Abstract: Pain usually results from activation of nociceptive afferents by actually or potentially tissue-damaging stimuli. Pain may also arise by activity generated within the nervous system without adequate stimulation of its peripheral sensory endings. For this type of pain, the International Association for the Study of Pain introduced the term neuropathic pain, defined as "pain initiated or caused by a primary lesion or dysfunction in the nervous system." While this definition has been useful in distinguishing some characteristics of neuropathic and nociceptive types of pain, it lacks defined boundaries. Since the sensitivity of the nociceptive system is modulated by its adequate activation (e.g., by central sensitization), it has been difficult to distinguish neuropathic dysfunction from physiologic neuroplasticity. We present a more precise definition developed by a group of experts from the neurologic and pain community: pain arising as a direct consequence of a lesion or disease affecting the somatosensory system. This revised definition fits into the nosology of neurologic disorders. The reference to the somatosensory system was derived from a wide range of neuropathic pain conditions ranging from painful neuropathy to central poststroke pain. Because of the lack of a specific diagnostic tool for neuropathic pain, a grading system of definite, probable, and possible neuropathic pain is proposed. The grade possible can only be regarded as a working hypothesis, which does not exclude but does not diagnose neuropathic pain. The grades probable and definite require confirmatory evidence from a neurologic examination. This grading system is proposed for clinical and research purposes.

Abstract: Background: Reduced brain insulin signaling and low CSF-to-plasma insulin ratios have been observed in patients with Alzheimer disease (AD). Furthermore, intracerebroventricular or IV insulin administration improve memory, alter evoked potentials, and modulate neurotransmitters, possibly by augmenting low brain levels. After intranasal administration, insulin-like peptides follow extracellular pathways to the brain within 15 minutes. Objective: We tested the hypothesis that daily intranasal insulin treatment would facilitate cognition in patients with early AD or its prodrome, amnestic mild cognitive impairment (MCI). The proportion of verbal information retained after a delay period was the planned primary outcome measure. Secondary outcome measures included attention, caregiver rating of functional status, and plasma levels of insulin, glucose, β-amyloid, and cortisol. Methods: Twenty-five participants were randomly assigned to receive either placebo (n = 12) or 20 IU BID intranasal insulin treatment (n = 13) using an electronic atomizer, and 24 participants completed the study. Participants, caregivers, and all clinical evaluators were blinded to treatment assignment. Cognitive measures and blood were obtained at baseline and after 21 days of treatment. Results: Fasting plasma glucose and insulin were unchanged with treatment. The insulin-treated group retained more verbal information after a delay compared with the placebo-assigned group ( p = 0.0374). Insulin-treated subjects also showed improved attention ( p = 0.0108) and functional status ( p = 0.0410). Insulin treatment raised fasting plasma concentrations of the short form of the β-amyloid peptide (Aβ40; p = 0.0471) without affecting the longer isoform (Aβ42), resulting in an increased Aβ40/42 ratio ( p = 0.0207). Conclusions: The results of this pilot study support further investigation of the benefits of intranasal insulin for patients with Alzheimer disease, and suggest that intranasal peptide administration may be a novel approach to the treatment of neurodegenerative disorders.

Abstract: I congratulate Norden et al. for their report of 55 patients with recurrent high-grade gliomas treated with chemotherapy (85% with irinotecan or CPT-11) and bevacizumab.1–3 Several aspects of this report merit commentary. 1. Unlike prior reports, 6-month progression free survival was best for glioblastoma (GBM) vs anaplastic gliomas (42% vs 32%).3 2. The contribution of chemotherapy in combination with bevacizumab remains unclear. A number of reports evaluating CPT-11 as a single agent for recurrent GBM concluded CPT-11 had little efficacy.4 3. At time of progression, continuation of bevacizumab resulted in a feeble response. Escape from anti-vascular endothelial growth factor (VEGF) therapy (bevacizumab) likely represents recruitment of compensatory proangiogenic stimuli.5 4. Radiographic assessment of response, determined primarily by change in the contrast enhancing tumor volume, is problematic with antiangiogenic therapies.3,5 Bevacizumab therapy normalizes GBM vascularity resulting in loss of contrast enhancement, normalization of tumor blood volume and perfusion, and improvement in peritumoral edema. As illustrated by Norden et al., failure of antiangiogenic therapy initially appears as an increase in FLAIR signal before re-emergence of contrast enhancement. 5. It is unclear whether the control group treated with chemotherapy had similar overall survival from time of retreatment as compared to the bevacizumab group, as longer survival is associated with increased glioma invasiveness. Nonetheless, when comparing these patient groups, no statistically significant increased incidence of diffuse spread was seen. 6. Toxicity of bevacizumab was modest and although a high incidence of deep vein thrombosis and pulmonary embolism was observed, …

Abstract: Background: Cerebral microbleeds are focal deposits of hemosiderin that can be visualized with MRI. Little is known on their prevalence in the general population and on their etiology. It has been suggested that, in analogy to spontaneous intracranial hemorrhage, the etiology of microbleeds differs according to their location in the brain, with lobar microbleeds being caused by cerebral amyloid angiopathy and deep or infratentorial microbleeds resulting from hypertension and atherosclerosis. We investigated the prevalence of and risk factors for microbleeds in the general population aged 60 years and older. Methods: This study is based on 1,062 persons (mean age 69.6 years) from the population-based Rotterdam Scan Study. MRI was performed at 1.5 T and included a sequence optimized to increase the conspicuity of microbleeds. We assessed the relation of APOE genotype, cardiovascular risk factors, and markers of small vessel disease to the presence and location of microbleeds with multiple logistic regression. Results: Overall prevalence of cerebral microbleeds was high and increased with age from 17.8% in persons aged 60-69 years to 38.3% in those over 80 years. APOE e4 carriers had significantly more often strictly lobar microbleeds than noncarriers. In contrast, cardiovascular risk factors and presence of lacunar infarcts and white matter lesions were associated with microbleeds in a deep or infratentorial location but not in a lobar location. Conclusion: The prevalence of cerebral microbleeds is high. Our data support the hypothesis that strictly lobar microbleeds are related to cerebral amyloid angiopathy, whereas microbleeds in a deep or infratentorial location result from hypertensive or atherosclerotic microangiopathy.

Abstract: Background: Numerous reports show that a centralized distribution of adiposity is a more dangerous risk factor for cardiovascular disease and diabetes than total body obesity. No studies have evaluated whether the same pattern exists with dementia. The objective was to evaluate the association between midlife central obesity and risk of dementia three decades later. Methods: A longitudinal analysis was conducted of 6,583 members of Kaiser Permanente of Northern California who had their sagittal abdominal diameter (SAD) measured in 1964 to 1973. Diagnoses of dementia were from medical records an average of 36 years later, January 1, 1994, to June 16, 2006. Cox proportional hazard models adjusted for age, sex, race, education, marital status, diabetes, hypertension, hyperlipidemia, stroke, heart disease, and medical utilization were conducted. Results: A total of 1,049 participants (15.9%) were diagnosed with dementia. Compared with those in the lowest quintile of SAD, those in the highest had nearly a threefold increased risk of dementia (hazard ratio, 2.72; 95% CI, 2.33–3.33), and this was only mildly attenuated after adding body mass index (BMI) to the model (hazard ratio, 1.92; 95% CI, 1.58 –2.35). Those with high SAD (25 cm) and normal BMI had an increased risk (hazard ratio, 1.89; 95% CI, 0.98 – 3.81) vs those with low SAD (25 cm) and normal BMI (18.5–24.9 kg/m 2 ), whereas those both obese (BMI 30 kg/m 2 ) and with high SAD had the highest risk of dementia (HR, 3.60; 95% CI,

Abstract: Background: Multiple sclerosis (MS) has been traditionally considered to be more frequent in women and in regions more distant from the equator. However, recent reports suggest that the latitude gradient could be disappearing and that the female-to-male ratio among patients with MS has increased in the last decades. We have conducted a systematic review of incidence studies of MS to assess the overall incidence of MS and explore possible changes in the latitude gradient and the female-to-male ratio over time. Methods: Systematic review of incidence studies of MS published in Medline between 1966 and February 2007. Age- and sex-specific incidence rates were collected from eligible publications. We computed age-adjusted rates using the world population as standard, and assessed differences in rates according to latitude and period of case ascertainment. Additionally, we evaluated the association between period of case ascertainment and the female-to-male ratio. Results: The overall incidence rate of MS was 3.6 cases per 100,000 person-years (95% CI 3.0, 4.2) in women and 2.0 (95% CI 1.5, 2.4) in men. Higher latitude was associated with higher MS incidence, though this latitude gradient was attenuated after 1980, apparently due to increased incidence of MS in lower latitudes. The female-to-male ratio in MS incidence increased over time, from an estimated 1.4 in 1955 to 2.3 in 2000. Conclusion: The latitude gradient present in older incidence studies of multiple sclerosis (MS) is decreasing. The female-to-male MS ratio has increased in the last five decades.

Abstract: Objective: Primary progressive aphasia (PPA) is characterized by isolated decline in language functions. Semantic dementia and progressive nonfluent aphasia are accepted PPA variants. A “logopenic” variant (LPA) has also been proposed, but its cognitive and anatomic profile is less defined. The aim of this study was to establish the cognitive and anatomic features of LPA. Methods: Six previously unreported LPA cases underwent extensive neuropsychological evaluation and an experimental study of phonological loop functions, including auditory and visual span tasks with digits, letters, and words. For each patient, a voxel-wise, automated analysis of MRI or SPECT data were conducted using SPM2. Results: In LPA, speech rate was slow, with long word-finding pauses. Grammar and articulation were preserved, although phonological paraphasias could be present. Repetition and comprehension were impaired for sentences but preserved for single words, and naming was moderately affected. Investigation of phonological loop functions showed that patients were severely impaired in digit, letter, and word span tasks. Performance did not improve with pointing, was influenced by word length, and did not show the normal phonological similarity effect. Atrophy or decreased blood flow was consistently found in the posterior portion of the left superior and middle temporal gyri and inferior parietal lobule. Conclusions: Logopenic progressive aphasia (LPA) is a distinctive variant of primary progressive aphasia. Cognitive and neuroimaging data indicate that a deficit in phonological loop functions may be the core mechanism underlying the LPA clinical syndrome. Recent studies suggest that Alzheimer disease may be the most common pathology underlying the LPA clinical syndrome. GLOSSARY: AD = Alzheimer disease; BA = Brodmann area; CDR = Clinical Dementia Rating; CVLT-MS = California Verbal Learning Test–Mental Status Edition; ECD = ethyl cysteinate dimer; FWHM = full-width at half-maximum; GM = gray matter; LPA = logopenic progressive aphasia; MMSE = Mini-Mental State Examination; PNFA = progressive nonfluent aphasia; PPA = primary progressive aphasia; Rey-O = Rey–Osterrieth; SemD = semantic dementia; VBM = voxel-based morphometry; WAB = Western Aphasia Battery; WAIS-III = Wechsler Adult Intelligence Scale, Third Edition.

Abstract: Objective: To perform an evidence-based review of the safety and efficacy of botulinum neurotoxin (BoNT) in the treatment of movement disorders. Methods: A literature search was performed including MEDLINE and Current Contents for therapeutic articles relevant to BoNT and selected movement disorders. Authors reviewed, abstracted, and classified articles based on American Academy of Neurology criteria (Class I–IV). Results: The highest quality literature available for the respective indications was as follows: blepharospasm (two Class II studies); hemifacial spasm (one Class II and one Class III study); cervical dystonia (seven Class I studies); focal upper extremity dystonia (one Class I and three Class II studies); focal lower extremity dystonia (one Class II study); laryngeal dystonia (one Class I study); motor tics (one Class II study); and upper extremity essential tremor (two Class II studies). Recommendations: Botulinum neurotoxin should be offered as a treatment option for the treatment of cervical dystonia (Level A), may be offered for blepharospasm, focal upper extremity dystonia, adductor laryngeal dystonia, and upper extremity essential tremor (Level B), and may be considered for hemifacial spasm, focal lower limb dystonia, and motor tics (Level C). While clinicians’ practice may suggest stronger recommendations in some of these indications, evidencebased conclusions are limited by the availability of data. Neurology ® 2008;70:1699–1706

Abstract: Background: Trigeminal neuralgia (TN) is a common cause of facial pain. Purpose: To answer the following questions: 1) In patients with TN, how often does routine neuroimaging (CT, MRI) identify a cause? 2) Which features identify patients at increased risk for symptomatic TN (STN; i.e., a structural cause such as a tumor)? 3) Does high-resolution MRI accurately identify patients with neurovascular compression? 4) Which drugs effectively treat classic and symptomatic trigeminal neuralgia? 5) When should surgery be offered? 6) Which surgical technique gives the longest pain-free period with the fewest complications and good quality of life? Methods: Systematic review of the literature by a panel of experts. Conclusions: In patients with trigeminal neuralgia (TN), routine head imaging identifies structural causes in up to 15% of patients and may be considered useful (Level C). Trigeminal sensory deficits, bilateral involvement of the trigeminal nerve, and abnormal trigeminal reflexes are associated with an increased risk of symptomatic TN (STN) and should be considered useful in distinguishing STN from classic trigeminal neuralgia (Level B). There is insufficient evidence to support or refute the usefulness of MRI to identify neurovascular compression of the trigeminal nerve (Level U). Carbamazepine (Level A) or oxcarbazepine (Level B) should be offered for pain control while baclofen and lamotrigine (Level C) may be considered useful. For patients with TN refractory to medical therapy, Gasserian ganglion percutaneous techniques, gamma knife, and microvascular decompression may be considered (Level C). The role of surgery vs pharmacotherapy in the management of TN in patients with MS remains uncertain. Neurology ® 2008;71:1183–1190

Abstract: Sporadic Parkinson disease (PD) is, after Alzheimer disease (AD), the second most frequent neurodegenerative disorder.1 The pathologic process in PD is progressive and takes years to reach its full extent. It does not affect nonhuman vertebrates or organ systems other than the nervous system, and, apparently, it does not go into remission. Unlike AD, however, the pathology is distributed throughout the entire nervous system—that is, not only the central but also the peripheral and the enteric nervous systems (CNS, PNS, ENS). As a result, PD has come to be acknowledged as more than a monosystemic disorder with preferential obliteration of nigral dopaminergic neurons.2–8,e1-e3 In the clinically recognizable, i.e., motor, phase of sporadic PD, most patients display signs of motor dysfunction (hypo- or bradykinesia, cogwheel rigidity, postural instability, resting tremor),9,e4,e5 but these symptoms also occur in other disorders associated with dopamine loss in the nigrostriatal system.e6,e7 Familial forms of parkinsonism exist,3,e8,e9 and the syndrome may also develop as a sequel to intoxication, trauma, vascular alterations, metabolic disease, or infection.e3,e10-e14 In addition, parkinsonism can develop in tauopathies, including corticobasal degeneration and progressive supranuclear palsy,e15-e17 or in synucleinopathies, such as multiple system atrophy and Lewy body disease.10,11,e18-e20 Lewy body disease has been subdivided further into pure autonomic failure, dementia with Lewy bodies, and sporadic PD.11,12 The latter two entities are nearly indistinguishable at neuropathologic examination, and there is a growing consensus that, clinically, they are closely related, if not identical.13–17 Here, we refer only to the Lewy body pathology associated with the synucleinopathy sporadic (or idiopathic) PD, the most widespread form of parkinsonism.1,8,e25 In PD, typical α-synuclein immunoreactive inclusions (Lewy neurites [LNs], Lewy bodies [LBs]) develop within specific types of projection neurons in all portions of the …

Abstract: Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) may protect against Alzheimer disease (AD), but observational studies and trials have offered contradictory results. Prior studies have also been relatively short and small. We examined the effects on AD risk of NSAID use for >5 years and of NSAIDs that suppress formation of Aβ 1-42 amyloid in a large health care database. Methods: Cases were veterans aged 55 years and older with incident AD using the US Veterans Affairs Health Care system. Matched controls were drawn from the same population. NSAID exposure was categorized into seven time periods: no use, ≤1 year, >1 but ≤2 years, and so on. Using conditional logistic regression, adjusted for race and comorbidities, we tested the association between AD development and the use of 1) any NSAID, 2) any NSAID excluding nonacetylated salicylates, 3) each NSAID class, 4) each individual NSAID, and 5) Aβ 1-42 -suppressing NSAIDs. Results: We identified 49,349 cases and 196,850 controls. Compared with no NSAID use, the adjusted odds ratios for AD among NSAID users decreased from 0.98 for ≤1 year of use (95% CI 0.95–1.00) to 0.76 for >5 years of use (0.68–0.85). For users of ibuprofen, it decreased from 1.03 (1.00–1.06) to 0.56 (0.42–0.75). Effects of other NSAID classes and individual NSAIDs were inconsistent. There was no difference between a group of Aβ 1-42 -suppressing NSAIDs and others. Discussion: Long-term nonsteroidal anti-inflammatory drug (NSAID) use was protective against Alzheimer disease. Findings were clearest for ibuprofen. Aβ 1-42 -suppressing NSAIDs did not differ from others.

Abstract: Background: Varicella zoster virus (VZV) vasculopathy produces stroke secondary to viral infection of cerebral arteries. Not all patients have rash before cerebral ischemia or stroke. Furthermore, other vasculitides produce similar clinical features and comparable imaging, angiographic, and CSF abnormalities. Methods: We review our 23 published cases and 7 unpublished cases of VZV vasculopathy. All CSFs were tested for VZV DNA by PCR and anti-VZV IgG antibody and were positive for either or both. Results: Among 30 patients, rash occurred in 19 (63%), CSF pleocytosis in 20 (67%), and imaging abnormalities in 29 (97%). Angiography in 23 patients revealed abnormalities in 16 (70%). Large and small arteries were involved in 15 (50%), small arteries in 11 (37%), and large arteries in only 4 (13%) of 30 patients. Average time from rash to neurologic symptoms and signs was 4.1 months, and from neurologic symptoms and signs to CSF virologic analysis was 4.2 months. CSF of 9 (30%) patients contained VZV DNA while 28 (93%) had anti-VZV IgG antibody in CSF; in each of these patients, reduced serum/CSF ratio of VZV IgG confirmed intrathecal synthesis. Conclusions: Rash or CSF pleocytosis is not required to diagnose varicella zoster virus (VZV) vasculopathy, whereas MRI/CT abnormalities are seen in almost all patients. Most patients had mixed large and small artery involvement. Detection of anti-VZV IgG antibody in CSF was a more sensitive indicator of VZV vasculopathy than detection of VZV DNA ( p GLOSSARY: EIA = enzyme immunoabsorbent assay; VZV = varicella zoster virus.

Abstract: Objective: To determine if a relationship exists between the clinical features of Rett syndrome, an X-linked dominant neurodevelopmental disorder, and specific mutations in MECP2 . Method: Cross-sectional study of 245 girls and women with typical Rett syndrome seen between 1990 and 2004 in tertiary academic outpatient specialty clinics and who had complete MECP2 mutation analysis. A structured clinical evaluation was completed for each participant. The results were grouped by MECP2 mutation and compared. Results: Participants with the R133C mutation are less severely affected than those with R168X or large DNA deletions ( p p p p = 0.008), retain hand use ( p = 0.002), or use words ( p = 0.001). In contrast, those with carboxy-terminal truncations are more likely to walk ( p = 0.007) and use words ( p p Conclusions: Specific mutations in MECP2 confer different severity. These results allow the design of therapies targeted toward the amelioration of expected problems. Furthermore, the distinct effects of MECP2 mutations on clinical severity must be considered in clinical intervention trials.

Abstract: Objective: To evaluate the cognitive effect of transcranial direct current stimulation (tDCS) over the temporoparietal areas in patients with Alzheimer disease (AD). Methods: In 10 patients with probable AD, we delivered anodal tDCS (AtDCS), cathodal tDCS (CtDCS), and sham tDCS (StDCS) over the temporoparietal areas in three sessions. In each session recognition memory and visual attention were tested at baseline (prestimulation) and 30 minutes after tDCS ended (poststimulation). Results: After AtDCS, accuracy of the word recognition memory task increased (prestimulation: 15.5 ± 0.9, poststimulation: 17.9 ± 0.8, p = 0.0068) whereas after CtDCS it decreased (15.8 ± 0.6 vs 13.2 ± 0.9, p = 0.011) and after StDCS it remained unchanged (16.3 ± 0.7 vs 16.0 ± 1.0, p = 0.75). tDCS left the visual attention-reaction times unchanged. Conclusion: Transcranial direct current stimulation (tDCS) delivered over the temporoparietal areas can specifically affect a recognition memory performance in patients with Alzheimer disease (AD). Because tDCS is simple, safe and inexpensive, our finding prompts studies using repeated tDCS, in conjunction with other therapeutic interventions for treating patients with AD.

Abstract: Background: The risk for dementia in Parkinson disease (PD) is high, with important clinical consequences for patients with PD. However, the absolute risk of dementia and how it affects survival in PD are not known. Such questions are important for patients, their families, and service providers but require long-term studies. Methods: This study is a prospective longitudinal cohort study with patients from a prevalence study of PD in Norway. Patients were reassessed 4, 8, 9, 10, 11, and 12 years after prevalence day. A dementia diagnosis according to Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised, criteria was based on a semistructured caregiver interview, cognitive rating scales, and neuropsychological tests. Progression from PD to PD with dementia and death was modeled using a continuous-time three-state irreversible Markov model. Results: A total of 233 PD patients were included, and 140 patients (60%, 95% CI 54% to 66%) had developed dementia by the end of the study period. The cumulative incidence of dementia steadily increases with age and duration of PD and, conditional on survival, increases to 80% to 90% by age 90 years. Women live with PD longer than men and spend more years with dementia. At age 70 years, a man with PD but no dementia has a life expectancy of 8 years, of which 5 years would be expected to be dementia free and 3 years would be expected to be with dementia. Conclusion: Dementia is a key part of survival in Parkinson disease and must be planned for in services for this condition.

Abstract: Objective: In the Leukoaraiosis and Disability (LADIS) Study, 11 European centers are evaluating the role of age-related white matter changes (ARWMC) as an independent determinant of the transition to disability in the elderly (65 to 84 years). We aimed at determining the influence of ARWMC on different objective measures of gait and balance. Methods: Six hundred thirty-nine nondisabled individuals were prospectively enrolled and are being followed-up for 3 years. Subjects are graded in three standardized categories of ARWMC (mild, moderate, and severe) according to central MRI reading. Quantitative tests of gait and balance include the Short Physical Performance Battery (SPPB; range: 0 [poor] to 12 [normal]), a timed 8-m walk, and a timed single leg stance test. Results: In cross-sectional analysis, deficiencies in gait and balance performance were correlated with the severity of ARWMC (SPPB: 10.2 ± 2.1 in the mild, 9.9 ± 2.0 in the moderate, 8.9 ± 2.6 in the severe group; p Conclusions: Our findings support a strong association between the severity of age-related white matter changes and the severity of gait and motor compromise. Physical activity might have the potential to reduce the risk of limitations in mobility.

Abstract: Objective: To evaluate the disability profile and patterns of treatment and health care use for chronic migraine (CM) in the general population, in contrast to episodic migraine. Methods: We identified 24,000 headache sufferers, drawn from more than 165,000 individuals representative of the US population. This sample has been followed up with annual surveys using validated questionnaires for the diagnosis of episodic migraine and CM. As a part of the survey, subjects were asked to report the specific medications currently used for their most severe headaches, as well as level of satisfaction with treatment. Results: Our sample consisted of 520 individuals with CM and 9,424 with episodic migraine. Over a 3-month period, more than half of the individuals with CM missed at least 5 days of household work, compared with 24.3% of those with episodic migraine ( p p p Conclusion: Chronic migraine (CM) is more disabling than episodic migraine in the population. Although most individuals with CM sought medical care for this disorder, the majority did not receive specific acute or preventive medications.

Abstract: Background: Quantitative head impulse test (HIT) measures the gain of the angular vestibulo-ocular reflex (VOR) during head rotation as the ratio of eye to head acceleration. Bedside HIT identifies subsequent catch-up saccades after the head rotation as indirect signs of VOR deficit. Objective: To determine the VOR deficit and catch-up saccade characteristics in unilateral vestibular disease in response to HIT of varying accelerations. Methods: Eye and head rotations were measured with search coils during manually applied horizontal HITs of varying accelerations in patients after vestibular neuritis (VN, n = 13) and unilateral vestibular deafferentation (UVD, n = 15) compared to normal subjects (n = 12). Results: Normal VOR gain was close to unity and symmetric over the entire head-acceleration range. Patients with VN and UVD showed VOR gain asymmetry, with larger ipsilesional than contralesional deficits. As accelerations increased from 750 to 6,000 °/sec 2 , ipsilesional gains decreased from 0.59 to 0.29 in VN and from 0.47 to 0.13 in UVD producing increasing asymmetry. Initial catch-up saccades can occur during or after head rotation. Covert saccades during head rotation are most likely imperceptible, while overt saccades after head rotation are detectable by clinicians. With increasing acceleration, the amplitude of overt saccades in patients became larger; however, initial covert saccades also became increasingly common, occurring in up to about 70% of trials. Conclusions: Head impulse test (HIT) with high acceleration reveals vestibulo-ocular reflex deficits better and elicits larger overt catch-up saccades in unilateral vestibular patients. Covert saccades during head rotation, however, occur more frequently with higher acceleration and may be missed by clinicians. To avoid false-negative results, bedside HIT should be repeated to improve chances of detection.

Abstract: Objective: We evaluated the cross-sectional association between restless legs syndrome (RLS) and prevalent cardiovascular disease (CVD) in a large community-based sample of middle-aged and elderly subjects. Methods: This is a cross-sectional observational study of 1,559 men and 1,874 women (mean age of 67.9 years) who were enrolled in the Sleep Heart Health Study, a community-based study of the cardiovascular consequences of sleep-disordered breathing. RLS was defined by positive responses on a self-administered questionnaire to the four diagnostic criteria, with symptoms occurring at least five times per month and associated with at least moderate distress. Coronary artery disease (CAD) was determined by self-report of doctor-diagnosed angina, myocardial infarction, or coronary revascularization procedure. Total CVD included CAD or history of physician-diagnosed stroke or heart failure. The relation of RLS to prevalent CAD and CVD was examined by multivariable logistic regression models Results: RLS was present in 6.8% of women (n = 128) and 3.3% of men (n = 51). After adjustment for age, sex, race, body mass index, diabetes mellitus, systolic blood pressure, antihypertensive medication use, total:high-density lipoprotein cholesterol ratio, and smoking history, the ORs for CAD were 2.05 (95% CI 1.38 to 3.04) and for CVD were 2.07 (1.43 to 3.00) for subjects with RLS compared to those without RLS. The associations of RLS with CAD and CVD were stronger in those with RLS symptoms at least 16 times per month and were stronger in those with severe than in those with moderately bothersome symptoms. Conclusions: Restless legs syndrome (RLS) is associated with prevalent coronary artery disease and cardiovascular disease. This association appears stronger in those with greater frequency or severity of RLS symptoms. GLOSSARY: AHI = apnea-hypopnea index; CAD = coronary artery disease; CVD = cardiovascular disease; DBP = diastolic blood pressure; ESRD = end-stage renal disease; HDL = high-density lipoprotein; IQR = interquartile range; LDL = low-density lipoprotein; OSA = obstructive sleep apnea; OSAH = obstructive sleep apnea/hypopnea; PLMS = periodic leg movements of sleep; RLS = restless legs syndrome; SBP = systolic blood pressure; SHHS = Sleep Heart Health Study.

Abstract: Gordon-Lipkin et al. reported the correlation between the thickness of the retinal nerve fiber layer (RNFL) and brain parenchymal atrophy in multiple sclerosis (MS).1 These results confirm our previous study where we found correlation between RNFL thickness and gray matter and white matter volume.2 Using two different approaches for measuring brain atrophy, both studies demonstrate that the thickness of the RNFL correlates with brain atrophy. In both cases, we studied patients at the early to medium stage of the disease, indicating that the atrophy identified, both at the head of the optic nerve and in the brain, is …

Abstract: The 2008 AAN guideline “Practice Parameter: Therapies for benign paroxysmal positional vertigo (an evidence-based review)” has been retired by the Guideline Development, Dissemination, and Implementation Subcommittee …

Abstract: Background: In a primate model of Parkinson disease (PD), intrastriatal infusion of an adeno-associated viral (AAV) vector containing the human aromatic l-amino acid decarboxylase ( hAADC ) gene results in robust gene expression. After gene transfer, low doses of systemically administered l-dopa are converted to dopamine in the transduced striatal neurons, resulting in behavioral improvement without the side effects typically associated with higher doses of l-dopa. These studies led to the initiation of a phase I safety trial. Here we report the findings for the first cohort of five patients. Methods: Patients with moderate to advanced PD received bilateral infusion of a low dose of the AAV-hAADC vector into the putamen. PET scans using the AADC tracer, 6-[18F]fluoro-l-m-tyrosine (FMT), were performed at baseline and at 1 and 6 months after infusion as an in vivo measure of gene expression. Results: PET results showed an average 30% increase in FMT uptake (K i c ) in the putamen after gene transfer. Preliminary analysis of clinical data indicates a modest improvement, but absence of a control and the nonblinded analyses make interpretation difficult. Conclusions: Thus far, this gene therapy approach has been well tolerated and shows PET evidence of sustained gene expression. These initial findings demonstrate the safety of the therapy; higher doses of adeno-associated viral vector containing the human aromatic l-amino acid decarboxylase gene in the next cohort of patients may further increase dopamine production in the putamen and provide more profound clinical benefit. GLOSSARY: AADC = aromatic l-amino acid decarboxylase; AAV = adeno-associated viral; DA = dopamine; FMT =6-[18F]fluoro-l-m-tyrosine; hAADC = human aromatic l-amino acid decarboxylase; l-dopa = levodopa; PD = Parkinson disease; ROI = region of interest; UPDRS = Unified Parkinson’s Disease Rating Scale.

Abstract: Objectives: The primary objective was to investigate whether nonadherence to antiepileptic drugs (AEDs) is associated with increased mortality and the secondary objective to examine whether nonadherence increases the risk of serious clinical events, including emergency department (ED) visits, hospitalizations, motor vehicle accident (MVA) injuries, fractures, and head injuries. Methods: A retrospective open-cohort design was employed using Medicaid claims data from Florida, Iowa, and New Jersey from January 1997 through June 2006. Patients aged ≥18 years with ≥1 diagnosis of epilepsy by a neurologist and ≥2 AED pharmacy dispensings were selected. Medication possession ratio (MPR) was used to evaluate AED adherence on a quarterly basis with MPR ≥0.80 considered adherent and Results: The 33,658 study patients contributed 388,564 AED-treated quarters (26% nonadherent). Nonadherence was associated with an over threefold increased risk of mortality compared to adherence (hazard ratio = 3.32, 95% CI = 3.11–3.54) after multivariate adjustments. Time periods of nonadherence were also associated with a significantly higher incidence of ED visits (IRR = 1.50, 95% CI = 1.49–1.52), hospital admissions (IRR = 1.86, 95% CI = 1.84–1.88), MVA injuries (IRR = 2.08, 95% CI = 1.81–2.39), and fractures (IRR = 1.21, 95% CI = 1.18–1.23) than periods of adherence. Conclusion: These findings suggest that nonadherence to antiepileptic drugs can have serious or fatal consequences for patients with epilepsy.

Abstract: Objective: To test the diagnostic accuracy of the horizontal head impulse test (h-HIT) of vestibulo-ocular reflex (VOR) function in distinguishing acute peripheral vestibulopathy (APV) from stroke. Most patients with acute vertigo, nausea/vomiting, and unsteady gait have benign APV (vestibular neuritis or labyrinthitis) as a cause. However, some harbor life-threatening brainstem or cerebellar strokes that mimic APV. A positive h-HIT (abnormal VOR) is said to predict APV. Methods: Cross-sectional study at an urban, academic hospital over 6 years. Consecutive acute vestibular syndrome patients at high risk for stroke underwent structured examination (including h-HIT), neuroimaging, and admission. Stroke was confirmed by neuroimaging (MRI or CT). APV was diagnosed by normal MRI and appropriate clinical evolution in follow-up. Results: Forty-three subjects enrolled. One had an equivocal h-HIT. Patients with APV had a positive h-HIT (n = 8/8, 100%). Most patients with stroke had a negative h-HIT (n = 31/34, 91%). However, contrary to conventional wisdom, three patients with stroke (9%) demonstrated a positive h-HIT (1 vestibulocerebellar, 1 pontocerebellar, 1 pontocerebello-labyrinthine stroke). Conclusions: Patients with lateral pontine and cerebellar strokes can have a positive horizontal head impulse test (h-HIT), so the sign’s presence cannot be solely relied upon to identify a benign pathology. Additional clinical features (e.g., directionality of nystagmus, severity of truncal instability, nature of hearing loss) must be considered in patients with acute vestibular syndrome with a positive h-HIT before a central localization can be confidently excluded. Nonetheless, the h-HIT remains a useful bedside test—in acute vestibular syndrome patients, a negative h-HIT (i.e., normal VOR) strongly suggests a central lesion with a pseudo-labyrinthine presentation.

Abstract: Background: Severe gait disturbances and freezing episodes (frequently resistant to optimal dopaminergic treatment) often appear in advanced Parkinson disease (PD). Even several years after initiation, high-frequency subthalamic nucleus deep brain stimulation (STN-DBS) is still very effective for controlling segmental symptoms. However, there are no long-term data on the management of gait disorders and freezing in STN-DBS. Objectives: To compare the effects of various STN-DBS parameters on freezing of gait and to determine whether such effects are more related to stimulation energy (usual voltages vs high voltages at 130 Hz) or frequency (130 Hz vs approximately half this frequency: 60 Hz). Methods: We blindly assessed STN-DBS parameters in 13 PD patients reporting severe gait disorders. We compared the effects on gait of two different voltages (the patient’s usual voltage [median 3 volts] and a high voltage [median 3.7 volts]) and two different frequencies (60 and 130 Hz, while maintaining the same total energy delivered) vs “off-stimulation” conditions. Results: The number of freezing episodes was significantly lower at the 60-Hz “high voltage/ equivalent energy” and higher at the 130-Hz/high voltage than for “off stimulation.” The slight improvement in the Unified Parkinson’s Disease Rating Scale motor score observed (at 130 Hz) did not achieve statistical significance. Conclusions: Our results prompt consideration of a new strategy for two-stage subthalamic nucleus deep brain stimulation (STN-DBS) frequency optimization, with stimulation at 130 Hz and the usual voltage during the initial years of STN-DBS and then at 60 Hz at a high voltage in Parkinson disease patients who develop severe gait disorders. Neurology ® 2008;71:80–84

Abstract: Background: Older adults get lost, in many cases because of recognized or incipient Alzheimer disease (AD). In either case, getting lost can be a threat to individual and public safety, as well as to personal autonomy and quality of life. Here we compare our previously described real-world navigation test with a virtual reality (VR) version simulating the same navigational environment. Methods: Quantifying real-world navigational performance is difficult and time-consuming. VR testing is a promising alternative, but it has not been compared with closely corresponding real-world testing in aging and AD. We have studied navigation using both real-world and virtual environments in the same subjects: young normal controls (YNCs, n = 35), older normal controls (ONCs, n = 26), patients with mild cognitive impairment (MCI, n = 12), and patients with early AD (EAD, n = 14). Results: We found close correlations between real-world and virtual navigational deficits that increased across groups from YNC to ONC, to MCI, and to EAD. Analyses of subtest performance showed similar profiles of impairment in real-world and virtual testing in all four subject groups. The ONC, MCI, and EAD subjects all showed greatest difficulty in self-orientation and scene localization tests. MCI and EAD patients also showed impaired verbal recall about both test environments. Conclusions: Virtual environment testing provides a valid assessment of navigational skills. Aging and Alzheimer disease (AD) share the same patterns of difficulty in associating visual scenes and locations, which is complicated in AD by the accompanying loss of verbally mediated navigational capacities. We conclude that virtual navigation testing reveals deficits in aging and AD that are associated with potentially grave risks to our patients and the community.

Abstract: Background: High intake of n-3 polyunsaturated fatty acids may protect against age-related cognitive decline. However, results from epidemiologic studies are inconclusive, and results from randomized trials in elderly subjects without dementia are lacking. Objective: To investigate the effect of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) supplementation on cognitive performance. Methods: Double-blind, placebo-controlled trial involving 302 cognitively healthy (Mini-Mental State Examination score > 21) individuals aged 65 years or older. Participants were randomly assigned to 1,800 mg/d EPA–DHA, 400 mg/d EPA–DHA, or placebo capsules for 26 weeks. Cognitive performance was assessed using an extensive neuropsychological test battery that included the cognitive domains of attention, sensorimotor speed, memory, and executive function. Results: The mean age of the participants was 70 years, and 55% were male. Plasma concentrations of EPA–DHA increased by 238% in the high-dose and 51% in the low-dose fish oil group compared with placebo, reflecting excellent compliance. Baseline scores on the cognitive tests were comparable in the three groups. Overall, there were no significant differential changes in any of the cognitive domains for either low-dose or high-dose fish oil supplementation compared with placebo. Conclusions: In this randomized, double-blind, placebo-controlled trial, we observed no overall effect of 26 weeks of eicosapentaenoic acid and docosahexaenoic acid supplementation on cognitive performance.

Abstract: Background: Optimal treatment remains uncertain for patients with cognitive impairment that persists or returns after standard IV antibiotic therapy for Lyme disease. Methods: Patients had well-documented Lyme disease, with at least 3 weeks of prior IV antibiotics, current positive IgG Western blot, and objective memory impairment. Healthy individuals served as controls for practice effects. Patients were randomly assigned to 10 weeks of double-masked treatment with IV ceftriaxone or IV placebo and then no antibiotic therapy. The primary outcome was neurocognitive performance at week 12—specifically, memory. Durability of benefit was evaluated at week 24. Group differences were estimated according to longitudinal mixed-effects models. Results: After screening 3368 patients and 305 volunteers, 37 patients and 20 healthy individuals enrolled. Enrolled patients had mild to moderate cognitive impairment and marked levels of fatigue, pain, and impaired physical functioning. Across six cognitive domains, a significant treatment-by-time interaction favored the antibiotic-treated group at week 12. The improvement was generalized (not specific to domain) and moderate in magnitude, but it was not sustained to week 24. On secondary outcome, patients with more severe fatigue, pain, and impaired physical functioning who received antibiotics were improved at week 12, and this was sustained to week 24 for pain and physical functioning. Adverse events from either the study medication or the PICC line were noted among 6 of 23 (26.1%) patients given IV ceftriaxone and among 1 of 14 (7.1%) patients given IV placebo; these resolved without permanent injury. Conclusion: IV ceftriaxone therapy results in short-term cognitive improvement for patients with posttreatment Lyme encephalopathy, but relapse in cognition occurs after the antibiotic is discontinued. Treatment strategies that result in sustained cognitive improvement are needed.

Abstract: Background: Parkinson disease (PD) is a progressive neurodegenerative disorder in which the major pathologic substrate is a loss of dopaminergic neurons from the lateral substantia nigra pars compacta (SNc). Our objective was to determine whether, in patients with early PD, SNc changes evident on MRI sequences sensitive to iron content corresponded anatomically to the pathologic changes reported previously, and to correlate these changes to the duration and severity of clinical manifestations of PD. Methods: Twenty-six untreated patients with early PD and 13 age- and gender-matched control subjects had MRI with a 3 tesla magnet using a multiple gradient echo sequence designed for rapid single-scan mapping of the proton transverse relaxation rate ( R 2 * ). R 2 * was calculated for midbrain and forebrain basal ganglia regions. Clinical features were rated with the Unified Parkinson9s Disease Rating Scale. Results: A difference in measured R 2 * values between patients and controls was observed in the lateral SNc ( p ≤ 0.005). Linear regression indicated a correlation between the lateralized motor score from the clinically most affected side and R 2 * values from the opposite lateral SNc ( p = 0.01). Conclusions: High field strength MRI demonstrates lateral substantia nigra pars compacta abnormalities in early Parkinson disease (PD) consistent with increased iron content and corresponding to the known distribution of neuronal loss occurring in this disorder. This may ultimately provide an imaging marker for disease progression in PD, although longitudinal studies are required. GLOSSARY: AC = anterior commissure; CN = caudate nucleus; GP = globus pallidus; LantGP = left anterior GP; LantPu = left anterior Pu; LlatSNc = left lateral SNc; LlatSNr = left lateral SNr; LmedSNc = left medial SNc; LmedSNr = left medial SNr; LpostGP = left posterior GP; LpostPu = left posterior Pu; PC = posterior commissure; PD = Parkinson disease; Pu = putamen; RantGP = right anterior GP; RantPu = right anterior Pu; RlatSNc = right lateral SNc; RlatSNr = right lateral SNr; RmedSNc = right medial SNc; RmedSNr = right medial SNr; RN = red nucleus; ROI = region of interest; RpostGP = right posterior GP; RpostPu = right posterior Pu; SNc = substantia nigra compacta; SNr = substantia nigra reticulata; TE = echo times; UPDRS = Unified Parkinson9s Disease Rating Scale.