High-resolution mapping identifies HLA class II associations with multifocal motor neuropathy

Objective: To gain further insight in the immunopathology underlying multifocal motor neuropathy (MMN) by exploring the association between MMN and the human leukocyte antigen (HLA) class II DRB1, DQB1, and DQA loci in depth and by correlating associated haplotypes to detailed clinical and anti-ganglioside antibody data. Methods: We performed high-resolution HLA-class II typing for the DRB1, DQB1, and DQA1 loci in 126 well-characterized MMN patients and assessed disease associations with haplotypes. We used a cohort of 1305 random individuals as a reference for haplotype distribution in the Dutch population. Results: The DRB1*15:01-DQB1*06:02 haplotype (OR 1.6 [95% CI 1.1–2.2], p < 0.05) and the DRB1*12:01-DQB1*03:01 haplotype (OR 2.7 [95% CI 1.2–5.5], p < 0.05) were more frequent in patients with MMN than in controls. These haplotypes were not associated with disease course, response to treatment or anti-ganglioside antibodies. Conclusions: MMN is associated with the DRB1*15:01-DQB1*06:02 and DRB1*12:01-DQB1*03:01 haplotypes. These HLA molecules or gene variants in their immediate vicinity may promote the specific inflammatory processes underlying MMN

The diagnostic value of nerve ultrasound in inflammatory neuropathies

Distinction of chronic inflammatory neuropathies (CIN) from the more common axonal neuropathies or motor neuron disease is important since treatment can improve outcome. Nerve conduction studies (NCS) play a key role in diagnosing CIN. However, NCS are not a flawless technique that allows identification of all patients who would respond to treatment. New and better diagnostic tools for identification of CIN are therefore required and nerve ultrasound (NU) is a promising candidate, because of its relatively low-cost, time-efficient imaging of multiple nerves and the lack of burden for patients. In this thesis we examined the diagnostic and prognostic value of NU and the natural history of multifocal motor neuropathy (MMN). Moreover, we examined a new treatment in MMN. In chapter 2 we investigated interobserver variability of NU and found variability between investigators primarily in leg nerves and C6 and C7 nerve roots. The multilevel mixed model showed that different devices and different hospitals had no influence on interobserver variability. These findings indicate that NU of arm nerves and the C5 root can be reliably used in clinical practice. In chapter 3 we examined the sonographic pattern in Wartenberg’s migrant sensory neuritis and found mild multifocal enlargement in clinically affected and non-affected nerves at both entrapment sites and non-entrapment sites. In chapter 4 we compared NCS and NU results in CIN and found no correlation between NCS features of demyelination and sonographic nerve enlargement. This suggests that NU and NCS detect distinctive pathophysiological mechanisms. In chapter 5 we visualized the entire tract of both the median and ulnar nerve to complement previous findings at specific nerve sites. The distinct sonographic patterns between the different forms of CIN seem to be of additional diagnostic value and support the hypothesis of different disease entities. In chapter 6-8 we examined the diagnostic value of NU in CIN. In our studies, compared to NCS, sensitivity of NU was higher and specificity much lower. Therefore, these investigations are complementary rather than comparable techniques. The added value of NU in the detection of treatment-responsive CIN was 25%. In chapter 10 we performed a multicenter study on the prognostic value of NU and found that the distribution and development over time of nerve enlargement in CIN was very heterogeneous and thus the prognostic value of NU seems limited. In chapter 9 we performed a longitudinal study in MMN and found that almost all clinical outcome measures significantly deteriorated. This confirms that MMN is a progressive disorder. In chapter 11 we investigated Human Immune Globulin 10% with Recombinant Hyaluronidase, a new subcutaneous immunoglobulin therapy, and found comparable safety, efficacy and treatment satisfaction to intravenous immunoglobulin therapy. In conclusion, we found that NU could be reliably implemented in clinical practice and that addition of NU to routine diagnostic work-up improves identification of patients who may benefit from treatment by 25%. Therefore, our results indicate that NU deserves a prominent place in future revisions of diagnostic consensus criteria and that this promising diagnostic tool should be implemented in general neurologic practices

Can an early 24-hour EEG predict the response to the ketogenic diet? A prospective study in 34 children and adults with refractory epilepsy treated with the ketogenic diet

Purpose We examined whether early EEG changes in a 24-h EEG at 6 weeks of treatment were related to the later clinical response to the ketogenic diet (KD) in a 6-month period of treatment. Methods We examined 34 patients with heterogeneous epilepsy syndromes (21 children, 13 adults) and found 9 clinical responders (=50% seizure reduction); this is a responder rate of 26%. We visually counted the interictal epileptic discharge index (IED index) in % during 2 h of wakefulness and in the first hour of sleep (method 1), and also globally reviewed EEG changes (method 2), while blinded to the effect of the KD. Results At group level we saw a correlation between nocturnal reduction of IED-index at 6 weeks and seizure reduction in the follow-up period. A proportional reduction in IED index of 30% from baseline in the sleep EEG, was associated with being a responder to the diet (Pearson Chi-square p = 0.04). EEG scoring method 2 observed a significantly larger proportion of patients with EEG-improvement in sleep in KD responders than in non-responders (p = 0.03). At individual level, however, EEG changes did not correlate very strongly to the response to the diet, as IED reduction in sleep was also seen in 15% (method 1) to 26% (method 2) of the non-responders. Conclusion Nocturnal reduction of IEDs is related to the response to the KD, however in daily clinical practice, an early EEG to predict seizure reduction should not be advised for individual patients

Human immune globulin 10% with recombinant human hyaluronidase in multifocal motor neuropathy

Objective: The primary aim was to determine the safety of treatment with human immune globulin 10% with recombinant human hyaluronidase (fSCIg) compared to intravenous immunoglobulin (IVIg) in a prospective open-label study in patients with multifocal motor neuropathy (MMN). Methods: Our study consisted of two phases: the IVIg phase (visits 1–3; 12 weeks), in which patients remained on IVIg treatment, and the fSCIg phase (visits 4–7; 36 weeks), in which patients received fSCIg treatment. After visit 3, IVIg was switched to an equivalent dose and frequency of fSCIg. Outcome measures were safety, muscle strength, disability and treatment satisfaction. Results: Eighteen patients were enrolled in this study. Switching to fSCIg reduced the number of systemic adverse events (IVIg 11.6 vs. fSCIg 5.0 adverse events/per person-year, p < 0.02), and increased the number of local reactions at the injection site (IVIg 0 vs. fSCIg 3.3 local reactions/per person-year, p < 0.01). Overall, no significant differences in muscle strength and disability between fSCIg and IVIg were found. Treatment with fSCIg was perceived as optimal treatment option by 8 of the 17 patients (47.1%) and they continued with fSCIg after study closure because of improved independence and flexibility to administer treatment. Conclusion: Treatment with fSCIg can be considered a safe alternative for patients with MMN on IVIg treatment. fSCIg could be a favorable option in patients who prefer self-treatment and more independency, and in patients who experience systemic adverse events on IVIg or have difficult intravenous access

Prevention of the metabolic syndrome in IGT subjects in a lifestyle intervention: Results from the SLIM study

AbstractBackground and aimsThe Study on Lifestyle intervention and Impaired glucose tolerance Maastricht (SLIM), a randomized controlled trial, directed at diet and physical activity in impaired glucose tolerant subjects was effective to improve glucose tolerance and prevent type 2 diabetes. The aim of this study was to determine the effects of the SLIM lifestyle intervention on the incidence and prevalence of the metabolic syndrome (MetS) during the active intervention and four years thereafter.Methods and resultsMetS was diagnosed according to the NCEP ATP III criteria. At baseline, 66.4% of all participants (n = 146, age 57 ± 7 years, BMI 29.7 ± 3.6, 51.3% female) fulfilled the criteria for MetS. No significant difference in MetS prevalence was observed between the intervention (63.9%) and control group (68.9%). At the end of active intervention (average duration 4.2 ± 2.0 years), prevalence of MetS was significantly lower in the intervention group (52.6%, n = 57) compared to the control group (74.6%, n = 59) (p = 0.014).Furthermore, in participants without MetS at baseline, cumulative incidence of MetS was 18.2% in the intervention group at the end of active intervention, compared to 73.7% in the control group (Log-rank test, p = 0.011). Four years after stopping active intervention, the reduced incidence of MetS was maintained (Log-rank test, p = 0.002).ConclusionIn conclusion, a combined diet-and-exercise intervention to improve glucose tolerance, not only prevented type 2 diabetes, but also reduced the prevalence of MetS and prevented MetS development, showing the long-term impact of lifestyle intervention on cardiovascular risk reduction.Clinical trial registration number: NCT 00381186 (www.clincialtrials.gov)

Can an early 24-hour EEG predict the response to the ketogenic diet?: a prospective study in 34 children and adults with refractory epilepsy treated with the ketogenic diet

AbstractPurposeWe examined whether early EEG changes in a 24-h EEG at 6 weeks of treatment were related to the later clinical response to the ketogenic diet (KD) in a 6-month period of treatment.MethodsWe examined 34 patients with heterogeneous epilepsy syndromes (21 children, 13 adults) and found 9 clinical responders (≥50% seizure reduction); this is a responder rate of 26%. We visually counted the interictal epileptic discharge index (IED index) in % during 2h of wakefulness and in the first hour of sleep (method 1), and also globally reviewed EEG changes (method 2), while blinded to the effect of the KD.ResultsAt group level we saw a correlation between nocturnal reduction of IED-index at 6 weeks and seizure reduction in the follow-up period. A proportional reduction in IED index of 30% from baseline in the sleep EEG, was associated with being a responder to the diet (Pearson Chi-square p=0.04). EEG scoring method 2 observed a significantly larger proportion of patients with EEG-improvement in sleep in KD responders than in non-responders (p=0.03). At individual level, however, EEG changes did not correlate very strongly to the response to the diet, as IED reduction in sleep was also seen in 15% (method 1) to 26% (method 2) of the non-responders.ConclusionNocturnal reduction of IEDs is related to the response to the KD, however in daily clinical practice, an early EEG to predict seizure reduction should not be advised for individual patients