A clinical, molecular genetics and pathological study of a FTDP-17 family with a heterozygous splicing variant c.823-10G>T at the intron 9/exon 10 of the MAPT gene.

We report the first clinical-radiological-genetic-molecular-pathological study of a kindred with c.823-10G>T MAPT intronic variant (rs63749974) associated with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). We describe the clinical spectrum within this family and emphasize the association between MAPT gene variants and motor neuron disease. This report of a second family with FTDP-17 associated with c.823-10G>T MAPT variant strongly supports pathogenicity of the variant and confirms it is a 4-repeat (4R) tauopathy. This intronic point mutation, probably strengthens the polypyrimidine tract and alters the splicing of exon 10 (10 nucleotides into intron 9) close to the 3' splice site.

The 5-year Tysabri global observational program in safety (TYGRIS) study confirms the long-term safety profile of natalizumab treatment in multiple sclerosis.

BACKGROUND: Natalizumab is an effective treatment for multiple sclerosis (MS) and has a well-characterized safety profile, with more than 10 years of postmarketing experience. TYGRIS was a 5-year observational cohort study designed to obtain long-term safety data in natalizumab-treated MS patients. We examined the incidence and pattern of serious adverse events (SAEs) in this large postmarketing sample of natalizumab-treated patients. METHODS: Investigators reported SAEs in natalizumab-treated patients. Malignancy incidence rates were compared with rates in the general population using external databases. RESULTS: Of 6508 enrolled patients, 4938 (75.9%) completed the study. SAEs occurring in more than 0.5% of patients included urinary tract infection (n = 50; 0.8%), pneumonia (n = 46; 0.7%), progressive multifocal leukoencephalopathy (PML; n = 44; 0.7%), and immune reconstitution inflammatory syndrome (n = 44; 0.7%). Fifty-five patients (0.9%) experienced treatment-emergent serious opportunistic infections, 44 of which were PML. Two patients with PML died. The overall malignancy incidence rate was 449.0 per 100,000 patient-years (95% confidence interval [CI], 375.1-533.1). With few exceptions, incidence rates for individual malignancies had 95% CIs encompassing incidence rates in the general population. Hepatotoxic events occurred in 6 patients; 4 patients had evidence of alternative cause or confounders. Of 96 fatal events, investigators considered 81 unrelated or unlikely to be related to treatment and 5 related or possibly related; causality was not provided for 10. CONCLUSION: Data from this large, long-term study indicate that the nature, character, and frequency of SAEs in real-world settings are consistent with natalizumab's known safety profile. (Funded by Biogen; ClinicalTrials.gov identifiers: NCT00477113 and NCT00483847.).

An evaluation of the role of environmental factors in the disease penetrance of cervical dystonia.

BACKGROUND: Adult onset primary torsion dystonia (AOPTD) is a poorly penetrant autosomal dominant disorder; most gene carriers are non-manifesting despite having reached an adequate age for penetrance. It is hypothesised that genetic, epigenetic and environmental factors may exert protective or deleterious effects on penetrance of AOPTD. By examining environmental exposure history in cervical dystonia patients and their similarly aged unaffected siblings we aimed to determine the role of previous environmental exposures in relation to disease penetrance. METHODS: A case-control study of 67 patients with cervical dystonia and 67 of their age-matched unaffected siblings was performed. Past environmental exposures were assessed using a detailed 124-question standardised questionnaire. RESULTS: By univariate analysis, cervical dystonia patients, compared to their unaffected siblings, had an increased frequency of a history of car accidents with hospital attendance (OR 10.1, 95% CI 2.1 to 47.4, p=0.004) and surgical episodes (OR 6.5, 95% CI 1.76 to 23.61, p=0.005). Following multivariate analysis, car accidents with hospital attendance (OR 7.3, 95% CI 1.4 to 37.6, p=0.017) and all surgical episodes (OR 4.9, 95% CI 1.24 to 19.31, p=0.023) remained significantly associated with case status. CONCLUSIONS: Cervical dystonia patients had a history, prior to symptom onset, of significantly more frequent episodes of surgery and of car accidents with hospital attendance than their age-matched unaffected siblings. Soft tissue trauma appears to increase risk of development of cervical dystonia in genetically predetermined individuals.

Oral BG-12 (dimethyl fumarate) for relapsing-remitting multiple sclerosis: a review of DEFINE and CONFIRM. Evaluation of: Gold R, Kappos L, Arnold D, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 2012;367:1098-107; and Fox RJ, Miller DH, Phillips JT, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med 2012;367:1087-97.

INTRODUCTION: Multiple sclerosis (MS) is an autoimmune neurodegenerative disease of the central nervous system involving inflammation, chronic demyelination and axonal loss. MS affects more than 2 million people worldwide. AREAS COVERED: This article aims to summarize the findings from two pivotal 2-year, randomized, double-blind, placebo-controlled, Phase III studies of BG-12 (dimethyl fumarate) for relapsing-remitting MS (RRMS): DEFINE (Determination of the Efficacy and Safety of Oral Fumarate in RRMS) and CONFIRM (Comparator and an Oral Fumarate in RRMS). Results from both studies demonstrated that BG-12 provides clinical and radiological efficacy over 2 years across a range of outcomes. These results were apparent as early as 12 weeks and sustained over the course of both studies. BG-12 was found to have an acceptable safety profile, with a similar overall incidence of adverse events across all treatment groups. EXPERT OPINION: The combination of robust efficacy, ease of administration and established safety profile is unique to a new therapy in MS. Findings from the pivotal Phase III studies support BG-12 as a potential initial oral treatment for patients with RRMS or as an alternative to other currently available therapies.

Clinical efficacy of BG-12 (dimethyl fumarate) in patients with relapsing-remitting multiple sclerosis: subgroup analyses of the CONFIRM study.

In the phase 3, randomized, placebo-controlled and active reference (glatiramer acetate) comparator CONFIRM study in patients with relapsing-remitting multiple sclerosis, oral BG-12 (dimethyl fumarate) reduced the annualized relapse rate (ARR; primary endpoint), as well as the proportion of patients relapsed, magnetic resonance imaging lesion activity, and confirmed disability progression, compared with placebo. We investigated the clinical efficacy of BG-12 240 mg twice daily (BID) and three times daily (TID) in patient subgroups stratified according to baseline demographic and disease characteristics including gender, age, relapse history, McDonald criteria, treatment history, Expanded Disability Status Scale score, T2 lesion volume, and gadolinium-enhancing lesions. BG-12 treatment demonstrated generally consistent benefits on relapse-related outcomes across patient subgroups, reflecting the positive findings in the overall CONFIRM study population. Treatment with BG-12 BID and TID reduced the ARR and the proportion of patients relapsed at 2 years compared with placebo in all subgroups analyzed. Reductions in ARR with BG-12 BID versus placebo ranged from 34% [rate ratio 0.664 (95% confidence interval 0.422-1.043)] to 53% [0.466 (0.313-0.694)] and from 13% [0.870 (0.551-1.373)] to 67% [0.334 (0.226-0.493)] with BG-12 TID versus placebo. Treatment with glatiramer acetate reduced the ARR and the proportion of patients relapsed at 2 years compared with placebo in most patient subgroups. The results of these analyses indicate that treatment with BG-12 is effective on relapses across a broad range of patients with relapsing-remitting multiple sclerosis with varied demographic and disease characteristics.

Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis.

BACKGROUND: BG-12 (dimethyl fumarate) is in development as an oral treatment for relapsing-remitting multiple sclerosis, which is commonly treated with parenteral agents (interferon or glatiramer acetate). METHODS: In this phase 3, randomized study, we investigated the efficacy and safety of oral BG-12, at a dose of 240 mg two or three times daily, as compared with placebo in patients with relapsing-remitting multiple sclerosis. An active agent, glatiramer acetate, was also included as a reference comparator. The primary end point was the annualized relapse rate over a period of 2 years. The study was not designed to test the superiority or noninferiority of BG-12 versus glatiramer acetate. RESULTS: At 2 years, the annualized relapse rate was significantly lower with twice-daily BG-12 (0.22), thrice-daily BG-12 (0.20), and glatiramer acetate (0.29) than with placebo (0.40) (relative reductions: twice-daily BG-12, 44%, P<0.001; thrice-daily BG-12, 51%, P<0.001; glatiramer acetate, 29%, P=0.01). Reductions in disability progression with twice-daily BG-12, thrice-daily BG-12, and glatiramer acetate versus placebo (21%, 24%, and 7%, respectively) were not significant. As compared with placebo, twice-daily BG-12, thrice-daily BG-12, and glatiramer acetate significantly reduced the numbers of new or enlarging T(2)-weighted hyperintense lesions (all P<0.001) and new T(1)-weighted hypointense lesions (P<0.001, P<0.001, and P=0.002, respectively). In post hoc comparisons of BG-12 versus glatiramer acetate, differences were not significant except for the annualized relapse rate (thrice-daily BG-12), new or enlarging T(2)-weighted hyperintense lesions (both BG-12 doses), and new T(1)-weighted hypointense lesions (thrice-daily BG-12) (nominal P<0.05 for each comparison). Adverse events occurring at a higher incidence with an active treatment than with placebo included flushing and gastrointestinal events (with BG-12) and injection-related events (with glatiramer acetate). There were no malignant neoplasms or opportunistic infections reported with BG-12. Lymphocyte counts decreased with BG-12. CONCLUSIONS: In patients with relapsing-remitting multiple sclerosis, BG-12 (at both doses) and glatiramer acetate significantly reduced relapse rates and improved neuroradiologic outcomes relative to placebo. (Funded by Biogen Idec; CONFIRM ClinicalTrials.gov number, NCT00451451.).

Reactivation of BK polyomavirus in patients with multiple sclerosis receiving natalizumab therapy.

Natalizumab therapy in multiple sclerosis has been associated with JC polyomavirus-induced progressive multifocal leucoencephalopathy. We hypothesized that natalizumab may also lead to reactivation of BK, a related human polyomavirus capable of causing morbidity in immunosuppressed groups. Patients with relapsing remitting multiple sclerosis treated with natalizumab were prospectively monitored for reactivation of BK virus in blood and urine samples, and for evidence of associated renal dysfunction. In this cohort, JC and BK DNA in blood and urine; cytomegalovirus (CMV) DNA in blood and urine; CD4 and CD8 T-lymphocyte counts and ratios in peripheral blood; and renal function were monitored at regular intervals. BK subtyping and noncoding control region sequencing was performed on samples demonstrating reactivation. Prior to commencement of natalizumab therapy, 3 of 36 patients with multiple sclerosis (8.3%) had BK viruria and BK reactivation occurred in 12 of 54 patients (22.2%). BK viruria was transient in 7, continuous in 2 patients, and persistent viruria was associated with transient viremia. Concomitant JC and CMV viral loads were undetectable. CD4:CD8 ratios fluctuated, but absolute CD4 counts did not fall below normal limits. In four of seven patients with BK virus reactivation, transient reductions in CD4 counts were observed at onset of BK viruria: these resolved in three of four patients on resuppression of BK replication. No renal dysfunction was observed in the cohort. BK virus reactivation can occur during natalizumab therapy; however, the significance in the absence of renal dysfunction is unclear. We propose regular monitoring for BK reactivation or at least for evidence of renal dysfunction in patients receiving natalizumab.

Self-referral of imaging does not imply overutilization.

For several years, some sectors of the specialty of Radiology have complained about the practice of self-referral, where a nonradiologist physician provides and interprets an imaging procedure. It is argued that such practice leads to increased costs since a physician will overutilize technology because of financial incentives. Here we review the literature. The most extensive analysis to date is at odds with the conclusions drawn in the older literature in that it provides little, if any, evidence for overutilization. We performed our own investigation using a poll study and found no suggestion of overutilization in 33 self-referring neurologists when compared with 900 neurologists who referred imaging to radiologists. The main period of growth in demand for imaging was between 1999 and 2002. Since 2002 there has been a steep decline in the rate of growth, so that it is possible to predict roughly zero growth in MRI utilization by 2009 without any intervention. It is shown why the rise in demand for imaging studies cannot be explained by self-referral, and it is argued that the sudden expansion of demand 8 years ago was caused by simultaneous technological improvements in the 3 major imaging modalities. Finally, it is shown how self-referral may actually reduce costs by facilitating the transfer of care from the hospital and ER to the office.

Factors contributing to the temperature beneath plaster or fiberglass cast material.

BACKGROUND: Most cast materials mature and harden via an exothermic reaction. Although rare, thermal injuries secondary to casting can occur. The purpose of this study was to evaluate factors that contribute to the elevated temperature beneath a cast and, more specifically, evaluate the differences of modern casting materials including fiberglass and prefabricated splints. METHODS: The temperature beneath various types (plaster, fiberglass, and fiberglass splints), brands, and thickness of cast material were measured after they were applied over thermometer which was on the surface of a single diameter and thickness PVC tube. A single layer of cotton stockinette with variable layers and types of cast padding were placed prior to application of the cast. Serial temperature measurements were made as the cast matured and reached peak temperature. Time to peak, duration of peak, and peak temperature were noted. Additional tests included varying the dip water temperature and assessing external insulating factors. Ambient temperature, ambient humidity and dip water freshness were controlled. RESULTS: Outcomes revealed that material type, cast thickness, and dip water temperature played key roles regarding the temperature beneath the cast. Faster setting plasters achieved peak temperature quicker and at a higher level than slower setting plasters. Thicker fiberglass and plaster casts led to greater peak temperature levels. Likewise increasing dip-water temperature led to elevated temperatures. The thickness and type of cast padding had less of an effect for all materials. With a definition of thermal injury risk of skin injury being greater than 49 degrees Celsius, we found that thick casts of extra fast setting plaster consistently approached dangerous levels (greater than 49 degrees for an extended period). Indeed a cast of extra-fast setting plaster, 20 layers thick, placed on a pillow during maturation maintained temperatures over 50 degrees of Celsius for over 20 minutes. CONCLUSION: Clinicians should be cautious when applying thick casts with warm dip water. Fast setting plasters have increased risk of thermal injury while brand does not appear to play a significant role. Prefabricated fiberglass splints appear to be safer than circumferential casts. The greatest risk of thermal injury occurs when thick casts are allowed to mature while resting on pillow.

Further evidence of dementia in SPG4-linked autosomal dominant hereditary spastic paraplegia.

OBJECTIVE: To investigate the progression of cognitive impairment and its behavioral aspects in patients with SPG4-linked autosomal dominant hereditary spastic paraplegia (SPG4-ADHSP). METHODS: Sixteen patients, 45 years or older, from five families with SPG4-ADHSP were prospectively assessed. Eleven of these, from three families, were followed and 10 had two cognitive examinations using the Cambridge Cognitive Assessment (CAMCOG) 2.9 years apart. The Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), the Neuropsychiatric Inventory (NPI), and the Nurses' Observation Scale for Geriatric Patients (NOSGER) were completed by close relatives of the 11 patients at the second assessment. Eleven matched control subjects had CAMCOG examinations 3.1 years apart. RESULTS: The mean CAMCOG score at the initial assessment was lower for the 10 HSP patients (73.5/107) than for 10 control subjects (91.7/107, p = 0.005). After 2.9 years, the HSP patients experienced a fall in the mean CAMCOG by 9.1 points to 64.4/107 (p = 0.008). The mean CAMCOG score for the control subjects (90.8/107) fell by only 0.9 points after 3.1 years (p = 0.36). The CAMCOG scores of two HSP patients moved from the mild (60 to 80) into the moderate dementia category (35 to 59) and in three other patients into the mild dementia range from borderline normal scores (81 to 85). IQCODE scores were abnormal in 9/11 HSP patients and 1/11 controls (p = 0.001). Seven of the 11 HSP patients were considered as having dementia. CONCLUSION: This study indicates an active progression of cognitive deterioration and dementia in older patients with SPG4-ADHSP.