Rémy Phan-Ba

Natalizumab induces a rapid improvement of disability status and ambulation after failure of previous therapy in relapsing-remitting multiple sclerosis.

Background:  Natalizumab (Tysabri) is a monoclonal antibody that was recently approved for the treatment of relapsing‐remitting multiple sclerosis (RRMS). Our primary objective was to analyse the efficacy of natalizumab on disability status and ambulation after switching patients with RRMS from other disease‐modifying treatments (DMTs).

MRI preclinical detection and asymptomatic course of a progressive multifocal leucoencephalopathy (PML) under natalizumab therapy.

Early detection of progressive multifocal leucoencephalopathy (PML) in the setting of natalizumab therapy currently is performed by rapid evaluation of new symptoms occurring in treated patients. The role of MR scanning has not been investigated but holds promise since MR detection is highly sensitive for PML lesions. The authors report a case of presymptomatic PML of the posterior fossa detected by MR scans. Immediate suspension of natalizumab and plasma exchanges resulted in a rapid decline of natalizumab serum concentration. Intravenous steroids started together with plasma exchanges followed by an oral tapering course were used to minimise the immune reconstitution inflammatory syndrome. No symptoms (beyond mild headache) developed, and the repeat PCR for JC Virus (JCV) DNA detection performed 10 weeks later was negative. This case suggests that: (1) periodic brain MR scans may detect signs of presymptomatic PML in MS patients treated with natalizumab, (2) corticosteroid management of inflammatory reaction may contribute to optimal control of the immune reconstitution inflammatory syndrome routinely seen with natalizumab-associated PML and (3) early radiological detection of PML can have an excellent outcome even in a clinically critical region and despite prior immunosuppressant exposure. The potential benefit of regular MR scanning just using the T2/FLAIR modalities could be further investigated in order to detect early natalizumab-associated PML, leading to benign outcomes.

Comparison of the Timed 25-Foot and the 100-Meter Walk as Performance Measures in Multiple Sclerosis

Background. Ambulation impairment is a major component of physical disability in multiple sclerosis (MS) and a major target of rehabilitation programs. Outcome measures commonly used to evaluate walking capacities suffer from several limitations. Objectives. To define and validate a new test that would overcome the limitations of current gait evaluations in MS and ultimately better correlate with the maximum walking distance (MWD). Methods. The authors developed the Timed 100-Meter Walk Test (T100MW), which was compared with the Timed 25-Foot Walk Test (T25FW). For the T100MW, the subject is invited to walk 100 m as fast as he/she can. In MS patients and healthy control volunteers, the authors measured the test–retest and interrater intraclass correlation coefficient. Spearman rank correlations were obtained between the T25FW, the T100MW, the Expanded Disability Status Scale (EDSS), and the MWD. The coefficient of variation, Bland–Altman plots, the coefficient of determination, and the area under the receiver operator characteristic curve were measured. The mean walking speed (MWS) was compared between the 2 tests. Results. A total of 141 MS patients and 104 healthy control volunteers were assessed. Minor differences favoring the T100MW over the T25FW were observed. Interestingly, the authors demonstrated a paradoxically higher MWS on a long (T100MW) rather than on a short distance walk test (T25FW). Conclusion. The T25FW and T100MW displayed subtle differences of reproducibility, variability, and correlation with MWD favoring the T100MW. The maximum walking speed of MS patients may be poorly estimated by the T25FW since MS patients were shown to walk faster over a longer distance.

Motor fatigue measurement by distance-induced slow down of walking speed in multiple sclerosis

Background and rationale Motor fatigue and ambulation impairment are prominent clinical features of people with multiple sclerosis (pMS). We hypothesized that a multimodal and comparative assessment of walking speed on short and long distance would allow a better delineation and quantification of gait fatigability in pMS. Our objectives were to compare 4 walking paradigms: the timed 25-foot walk (T25FW), a corrected version of the T25FW with dynamic start (T25FW+), the timed 100-meter walk (T100MW) and the timed 500-meter walk (T500MW). Methods Thirty controls and 81 pMS performed the 4 walking tests in a single study visit. Results The 4 walking tests were performed with a slower WS in pMS compared to controls even in subgroups with minimal disability. The finishing speed of the last 100-meter of the T500MW was the slowest measurable WS whereas the T25FW+ provided the fastest measurable WS. The ratio between such slowest and fastest WS (Deceleration Index, DI) was significantly lower only in pMS with EDSS 4.0–6.0, a pyramidal or cerebellar functional system score reaching 3 or a maximum reported walking distance ≤4000 m. Conclusion The motor fatigue which triggers gait deceleration over a sustained effort in pMS can be measured by the WS ratio between performances on a very short distance and the finishing pace on a longer more demanding task. The absolute walking speed is abnormal early in MS whatever the distance of effort when patients are unaware of ambulation impairment. In contrast, the DI-measured ambulation fatigability appears to take place later in the disease course.

The earlier, the smaller, the better for natalizumab-associated PML: In MRI vigilance veritas?

Natalizumab-associated progressive multifocal leukoencephalopathy (N-PML) in multiple sclerosis (MS) is due to CNS infection by the opportunistic JC virus (JCV). As of December 2011, 193 confirmed cases of N-PML have been observed, giving rise to an overall risk of approximately 0.202%.[1][1] N-PML

A corrected version of the Timed-25 Foot Walk Test with a dynamic start to capture the maximum ambulation speed in multiple sclerosis patients

BACKGROUND No clinical test is currently available and validated to measure the maximum walking speed (WS) of multiple sclerosis (MS) patients. Since the Timed 25-Foot Walk Test (T25FW) is performed with a static start, it takes a significant proportion of the distance for MS patients to reach their maximum pace. OBJECTIVES In order to capture the maximum WS and to quantify the relative impact of the accelerating phase during the first meters, we compared the classical T25FW with a modified version (T25FW(+)allowing a dynamic start after a 3 meters run-up. METHODS Sixty-four MS patients and 30 healthy subjects performed successively the T25FW and the T25FW(+). RESULTS The T25FW(+)was performed faster than the T25FW for the vast majority of MS and healthy subjects. In the MS population, the mean relative gain of speed due to the dynamic start on T25FW(+) was independent from the EDSS and from the level of ambulation impairment. Compared to healthy subjects, the relative difference between dynamic versus static start was more important in the MS population even in patients devoid of apparent gait impairment according to the T25FW. CONCLUSION The T25FW(+)allows a more accurate measurement of the maximum WS of MS patients, which is a prerequisite to reliably evaluate deceleration over longer distance tests. Indirect arguments suggest that the time to reach the maximum WS may be partially influenced by the cognitive impairment status. The maximum WS and the capacity of MS patients to accelerate on a specific distance may be independently regulated and assessed separately in clinical trials and rehabilitation programs.

Post-mortem assessment of rat spinal cord injury and white matter sparing using inversion recovery-supported proton density magnetic resonance imaging

Study design:This was an experimental study.Objectives:White matter sparing influences locomotor recovery after traumatic spinal cord injury (SCI). The objective of the present post-mortem magnetic resonance imaging (MRI) investigation was to assess the potential of a simple inversion recovery (IR) sequence in combination with high-resolution proton density (PD) images to selectively depict spared white matter after experimental SCI in the rat.Setting:This study was conducted at University of Liège and Centre Hospitalier Universitaire, Liège, Belgium and Hasselt University, Diepenbeek, Belgium.Methods:Post-mortem 9.4 tesla (T) MRI was obtained from five excised rat spines 2 months after compressive SCI. The locomotor recovery had been followed weekly using the standardized Basso–Beattie–Bresnahan scale. IR MRI was used to depict normal white matter as very hypo-intense. Preserved white matter, cord atrophy and lesion volume were assessed, and histology was used to confirm MRI data.Results:MRI showed lesion severity and white matter sparing in accordance with the degree of locomotor recovery. IR MRI enhanced detection of spared and injured white matter by selectively altering the signal of spared white matter. Even subtle white matter changes could be detected, increasing diagnostic accuracy as compared to PD alone. MRI accuracy was confirmed by histology.Conclusion:High-resolution IR-supported PD MRI provides useful micro-anatomical information about white matter damage and sparing in the post-mortem assessment of chronic rat SCI.

Rapid, postmortem 9.4 T MRI of spinal cord injury: correlation with histology and survival times.

High field magnetic resonance imaging (MRI) has been increasingly used to assess experimental spinal cord injury (SCI). In the present investigation, after partial spinal cord injury and excision of the whole spine, pathological changes of the spinal cord were studied in spinal cord-spine blocks, from the acute to the chronic state (24 h to 5 months). Using proton density (PD) weighted imaging parameters at a magnetic field strength of 9.4 tesla (T), acquisition times ranging from <1 to 10 h per specimen were used. High in-plane pixel resolution (68 and 38 microm, respectively) was obtained, as well as high signal-to-noise ratio (SNR), which is important for optimal contrast settings. The quality of the resulting MR images was demonstrated by comparison with histology. The cord and the lesion were shown in their anatomical surroundings, detecting cord swelling in the acute phase (24 h to 1 week) and cord atrophy at the chronic stage. Haemorrhage was detected as hypo-intense signal. Oedema, necrosis and scarring were hyper-intense but could not be distinguished. Histology confirmed that the anatomical delimitation of the lesion extent by MRI was precise, both with high and moderate resolution. The present investigation thus demonstrates the precision of spinal cord MRI at different survival delays after compressive partial SCI and establishes efficient imaging parameters for postmortem PD MRI.

Immune Reconstitution Inflammatory Syndrome in Natalizumab-Associated PMLAuthor Response

# {#article-title-2} Tan et al.1 dichotomized early vs late types of the immune reconstitution inflammatory syndrome (IRIS), which appears to be universal in patients with multiple sclerosis (MS) who develop progressive multifocal leukoencephalopathy (PML) in the setting of natalizumab therapy. The authors identified early PML-IRIS based on gadolinium enhancement in the lesions on brain MRI at the time of PML diagnosis, before natalizumab withdrawal. Early PML-IRIS occurred approximately 19 days after the last natalizumab …