurologic impairment with tafamidis, which was well tolerated over 18 months.GLOSSARY: AE: adverse eventANCOVA: analysis of covarianceARR: absolute risk reductionCI: confidence intervalDPN: diabetic polyneuropathyEE: efficacy-evaluableITT: intent-to-treatLS Mean: least-squares meanmBMI: modified body mass indexNIS-LL: Neuropathy Impairment Score-Lower LimbsNNT: number needed to treatQOL: quality of lifeQOL-DN: Quality of Life-Diabetic Neuropathy QuestionnaireTQOL: total quality of lifeTTR-FAP: transthyretin familial amyloid polyneuropathy(C)2012 American Academy of Neurology

Objective: To test the hypothesis that patients with multiple sclerosis (MS) with intereye asymmetry on low contrast letter acuity, and thickness of the retinal nerve fiber layer (RNFL), would exhibit corresponding changes in cortical timing and amplitude responses on pattern reversal multifocal visual evoked potentials (mfVEP), contingent upon variable stimulus contrast.Methods: In a cross-sectional study, we investigated a cohort of 11 normal subjects and 40 patients with MS, 21 of whom had a history of acute optic neuritis (MS-AON) with an intereye asymmetry with respect to RNFL thickness, and on low contrast letter acuity performance. Pattern reversal mfVEP was performed at high (100%), low (33.3%), and very low (14.2%) Michelson-contrast levels.Results: Compared to baseline measures at 100% contrast, the mean amplitude of the mfVEP was reduced in MS-AON eyes, upon pattern-reversal stimulation at the 2 lower contrast levels (p < 0.0001). With respect to changes in timing responses, the intereye asymmetry was increased in the MS-AON patients upon lower contrast pattern-reversal stimulation (p < 0.0001 for 33.3% compared to 100%, and p < 0.001 for 14.2% compared to 100%). The fellow eye in 12 (57%; p < 0.001) of the patients with an abnormal eye, and a history of AON, revealed abnormal amplitude and timing responses upon low contrast stimulation (signifying unmasking of occult damage).Conclusions: Our findings support the hypothesis that mfVEP metric abnormalities are contingent upon contrast magnitude during pattern reversal stimulation. Further, this paradigm was capable of unmasking occult abnormalities in a significant number of apparently unaffected eyes.GLOSSARY: AON: acute optic neuritismfVEP: multifocal visual evoked potentialMS: multiple sclerosisMS-AON: multiple sclerosis with a history of acute optic neuritisMS-FON: unaffected fellow eyeOCT: optical coherence tomographyRNFL: retinal nerve fiber layerVEP: visual evoked potential(C)2012 American Academy of Neurology

GLOSSARY: DRG: dorsal root ganglionGABA: [gamma]-aminobutyric acidGPCR: G-protein-coupled receptorLeu: leucineLID: levodopa-induced dyskinesiaMet: methionineNOP: nociceptin receptorPAG: periaqueductal grayPD: Parkinson diseasePDYN: preprodynorphinPENK: preproenkephalinPhe: phenylalaninePNOC: pronociceptinPOMC: proopiomelanocortinRVM: rostral ventromedial medullaVTA: ventral tegmental area(C)2012 American Academy of Neurology

: The essence of medical professionalism is placing dedication to the welfare of patients above physicians' personal or proprietary interests. Medicine has become deprofessionalized as a consequence of socioeconomic factors leading to increasing commercialization and perverse financial incentives converting it into a business, the presence of unmanaged conflicts of interest, challenges to medical authority by insurance companies and the consumerism movement, and by gradual changes in the attitudes of physicians. Organized medicine has responded by making explicit its standards of professionalism and its dedication to preserving them. Medical educators have studied the means to develop professional attitudes and behaviors among medical students and residents. Modeling the characteristics of professional behavior by virtuous physicians remains the most effective method to instill professional behaviors in trainees. Restoring professionalism may be abetted by changes in physicians' financial incentives through innovative models of health care delivery, by physicians reducing their conflicts of interest, and by medical societies rejecting a guild identity.GLOSSARY: AAN: American Academy of NeurologyACGME: Accreditation Council on Graduate Medical Education(C)2012 American Academy of Neurology