Pharmacological Approaches to the Management of Secondary Progressive Multiple Sclerosis.

It is well recognised that the majority of the impact of multiple sclerosis (MS), both personal and societal, arises in the progressive phase where disability accumulates inexorably. As such, progressive MS (PMS) has been the target of pharmacological therapies for many years. However, there are no current licensed treatments for PMS. This stands in marked contrast to relapsing remitting MS (RRMS) where trials have resulted in numerous licensed therapies. PMS has proven to be a more difficult challenge compared to RRMS and this review focuses on secondary progressive MS (SPMS), where relapses occur before the onset of gradual, irreversible disability, and not primary progressive MS where disability accumulation occurs without prior relapses. Although there are similarities between the two forms, in both cases pinpointing when PMS starts is difficult in a condition in which disability can vary from day to day. There is also an overlap between the pathology of relapsing and progressive MS and this has contributed to the lack of well-defined outcomes, both surrogates and clinically relevant outcomes in PMS. In this review, we used the search term 'randomised controlled clinical drug trials in secondary progressive MS' in publications since 1988 together with recently completed trials where results were available. We found 34 trials involving 21 different molecules, of which 38% were successful in reaching their primary outcome. In general, the trials were well designed (e.g. double blind) with sample sizes ranging from 35 to 1949 subjects. The majority were parallel group, but there were also multi-arm and multidose trials as well as the more recent use of adaptive designs. The disability outcome most commonly used was the Expanded Disability Status Scale (EDSS) in all phases, but also magnetic resonance imaging (MRI)-measured brain atrophy has been utilised as a surrogate endpoint in phase II studies. The majority of the treatments tested in SPMS over the years were initially successful in RRMS. This has a number of implications in terms of targeting SPMS, but principally implies that the optimal strategy to target SPMS is to utilise the prodrome of relapses to initiate a therapy that will aim to both prevent progression and slow its accumulation. This approach is in agreement with the early targeting of MS but requires treatments that are both effective and safe if it is to be used before disability is a major problem. Recent successes will hopefully result in the first licensed therapy for PMS and enable us to test this approach.

Anti-JC virus antibody titres increase over time with natalizumab treatment.

BACKGROUND: Anti-JC virus antibody status is a risk factor for progressive multifocal leukoencephalopathy after natalizumab treatment in multiple sclerosis. Previous studies have used a cross-sectional approach to conclude that the presence and duration of natalizumab treatment does not influence anti-JCV Ab seropositivity. OBJECTIVES: Using a longitudinal approach, we measured change in anti-JCV Ab results after natalizumab treatment. METHODS: Anti-JCV Ab results (n = 1154) from the second-generation STRATIFY JCV™ DxSelect™ test were analysed from an observational cohort of MS patients on natalizumab (n = 485; n = 340 with repeat testing; n = 657 repeat tests on natalizumab). RESULTS: Across sequential paired tests, seroconversion rate was greater than seroreversion rate (40/364 (11.0%) versus 18/293 (6.1%); p < 0.05). Moreover, anti-JCV Ab index increased across longitudinal paired tests (mA-B 0.102; paired t(656) = 5.0; p < 0.0001). This magnitude of Ab level increase far exceeds that expected due to increasing age alone. CONCLUSION: Our data suggest that natalizumab therapy is associated with a significant and substantial increase in anti-JCV Ab index over time. Further work should focus on the underlying mechanisms of this phenomenon, and the clinical relevance to risk stratification.

Assessing dalfampridine efficacy in the physician's office.

Dalfampridine (extended release 4-aminopyridine) is shown in three recent randomised controlled trials to improve walking speed in people with multiple sclerosis; however, the trial literature makes it clear that dalfampridine is effective in only a subset of patients. For the neurologist working in an everyday physician's office, a key question arises: How to distinguish the few who experience a meaningful clinical benefit, from the many who do not? This question has not yet been adequately addressed in the available literature.

Painless urethral bleeding: an unusual presentation of Von Willebrand disease.

Von Willebrand disease (vWD) is the most common bleeding disorder, and usually presents with either easy bruising or mucus membrane bleeding. Many patients are also diagnosed as a result of abnormal pre-operative laboratory tests. In this report, we describe two patients presenting with painless, persistent urethral bleeding as their initial manifestation of vWD. The first patient began bleeding after a Foley catheter was placed during a hospital admission for status epilepticus. A urologic examination demonstrated a wound in the posterior urethra. Despite repeated attempts at controlling the bleeding with cautery, the bleeding persisted. The second patient presented with spontaneous urethral bleeding and a normal urologic examination. Due to persistent bleeding, both patients underwent a coagulation evaluation that demonstrated the presence of type 1 vWD. The first patient had resolution of his bleeding following 5 weeks of Alphanate, a von Willebrand factor containing factor VIII concentrate, and aminocaproic acid. The second patient initially responded to desmopressin, but subsequently required Humate-P to achieve complete resolution. These cases illustrate the importance of an evaluation for bleeding disorders in patients with persistent bleeding from any site.

The epidemiology of early syphilis in Houston, Texas, 1994-1995.

BACKGROUND AND OBJECTIVES: Since 1990, rates of syphilis in the United States have steadily declined. However, the South still records disproportionately high rates of syphilis infection. GOAL: The objective of this study is to describe the epidemiology of early syphilis in Houston, TX, the largest urban center in the South, in 1994 and 1995. STUDY DESIGN: The study is cross-sectional and descriptive, and uses data collected by Disease Intervention Specialists on the Interview Form 73.54 from interviews with men and women diagnosed with early syphilis. RESULTS: Early syphilis in Houston is highly concentrated in a "belt" that extends north to south in a line just east of the city center. Although sex-specific rates of early syphilis are roughly equal, men are 3.5 times more likely than women to be diagnosed with primary syphilis, whereas women are nearly 2 times more likely than men to be diagnosed with secondary syphilis and 1.5 times more likely to be diagnosed with early latent syphilis. CONCLUSION: Routine surveillance data indicate that young, African-American men and women in Houston's inner-city neighborhoods are disproportionately affected by syphilis. Particular efforts must be made to reach women, who are detected and treated at later stages of the disease than men.

Anterior urethral valve presenting in an adult male.

Anterior urethral valves are a rare congenital anomaly which can occur singly or in combination with a proximal urethral diverticulum. A retrograde urethrogram and voiding cystourethrogram can easily make the diagnosis unless the valve is located with the glandular urethra. Cystoscopic examination of the urethra can overlook anterior urethral valves, but by altering the flow of the irrigant, the cystoscope can be used to make these valves very apparent.

Neonatal renomegaly.

A retrospective clinical review was done to study the value of ultrasound and renography in the investigation of 100 neonates with renomegaly. Abnormalities in 73 patients were detected antenatally with ultrasonography. Of the neonates 47 had lower urinary tract pathological conditions and ultrasound was more than 90 per cent accurate in identifying the accompanying ureteral dilatation. A total of 53 neonates had upper tract anomalies (ureteropelvic junction obstruction or cystic dysplasia). With ultrasonography the degree of pyelocaliectasis in patients with ureteropelvic junction obstruction was classified as mild (22 units), moderate (13) or severe (7). Initial treatment and followup were reviewed to study the clinical course of neonates with mild to moderate degrees of pyelocaliectasis followed nonoperatively, and to determine whether the diuretic renogram had a predictive role in identifying which kidneys were most likely to deteriorate.