Methods: We conducted a retrospective review of 2,477 patients with definite relapsing-onset MS followed until July 2003 in British Columbia, Canada. Time-dependent Cox proportional hazards models examined the effect of relapses at different time periods (0–5; >5–10; >10 years postonset) on time to cane (Expanded Disability Status Scale [EDSS]) and secondary progressive MS (SPMS). Findings were derived from hazard ratios with 95% confidence intervals (CIs), adjusted for sex, onset age, and symptoms.

Results: Mean follow-up was 20.6 years; 11,722 postonset relapses were recorded. An early relapse (within 5 years postonset) was associated with an increased hazard in disease progression over the short term, by 48%; 95% CI 37%–60% for EDSS 6 and 29%; 95% CI 20%–38% for SPMS. However, this substantially lessened to 10%; 95% CI 4%–16% (EDSS 6) and 2%; 95% CI –2%–7% (SPMS) after 10 years postonset. The impact of later relapses (>5–10 years postonset) also lessened over time. Effects were modulated by age, impact being greatest in younger (<25 years at onset) and least in older (≥35 years) patients where relapses beyond 5–years postonset typically failed to reach significance. Relapses during SPMS had no measurable impact on time to EDSS 6 from SPMS.

Conclusion: Relapses within the first 5 years of disease impacted on disease progression over the short term. However, the long-term impact was minimal, either for early or later relapses. Long-term disease progression was least affected by relapses in patients with an extended disease duration (>10 years) or already in the secondary progressive phase.

Methods: In this longitudinal correlational research study, 75 patients with relapsing-remitting MS (48 women and 27 men, mean age 36 years, mean disease duration 5 years, mean Expanded Disability Status Scale [EDSS] 1.7) without clinical signs of a relapse underwent 2 MRI measurements (number and volume of T1 contrast-enhancing lesions and of T2 lesions) and clinical examinations (EDSS and Multiple Sclerosis Functional Composite [MSFC]) with a mean interscan interval of 10 weeks. Patients were divided into 3 groups: A (n = 38), Gd on 1 scan; B (n = 12), Gd on both scans; and C (n = 25), Gd on neither scan.

Results: In group A, PASAT was better at the Gd-negative time point (p = 0.002), whereas the other MSFC subscores remained unchanged. Subgroup analysis confirmed the finding in patients with a Gd-positive scan first, whereas this was not the case for patients with a Gd-negative scan first, presumably owing to the small sample size of this subgroup. In groups B and C, there was no difference between both time points regarding MSFC and its subscores. EDSS remained stable in all groups during the investigation.

Conclusions: Paced Auditory Serial Addition Test performance is affected by the appearance of Gd enhancement as surrogate marker of inflammatory activity in otherwise physically stable patients with multiple sclerosis, which may indicate that Gd enhancement causes a diffuse impairment of cerebral connectivity with a negative impact on cognitive functioning.

Methods: We investigated 8 patients with the limited form of NMO with myelitis in comparison with 9 patients with the definite form.

Result: All patients with limited and definite form showed uniform relapsing-remitting courses, with no secondary progressive courses. Pathologic findings of biopsy specimens from the limited form were identical to those of autopsy from the definite form, demonstrating extremely active demyelination of plaques, extensive loss of AQP4 immunoreactivity in plaques, and diffuse infiltration by macrophages containing myelin basic proteins with thickened hyalinized blood vessels. Moreover, the definite form at the nadir of relapses displayed significantly higher amounts of the inflammatory cytokines interleukin (IL)-1β and IL-6 in CSF than the limited form and multiple sclerosis.

Conclusion: This consistency of pathologic findings and uniformity of courses indicates that aquaporin 4–specific autoantibodies as the initiator of the neuromyelitis optica (NMO) lesion consistently play an important common role in the pathogenicity through the entire course, consisting of both limited and definite forms, and NMO continuously displays homogeneity of pathogenic effector immune mechanisms through terminal stages, whereas multiple sclerosis should be recognized as the heterogeneous 2-stage disease that could switch from inflammatory to degenerative phase. This report is a significant description comparing the pathologic and immunologic data of limited NMO with those of definite NMO.

Methods: We retrospectively examined 237 consecutive acute ischemic stroke patients who underwent MRI within 24 hours and follow-up MRI during the week after symptom onset. We defined new MBs as MBs that newly appeared on follow-up GRE outside the infarcted area. We examined the association of new MBs with demographics, risk factors, laboratory data, baseline MBs, and small vessel disease (SVD; leukoaraiosis and lacunar infarctions).

Results: Seventy-five patients (31.6%) had baseline MBs, and 30 (12.7%) developed new MBs. Multiple logistic regression analysis indicated that the presence of baseline MBs (odds ratio [OR] 5.72, 95% confidence interval [CI] 2.12–15.42, p = 0.001) and severe SVD (OR 2.94, 95% CI 1.12–7.77, p = 0.03) independently predicted the development of new MBs. Of the 56 new MBs, 29 (51.8%) appeared in the lobar location, 17 (30.4%) appeared in the deep location, and 10 (17.9%) appeared in the infratentorial location.

Conclusions: This study suggests that new microbleeds (MBs) can develop rapidly after acute ischemic stroke. Baseline MBs and severe small vessel disease are predictors for the development of new MBs. Further studies will be needed to investigate the clinical implications and mechanisms of these findings.

Methods: We retrospectively examined consecutive acute ischemic stroke patients who underwent gradient echo MRI. The presence of cerebral microbleeds on gradient echo MRI was independently interpreted. The number and location of microbleeds were assessed. Demographics including age, sex, risk factors, and stroke subtype were obtained. Kidney function was estimated by measuring glomerular filtration rate (GFR) with the modification of diet in renal disease method.

Results: Of the 152 patients included, 45 (29.6%) patients had cerebral microbleeds on gradient echo MRI. The cerebral microbleeds were most commonly located in deep or infratentorial location (27/45 [60%]). Hypertension, presence of leukoaraiosis, old age, and low GFR were associated with the presence of cerebral microbleeds (p = 0.064, <0.001, 0.014, and <0.001). The mean GFR levels were lower in patients with cerebral microbleeds (65.15 ± 22.54 vs 78.82 ± 19.11 mL/min/1.73 m²). After the adjustment of risk factors, age, and sex, low GFR levels were associated with the presence of cerebral microbleeds (odds ratio, 3.85; 95% confidence interval, 1.52 to 9.76, p = 0.004).

Conclusion: Impaired kidney function is associated with the presence of cerebral microbleeds in acute ischemic stroke.

Methods: Twenty-six subjects with a family history of FAD were divided into 2 subgroups according to genotype (FAD mutation carriers, n = 15; FAD noncarriers, n = 11). Subjects were given standardized tests of cognitive function and the Clinical Dementia Rating scale (CDR). Sensory (P50, N100, P200) and cognitive (N200, P300) event-related potentials were recorded during an auditory discrimination task. Amplitudes and latencies of cortical potentials were compared among FAD mutation carriers and noncarriers.

Results: FAD mutation carriers and noncarriers did not significantly differ in age or on measures of cognitive function, but FAD carriers had a greater incidence of 0.5 CDR scores (1/10 noncarriers, 5/15 carriers). Relative to noncarriers, FAD mutation carriers had significantly longer latencies of the N100, P200, N200, and P300 components, and smaller slow wave amplitudes. Subanalyses of subjects having CDR scores of 0.0 also showed latency increases in FAD mutation carriers.

Conclusions: Auditory sensory and cognitive cortical potentials in persons with familial Alzheimer disease (FAD) mutations are abnormal approximately 10 years before dementia will be manifest. Longer event-related potential latencies suggest slowing of cortical information processing in FAD mutation carriers.

Methods: We analyzed survival in a large group of clinically diagnosed bvFTD patients (n = 91) with particular attention to demographic and clinical features at presentation. Of the 91 cases, 50 have died, with pathologic confirmation in 28.

Results: Median survival in the whole group was 9.0 years from symptom onset, and 5.4 years from diagnosis. After the exclusion of 24 "phenocopy" cases, the analysis was repeated in a subgroup of 67 patients. The mean age at symptom onset of the pathologic group was 58.5 years and 16% had a positive family history. Their median survival was 7.6 years (95% confidence interval [CI] 6.6–8.6) from symptom onset and 4.2 years (95% CI 3.4–5.0) from diagnosis. The only factor associated with shorter survival was the presence of language impairment at diagnosis.

Conclusions: Patients with definite frontotemporal dementia have a poor prognosis which is worse if language deficits are also present. This contrasts with the extremely good outcome in those with the phenocopy syndrome: of our 24 patients only 1 has died (of coincident pathology) despite, in some cases, many years of follow-up.

Methods: Patients with moderately advanced PD received bilateral intraputaminal infusion of AAV-hAADC vector. Low-dose and high-dose cohorts (5 patients in each) were studied using standardized clinical rating scales at baseline and 6 months. PET scans using the AADC tracer [¹⁸F]fluoro-l-m-tyrosine (FMT) were performed as a measure of gene expression.

Results: The gene therapy was well tolerated, but 1 symptomatic and 2 asymptomatic intracranial hemorrhages followed the operative procedure. Total and motor rating scales improved in both cohorts. Motor diaries also showed increased on-time and reduced off-time without increased "on" time dyskinesia. At 6 months, FMT PET showed a 30% increase of putaminal uptake in the low-dose cohort and a 75% increase in the high-dose cohort.

Conclusion: This study provides class IV evidence that bilateral intrastriatal infusion of adeno-associated viral type 2 vector containing the human AADC gene improves mean scores on the Unified Parkinson’s Disease Rating Scale by approximately 30% in the on and off states, but the surgical procedure may be associated with an increased risk of intracranial hemorrhage and self-limited headache.

Background: There is a need to explore nondopaminergic mechanisms of gait control as the majority of motor impairments associated with falls in PD are resistant to dopaminergic treatment. Alterations in cholinergic neurotransmission in PD may be implicated because of evidence that gait control depends on cholinergic system–mediated higher-level cortical and subcortical processing, including pedunculopontine nucleus (PPN) function.

Methods: In this cross-sectional study, 44 patients with PD (Hoehn & Yahr stages I–III) without dementia and 15 control subjects underwent a clinical assessment and [¹¹C]methyl-4-piperidinyl propionate (PMP) acetylcholinesterase (AChE) and [¹¹C]dihydrotetrabenazine (DTBZ) vesicular monoamine transporter type 2 (VMAT2) brain PET imaging.

Results: Seventeen patients (38.6%) reported a history of falls and 27 patients had no falls. Analysis of covariance of the cortical AChE hydrolysis rates demonstrated reduced cortical AChE in the PD fallers group (–12.3%) followed by the PD nonfallers (–6.6%) compared to control subjects (F = 7.22, p = 0.0004). Thalamic AChE activity was lower only in the PD fallers group (–11.8%; F = 4.36, p = 0.008). There was no significant difference in nigrostriatal dopaminergic activity between PD fallers and nonfallers.

Conclusions: Unlike nigrostriatal dopaminergic denervation, cholinergic hypofunction is associated with fall status in Parkinson disease (PD). Thalamic AChE activity in part represents cholinergic output of the pedunculopontine nucleus (PPN), a key node for gait control. Our results are consistent with other data indicating that PPN degeneration is a major factor leading to impaired postural control and gait dysfunction in PD.

Methods: In this Institutional Review Board–approved study, we retrospectively analyzed the records of 8 adult patients treated for recurrent ependymoma and anaplastic ependymoma with bevacizumab containing chemotherapy regimens. We determined radiographic response (Macdonald criteria), median time to progression (TTP), and median overall survival (OS; Kaplan-Meier method).

Results: There were 4 men and 4 women with a median age of 40 years (range, 20–65). Prior treatment included surgery (n = 8), RT (8), temozolomide (5), and carboplatin (4). Bevacizumab (5–15 mg/kg every 2–3 weeks) was administered alone (2) or concurrently with cytotoxic chemotherapy including irinotecan (3), carboplatin (2), or temozolomide (1). Six patients achieved a partial response (75%) and 1 remained stable for over 8 months. Median TTP was 6.4 months (95% confidence interval 1.4–7.4) and median OS was 9.4 months (95% confidence interval 7.0–not reached), with a median follow-up of 5.2 months among 5 surviving patients (63%).

Conclusions: The radiographic response rate to bevacizumab-containing regimens is high. A prospective study is warranted.

Methods: The study population included 658 patients with ALS consecutively observed in 2 Italian ALS centers between 2000 and 2006. They were compared to a series of 658 healthy subjects, matched by age and gender.

Results: The mean levels of total cholesterol, triglycerides, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and the LDL/HDL ratio were similar in patients with ALS and controls. Total cholesterol, HDL, triglyceride, and LDL/HDL ratio levels showed a significant decrease in patients with forced vital capacity <70% compared to those with FVC ≥90%. For each level of ALS-FRS, poorer respiratory function was related to a lower LDL/HDL ratio. Univariate survival analysis did not find any significant effect of LDL/HDL ratio on survival, either when comparing patients with ratios ≤2.99 vs >2.99 or patients in the first quartile of LDL/HDL ratio (≤1.67) vs those in the fourth quartile (>2.79). No dose-response was found for LDL/HDL ratio subdividing patients into 5 quintiles.

Conclusion: Our findings do not support the observation that patients with amyotrophic lateral sclerosis have hyperlipidemia or that hyperlipidemia in this population is related to longer survival. However, some evidence emerged that respiratory impairment, but not a worse clinical status or a lower body mass index, is related to a decrease in blood lipids and LDL/HDL ratio.

Methods: We reviewed the medical records of patients with PMA (n = 91) or ALS (n = 871) from our ALS Center and verified survival by telephoning the families or using the National Death Index.

Results: In PMA, patients were more likely to be male (p < 0.001), older (p = 0.007), and lived longer (p = 0.01) than in ALS. Cox model analysis suggested that the risk of death increased with age at onset in both patient groups (p < 0.005). Upper motor neuron (UMN) signs developed in 22% of patients with PMA within 61 months after diagnosis. Demographic and other clinical variables did not differ at diagnosis between those who did or did not develop UMN signs. In PMA, the factors present at diagnosis that predicted shorter survival were greater number of body regions affected, lower forced vital capacity, and lower ALS Functional Rating Scale–Revised score. Noninvasive ventilation and gastrostomy were used frequently in PMA.

Conclusion: Although patients with progressive muscular atrophy (PMA) tended to live longer than those with amyotrophic lateral sclerosis (ALS), shorter survival in PMA is associated with the same risk factors that predict poor survival in ALS. Additionally, PMA is relentlessly progressive, and UMN involvement can occur, as also reported in imaging and postmortem studies. For these reasons, PMA should be considered a form of ALS.

Methods: A Medline literature search was conducted for the period between 2003 and April 2009 using the search terms smoking and (ALS or "amyotrophic lateral sclerosis" or MND or "motor neuron disease"). The references of primary articles and reviews were checked to assure completeness of the search. Primary articles published since the previous review were classified as before.

Results: Twenty-eight titles were identified, but only 7 articles met inclusion criteria. Of these, 1 provided class II evidence, and 1 class III evidence: both showed increased risk of ALS with smoking. The class II study showed a dose-response effect, and risk decreasing with number of years since quitting smoking. Five articles provided class IV or V evidence, which may not be relied upon to draw conclusions.

Conclusions: Smoking may be considered an established risk factor for sporadic amyotrophic lateral sclerosis (ALS) (level A rating; 3 class II studies, 1 class III study). Evidence-based analysis of epidemiologic data shows concordance among results of better-designed studies linking smoking to ALS, and lets those results drive the conclusions.