Long-term effectiveness of enzyme replacement therapy in Fabry disease with the p.Arg227Ter variant: Fabry disease in Ostrobothnia (FAST) study.

Fabry disease (FD) is an X chromosome-linked, life-threatening lysosomal disease caused by one of more than 1000 currently known variants in the α-galactosidase A (GLA) gene. The follow-up part of the Fabry Disease in Ostrobothnia (FAST) study reports the long-term effect of enzyme replacement therapy (ERT) on a prospectively collected cohort of 12 patients, 4 males and 8 females, mean age 46 years (SD 16), with the classical variant c.679C > T p.Arg227Ter, which is one of the most common FD variants worldwide. In the natural history period of the FAST study, half of the patients in both sexes had at least one major event, of which 80% were of cardiac origin. During 5 years of ERT, four patients had a total of six major clinical events consisting of one silent ischemic stroke, three ventricular tachycardias and two increased left ventricular mass indexes. In addition, four patients developed minor cardiac events, four patients minor renal events, and one patient a minor neurological event. ERTs may delay but not prevent the progression of the disease in most patients with the variant Arg227Ter. This variant might be suitable for investigating the efficacy of second-generation ERTs compared to the currently used ERTs regardless of sex.

Natural course of Fabry disease with the p. Arg227Ter (p.R227*) mutation in Finland: Fast study.

BACKGROUND: Fabry disease is caused by a deficient or an absent alfa-galactosidase A activity and is an X-linked disorder that results in organ damage and a shortened life span, especially in males. The severity of the disease depends on the type of mutation, gender, skewed X-chromosome inactivation, and other still unknown factors. METHODS: In this article, we describe the natural course of a common classic Fabry disease mutation, p.Arg227Ter or p.R227*, in Finland. RESULTS: Four males and ten females belonged to two extended families. The mean age was 46 years (SD 18.4). Six patients (43%) had cardiac hypertrophy, three patients (21%) had ischemic stroke, and none had severe kidney dysfunction. Three patients had atrial fibrillation; two patients who had atrial fibrillation also had pacemakers. All males over 30 years of age had at least one of the following manifestations: cardiac hypertrophy, stroke, or proteinuria. In females, the severity of Fabry disease varied from classic multiorgan disease to a condition that mimicked the attenuated cardiac variant. No one was totally asymptomatic without any signs of Fabry disease. Cardiac magnetic resonance imaging was performed on nine of 14 patients was the most sensitive for detecting early cardiac manifestations. Five patients (55%) had late gadolinium enhancement-positive segments. CONCLUSION: Cardiac involvement should be effectively detected in females before considering them asymptomatic mutation carriers.

The effect of infliximab, a monoclonal antibody against TNF-alpha, on disc herniation resorption: a randomized controlled study.

STUDY DESIGN: Randomized, controlled study. OBJECTIVE: To evaluate the effect of infliximab on herniated nucleus pulposus (HNP) resorption. SUMMARY OF BACKGROUND DATA: Although the effects of tumor necrosis factor alpha (TNF-alpha) on HNP resorption are not fully understood, TNF-alpha appears to be an essential mediator in HNP resorption. METHODS: As part of a substudy of the FIRST II study, magnetic resonance images (MRIs) were obtained from 21 patients who were candidates for discectomy at weeks 0, 2, 12, and 26 after receiving a single infusion of either 5 mg/kg infliximab (11 patients) or placebo (10 patients). The volume (mm3) of HNP, thickness (mm) and extent (%) of rim enhancement, and presence of nerve root edema were assessed. RESULTS: HNP volume decreased significantly from baseline to 6 months in both treatment groups (P < 0.01), with no difference noted between the infliximab and placebo groups. By week 2, rim enhancement thickness increased significantly in the infliximab group compared with the placebo group (P = 0.003). Two patients in each group required back surgery before the 6-month assessment. CONCLUSIONS: Infliximab did not appear to interfere with disc herniation resorption over a 6-month period.

Determinants of spontaneous resorption of intervertebral disc herniations.

STUDY DESIGN: A follow-up of disc herniation (herniated nucleus pulposus [HNP]) resorption on magnetic resonance imaging (MRI). OBJECTIVE: To assess the determinants of resorption of HNP. SUMMARY OF BACKGROUND DATA: Neovascularization in the outermost areas of HNP, presenting as an enhancing rim in gadolinium diethylenetriamine pentaacetic acid MR images, is thought to be a major determinant of spontaneous resorption of HNP. METHODS: Patients with HNP-induced sciatica at baseline were rescanned at 2 months (N = 74) and after 12 months (N = 53). The volume of HNP (mm), thickness (mm) and extent (%) of enhancement, and the degree of HNP migration (Komori classification) were analyzed. Repeated measures analysis of covariance was used in statistical analysis. RESULTS: Significant resorption of HNP occurred from baseline to 2 months, although the resorption rate was more pronounced over the whole 1-year follow-up. Higher baseline scores of rim enhancement thickness, higher degree of HNP displacement in the Komori classification, and age category 41-50 years were associated with a higher resorption rate. Thickness of rim enhancement was a stronger determinant of spontaneous resorption than extent of rim enhancement. Clinical symptom alleviation occurs concordantly with a faster resorption rate. CONCLUSIONS: MRI is a useful prognostic tool for identifying patients with HNP-induced sciatica with a benign natural course.

Efficacy of infliximab for disc herniation-induced sciatica: one-year follow-up.

STUDY DESIGN: An open-label trial. OBJECTIVES: To test the long-term efficacy of infliximab, a monoclonal antibody against tumor necrosis factor-alpha (TNF-alpha), in disc herniation-induced sciatica. SUMMARY OF BACKGROUND DATA: Our recent trial indicated that a single infusion of 3 mg/weight-kg of infliximab produced a rapid curative effect in disc herniation-induced sciatica. Here, we describe the 1-year effect of a 3 mg/kg of infliximab in these 10 patients and our experience with a lower dose of 1 mg/kg of infliximab for the same indication in 2 additional patients. METHODS: Patients with severe sciatica were treated with a single infusion of infliximab, 3 mg/weight-kg in 10 patients and 1 mg/kg in 2 patients, intravenously over 2 hours. The outcomes (leg and back pain on a 100-mm visual scale, Oswestry disability, clinical signs) were assessed at 1 week, 2 weeks, 1 month, 3 months, 6 months, and 1 year after the infusion. The outcomes with 3 mg/kg of infliximab were compared to 62 patients who received periradicular saline for sciatica in a previous trial. The resorption rate of disc herniations from baseline to 1 year was compared between infliximab and control groups. RESULTS: The response to 1 mg/kg of infliximab for leg pain was good only in 1 of the 2 patients treated, whereas the response to 3 mg/kg of infliximab for leg pain was sustained in most patients over the 1-year follow-up. The 1-year response significantly favored 3 mg/kg of infliximab over periradicular saline in leg pain (P = 0.005) and disability (P = 0.003). Neurologic abnormalities normalized more comprehensively in the infliximab group (P = 0.001). Reduction in disc herniation volume did not differ between the infliximab-treated patients and controls. CONCLUSIONS: The results showed that the beneficial effect of a single infusion of 3 mg/kg of infliximab for herniation-induced sciatica is sustained in most patients over a 1-year follow-up period. Furthermore, infliximab does not seem to interfere with the spontaneous resorption of disc herniations.

Three-year follow-up of lumbar artery occlusion with magnetic resonance angiography in patients with sciatica: associations between occlusion and patient-reported symptoms.

STUDY DESIGN: Comparison of occlusion of lumbar arteries in magnetic resonance angiography (MRA) with patient-reported sciatica symptoms during a 3-year follow-up. OBJECTIVES: To evaluate whether occlusion of lumbar arteries is associated with subjective pain symptoms and physical ability among sciatica patients. SUMMARY OF BACKGROUND DATA: Cadaveric studies indicate that atherosclerotic manifestations of the abdominal aorta are associated with low back pain (LBP). Impaired blood flow may disturb diffusion of nutrients into the disc, causing degeneration and possibly back pain. METHODS: Two-dimensional time-of-flight MRA was used to evaluate lumbar arteries at baseline and 3 years. The arteries on both sides (L1-L4) were evaluated visually and scored as normal, narrowed, or occluded. Incidence of new stenosis was estimated. The associations of stenosis with self-reported previous medical consultations, pain duration through the first year, and number of pain episodes through the last 2 years of follow-up were calculated. Additionally, leg and back pain (10-cm VAS), disability (Oswestry), and self-reported physical ability (self-efficacy) were inquired at 1, 2, and 3 years. In the statistical analysis, bivariate correlation, and the chi or Fisher's test were used. RESULTS: MRA was obtained at baseline for 147 patients and at 3 years for 134 patients. Baseline stenosis associated with intensity of back pain at 1 year, leg pain at 2 years, and self-efficacy at every follow-up assessment, but not with disability, previous LBP history, or future pain episodes. The associations of stenosis at 3 years were similar but weaker. Newly formed stenosis was associated with the preceding year's medical consultations due to LBP and prolonged LBP during the first follow-up year. CONCLUSIONS: Arterial stenosis is associated strongly and consistently with patient-estimated physical ability,but only slightly with subjective pain symptoms. Interestingly, new stenosis is preceded by pain symptoms. The evaluation of lumbar blood flow may thus be useful in clinical practice.

Effect of periradicular methylprednisolone on spontaneous resorption of intervertebral disc herniations.

STUDY DESIGN: Prospective comparison of periradicular infiltration with steroid versus saline on the spontaneous resorption of herniated nucleus pulposus in a randomized controlled trial. OBJECTIVES: To evaluate whether periradicular steroid retards the resorption of herniated nucleus pulposus. SUMMARY OF BACKGROUND DATA: Rim enhancement around herniated nucleus pulposus is associated with spontaneous resorption of disc herniations. As rim enhancement consists of a macrophage infiltrate, periradicular steroid could theoretically interfere with the resorption process. METHODS.: Patients with disc herniation-induced sciatica were randomized to receive either periradicular methylprednisolone (in combination with bupivacaine) or saline. Lumbar magnetic resonance imaging (MRI) was performed at baseline, at 2 months, and at 12 months. Disc herniation volume (mm3), coverage of rim enhancement (%), and rim enhancement thickness (mm) were evaluated by a radiologist blinded to the allocation. Operated patients were excluded from the 1-year imaging. Changes in the parameters from baseline to 2 months, and from 2 to 12 months, were evaluated with the Mann-Whitney U test. RESULTS: Change in herniation volume from baseline to 2 months was measurable in 34 patients of both groups, and from 2 to 12 months in 26 patients of the steroid group and 24 patients of the saline group. Significant spontaneous resorption of disc herniations occurred in both groups during the 1-year follow-up. In the subgroup analysis, there tended to be even faster resorption in the steroid group from baseline to 2 months for extrusions, and from 2 months to 12 months for contained herniations. No significant differences were observed in the enhancement parameters (coverage and thickness) between the two treatments. CONCLUSIONS: Periradicular corticosteroid does not have a negative effect on the spontaneous resorption of the herniated nucleus pulposus.

Gadolinium diethylenetriaminepentaacetic acid enhancement in magnetic resonance imaging in relation to symptoms and signs among sciatic patients: a cross-sectional study.

STUDY DESIGN: A cross-sectional descriptive study. OBJECTIVES: Gadolinium enhancement in lumbar magnetic resonance imaging is not used routinely. The current study explored the possible intercorrelations of enhancement patterns with clinical symptoms and signs. SUMMARY OF BACKGROUND DATA: Rim enhancement has been reported to occur in the periphery of disc herniations, and it is thought to represent neovascularization. To the authors' knowledge, the significance of the enhancement in relation to clinical symptoms has not been studied. METHODS: Magnetic resonance imaging of the lumbar spine with intravenous gadolinium diethylenetriaminepentaacetic acid was performed in each patient. Various contrast enhancement parameters and volume of herniation were evaluated, and their correlations with clinical signs and symptoms (straight leg raising, motor defect, Achilles reflex, leg and back pain, disability) were analyzed. RESULTS: The extent of rim enhancement correlated highly significantly with the degree of disc displacement, being most pronounced in the case of sequesters. The duration of sciatic symptoms correlated negatively with enhancement. The clinical symptoms did not correlate significantly with the different enhancement parameters or disc herniation volume. Straight leg raising correlated only slightly with the extent of rim enhancement (P = 0.04) when bulges were excluded. Achilles reflex abnormality correlated significantly with all enhancement parameters for lesions at L5-S1. In the final stepwise logistic regression model, contrast enhancement extent correlated most significantly with abnormal Achilles reflex (P = 0.0002). CONCLUSIONS: Although rim enhancement of disc herniation is thought to represent a beneficial phagocytotic phenomenon, it may also have a harmful effect on the adjacent nerve root.