Showing papers in "Neurology in 2003"

Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization.

Abstract: Background: AD is characterized by cerebral deposition of β-amyloid plaques with amyloid β-peptide (Aβ) 42 as the major peptide constituent, along with neurofibrillary tangles and neuronal loss. In transgenic mice, active immunization against Aβ42 removes these plaques and improves cognitive function. A Phase I study in AD patients demonstrated good safety and tolerability of multiple injections of aggregated Aβ42 (AN1792) with QS-21 as adjuvant. Methods: Three hundred seventy-two patients with mild to moderate AD were randomized to receive IM injections of AN1792 or placebo (4:1) at baseline and at months 1, 3, 6, 9, and 12 in a multicenter Phase II safety, tolerability, and pilot efficacy study. Dosing was terminated after four early reports of meningoencephalitis, but follow-up continued. The study remains blinded, and further results will be reported after its termination. Results: Symptoms and laboratory findings consistent with meningoencephalitis occurred in 18 of 298 (6%) patients treated with AN1792 compared with 0 of 74 on placebo ( p = 0.020). Sixteen of the 18 had received two doses, one had received one dose, and one had received three doses of the study drug before symptoms occurred. The median latency from the first and last injections to symptoms was 75 and 40 days. No case occurred later than 6 months after the first immunization. Anti-Aβ42 antibody titers were not correlated with the occurrence or severity of symptoms or relapses. Twelve patients recovered to or close to baseline within weeks, whereas six remain with disabling cognitive or neurologic sequelae. All 18 patients remain alive to date (December 31, 2002), 6 months to >1 year after symptom onset. Conclusions: Postvaccination meningoencephalitis occurred without clear relation to serum anti-Aβ42 antibody titers. Potential mechanisms such as T-cell and microglial activation may be responsible and are under consideration to develop a safer anti-Aβ immunotherapy for AD.

Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer's disease.

Abstract: Objective: To examine the relationship between stereologic estimates of AD-related pathology and severity of cognitive deficits in brain aging. Background: Previous studies reported substantial contributions of neurofibrillary tangles (NFT), amyloid deposits, and neuronal loss to the development of dementia. However, the prediction of cognitive status based on nonstereologic quantification of these measures has led to conflicting results. Such studies have measured densities, rather than absolute numbers, and most do not take into account the potential interaction between the above pathologic hallmarks in a global multivariate analysis. Methods: Clinicopathologic study in 22 elderly cases. Cognitive status assessed prospectively using the Mini-Mental State Examination (MMSE); stereologic assessment of NFT, unaffected neurons, and total amyloid volume in the CA1 field of the hippocampus, entorhinal cortex, and area 9. Statistical analysis was performed using both univariate and multivariate linear regression models. Results: High total NFT counts but not amyloid volume were strongly associated with a lower number of unaffected neurons in all areas studied. A high proportion of variability in MMSE scores was explained by NFT and neuronal counts in the CA1 field (83% and 85.4%), entorhinal cortex (87.8% and 83.7%), and area 9 (87% and 79%); amyloid volume in the entorhinal cortex, but not in the CA1 field and area 9, accounted for 58.5% of MMSE variability. Multivariate analyses showed that total NFT counts in the entorhinal cortex and area 9 as well as neuron numbers in the CA1 field were the best predictors of MMSE score. Conclusions: These new stereologic data indicate that neuronal pathology in hippocampal formation and frontal cortex closely reflects the progression of cognitive deficits in brain aging and AD. They also demonstrate that amyloid volume has no additional predictive value, in terms of clinicopathologic correlations, beyond its interaction with NFT.

Practice parameter: Temporal lobe and localized neocortical resections for epilepsy Report of the Quality Standards Subcommittee of the American Academy of Neurology, in Association with the American Epilepsy Society and the American Association of Neurological Surgeons

Abstract: Objectives/Methods: To examine evidence for effectiveness of anteromesial temporal lobe and localized neocor- tical resections for disabling complex partial seizures by systematic review and analysis of the literature since 1990. Results: One intention-to-treat Class I randomized, controlled trial of surgery for mesial temporal lobe epilepsy found that 58% of patients randomized to be evaluated for surgical therapy (64% of those who received surgery) were free of disabling seizures and 10 to 15% were unimproved at the end of 1 year, compared with 8% free of disabling seizures in the group randomized to continued medical therapy. There was a significant improvement in quantitative quality-of-life scores and a trend toward better social function at the end of 1 year for patients in the surgical group, no surgical mortality, and infrequent morbidity. Twenty-four Class IV series of temporal lobe resections yielded essentially identical results. There are similar Class IV results for localized neocortical resections; no Class I or II studies are available. Conclusions: A single Class I study and 24 Class IV studies indicate that the benefits of anteromesial temporal lobe resection for disabling complex partial seizures is greater than continued treatment with antiepileptic drugs, and the risks are at least compara- ble. For patients who are compromised by such seizures, referral to an epilepsy surgery center should be strongly considered. Further studies are needed to determine if neocortical seizures benefit from surgery, and whether early surgical intervention should be the treatment of choice for certain surgically remediable epileptic syndromes.

Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD

Abstract: Objective: To assess the safety, tolerability, and biological activity of glial cell line-derived neurotrophic factor (GDNF) administered by an implanted intracerebroventricular (ICV) catheter and access port in advanced PD. Background: GDNF is a peptide that promotes survival of dopamine neurons. It improved 6-OHDA- or MPTP-induced behavioral deficits in rodents and monkeys. Methods: A multicenter, randomized, double-blind, placebo-controlled, sequential cohort study compared the effects of monthly ICV administration of placebo and 25, 75, 150, 300, and 500 to 4,000 μg of GDNF in 50 subjects with PD for 8 months. An open-label study extended exposure up to an additional 20 months and maximum single doses of up to 4,000 μg in 16 subjects. Laboratory testing, adverse events (AE), and Unified Parkinson’s Disease Rating Scale (UPDRS) scoring were obtained at 1- to 4-week intervals throughout the studies. Results: Twelve subjects received placebo and seven or eight subjects were assigned to each of the other GDNF dose groups. “On” and “off” total and motor UPDRS scores were not improved by GDNF at any dose. Nausea, anorexia, and vomiting were common hours to several days after injections of GDNF. Weight loss occurred in the majority of subjects receiving 75 μg or larger doses of GDNF. Paresthesias, often described as electric shocks (Lhermitte sign), were common in GDNF-treated subjects, were not dose related, and resolved on discontinuation of GDNF. Asymptomatic hyponatremia occurred in over half of subjects receiving 75 μg or larger doses of GDNF; it was symptomatic in several subjects. The open-label extension study had similar AE and lack of therapeutic efficacy. Conclusions: GDNF administered by ICV injection is biologically active as evidenced by the spectrum of AE encountered in this study. GDNF did not improve parkinsonism, possibly because GDNF did not reach the target tissues—putamen and substantia nigra.

Pregabalin for the treatment of postherpetic neuralgia A randomized, placebo-controlled trial

Abstract: Objective: To evaluate the efficacy and safety of pregabalin in the treatment of postherpetic neuralgia (PHN). Methods: The authors conducted a multicenter, parallel-group, double-blind, placebo-controlled, 8-week, randomized clinical trial in PHN, defined as pain for 3 or more months following herpes zoster rash healing. Patients (n = 173) were randomized to treatment with pregabalin or placebo. Patients randomized to pregabalin received either 600 mg/day (creatinine clearance > 60 mL/min) or 300 mg/day (creatinine clearance 30 to 60 mL/min). The primary efficacy measure was the mean of the last seven daily pain ratings. Secondary endpoints included additional pain ratings, sleep interference, quality of life, mood, and patient and clinician ratings of global improvement. Results: Pregabalin-treated patients had greater decreases in pain than patients treated with placebo (endpoint mean scores 3.60 vs 5.29, p = 0.0001). Pain was significantly reduced in the pregabalin-treated patients after the first full day of treatment and throughout the study, and significant improvement on the McGill Pain Questionnaire total, sensory, and affective pain scores was also found. The proportions of patients with ≥30% and ≥50% decreases in mean pain scores were greater in the pregabalin than in the placebo group (63% vs 25% and 50% vs 20%, p = 0.001). Sleep also improved in patients treated with pregabalin compared to placebo ( p = 0.0001). Both patients and clinicians were more likely to report global improvement with pregabalin than placebo ( p = 0.001). Given the maximal dosage studied, pregabalin had acceptable tolerability compared to placebo despite a greater incidence of side effects, which were generally mild to moderate in intensity. Conclusions: Treatment of PHN with pregabalin is safe, efficacious in relieving pain and sleep interference, and associated with greater global improvement than treatment with placebo.

Practice parameter: Evaluation of the child with global developmental delay Report of the Quality Standards Subcommittee of the American Academy of Neurology and The Practice Committee of the Child Neurology Society

Abstract: Objective: To make evidence-based recommendations concerning the evaluation of the child with a nonprogres- sive global developmental delay. Methods: Relevant literature was reviewed, abstracted, and classified. Recommendations were based on a four-tiered scheme of evidence classification. Results: Global developmental delay is common and affects 1% to 3% of children. Given yields of about 1%, routine metabolic screening is not indicated in the initial evaluation of a child with global developmental delay. Because of the higher yield (3.5% to 10%), even in the absence of dysmorphic features or features suggestive of a specific syndrome, routine cytogenetic studies and molecular testing for the fragile X mutation are recommended. The diagnosis of Rett syndrome should be considered in girls with unexplained moderate to severe developmental delay. Additional genetic studies (e.g., subtelomeric chromosomal rearrangements) may also be considered in selected children. Evaluation of serum lead levels should be restricted to those children with identifiable risk factors for excessive lead exposure. Thyroid studies need not be undertaken (unless clinically indicated) if the child underwent newborn screening. An EEG is not recommended as part of the initial evaluation unless there are historical features suggestive of epilepsy or a specific epileptic syndrome. Routine neuroimaging, with MRI preferred to CT, is recommended particularly if abnormalities are found on physical examination. Because of the increased incidence of visual and auditory impairments, children with global developmental delay may undergo appropriate visual and audiometric assessment at the time of diagnosis. Conclusions: A specific etiology can be determined in the majority of children with global developmental delay. Certain routine screening tests are indicated and depending on history and examination findings, additional specific testing may be performed. NEUROLOGY 2003;60:367-380

Inflammatory markers and cognition in well-functioning African-American and white elders

Abstract: Background: Several lines of evidence suggest that inflammatory mechanisms contribute to AD. Objective: To examine whether several markers of inflammation are associated with cognitive decline in African-American and white well-functioning elders. Methods: The authors studied 3,031 African-American and white men and women (mean age 74 years) enrolled in the Health, Aging, and Body Composition Study. Serum levels of interleukin-6 (IL-6) and C-reactive protein (CRP) and plasma levels of tumor necrosis factor-α (TNFα) were measured at baseline; cognition was assessed with the Modified Mini-Mental State Examination (3MS) at baseline and at follow-up. Cognitive decline was defined as a decline of >5 points. Results: In age-adjusted analyses, participants in the highest tertile of IL-6 or CRP performed nearly 2 points lower (worse) on baseline and follow-up 3MS ( p 2 years ( p = 0.01 for IL-6 and p = 0.04 for CRP) compared with those in the lowest tertile. After multivariate adjustment, 3MS scores among participants in the highest tertile of IL-6 and CRP were similar at baseline but remained significantly lower at follow-up ( p ≤ 0.05 for both). Those in the highest inflammatory marker tertile were also more likely to have cognitive decline compared with the lowest tertile for IL-6 (26 vs 20%; age-adjusted odds ratio [OR] = 1.34; 95% CI 1.06 to 1.69) and for CRP (24 vs 19%; OR = 1.41; 95% CI 1.10 to 1.79) but not for TNFα (23 vs 21%; OR = 1.12; 95% CI 0.88 to 1.43). There was no significant interaction between race and inflammatory marker or between nonsteroidal anti-inflammatory drug use and inflammatory marker on cognition. Conclusions: Serum markers of inflammation, especially IL-6 and CRP, are prospectively associated with cognitive decline in well-functioning elders. These findings support the hypothesis that inflammation contributes to cognitive decline in the elderly.

Measuring the impact of MS on walking ability: the 12-Item MS Walking Scale (MSWS-12).

Abstract: Objective: To develop a patient-based measure of walking ability in MS. Methods: Twelve items describing the impact of MS on walking (12-Item MS Walking Scale [MSWS-12]) were generated from 30 patient interviews, expert opinion, and literature review. Preliminary psychometric evaluation (data quality, scaling assumptions, acceptability, reliability, validity) was undertaken in the data generated by 602 people from the MS Society membership database. Further psychometric evaluation (including comprehensive validity assessment, responsiveness, and relative efficiency) was conducted in two hospital-based samples: people with primary progressive MS (PPMS; n = 78) and people with relapses admitted for IV steroid treatment (n = 54). Results: In all samples, missing data were low (≤3.8%), item test–retest reproducibility was high (≥0.78), scaling assumptions were satisfied, and reliability was high (≥0.94). Correlations between the MSWS-12 and other scales were consistent with a priori hypotheses. The MSWS-12 (relative efficiency = 1.0) was more responsive than the Functional Assessment of Multiple Sclerosis mobility scale (0.72), the 36-Item Short Form Health Survey physical functioning scale (0.33), the Expanded Disability Status Scale (0.03), the 25-ft Timed Walk Test (0.44), and Guy’s Neurologic Disability Scale lower limb disability item (0.10). Conclusions: The MSWS-12 satisfies standard criteria as a reliable and valid patient-based measure of the impact of MS on walking. In these samples, the MSWS-12 was more responsive than other walking-based scales.

The spectrum of neuropathy in diabetes and impaired glucose tolerance

Abstract: Objective: To compare the neuropathy associated with impaired glucose tolerance (IGT) and diabetes mellitus (DM) determined by oral glucose tolerance testing (OGTT). Methods: Patients with peripheral neuropathy of unknown cause were prescribed OGTT. Duration of neuropathic symptoms, neuropathic pain, neuropathy classification, nerve conduction test results, and intraepidermal nerve fiber densities (IENFD) were compared between IGT and DM groups. Results: Seventy-three patients completed OGTT; 41 (56%) had abnormal results. Of these 41 patients, 26 had IGT and 15 had DM. Patients with IGT had less severe neuropathy than patients with diabetes, as measured by sural nerve amplitudes ( p = 0.056), sural nerve conduction velocities ( p = 0.03), and distal leg IENFD ( p = 0.01). Patients with IGT had predominantly small fiber neuropathy, compared to patients with DM ( p = 0.05), who had more involvement of large nerve fibers. Conclusions: The neuropathy associated with IGT is milder than the neuropathy associated with DM. Small nerve fibers are prominently affected and may be the earliest detectable sign of neuropathy in glucose dysmetabolism. OGTT is appropriate in patients with idiopathic neuropathy.

Proposed diagnostic criteria and nosology of acute transverse myelitis

Abstract: To the Editor: The Transverse Myelitis Consortium Working Group should be congratulated for the proposed diagnostic criteria and nosology of acute transverse myelitis (ATM).1 However, in the differential diagnosis only scarce attention was given to fibrocartilaginous embolization from nucleus pulposus embolism (NPE), a condition that is often undiagnosed and frequently confused—clinically and pathologically—with ATM.2 For instance, Bots et al.3 reexamined a teaching specimen of so-called ATM and found an acute transverse myelopathy due to NPE. Although the exclusion criterion of <4 hours from onset to nadir would effectively exclude most vascular cases, in our review of the natural history of NPE,2 we found that at least 42% of the cases had progressed for periods of ≥4 hours; furthermore, a prodromal history of intermittent back pain is not uncommon, lasting for periods of weeks to up to 4 months.4 …

Are amyotrophic lateral sclerosis patients cognitively normal

Abstract: Background: Patients with ALS are often told that the disease spares cognition; however, recent evidence suggests deficits in frontal executive skills occur in a sizable minority of ALS patients. In many instances, the frontal executive deficits represent the co-occurrence of frontotemporal lobar dementia (FTLD) and ALS. Methods: Word generation, a simple frontal task that takes Results: Diminished word generation was found in one-third. Of the patients with abnormal word generation who agreed to further evaluation, nearly all were shown to meet research criteria for FTLD. In addition, one-quarter of the patients with normal word generation who agreed to further evaluation met research criteria for FTLD; these patients had new-onset personality changes. Conclusions: This study suggests that frontal executive deficits are present in half of ALS patients, many of whom meet strict research criteria for FTLD. Word generation tests are a useful screening tool in this cohort.

CSF Aβ 42 levels correlate with amyloid-neuropathology in a population-based autopsy study

Abstract: Objective: To investigate the relationship of amyloid neuropathology to postmortem CSF Aβ 42 levels in an autopsy sample of Japanese American men from the population-based Honolulu–Asia Aging Study Methods: In 1991, participants were assessed and diagnosed with dementia (including subtype) based on published criteria At death CSF was obtained from the ventricles Neuritic plaques (NP) and diffuse plaques in areas of the neocortex and hippocampus were examined using Bielschowsky silver stains Cerebral amyloid angiopathy (CAA) was measured by immunostaining for β4 amyloid in cerebral vessels in the neocortex Neuropathologically confirmed AD was diagnosed using Consortium to Establish a Registry for Alzheimer’s Disease criteria In 155 autopsy samples, log transformed linear regression models were used to examine the association of NP and CAA to Aβ 42 levels, controlling for clinical dementia severity, time between diagnosis and death, age at death, brain weight, hours between death and collection of CSF, education, and APOE genotype Results: Higher numbers of NP in the neocortex ( p trend = 0001) and in the hippocampus ( p trend = 003) were strongly associated with lower levels of Aβ 42 Individuals with CAA had lower Aβ 42 levels (β coefficient = −048; 95% CI −09, −01) Compared to participants with a diagnosis of clinical dementia, those with pathologically confirmed AD had lower Aβ 42 levels (β coefficient = −074; 95% CI −14, −01) Conclusion: The current study suggests that lower Aβ 42 levels reflect neuropathologic processes implicated in amyloid-related pathologies, such as NP and CAA

Comorbidity of migraine and depression: Investigating potential etiology and prognosis

Abstract: Background: An association between migraine and major depression has been observed in clinical and community samples. The factors that contribute to this association and their implications remain unclear. Objective: To determine the factors contributing to the association of migraine and major depression. Methods: A cohort study of persons aged 25 to 55 years with migraine (n = 496) or with other headaches of comparable severity (n = 151) and control subjects with no history of severe headaches (n = 539) randomly selected from the general community were interviewed first in 1997 and then reinterviewed in 1999. Results: Major depression at baseline predicted the first-onset migraine during the 2-year follow-up period (odds ratio [OR] = 3.4; 95% CI = 1.4, 8.7) but not other severe headaches (OR = 0.6; 95% CI = 0.1, 4.6). Migraine at baseline predicted the first-onset major depression during follow-up (OR = 5.8; 95% CI = 2.7, 12.3); the prospective association from severe headaches to major depression was not significant (OR = 2.7; 95% CI = 0.9, 8.1). Comorbid major depression did not influence the frequency of migraine attacks, their persistence, or the progression of migraine-related disability over time. Conclusions: Major depression increased the risk for migraine, and migraine increased the risk for major depression. This bidirectional association, with each disorder increasing the risk for first onset of the other, was not observed in relation to other severe headaches. With respect to other severe headaches, there was no increased risk associated with pre-existing major depression, although the possibility of an influence in the reverse direction (i.e., from severe headaches to depression) cannot be securely ruled out.

Patterns of cortical reorganization in complex regional pain syndrome

Abstract: Objective To use magnetoencephalography to assess possible cortical reorganization in the primary somatosensory cortex (S1) of patients with complex regional pain syndrome (CRPS). Background Patterns of pain and sensory symptoms in CRPS may indicate plastic changes of the CNS. Methods Magnetic source imaging was used to explore changes in the cortical representation of digits (D) 1 and 5 in relation to the lower lip on the unaffected and affected CRPS side in 12 patients. Results The authors found a significant shrinkage of the extension of the cortical hand representation for the CRPS affected side. The center of the hand was shifted toward the cortical representation of the lip. The cortical reorganization correlated with the amount of CRPS pain (r = 0.792), as measured by the McGill questionnaire, and the extent of mechanical hyperalgesia (r = 0.860). Using multiple regression analysis, the best predictor for the plastic changes was found to be mechanical hyperalgesia. Additionally, S1 sources following tactile stimulation were significantly increased on the CRPS side compared to the unaffected limb. Conclusions This study showed reorganization of the S1 cortex contralateral to the CRPS affected side. The reorganization appeared to be linked to complaints of neuropathic pain.

Premonitory symptoms in migraine: an electronic diary study.

Abstract: Background: Migraine is frequently associated with nonheadache symptoms before, during, and after the headache. Premonitory symptoms occurring before the attack have not been rigorously studied. Should these symptoms accurately predict headache, there are considerable implications for the pathophysiology and management of migraine. Methods: Electronic diaries were used in a 3-month multicenter study to record nonheadache symptoms before, during, and after migraine. The authors recruited subjects who reported nonheadache symptoms in at least two of three attacks that they believed predicted headache. Symptoms were entered in the diaries by patient initiation and through prompted entries at random times daily. Entries could not be altered retrospectively. Data recorded included nonheadache symptoms occurring during all three phases of the migraine, prediction of the attack from premonitory symptoms, general state of health, and action taken to prevent the headache. Results: One hundred twenty patients were recruited: 97 provided usable data. Patients correctly predicted migraine headaches from 72% of diary entries with premonitory symptoms. A range of cognitive and physical symptoms was reported at a similar rate through all three phases of the migraine. The most common premonitory symptoms were feeling tired and weary (72% of attacks with warning features), having difficulty concentrating (51%), and a stiff neck (50%). Subjects who functioned poorly in the premonitory phase were the most likely to correctly predict headache. Conclusions: Using an electronic diary system, the authors show that migraineurs who report premonitory symptoms can accurately predict the full-blown headache.

Mild cognitive impairment: Can FDG-PET predict who is to rapidly convert to Alzheimer’s disease?

Abstract: Patients with mild cognitive impairment (MCI) were assessed, and a metabolic profile associated with conversion to AD at 18-month follow-up was sought. As compared with nonconverters (n = 10), converters (n = 7) had lower fluorodeoxyglucose uptake in the right temporoparietal cortex (p = 0.02, corrected for cluster size), without individual overlap. Awaiting replication in an independent sample, these findings suggest that among patients with MCI, fluorodeoxyglucose PET may accurately identify rapid converters.

Idiopathic intracranial hypertension The prevalence and morphology of sinovenous stenosis

Abstract: To the Editor: We congratulate Farb et al. on their discovery, introduction, and use of the auto-triggered elliptic-centric-ordered three-dimensional gadolinium-enhanced MR venogram (ATECO MRV) to diagnose idiopathic intracranial hypertension (IIH) with unprecedented sensitivity and specificity.1 The similarities between IIH and cerebral venous thrombosis (CVT) and their established pathophysiologic tie to cranial venous outflow obstruction are clear and may change the way we diagnose and treat these conditions. CVT and IIH overlap in risk factor profiles and in their relation to hyperestrogenemic exacerbation. It was recently found that both have a high incidence of hypercoagulable states and systemic inflammatory disease is recognized.2–4⇓⇓ CVT has long been considered to mimic or masquerade as IIH and is frequently underdiagnosed.2,5⇓ The increased incidence of CVT has allowed the detection of increasingly smaller venous flow abnormalities or thrombus and has paralleled the advent of the conventional CT and MRI scanners.3 It appears that the ATECO MRV has jumped the barrier and found consistent flow abnormality without radiologically confirmed thrombus in patients with IIH. Although it is unclear if cranial venous outflow obstruction is the primary or a secondary process in IIH, the following question is raised: “Is it time to approach these two conditions as a spectrum of the same disease process?” Bousser et al. have established heparin anticoagulation as the gold standard of treatment for CVT.2 Heparin is now advocated in CVT patients regardless …

Education modifies the relation of AD pathology to level of cognitive function in older persons

Abstract: Objective: To test the hypothesis that years of formal education modifies the relation of AD pathology to level of cognitive function. Methods: A total of 130 older Catholic clergy participating in the Religious Orders Study underwent annual cognitive function testing and brain autopsy at the time of death. Individual cognitive function tests were z-scored and averaged to yield a global measure of cognitive function and summary measures of five different cognitive abilities. Neuritic and diffuse plaques and neurofibrillary tangles were counted in separate 1 mm 2 areas of maximal density. Counts were converted to standard scores by dividing by their SD, and combined to yield a global AD pathology score and summary scores of each postmortem index. Linear regression was used to examine the relation of education and AD pathology scores to level of cognitive function proximate to death, controlling for age and sex. Subsequent analyses tested the interaction between education and each AD pathology score to determine whether education modified the relation of AD pathology to level of cognitive function. Additional analyses examined these associations on five specific cognitive abilities. Results: Both years of formal education (regression coefficient = 0.073, p = 0.0001) and the global AD pathology score (regression coefficient = −0.689, p p = 0.0078) standard unit less for each year of education than the level predicted from the model without the interaction term. Whereas neuritic plaques, diffuse plaques, and neurofibrillary tangles were all strongly related to cognitive function, education only modified the relation of neuritic plaques ( p = 0.002) and diffuse plaques ( p = 0.03) to cognition, but not neurofibrillary tangles. In analyses examining five different cognitive abilities, the interaction between education and the neuritic plaque score was strongest for perceptual speed and weakest for episodic memory. Conclusions: These data provide strong evidence that the relation between senile plaques and level of cognitive function differs by years of formal education.

Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome.

Abstract: Objective: To assess neuropathology in individuals with restless legs syndrome (RLS). Methods: A standard neuropathologic evaluation was performed on seven brains from individuals who had been diagnosed with RLS. The substantia nigra was examined in greater detail for iron staining and with immunohistochemistry for tyrosine hydroxylase and proteins involved in iron management. Five age-matched individuals with no neurologic history served as controls. Results: There were no histopathologic abnormalities unique to the RLS brains. Tyrosine hydroxylase staining in the major dopaminergic regions appeared normal in the RLS brains. Iron staining and H-ferritin staining was markedly decreased in the RLS substantia nigra. Although H-ferritin was minimally detected in the RLS brain, L-ferritin staining was strong. However, the cells staining for L-ferritin in RLS brains were morphologically distinct from those in the control brains. Transferrin receptor staining on neuromelanin-containing cells was decreased in the RLS brains compared to normal, whereas transferrin staining in these cells was increased. Conclusions: RLS may not be rooted in pathologies associated with traditional neurodegenerative processes but may be a functional disorder resulting from impaired iron acquisition by the neuromelanin cells in RLS. The underlying mechanism may be a defect in regulation of the transferrin receptors.

A self-administered screener for migraine in primary care: The ID Migraine™ validation study

Abstract: Background: Migraine is a highly prevalent and disabling illness that remains substantially undiagnosed in primary care. Because of the potential value of a screening tool, the current study was designed to establish the validity and reliability of a brief, self-administered migraine screener in patients with headache complaints in the primary care setting. Methods: A total of 563 patients presenting for routine primary care appointments and reporting headaches in the past 3 months completed a self-administered migraine screener. All patients were then referred for an independent diagnostic evaluation by a headache expert, of whom 451 (80%) completed a full evaluation. Migraine diagnosis was assigned based on International Headache Society criteria after completing a semi-structured diagnostic interview. Results: Of nine diagnostic screening questions, a three-item subset of disability, nausea, and sensitivity to light provided optimum performance, with a sensitivity of 0.81 (95% CI, 0.77 to 0.85), a specificity of 0.75 (95% CI, 0.64 to 0.84), and positive predictive value of 0.93 (95% CI, 89.9 to 95.8). Test-retest reliability was good, with a kappa of 0.68 (95% CI, 0.54 to 0.82). The sensitivity and specificity of the three-item migraine screener was similar regardless of sex, age, presence of other comorbid headaches, or previous diagnostic status. Conclusions: The three-item ID Migraine™ migraine screener was found to be a valid and reliable screening instrument for migraine headaches. Its ease of use and operating characteristics suggest that it could significantly improve migraine recognition in primary care.

The effect of pneumonia on mortality among patients hospitalized for acute stroke

Abstract: Objective: To determine the effect of pneumonia on 30-day mortality in patients hospitalized for acute stroke. Methods: Subjects in the initial cohort were 14,293 Medicare patients admitted for stroke to 29 greater Cleveland hospitals between 1991 and 1997. The relative risk (RR) of pneumonia for 30-day mortality was determined in a final cohort (n = 11,286) that excluded patients dying or having a do not resuscitate order within 3 days of admission. Clinical data were obtained from chart abstraction and were merged with Medicare Provider Analysis and Review files to obtain deaths within 30 days. A predicted-mortality model (c-statistic = 0.78) and propensity score for pneumonia (c-statistic = 0.83) were used for risk adjustment in logistic regression analyses. Results: Pneumonia was identified in 6.9% (n = 985) of all patients and in 5.6% (n = 635) of the final cohort. The rates of pneumonia were higher in patients with greater stroke severity and features indicating general frailty. Unadjusted 30-day mortality rates were six times higher for patients with pneumonia than for those without (26.9% vs 4.4%, p Conclusion: In this large community-wide study of stroke outcomes, pneumonia conferred a threefold increased risk of 30-day death, adding impetus to efforts to identify and reduce the risk of pneumonia in patients with stroke.

Evidence of early cortical atrophy in MS Relevance to white matter changes and disability

Abstract: Objective: To assess cortical gray matter (GM) changes in MS and establish their relevance to clinical disability and to inflammatory changes of white matter (WM) in patients with the relapsing–remitting (RR) and primary progressive (PP) forms of the disease. Methods: Conventional MRI examinations were obtained in patients with definite MS who had either the RR or the PP form of the disease. An automated analysis tool was used with conventional T1-weighted MR images to obtain total and cortical brain volumes normalized for head size. Total brain lesion load was estimated on conventional proton density and T2-weighted MR images. The relationship between volumetric MR measures and scores of clinical disability was assessed. Results: Normalized cortical volumes (NCV) were lower for both RR and PP MS patients than for normal control subjects ( p p > 0.5). NCV decreases in both patients groups were detected even in those patients with short disease duration ( p p p p r = −0.47, p r = −0.25, p p r = −0.64, p r = −0.27, p = 0.04) MS patients. Conclusions: These data confirm substantial neocortical volume loss in MS patients and suggest that neocortical GM pathology may occur early in the course of the disease in both RR and PP MS patients and contribute significantly to neurologic impairment. Although a proportion of this neocortical pathology may be secondary to WM inflammation, the extent of the changes suggests that, especially in patients with PP MS, an independent neurodegenerative process also is active.

Major depression in multiple sclerosis A population-based perspective

Abstract: Objective: To determine the prevalence of major depression in multiple sclerosis (MS) in a population-based sample controlling for nonspecific illness effects. Methods: This study used data from a large-scale national survey conducted in Canada: the Canadian Community Health Survey (CCHS). The analysis included 115,071 CCHS subjects who were 18 years or older at the time of data collection. The CCHS interview obtained self-reported diagnoses of MS and employed a brief predictive interview for major depression: the Composite International Diagnostic Interview Short Form for Major Depression. The 12-month period prevalence of major depression was estimated in subjects with and without MS and with and without other long-term medical conditions. Results: The prevalence of major depression was elevated in persons with MS relative to those without MS and those reporting other conditions. The association persisted after adjustment for age and sex (adjusted odds ratio = 2.3, 95% CI 1.6 to 3.3). Major depression prevalence in MS for those in the 18- to 45-year age range was high at 25.7% (95% CI 15.6 to 35.7). Conclusions: The prevalence of major depression in the population with MS is elevated. This elevation is not an artifact of selection bias and exceeds that associated with having one or more other long-term conditions.

Acute seizures after intracerebral hemorrhage A factor in progressive midline shift and outcome

Abstract: Objective: To determine whether early seizures that occur frequently after intracerebral hemorrhage (ICH) lead to increased brain edema as manifested by increased midline shift. Methods: A total of 109 patients with ischemic stroke (n = 46) and intraparenchymal hemorrhage (n = 63) prospectively underwent continuous EEG monitoring after admission. The incidence, timing, and factors associated with seizures were defined. Serial CT brain imaging was conducted at admission, 24 hours, and 48 to 72 hours after hemorrhage and assessed for hemorrhage volume and midline shift. Outcome at time of discharge was assessed using the Glasgow Outcome Scale score. Results: Electrographic seizures occurred in 18 of 63 (28%) patients with ICH, compared with 3 of 46 (6%) patients with ischemic stroke (OR = 5.7, 95% CI 1.4 to 26.5, p p p p Conclusion: Seizures occur commonly after ICH and may be nonconvulsive. Seizures are independently associated with increased midline shift after intraparenchymal hemorrhage.

Evidence for more widespread cerebral pathology in early HD: An MRI-based morphometric analysis

Abstract: Background: Most clinical symptoms of Huntington disease (HD) have been attributed to striatal degeneration, but extrastriatal degeneration may play an important role in the clinical symptoms because postmortem studies demonstrate that almost all brain structures atrophy. Objective: To fully characterize the morphometric changes that occur in vivo in HD. Methods: High-resolution 1.5 mm T1-weighted coronal scans were acquired from 18 individuals in early to mid-stages of HD and 18 healthy age-matched controls. Cortical and subcortical gray and white matter were segmented using a semiautomated intensity contour-mapping algorithm. General linear models for correlated data of the volumes of brain regions were used to compare groups, controlling for age, education, handedness, sex, and total brain volumes. Results: Subjects with HD had significant volume reductions in almost all brain structures, including total cerebrum, total white matter, cerebral cortex, caudate, putamen, globus pallidus, amygdala, hippocampus, brainstem, and cerebellum. Conclusions: Widespread degeneration occurs in early to mid-stages of HD, may explain some of the clinical heterogeneity, and may impact future clinical trials.

Controlled-release oxycodone for pain in diabetic neuropathy: A randomized controlled trial

Abstract: Background and objective: Opioid treatment has played a limited role in the management of diabetic neuropathy, in part because of concerns about the responsiveness of neuropathic pain to opioid treatment. This controlled study evaluated the efficacy and safety of controlled-release (CR) oxycodone in subjects with moderate to severe pain due to diabetic neuropathy. Methods: This multicenter, randomized, double-blind, placebo-controlled, parallel-group study included 159 subjects with moderate to severe pain due to diabetic neuropathy. Treatment began with either one 10-mg tablet of CR oxycodone (n = 82) or identical placebo (n = 77) every 12 hours. Doses could be increased every 3 days to a maximum of 6 tablets (60 mg CR oxycodone) every 12 hours. Treatment lasted up to 6 weeks. The primary efficacy variable was overall average daily pain intensity during study days 28 to 42. Results: At an average (SD) dose of 37 (21) mg per day (range 10 to 99 mg/d), CR oxycodone provided more analgesia than placebo ( p = 0.002) in the intent-to-treat cohort. From days 28 to 42, overall average daily pain intensity (least squares mean ±SE), rated in subject diaries on a numeric scale of 0 (no pain) to 10 (pain as bad as you can imagine), was 4.1 ± 0.3 in subjects given CR oxycodone and 5.3 ± 0.3 in placebo-treated subjects. Overall, 80 (96%) of 82 subjects given CR oxycodone and 52 (68%) of 77 subjects who received placebo reported adverse events. The most common adverse events in the CR oxycodone group were opioid related. Conclusions: In this 6-week trial, CR oxycodone was effective for the treatment of moderate to severe pain due to diabetic neuropathy. Adverse events were typical of opioid-related side effects.

Quantitative sensory testing: Report of the therapeutics and technology assessment subcommittee of the American academy of neurology

Abstract: Objective: This assessment evaluates the clinical utility, efficacy, and safety of quantitative sensory testing (QST). Methods: By searching MEDLINE, Current Contents, and their personal files, the authors identified 350 articles. Selected articles utilized computer operated threshold systems, manually operated threshold systems, and electrical threshold devices. The authors evaluated the use of normal values and the degree of reproducibility between the same and different systems. Articles were rated using a standard classification of evidence scheme. Results: Because of differences between systems, normal values from one system cannot be transposed to others. Reproducibility of results was also an important concern, and there is no consensus on how it should be defined. The authors identified no adequately powered class I studies demonstrating the effectiveness of QST in evaluating any particular disorder. A number of class II and III studies demonstrated that QST is probably or possibly useful in identifying small or large fiber sensory abnormalities in patients with diabetic neuropathy, small fiber neuropathies, uremic neuropathies, and demyelinating neuropathy. Conclusions: QST is a potentially useful tool for measuring sensory impairment for clinical and research studies. However, QST results should not be the sole criteria used to diagnose pathology. Because malingering and other nonorganic factors can influence the test results, QST is not currently useful for the purpose of resolving medicolegal matters. Well-designed studies comparing different QST devices and methodologies are needed and should include patients with abnormalities detected solely by QST.

Risk of stroke in children Ethnic and gender disparities

Abstract: Methods: Using a California-wide hospital discharge database, the authors analyzed all first admissions for stroke in children 1 month through 19 years of age from 1991 through 2000. Incidence rates were estimated as the number of first hospitalizations divided by the person-years at risk; case fatality rates were based on in-hospital deaths. Results: The authors identified 2,278 first admissions for childhood stroke, yielding an annual incidence rate of 2.3 per 100,000 children (1.2 for ischemic stroke, 1.1 for hemorrhagic stroke). Compared with whites, black children were at higher risk of stroke (for ischemic stroke, relative risk [RR] 2.59, 95% CI 2.17 to 3.09, p p = 0.02; intracerebral hemorrhage [ICH], RR 1.66, CI 1.23 to 2.13, p = 0.0001). Hispanics, however, had a lower risk of ischemic stroke (RR 0.70, CI 0.60 to 0.82, p p = 0.0004), whereas Asians had similar risks as whites. Boys were at higher risk for all stroke types than girls (ischemic stroke, RR 1.25, CI 1.11 to 1.40, p = 0.0002; SAH, RR 1.24, CI 1.00 to 1.53, p = 0.047; ICH, RR 1.34, CI 1.16 to 1.56, p = 0.0001). After eliminating cases with coexisting sickle cell disease, excess stroke risk persisted in blacks; after elimination of trauma, excess stroke risk persisted in boys. Case fatality rates were similar among different ethnic groups. Compared with girls, boys had a higher case fatality rate for ischemic stroke (17 vs 12%; p = 0.002) but not for ICH or SAH. Conclusions: Rates of hospitalization for stroke are higher among black children and boys; sickle cell disease and trauma do not fully account for these findings.

Plasma Aβ40 and Aβ42 and Alzheimer’s disease: Relation to age, mortality, and risk

Abstract: Background: Plasma amyloid β-peptide (Aβ) 40 and Aβ42 levels are increased in persons with mutations causing early-onset familial Alzheimer’s disease (AD). Plasma Aβ42 levels were also used to link microsatellite genetic markers to a putative AD genetic locus on chromosome 10 and were observed in patients with incipient sporadic AD. Methods: The authors measured plasma Aβ40 and Aβ42 levels using a sandwich ELISA after the initial examination of 530 individuals participating in an epidemiologic study of aging and dementia. Participants were examined at 18-month intervals, and plasma Aβ40 and Aβ42 levels were repeated in 307 subjects 3 years after baseline. Results: Compared with individuals who never developed AD, patients with AD at baseline and those who developed AD during the follow-up had significantly higher Aβ42, but not Aβ40, plasma levels. The risk of AD in the highest quartile of plasma Aβ42 was increased by more than twofold over that in the lowest quartile. The highest plasma Aβ42 levels were observed in patients with AD who died during the follow-up. Plasma Aβ42, but not Aβ40, levels decreased over time in patients with newly acquired AD. Conclusions: Plasma Aβ40 and Aβ42 increase with age and are strongly correlated with each other. Plasma Aβ40 and Aβ42 levels are elevated in some patients before and during the early stages of AD but decline thereafter. High plasma Aβ42 levels may also be associated with mortality in patients with AD.

Prognosis in amyotrophic lateral sclerosis: A population-based study

Abstract: Background: Accurate information on prognosis of ALS is useful to patients, families, and clinicians. Methods: In a population-based study of ALS in western Washington, the authors assembled a cohort of 180 patients with incident ALS between 1990 and 1994. Information on potential prognostic factors was collected during an in-person interview. Patients also completed the Medical Outcomes Study Short Form 36 (SF-36). Vital status through December 1999 was known for all patients. Results: Median survival was 32 months from onset of symptoms and 19 months from diagnosis. The 5-year survival after diagnosis was 7%. Older age and female sex were strongly associated with poor survival. In multivariable Cox proportional hazards regression models, factors significantly and independently associated with a worse prognosis included older age, any bulbar features at onset, shorter time from symptom onset to diagnosis, lack of a marital partner, and residence in King County. Recursive partitioning identified age, time from symptom onset to diagnosis, and marital status as the strongest predictors of survival. Good summary scores for physical health on the SF-36, but not for mental health, were significantly associated with longer survival than poor scores. Conclusion: These findings are consistent with other population-based studies of ALS and confirm its pernicious nature. Older age, female sex, any bulbar features at onset, short time from symptom onset to diagnosis, lack of a marital partner, and disease severity are key prognostic factors. Serial measurement of severity would likely improve predictions.