Red flags and adjusted suspicion index for distinguishing hereditary transthyretin amyloid polyneuropathy from idiopathic axonal polyneuropathy.

BACKGROUND: Early diagnosis of hereditary ATTR polyneuropathy (ATTRv-PN) is important since treatment options have become available, which are most effective early in the disease course. ATTRv-PN is likely underdiagnosed as patients might be misdiagnosed with idiopathic polyneuropathy. It is uncertain if it is useful to test for TTR gene mutations in patients with a typical presentation for chronic idiopathic axonal polyneuropathy (CIAP) and which are the distinguishing clinical features. METHODS: We carried out a retrospective cohort study to assess the yield of TTR gene sequencing in patients with polyneuropathy and assessed if the identified patients with ATTRv-PN had a clinical presentation typical of CIAP. Additionally, we assessed which clinical features, including previously defined red flag symptoms, can differentiate between patients with CIAP and ATTRv-PN and assessed the performance of the TTR suspicion index. RESULTS: Out of 338 patients with polyneuropathy, 10 patients had a pathogenic TTR gene mutation (all p.Val50Met) and none had a clinical presentation typical of CIAP. Patients with ATTRv-PN more often had bilateral CTS, motor involvement of arms, cardiac involvement, family history suggestive of hATTRv, and autonomic symptoms than patients with CIAP. All patients with ATTRv-PN as well as 70% of patients with CIAP fulfilled the suspicion index. CONCLUSION: Routine TTR gene sequencing in patients with a typical presentation for CIAP is not useful. However, red flag symptoms can differentiate patients with ATTRv-PN from patients with CIAP. We propose an adjusted version of the TTR suspicion index to increase diagnostic yield.

IgM anti-MAG± peripheral neuropathy (IMAGiNe) study protocol: An international, observational, prospective registry of patients with IgM M-protein peripheral neuropathies.

BACKGROUND: International consensus on IgM ± anti-MAG ± PNP (IgM PNP) is lacking. Despite increasing interest in clinical trials, validated disease-specific measures are needed to adequately capture limitations and changes over time. The IMAGiNe (IgM ± anti-myelin associated glycoprotein [MAG] peripheral neuropathy) study surges as an international collaboration to create a standardized registry of patients with IgM ± anti-MAG PNP. The consortium, which currently consists of 11 institutions from 7 countries, presents here the IMAGiNe study design and protocol. AIMS: Functional outcome measures will be constructed at the level of impairment, as well as activity and participation. We aim to describe the natural history of the cohort, the role of anti-MAG antibodies, the presence of clinical subtypes, and potential biomarkers. METHODS: The IMAGiNe study is a prospective, observational cohort study with a 3-year follow-up. At each assessment, researchers collect clinical data and subjects complete a list of preselected outcome measures. Among these, the "Pre-Rasch-built Overall Disability Scale (Pre-RODS)" questionnaire will be submitted to Rasch analysis to assess classic and modern clinimetric requirements. RESULTS: The final measures will include the IgM-PNP-specific RODS and Ataxia Rating Scale (IgM-PNP-ARS). Descriptions of the disease course, clinical heterogeneity, treatment regimes, variations in laboratory values, and antibody titers will help reach consensus on diagnosis and follow-up strategies. CONCLUSION: The constructed interval scales will be cross-culturally valid and suitable for use in future clinical trials and daily practice. The ultimate goals are to improve functional individualized assessment, reach international consensus, and lay the foundations for successful designs in future studies.

Enriched enrollment randomized double-blind placebo-controlled cross-over trial with phenytoin cream in painful chronic idiopathic axonal polyneuropathy (EPHENE): a study protocol.

BACKGROUND: Patients with chronic idiopathic axonal polyneuropathy (CIAP) can have neuropathic pain that significantly impacts quality of life. Oral neuropathic pain medication often has insufficient pain relief and side effects. Topical phenytoin cream could circumvent these limitations. The primary objectives of this trial are to evaluate (1) efficacy in pain reduction and (2) safety of phenytoin cream in patients with painful CIAP. The main secondary objective is to explore the usefulness of a double-blind placebo-controlled response test (DOBRET) to identify responders to sustained pain relief with phenytoin cream. METHODS: This 6-week, enriched enrollment randomized double-blind, placebo-controlled triple cross-over trial compares phenytoin 20%, 10% and placebo cream in 48 participants with painful CIAP. Enriched enrollment is based on a positive DOBRET in 48 participants who experience within 30 minutes ≥2 points pain reduction on the 11-point numerical rating scale (NRS) in the phenytoin 10% cream applied area and ≥1 point difference in pain reduction on the NRS between phenytoin 10% and placebo cream applied area, in favour of the former. To explore whether DOBRET has predictive value for sustained pain relief, 24 DOBRET-negative participants will be included. An open-label extension phase is offered with phenytoin 20% cream for up to one year, to study long-term safety. The main inclusion criteria are a diagnosis of CIAP and symmetrical neuropathic pain with a mean weekly pain score of ≥4 and <10 on the NRS. The primary outcome is the mean difference between phenytoin 20% versus placebo cream in 7-day average pain intensity, as measured by the NRS, over week 2 in DOBRET positive participants. Key secondary outcomes include the mean difference in pain intensity between phenytoin 10% and phenytoin 20% cream, and between phenytoin 10% and placebo cream. Furthermore, differences between the 3 interventions will be evaluated on the Neuropathic Pain Symptom Inventory, EuroQol EQ5-5D-5L, and evaluation of adverse events. DISCUSSION: This study will provide evidence on the efficacy and safety of phenytoin cream in patients with painful CIAP and will give insight into the usefulness of DOBRET as a way of personalized medicine to identify responders to sustained pain relief with phenytoin cream. TRIAL REGISTRATION: ClinicalTrials.gov NCT04647877 . Registered on 1 December 2020.

Vegetarians, Pescatarians and Flexitarians with Adequate Vitamin B12 Levels Have No Increased Risk of Polyneuropathy.

BACKGROUND: In recent years, an increasing number of people adapt to a vegetarian, pescatarian or flexitarian dietary pattern that reduces the consumption of meat and fish. Although these dietary patterns have a risk for developing vitamin B12 deficiency associated polyneuropathy, it is unknown whether this risk is still increased when vitamin B12 levels are adequate. OBJECTIVE: To examine whether a vegetarian, pescatarian or flexitarian dietary pattern is associated with an increased risk for idiopathic axonal polyneuropathy. METHODS: We conducted a case-control study that included 256 idiopathic axonal polyneuropathy patients with adequate vitamin B12 blood levels and 630 controls. We used questionnaire data to determine the frequency of meat and fish consumption and defined dietary patterns. RESULTS: The vegetarian (no meat or fish consumption) and the pescatarian (fish consumption, no meat consumption) dietary patterns showed no increased risk of axonal polyneuropathy. Frequency-effect analysis and quantity-effect analysis also did not show that a reduction of meat or fish consumption (flexitarian dietary pattern), either small or large, changed the risk of axonal polyneuropathy. CONCLUSIONS: We did not find an increased risk for axonal polyneuropathy among people with a vegetarian, pescatarian or flexitarian diet and an adequate vitamin B12 level.

Withdrawal of intravenous immunoglobulin in chronic inflammatory demyelinating polyradiculoneuropathy.

Intravenous immunoglobulins are an efficacious treatment for chronic inflammatory demyelinating polyradiculoneuropathy. Biomarkers for disease activity are lacking, making the need for ongoing treatment difficult to assess, leading to potential overtreatment and high health-care costs. Our objective was to determine whether intravenous immunoglobulin withdrawal is non-inferior to continuing intravenous immunoglobulin treatment and to determine how often patients are overtreated. We performed a randomized, double-blind, intravenous immunoglobulin-controlled non-inferiority trial in seven centres in the Netherlands (Trial registration: ISRCTN 13637698; www.isrctn.com/ISRCTN13637698). Adults with clinically stable chronic inflammatory demyelinating polyradiculoneuropathy using intravenous immunoglobulin maintenance treatment for at least 6 months were included. Patients received either intravenous immunoglobulin withdrawal (placebo) as investigational treatment or continuation of intravenous immunoglobulin treatment (control). The primary outcome was the mean change in logit scores from baseline to 24-week follow-up on the patient-reported Inflammatory Rasch-Overall Disability Scale. The non-inferiority margin was predefined as between-group difference in mean change scores of -0.65. Patients who deteriorated could reach a relapse end point according to predefined criteria. Patients with a relapse end point after intravenous immunoglobulin withdrawal entered a restabilization phase. All patients from the withdrawal group who remained stable were included in an open-label extension phase of 52 weeks. We included 60 patients, of whom 29 were randomized to intravenous immunoglobulin withdrawal and 31 to continuation of treatment. The mean age was 58 years (SD 14.7) and 67% was male. The between-group difference in mean change Inflammatory Rasch-Overall Disability Scale scores was -0.47 (95% CI -1.24 to 0.31), indicating that non-inferiority of intravenous immunoglobulin withdrawal could not be established. In the intravenous immunoglobulin withdrawal group, 41% remained stable for 24 weeks, compared to 58% in the intravenous immunoglobulin continuation group (-17%; 95% CI -39 to 8). Of the intravenous immunoglobulin withdrawal group, 28% remained stable at the end of the extension phase. Of the patients in the restabilization phase, 94% restabilized within 12 weeks. In conclusion, it remains inconclusive whether intravenous immunoglobulin withdrawal is non-inferior compared to continuing treatment, partly due to larger than expected confidence intervals leading to an underpowered study. Despite these limitations, a considerable proportion of patients could stop treatment and almost all patients who relapsed were restabilized quickly. Unexpectedly, a high proportion of intravenous immunoglobulin-treated patients experienced a relapse end point, emphasizing the need for more objective measures for disease activity in future trials, as the patient-reported outcome measures might not have been able to identify true relapses reliably. Overall, this study suggests that withdrawal attempts are safe and should be performed regularly in clinically stable patients.

Serum neurofilament light chain, contactin-1 and complement activation in anti-MAG IgM paraprotein-related peripheral neuropathy.

INTRODUCTION: In anti-myelin-associated glycoprotein IgM paraprotein-related peripheral neuropathy (anti-MAG PN), there is a lack of reliable biomarkers to select patients eligible for therapy and for evaluating treatment effects, both in routine practice and in clinical trials. Neurofilament light chain (NfL) and contactin-1 (CNTN1) can serve as markers of axonal and paranodal damage. Complement activation is involved in the pathogenesis in anti-MAG PN. We, therefore, hypothesized that serum NfL, CNTN1, C3b/c and C4b/c may function as biomarkers of disease activity in anti-MAG PN. METHODS: In this prospective cohort study, we included 24 treatment-naïve patients with anti-MAG PN (mean age 69 years, 57% male) that had IgM paraproteinemia, a high IgM MAG-antibody, and clinical diagnosis of anti-MAG PN by a neurologist specialized in peripheral nerve disorders. We measured serum NfL, CNTN1, C3b/c and C4b/c, reference values were based on healthy controls. As controls, 10 treatment-naïve patients with IgM Monoclonal gammopathy of undetermined significance (MGUS) or Waldenström's Macroglobulinemia (mean age 69 years, 60% male) without signs of neuropathy were included (non-PN). RESULTS: NfL, CNTN1 levels in serum were mostly normal in anti-MAG PN patients and comparable to non-PN patients. C3b/c and C4b/c levels were normal in anti-MAG PN patients. CONCLUSION: Our results do not support serum NfL, CNTN1, and C3b/c and C4b/c as potential biomarkers in anti-MAG PN, although we cannot exclude that subgroups or subtle abnormalities could be found in a much larger cohort with longitudinal follow-up.

Clinical relevance of testing for metabolic vitamin B12 deficiency in patients with polyneuropathy.

OBJECTIVE: Determine vitamin B12 threshold levels below which additional testing of methylmalonic acid (MMA) and/or homocysteine (Hcy) is useful to diagnose metabolic vitamin B12 deficiency in patients with polyneuropathy, and how vitamin B12, MMA and Hcy levels relate to the effect of supplementation therapy. METHODS: In a retrospective cohort study of 331 patients with polyneuropathy, vitamin B12, MMA and Hcy were measured. Linear regression models with vitamin B12 as dependent and Hcy or MMA as covariate were compared, to assess which was best related to vitamin B12. Threshold vitamin B12 levels for metabolic deficiency (defined as elevatede metabolites) were determined using logistic regression with elevated metabolites as dependent and vitamin B12 as covariate. A structured interview was conducted in 42 patients to evaluate response to vitamin B12 supplementation. RESULTS: MMA was best related to vitamin B12. Using elevated MMA for metabolic deficiency, we found 90% sensitivity at a vitamin B12 threshold level <264 pmol/L (358 pg/mL) and 95% sensitivity at <304 pmol/L (412 pg/mL). Improvement after supplementation was reported by 19% patients and stabilization by 24%. 88% of patients with improvement and 90% with stabilization either had absolute deficiency (Vitamin B12 < 148 pmol/L) or metabolic deficiency (elevated MMA and vitamin B12 ≥ 148 pmol/L). There were no additional patients with improvement or stabilization with isolated elevated Hcy. CONCLUSION: Testing of MMA has additional value in identifying patients with clinically relevant metabolic deficiency when vitamin B12 is below 304 pmol/L (412 pg/mL). Supplementation can be effective in patients with absolute and metabolic deficiency.

A hereditary spastic paraplegia predominant phenotype caused by variants in the NEFL gene.

INTRODUCTION: This study reports a large series of patients with a clinical picture dominated by spastic paraplegia in whom variants in the NEFL gene, a known cause for Charcot-Marie-Tooth disease, were identified. METHODS: Index patients referred for a suspicion of hereditary spastic paraplegia (HSP) were clinically assessed and genetic analysis by next-generation sequencing was undertaken. Additional family members were clinically examined and subjected to targeted testing. RESULTS: We identified two different heterozygous dominant variants in the NEFL gene in 25 patients from 14 families. Most of them (21/25) had a clinical diagnosis of HSP, often with a concomitant clinical diagnosis of polyneuropathy (16/21). Two patients were identified with a polyneuropathy with a pyramidal reflex pattern, but without spasticity. Two patients had isolated polyneuropathy. Out of the 21 patients with a diagnosis of HSP, two had co-occurring cerebellar signs. The c.262A > C p.(Thr88Pro) variant was detected in 13 families. Genealogical analysis showed shared ancestors or a similar geographical origin in 12, suggesting a founder effect. The other variant, c.296A > C p.(Asp99Ala), was found in only one family, in which limited segregation analysis could be performed. DISCUSSION: Variants in the NEFL gene can cause HSP, with or without co-existing polyneuropathy, and should be included in diagnostic testing strategies for HSP patients.

Performance and Self-reported Functioning of People With Chronic Idiopathic Axonal Polyneuropathy: A 4-Year Follow-up Study.

OBJECTIVE: To describe the course of performance of activities (observed and self-reported) of people with chronic idiopathic axonal polyneuropathy (CIAP) over 4 years and to assess the associations with muscle strength, sensory function, and psychological personal factors (intention, perceived behavior control [PBC], and feelings of depression or anxiety). DESIGN: Prospective observational study with measurement at baseline, 6 months, 1 year, and 4 years. SETTING: Outpatient neurology clinic. PARTICIPANTS: People with CIAP (N=92). MAIN OUTCOME MEASURES: Walking was measured using the shuttle-walk test (SWT), a pedometer (mean step count/d), and the "physical functioning" subscale of the Short Form-36 questionnaire. Muscle strength and sensory function were measured using a MicroFET handheld dynamometer and the Sensory Modality Sum score. Personal factors were assessed with the Hospital Anxiety and Depression Scale, and intention and PBC were assessed with a protocolized questionnaire. RESULTS: Multilevel model analysis showed a significant decrease over time in mean scores in performance of activities (SWT, step count), which was associated with older age and loss of muscle strength (SWT: ß=73.392, step count: ß=676.279, P<.001). Limitations in self-reported functioning (physical functioning) significantly increased and were associated with older age (ß=-0.916, P=.001), increased comorbidity (ß=-6.978, P=.024), loss of muscle strength (ß=7.074, P<.001), low PBC (ß=0.744, P<.001), and increased feelings of depression (ß=1.481, P<.001). CONCLUSIONS: Performance of activities of people with CIAP decreased over time (SWT, step count, physical functioning). Older age, loss of muscle strength, comorbidity, feelings of depression, and low perceived behavior control were associated with this decrease. However, there were considerable individual differences.

Usefulness of a Double-Blind Placebo-Controlled Response Test to Demonstrate Rapid Onset Analgesia with Phenytoin 10% Cream in Polyneuropathy.

PURPOSE: Topical analgesics are an upcoming treatment option for neuropathic pain. In this observational study, we performed a double-blind placebo-controlled response test (DOBRET) in patients with polyneuropathy to determine the personalized analgesic effect of phenytoin 10% cream. PATIENTS AND METHODS: In a double-blind fashion, 12 consecutive adult patients with symmetrical painful polyneuropathy and equal pain intensity of ≥4 on the 11-point numerical rating scale (NRS) applied phenytoin10% cream on one painful area and a placebo cream on the corresponding contralateral area. We defined responders as patients who experienced a pain reduction ≥2 NRS points from baseline and ≥1 NRS point difference in pain reduction in favour of phenytoin 10% cream compared with placebo cream within 30 minutes after application. We also evaluated the percentage of pain reduction and frequency of 30% and 50% pain relief from baseline. RESULTS: Six patients (50%) were responders. Compared with placebo cream, pain reduction was higher in phenytoin 10% cream-applied areas with mean difference in pain reduction of 1.3 (95% CI: 1.1 to 1.8; p<0.001) on the NRS and mean percentage difference in pain reduction of 22% (95% CI: 13% to 32%; p =0.03). All responders had at least 30% pain reduction, and 4 out of 6 had at least 50% pain reduction in the phenytoin 10% cream applied area. All non-responders had less than 30% pain reduction. No side effects were reported. CONCLUSION: A DOBRET is easy to perform, quickly identifies an analgesic effect in responders and could be a useful tool to personalize neuropathic pain treatment with topical formulations.

Neuropathy associated with immunoglobulin M monoclonal gammopathy: A combined sonographic and nerve conduction study.

INTRODUCTION: We assessed the specific sonographic pattern of structural nerve abnormalities in immunoglobulin M (IgM) neuropathy and disease controls. METHODS: We enrolled 106 incident patients-32 patients with IgM neuropathy, 42 treatment-naive patients with chronic inflammatory demyelinating polyneuropathy, and 32 patients with axonal neuropathies. All patients underwent standardized ancillary testing in addition to standardized sonography of the brachial plexus and the large arm and leg nerves bilaterally. RESULTS: We found widespread nerve enlargement in IgM neuropathy and chronic inflammatory demyelinating polyneuropathy (CIDP), with specific enlargement of brachial plexus and proximal segments of median nerve but not in axonal disease controls (P < .001). Sonographic nerve hypertrophy in IgM neuropathy was not associated with nerve conduction, clinical, or laboratory characteristics. DISCUSSION: Immunoglobulin M neuropathy is characterized by widespread nerve enlargement indistinguishable from CIDP. Our data provide evidence to confirm that the disease process is not confined to the more distal parts of nerves in either classical demyelinating or axonal variants of neuropathy with associated IgM.

Diagnostic value of symptoms in chronic polyneuropathy: The Erasmus Polyneuropathy Symptom Score.

In this study, we evaluated the diagnostic value of symptoms of chronic polyneuropathy and to construct and validate a simple questionnaire that can help diagnose chronic polyneuropathy. In a multi-step procedure, we initially compiled a 12-item questionnaire concerning polyneuropathy symptoms. The questionnaire was completed by 117 polyneuropathy patients and 188 controls (headache, transient ischemic attack, multiple sclerosis). First, we calculated sensitivity, specificity and likelihood ratios of each symptom. Next, we used multi-variable logistic regression to create a model that could discriminate patients from controls, using only the most informative symptoms and their frequency of occurrence. Based on the regression coefficients, we developed a simple scoring system (Erasmus Polyneuropathy Symptom Score, E-PSS), which was externally validated in 140 cases with chronic idiopathic axonal polyneuropathy and 96 controls without polyneuropathy. We assessed performance with discrimination (area under the curve, AUC) and calibration analyses. Numb and tingling feet were most frequently reported by polyneuropathy patients and had the highest sensitivity. Walking on cotton wool and allodynia had the highest specificity. Logistic regression yielded a model that contained these four symptoms, complemented with balance problems and tingling hands. Based on this analysis, the E-PSS was created, ranging from 0 to 14. The E-PSS had a good performance (AUC = 0.92) in the derivation set and proved to be valid in the external population (AUC = 0.95). In conclusion, the Erasmus Polyneuropathy Symptom Score (E-PSS) is a simple, validated six-item score that takes the presence and frequency of six different symptoms into account and it may be a helpful tool to screen individuals for the presence of chronic polyneuropathy.

Serum cytokine patterns in immunoglobulin m monoclonal gammopathy-associated polyneuropathy.

INTRODUCTION: Polyneuropathy with immunoglobulin M monoclonal gammopathy (IgM-PNP) is associated with the presence of IgM antibodies against nerve constituents such as myelin associated glycoprotein (MAG) and gangliosides. METHODS: To test whether B-cell-stimulating cytokines are increased in IgM-PNP, we measured serum concentrations of 11 cytokines in 81 patients with IgM-PNP and 113 controls. RESULTS: Median interleukin (IL)-6 concentrations were higher in patients with IgM-PNP, and median IL-10 concentrations were higher in the subgroup with anti-MAG IgM antibodies. These serum concentrations were not increased in 110 patients with multifocal motor neuropathy. DISCUSSION: Median IL-6 and IL-10 serum concentrations differ between patients with anti-MAG neuropathy and other patients with IgM-PNP compared with healthy and neuropathy controls. These differences may indicate differences in immune-mediated disease mechanisms. Muscle Nerve 59:694-698, 2019.

Statins do not increase risk of polyneuropathy: A case-control study and literature review.

OBJECTIVE: To investigate whether there is an association between cholesterol-lowering medication use, specifically statins, and chronic polyneuropathy. METHODS: A literature study was carried out to assess the current state of evidence on the association between chronic polyneuropathy and cholesterol-lowering medication use. We also conducted a prospective case-control study to compare exposure to cholesterol-lowering medication between patients with cryptogenic axonal polyneuropathy and controls prior to the index date (defined in patients as date of onset of polyneuropathy symptoms, in controls as date of first study survey). Outcomes were adjusted for potential confounders such as cardiovascular history and metabolic syndrome. RESULTS: The 13 studies identified in our literature search showed conflicting results (odds ratios [ORs] ranging from 0.66 to 14.2), but most studies had methodologic limitations. There was insufficient evidence that statin use is a risk factor for polyneuropathy. Our prospective case-control study included 333 patients with cryptogenic axonal polyneuropathy and 283 controls. Patients with polyneuropathy were less likely to have been exposed to statins than controls (OR 0.56, 95% confidence interval 0.34-0.95, p = 0.03). The odds of polyneuropathy decreased as exposure duration to statins increased. Cholesterol-lowering medication consisted almost exclusively of statins; therefore we only draw conclusions on the effect of statin use. CONCLUSIONS: Statin use does not increase the risk of chronic polyneuropathy. Therefore, statins should not be routinely withheld from polyneuropathy patients. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that statin use does not increase the risk of polyneuropathy.

Clinical relevance of serum antibodies to GD1b in immune-mediated neuropathies.

Antibodies to the ganglioside GD1b have been reported in various forms of immune-mediated neuropathy, but their clinical relevance for diagnosis and prognosis is unknown. We investigated the prevalence of anti-GD1b antibodies in acute and chronic immune-mediated neuropathies, and the clinical presentation and outcome in Guillain-Barré syndrome (GBS) and Miller Fisher-GBS overlap syndrome (MF-GBS). Anti-GD1b, anti-GM1 and anti-GQ1b antibodies were tested in serum of patients with GBS (N = 165), Miller Fisher syndrome (N = 10), MF-GBS (N = 28), monoclonal gammopathy of unknown significance neuropathy (MGUS; N = 101), chronic inflammatory demyelinating polyneuropathy (N = 29), paraneoplastic syndrome with anti-Hu-associated neuropathy (PNS; N = 11), other auto-immune diseases (AID; N = 60), and healthy controls (HC; N = 60). All samples were tested by enzyme-linked immunosorbent assay according to the Inflammatory Neuropathy Cause and Treatment protocol. IgM anti-GD1b antibodies were found in GBS (N = 4; 2.4%), MGUS (N = 3; 3.0%), and PNS patients (N = 1; 9.1%). IgG anti-GD1b antibodies were found in GBS (N = 20; 12.1%) and MF-GBS (N = 4; 14.3%) patients, but not in the AID and HC group. In the combined group of MF-GBS and GBS patients ((MF-)GBS), 14/36 (38.9%) patients with IgG anti-GD1b antibodies also had IgG anti-GM1 antibodies, and IgG anti-GD1b and IgG anti-GQ1b antibodies were found in 3/29 (10.3%) patients. Patients with (MF-)GBS and anti-GD1b without anti-GM1 antibodies did not differ regarding sensory disturbances or disease severity but recovered faster regarding the ability to walk independently compared with patients without anti-GD1b antibodies (P = 0.031) and with patients with both anti-GD1b and anti-GM1 antibodies (P = 0.034). In conclusion, testing for anti-GD1b antibodies may identify a specific group of immune-mediated neuropathies and (MF-)GBS patients with only anti-GD1b antibodies tend to recover faster.

Protocol of a dose response trial of IV immunoglobulin in chronic inflammatory demyelinating polyradiculoneuropathy (DRIP study).

High peak levels of serum IgG may not be needed for maintenance treatment of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) with intravenous immunoglobulin (IVIg). More frequent dosing of IVIg leads to more stable IgG levels and higher trough levels which may be related with improved clinical efficacy. More frequent lower dosing leads to lower peak levels and may induce less systemic side-effects. The DRIP study is a double-blind randomized controlled cross-over intervention study. CIDP patients ≥18 years old, proven IVIg dependent and receiving an individually established but stable maintenance dose and interval of IVIg (Kiovig) can be included. One group (A) will be treated with their normal dosage and interval of IVIg and receive a placebo (albumin 0.5%) infusion in between their regular IVIg infusions, for a total of four infusions. The other group (B) will be treated with half their normal IVIg dosage (with the same volume of placebo to maintain the total volume) at half their interval (double their frequency) for four infusions. After a wash-out phase (2 infusions), patients will cross-over to the other treatment group. During the study the total dose of IVIg administered will remain unchanged as before start of the trial. The main objective is to investigate whether high frequent low dosage IVIg treatment is more effective than low frequent high dosage IVIg treatment as maintenance treatment for CIDP. Hand grip strength, as measured by the Martin Vigorimeter, will be used as the primary outcome measure. Secondary objective is to investigate whether high frequent low dosage of IVIg results in less adverse events compared to low frequent high dosage treatment. The DRIP study is currently ongoing and the protocol is presented.

Maintenance IV immunoglobulin treatment in chronic inflammatory demyelinating polyradiculoneuropathy.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) patients treated with intravenous immunoglobulin (IVIg) usually start with a standard dosage of 2 g/kg bodyweight. Only a minority of patients has a sustained improvement, and most require ongoing maintenance treatment. Preferred IVIg regimens, however, vary considerably between doctors and at present it is unknown which is optimal. As there are also large differences in IVIg dosage and interval requirements between patients, optimal IVIg maintenance treatment of CIDP is even more complex. The lack of evidence-based guidelines on how IVIg maintenance treatment should be administered may potentially lead to under- or overtreatment of this expensive therapy. We provide an overview of published practical IVIg maintenance treatment regimens, IVIg maintenance schedules used in randomized controlled trials and one based upon our own long-term experience on how this treatment could be given in CIDP.