W-Ludo van der Pol

Randomized sequential trial of valproic acid in amyotrophic lateral sclerosis

To determine whether valproic acid (VPA), a histone deacetylase inhibitor that showed antioxidative and antiapoptotic properties and reduced glutamate toxicity in preclinical studies, is safe and effective in amyotrophic lateral sclerosis (ALS) using a sequential trial design.

The Fcγ Receptor Genotype as a Risk Factor for Generalized Early-Onset Periodontitis in Japanese Patients

BACKGROUND Genetic polymorphisms of immunoglobulin G (IgG) Fc receptors (FcγR) were recently shown to be associated with recurrence rates of adult periodontitis (AP). The purpose of this study was to evaluate whether FcγR polymorphisms are also associated with generalized early-onset periodontitis (G-EOP) in Japanese patients. METHODS Thirty-eight Japanese patients with G-EOP and 83 Japanese patients with AP were identified according to established clinical criteria, including measurements of probing depth, clinical attachment level, and alveolar bone level. FcγR genotypes for 3 bi-allelic polymorphisms were determined in these G-EOP and AP patients and 104 race-matched healthy controls by means of allele-specific polymerase chain reactions. RESULTS There was a significant difference in the distribution of FcγRIIIb genotypes between G-EOP patients and healthy controls (P = 0.02). Additionally, a significant over-representation of FcγRIIIb-NA2 allele was observed in G-EOP patients as compared to AP patients and controls (P = 0.02, P = 0.009, respectively). Moreover, we found a strong association between GEOP and the composite genotype comprising FcγRIIIb-NA2 and FcγRIIIa-158F (G-EOP versus controls: odds ratio 2.4, 95% CI 1.0-6.0, X2 = 4.13, P = 0.04). CONCLUSIONS This study indicates that the FcγRIIIb-NA2 allele and possibly FcγRIIIa-158F could be associated with susceptibility to G-EOP in Japanese patients. J Periodontol 2000;71:1425-1432.

The Fcγ Receptor Genotype as a Severity Factor for Chronic Periodontitis in Japanese Patients

BACKGROUND Functional polymorphisms of immunoglobulin G (IgG) Fc receptors (FcγR) have been shown to be associated with generalized aggressive periodontitis (GAgP) or recurrence of chronic periodontitis (CP) in Japanese patients. The purpose of this study was to evaluate whether FcγR polymorphisms are also associated with severity of CP. METHODS Fifty Japanese non-smoking patients with severe CP and 39 Japanese non-smoking patients with moderate CP were identified according to established clinical criteria, including measurements of probing depth (PD), clinical attachment level (CAL), and alveolar bone loss (BL). FcγR genotypes for 3 bi-allelic polymorphisms (FcγRIIa-R/H131, FcγRIIIa-158V/F, FcγRIIIb-NA1/NA2) were determined in these CP patients and 64 race-matched, non-smoking healthy controls by means of allele-specific polymerase chain reactions. RESULTS There was a significant over-representation of FcγRIIIa-158V allele in severe CP patients compared to moderate CP patients (odds ratio 2.03, 95% confidence interval [CI] 1.03-4.01, χ 2 = 4.86, P = 0.028). In addition, we found a strong association between CP severity and FcγR composite genotype comprising FcγRIIIa-158V plus FcγRIIIb-NA2 (severe CP versus moderate CP: odds ratio 4.69, 95% CI 1.52-15.10, χ 2 = 9.35, P = 0.002; severe CP versus healthy controls: odds ratio 4.10, 95% CI 1.62-10.59, χ 2 = 11.13, P = 0.0009). Moreover, CP patients positive for the composite genotype exhibited more severe signs of periodontitis than composite genotype-negative individuals (positive versus negative; mean PD: 3.8 mm versus 3.2 mm, P = 0.005; mean CAL: 4.5 mm versus 3.7 mm, P = 0.005; mean % BL: 37.6% versus 29.9%, P = 0.008). CONCLUSION Our results document the FcγRIIIa-158V allele and possibly FcγRIIIb-NA2 to be associated with severity of CP in Japanese patients. J Periodontol 2001;72:1324-1331.

Genetic Overlap between Apparently Sporadic Motor Neuron Diseases

Progressive muscular atrophy (PMA) and amyotrophic lateral sclerosis (ALS) are devastating motor neuron diseases (MNDs), which result in muscle weakness and/or spasticity. We compared mutation frequencies in genes known to be associated with MNDs between patients with apparently sporadic PMA and ALS. A total of 261 patients with adult-onset sporadic PMA, patients with sporadic ALS, and control subjects of Dutch descent were obtained at national referral centers for neuromuscular diseases in The Netherlands. Sanger sequencing was used to screen these subjects for mutations in the coding regions of superoxide dismutase-1 (SOD1), angiogenin (ANG), fused in sarcoma/translated in liposarcoma (FUS/TLS), TAR DNA-binding protein 43 (TARDBP), and multivesicular body protein 2B (CHMP2B). In our cohort of PMA patients we identified two SOD1 mutations (p.D90A, p.I113T), one ANG mutation (p.K17I), one FUS/TLS mutation (p.R521H), one TARDBP mutation (p.N352S), and one novel CHMP2B mutation (p.R69Q). The mutation frequency of these genes was similar in sporadic PMA (2.7%) and ALS (2.0%) patients, and therefore, our findings demonstrate a genetic overlap between apparently sporadic PMA and ALS.

Anti–GM1 IgG antibodies induce leukocyte effector functions via Fcγ receptors

Guillain–Barré syndrome (GBS) is an immune‐mediated neuropathy, in which leukocytes and humoral components of the immune system proposedly initiate localized inflammation. An important pathogenic role for anti–GM1 ganglioside antibodies has been suggested. Therefore, we evaluated anti‐GM1 IgG antibody‐induced leukocyte effector functions such as degranulation and phagocytosis using serum of 24 GBS patients. Serum without anti‐GM1 antibodies of 9 GBS patients as well as pooled serum from healthy individuals served as controls. Ten out of 15 (67%) of anti‐GM1 IgG positive sera were capable of inducing leukocyte degranulation, and 8 out of 15 (53%) of anti‐GM1 IgG positive sera were capable of inducing phagocytosis of GM1‐coated beads. In all of these sera anti‐GM1 antibody titers were ≥1:800. No leukocyte degranulation or phagocytosis was observed in control sera. Leukocyte activation was completely abrogated in the presence of IgG receptor (FcγR) blocking antibodies, suggesting a crucial role for leukocyte FcγR in GBS pathogenesis. No correlation of antibody titers with the extent of leukocyte activation, or severity of disease was observed. These data document the capacity of anti‐GM1 IgG antibodies to activate leukocyte inflammatory functions, and suggest an important role for anti‐ganglioside IgG antibodies in the pathogenesis of GBS.

Pharmacokinetics of intravenous immunoglobulin in multifocal motor neuropathy

Background Multifocal motor neuropathy (MMN) is often responsive to treatment with intravenous immunoglobulin (IVIg), but the optimal dose and intervals of IVIg maintenance treatment have not been established. Increase in IgG concentration (ΔIgG) after IVIg infusion has recently been identified as determinant of outcome in Guillain-Barré syndrome. ΔIgG may therefore represent a potentially useful biomarker to optimise IVIg dosing in patients with MMN. Objective The aims of this study were to determine variability of IVIg pharmacokinetics in patients with MMN in relation to treatment response, and to establish whether interindividual differences in IVIg pharmacokinetics were associated with genetic polymorphisms of the endothelial IgG receptor (FcRn) which determines IgG half-life. Methods Twenty-three patients with MMN receiving their first IVIg treatment at a cumulative dose of 2.0 g/kg in 5 days were included. A good treatment response was defined as an increase in muscle strength of at least one Medical Research Council point in minimally two muscle groups. IgG concentrations in serum were determined at baseline, at day 1 and day 5 of the IVIg course, and 3 weeks after treatment. FcRn copy number variation and differences in repeat length of the variable number of tandem repeats in the FcRn gene were determined by quantitative PCR and Sanger sequencing. Results Seventeen patients (74%) had a good response to treatment. Total IgG and ΔIgG levels showed large variation between patients. Mean ΔIgG was higher in IVIg responders than in non-responders, with the largest difference on day 1 (11.1 g/L vs 4.5 g/L, p=0.06), but our study lacked power to show statistically significant differences. Genetic variation in the FcRn gene was not associated with ΔIgG levels or response to treatment. Conclusions IVIg pharmacokinetics varies in patients with MMN and may be associated with clinical response.

Effect of non-invasive ventilation on survival, quality of life, respiratory function and cognition: a review of the literature.

Symptoms of nocturnal hypoventilation may negatively influence the quality of life (QoL) of ALS patients long before respiratory failure ensues. Non‐invasive mechanical ventilation (NIV) is considered a treatment option for nocturnal hypoventilation. The primary objective of NIV is improving quality of life (QoL). It may also prolong life by several months. A systematic review of the literature was performed to analyse what is known of the effect of NIV on survival, QoL and other outcome measures. A computerized literature search was performed to identify controlled clinical trials and observational studies of treatment of ALS‐associated nocturnal hypoventilation from 1985 until May 2005. Twelve studies fulfilled the inclusion criteria. Four studies were retrospective, seven prospective and in one study randomization was used. All studies reported beneficial effects of NIV on all outcome measures. In seven studies NIV was associated with prolonged survival in patients tolerant for NIV, and five studies reported an improved QoL. In conclusion, studies on the use of NIV in ALS differ in study design and endpoint definitions. All studies suggest a beneficial effect on QoL and other outcome measures (Evidence level Class II‐III). Well‐designed randomized controlled trials comparing the effect on QoL and survival have not been performed.

Quantification of SMN protein in leucocytes from spinal muscular atrophy patients: effects of treatment with valproic acid

Background Spinal muscular atrophy (SMA) is caused by the homozygous deletion of the survival motor neuron (SMN)1 gene. The nearly identical SMN2 gene produces small amounts of full-length mRNA and functional SMN protein, due to a point mutation in a critical splicing site. Increasing SMN protein production by histone deacetylase inhibiting drugs such as valproic acid (VPA) is an experimental treatment strategy for SMA. Objective To investigate whether an SMN-specific ELISA could detect changes in SMN protein expression in peripheral blood mononuclear cells (PBMCs) after treatment with VPA. Methods The authors developed a sensitive SMN-specific ELISA. Six patients with SMA types 2 and 3 participated in the study. Recombinant SMN calibration curves were used to calculate SMN protein levels in PBMCs before and after 4 months of VPA treatment. Results The SMN ELISA was able to detect small differences in SMN protein concentrations, and differences in SMN protein levels in Epstein–Barr virus immortalised lymphocyte cell lines from SMA type 1 and 2 patients, carriers and healthy individuals (p<0.05). The mean SMN protein level in PBMCs from SMA patients was 22% (SD 15%) of the value in a healthy control. VPA treatment resulted in significantly increased SMN protein levels in five out of six SMA patients compared with baseline values (p<0.05), but did not restore SMN levels to normal values. Conclusions SMN protein quantification by this SMN ELISA is a useful additional tool for evaluating the effects of experimental treatment in SMA.

Leukocyte and complement activation by GM1-specific antibodies is associated with acute motor axonal neuropathy in rabbits

Acute motor axonal neuropathy (AMAN) in humans is associated with the presence of GM1-specific antibodies. Immunization of rabbits with GM1-containing ganglioside mixtures, purified GM1, or Campylobacter jejuni lipo-oligosaccharide exhibiting a GM1-like structure elicits GM1-specific antibodies, but axonal polyneuropathy only occurs in a subset of animals. This study aimed to dissect the molecular basis for the variable induction of AMAN in rabbits. Therefore, we analyzed the pro-inflammatory characteristics of GM1-specific antibodies in plasma samples from ganglioside-immunized rabbits with and without neurological deficits. GM1-specific plasma samples from all rabbits with AMAN were capable of activating both complement and leukocytes, in contrast to none of the plasma samples from rabbits without paralysis. Furthermore, GM1-specific IgG-mediated activation of leukocytes was detected before the onset of clinical signs. These data suggest that AMAN only occurs in rabbits that develop GM1-specific antibodies with pro-inflammatory properties.

Rapid worsening of IgM anti-MAG demyelinating polyneuropathy during rituximab treatment

Dear Editor, There are no proven treatments for polyneuropathy associated with IgM monoclonal gammopathy and anti-myelin associated glycoprotein (anti-MAG) antibodies (Lunn and Nobile-Orazio, 2012). Two recent randomized trials (RCTs) comparing rituximab to placebo failed to demonstrate improvement on the primary endpoints (Dalakas et al., 2009; Leger et al., 2011). In these trials, treatment with rituximab was safe and well tolerated. The total published experience with rituximab in anti-MAG polyneuropathy encompasses fewer than 100 patients (Renaud et al., 2003; RojasGarcia et al., 2003; Niermeijer et al., 2009). Because rituximab is at best effective only in a small subgroup of patients, even fairly rare side effects would be relevant to the decision to prescribe it for antiMAG neuropathy. Some side effects could have been missed because of the low numbers of patients in published series. We report three patients with IgM monoclonal gammopathy-associated polyneuropathy and anti-MAG antibodies who rapidly worsened within weeks after the start of rituximab treatment. One patient presented with mild weakness of the dorsiflexors of foot and toes (Medical Research Council [MRC] grade 4), glove and sock-patterned hypoesthesia, and sensory ataxia, which had developed slowly over the previous 2 years. His anti-MAG titer before treatment was 7,180 BTU (Buehlmann Titer Units, normal values below 2,000 BTU), total serum IgM was 13 g/l, and the M protein was 9 g/l. Nerve conduction studies showed demyelination in nerves of both arms and legs, distally more than proximally, as well as axonal loss, more pronounced in the nerves of the legs than in those of the arms (Table 1). After the second of a planned four weekly rituximab infusions (375 mg/m2), he developed proximal weakness and severe progression of the distal weakness in the legs