Polyneuropathy Associated with IgM Monoclonal Gammopathy; Advances in Genetics and Treatment, Focusing on Anti-MAG Antibodies

With increasing age, the chances of developing either MGUS or polyneuropathy increase as well. In some cases, there is a causative relationship between the IgM M-protein and polyneuropathy. In approximately half of these cases, IgM targets the myelin-associated glycoprotein (MAG). This results in chronic polyneuropathy with slowly progressive, predominantly sensory neurological deficits and distally demyelinating features in nerve conduction studies. Despite the disease being chronic and developing slowly, it can cause considerable impairment. We reviewed English medical publications between 1980 and May 2022 on IgM gammopathy-associated polyneuropathy, with special attention to studies addressing the pathophysiology or treatment of anti-MAG polyneuropathy. Treatment options have been limited to a temporizing effect of intravenous immunoglobulins in some patients and a more sustained effect of rituximab but in only 30 to 55 percent of patients. An increase in our knowledge concerning genetic mutations, particularly the MYD88L265P mutation, led to the development of novel targeted treatment options such as BTK inhibitors. Similarly, due to the increasing knowledge of the pathophysiology of anti-MAG polyneuropathy, new treatment options are emerging. Since anti-MAG polyneuropathy is a rare disease with diverse symptomatology, large trials with good outcome measures are a challenge

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

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

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

Functioning of patients with chronic idiopathic axonal polyneuropathy (CIAP)

Although patients with Chronic Idiopathic Axonal Polyneuropathy (CIAP) report a slow deterioration of sensory and motor functions, the impact of this deterioration on daily functioning has not yet been investigated in detail. The first aim of this crosssectional study involving 56 patients with CIAP was, therefore, to assess patients’ functioning with use of the International Classification of Functioning, Disability and Health (ICF). The second aim was to find determinants of walking ability, dexterity, and autonomy. Fatigue and limited walking ability were present in most patients and differed considerably. In regression models, age, muscle strength, and fatigue together explained 63% of the variance in walking ability, which by itself explained almost 50% of the variance in patients’ autonomy indoors and outdoors (42% and 49%, respectively). Muscle strength and sensory function scores together explained 30% of the variance in dexterity scores, which in turn explained only 13% of the variance in autonomy indoors. The diminished autonomy of patients with CIAP might be improved by reducing fatigue, by means of training, and by improving walking ability

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

Wartenberg’s migrant sensory neuritis: a prospective follow-up study

Migrant sensory neuropathy (Wartenberg’s migrant sensory neuritis) is characterized by sudden numbness in the distribution of one or multiple cutaneous nerves. To study disease course and outcome, we prospectively followed 12 patients who presented to our tertiary referral neuromuscular outpatient clinic between January 2003 and January 2004. Medical history, neurological, laboratory and electrophysiological examinations were obtained from all patients. All patients were reviewed a second time in 2007, and five had a follow-up electrophysiological examination. At the first visit, 50% described an episode of stretching preceding the sensory complaints. All but three described pain in the affected area before or concomitant with sensory loss. At clinical examination a median of six skin areas were affected, and in 75% this could be confirmed by nerve conduction studies in at least one nerve. Forty-two percent had involvement of the trigeminal nerve. After a mean disease duration of 7.5 years, three patients reported a complete disappearance of sensory complaints and five that the pain had disappeared, but numbness remained. Three patients still had both painful and numb sensory deficits. One patient developed a distal symmetric sensory polyneuropathy. In conclusion, Wartenberg’s sensory neuritis is a distinct, exclusively sensory, neuropathy, marked by pain preceding numbness in affected nerves. An episode of stretching preceding pain is not necessary for the diagnosis. Wartenberg’s sensory neuritis often retains its spotty, exclusively sensory characteristics after long term follow-up