Electrical impedance myography correlates with standard measures of ALS severity.

INTRODUCTION: Electrical impedance myography (EIM) can be used to assess amyotrophic lateral sclerosis (ALS) progression. The relationship between EIM values and standard assessment measures, however, is unknown. METHODS: EIM 50 kHz phase data from 60 subjects who participated in a longitudinal natural history study of ALS were correlated with handheld dynamometry (HHD), the ALS Functional Rating Scale-Revised (ALSFRS-R) score, and motor unit number estimation (MUNE). RESULTS: Moderate strength correlations between EIM parameters and HHD were observed for both whole-body and individual upper and lower extremity values. Similarly, moderate strength correlations were observed between EIM and ALSFRS-R upper and lower extremity subscores, but not total ALSFRS-R scores. MUNE correlated significantly with single muscle EIM data but not with whole body or upper or lower extremity values. CONCLUSIONS: These results support the concept that EIM can serve as a meaningful measure of disease severity in ALS.

Diffuse large B-cell lymphoma presenting as Miller Fisher syndrome.

We report a patient with diffuse large B-cell lymphoma (DLBCL) who initially presented as Miller Fisher syndrome (MFS) responsive to high-dose immunoglobulin treatment. Detailed investigations for the recurrence of neurological symptoms revealed DLBCL that was responsive to chemotherapy. DLBCL should be considered in the differential diagnosis of patients with MFS who have worsening of their neurological condition after initial improvement with conventional therapy.

Electrical impedance myography as a biomarker to assess ALS progression.

Electrical impedance myography (EIM), a non-invasive, electrophysiological technique, has preliminarily shown value as an ALS biomarker. Here we perform a multicenter study to further assess EIM's potential for tracking ALS. ALS patients were enrolled across eight sites. Each subject underwent EIM, handheld dynamometry (HHD), and the ALS Functional Rating Scale-revised (ALSFRS-R) regularly. Techniques were compared by assessing the coefficient of variation (CoV) in the rate of decline and each technique's correlation to survival. Results showed that in the 60 patients followed for one year, EIM phase measured from the most rapidly progressing muscle in each patient had a CoV in the rate of decline of 0.62, compared to HHD (0.82) and the ALSFRS-R (0.74). Restricting the measurements to the first six months gave a CoV of 0.55 for EIM, 0.93 for HHD, and 0.84 for ALSFRS-R. For both time-periods, all three measures correlated with survival. Based on these data, a six-month clinical trial designed to detect a 20% treatment effect with 80% power using EIM would require only 95 patients/arm compared to the ALSFRS-R, which would require 220 subjects/arm. In conclusion, EIM can serve as a useful ALS biomarker that offers the prospect of greatly accelerating phase 2 clinical trials.

A Phase 1 study of GDC-0134, a dual leucine zipper kinase inhibitor, in ALS.

OBJECTIVE: Dual leucine zipper kinase (DLK), which regulates the c-Jun N-terminal kinase pathway involved in axon degeneration and apoptosis following neuronal injury, is a potential therapeutic target in amyotrophic lateral sclerosis (ALS). This first-in-human study investigated safety, tolerability, and pharmacokinetics (PK) of oral GDC-0134, a small-molecule DLK inhibitor. Plasma neurofilament light chain (NFL) levels were explored in GDC-0134-treated ALS patients and DLK conditional knockout (cKO) mice. METHODS: The study included placebo-controlled, single and multiple ascending-dose (SAD; MAD) stages, and an open-label safety expansion (OLE) with adaptive dosing for up to 48 weeks. RESULTS: Forty-nine patients were enrolled. GDC-0134 (up to 1200 mg daily) was well tolerated in the SAD and MAD stages, with no serious adverse events (SAEs). In the OLE, three study drug-related SAEs occurred: thrombocytopenia, dysesthesia (both Grade 3), and optic ischemic neuropathy (Grade 4); Grade ≤2 sensory neurological AEs led to dose reductions/discontinuations. GDC-0134 exposure was dose-proportional (median half-life = 84 h). Patients showed GDC-0134 exposure-dependent plasma NFL elevations; DLK cKO mice also exhibited plasma NFL compared to wild-type littermates. INTERPRETATION: This trial characterized GDC-0134 safety and PK, but no adequately tolerated dose was identified. NFL elevations in GDC-0134-treated patients and DLK cKO mice raised questions about interpretation of biomarkers affected by both disease and on-target drug effects. The safety profile of GDC-0134 was considered unacceptable and led to discontinuation of further drug development for ALS. Further work is necessary to understand relationships between neuroprotective and potentially therapeutic effects of DLK knockout/inhibition and NFL changes in patients with ALS.

1H MRS of basal ganglia and thalamus in amyotrophic lateral sclerosis.

Previous studies have evaluated motor and extramotor cerebral cortical regions in patients with amyotrophic lateral sclerosis (ALS) using (1) H MRS, but none have evaluated the thalamus or basal ganglia. The objective of this exploratory study was to evaluate the subclinical involvement of the basal ganglia and thalamus in patients with ALS using (1) H MRS. Fourteen patients (52±7 years) with sporadic definite ALS and 17 age-matched controls were studied using volumetric MRSI on a 3-T scanner. The concentration of the metabolites N-acetylaspartate (NAA), choline (Cho) and their ratio (NAA/Cho) were obtained bilaterally from the basal ganglia (lentiform nucleus, caudate) and thalamus. The maximum rates of finger and foot tap and lip and tongue movements were obtained to assess extrapyramidal and pyramidal tract function. In patients with ALS, relative to controls, the NAA concentration was significantly lower (p<0.02) in the basal ganglia and thalamus, and the Cho concentration was higher (p<0.01) in these structures, except in the caudate (p=0.04). Correspondingly, the NAA/Cho ratio was significantly lower (p<0.01) in these structures, except in the caudate (p=0.03), in patients than in controls. There were mild to strong correlations (r=0.4-0.7) between the metabolites of the basal ganglia and finger tap, foot tap and lip and tongue movement rates. In conclusion, decreased NAA in the basal ganglia and thalamus and increased Cho and decreased NAA/Cho in the lentiform nucleus and thalamus are indicative of neuronal loss or dysfunction and alterations in choline-containing membranes in these structures.

Individualizing Therapy in CIDP: A Mini-Review Comparing the Pharmacokinetics of Ig With SCIg and IVIg.

Immunoglobulin (Ig) therapy is a first-line treatment for CIDP, which can be administered intravenously (IVIg) or subcutaneously (SCIg) and is often required long term. The differences between these modes of administration and how they can affect dosing strategies and treatment optimization need to be understood. In general, the efficacy of IVIg and SCIg appear comparable in CIDP, but SCIg may offer some safety and quality of life advantages to some patients. The differences in pharmacokinetic (PK) profile and infusion regimens account for many of the differences between IVIg and SCIg. IVIg is administered as a large bolus every 3-4 weeks resulting in cyclic fluctuations in Ig concentration that have been linked to systemic adverse events (AEs) (potentially caused by high Ig levels) and end of dose "wear-off" effects (potentially caused by low Ig concentration). SCIg is administered as a smaller weekly, or twice weekly, volume resulting in near steady-state Ig levels that have been linked to continuously maintained function and reduced systemic AEs, but an increase in local reactions at the infusion site. The reduced frequency of systemic AEs observed with SCIg is likely related to the avoidance of high Ig concentrations. Some small studies in immune-mediated neuropathies have focused on serum Ig data to evaluate its potential use as a biomarker to aid clinical decision-making. Analyzing dose data may help understand how establishing and monitoring patients' Ig concentration could aid dose optimization and the transition from IVIg to SCIg therapy.

Chronic inflammatory demyelinating polyneuropathy responsive to mycophenolate mofetil therapy.

OBJECTIVE: To evaluate the efficacy of mycophenolate mofetil (MMF) in chronic inflammatory demyelinating polyneuropathy (CIDP). BACKGROUND: Evidence is growing that MMF is effective as an immunomodulatory drug in neuromuscular diseases. METHODS: A database of 184 patients with CIDP was analysed to obtain clinical, laboratory and electrophysiological information for patients with CIDP treated with MMF. RESULTS: Eight patients, who met the inclusion criteria, received MMF (mean dose 2 g/day; median duration 15.2 months). The average Neuropathy Impairment Score of the eight patients improved from baseline (72.3+/-35) after initiation of MMF therapy (37.8+/-37; p<0.001). Six of these eight patients were either able to stop concomitant medications (corticosteroid, intravenous immunoglobulin) or reduce their doses and frequency by > or = 50%. CONCLUSIONS: Our pilot data suggest that MMF appears to be an effective therapy for patients with naive or refractory CIDP, and further controlled studies are warranted for their confirmation.

Diabetic demyelinating polyneuropathy responsive to intravenous immunoglobulin therapy.

BACKGROUND: There is growing evidence that idiopathic chronic inflammatory demyelinating polyneuropathy (CIDP) and polyneuropathy in patients with diabetes mellitus (DM) that meets the electrophysiological criteria for CIDP (DM-CIDP) have many similarities. OBJECTIVE: To evaluate whether DM-CIDP responds to intravenous immunoglobulin (IVIG) therapy. PATIENTS AND METHODS: Twenty-six patients (mean [SD] age, 64 [8.9] years; age range, 40-80 years) with type 2 DM (n = 25), who met the electrophysiological criteria for CIDP, were given IVIG therapy (400 mg/kg body weight per day for 5 days) in a prospective open-label pilot study. All patients had quantitative evaluation using the Neuropathy Impairment Score at baseline and at the end of 4 weeks from the initiation of IVIG therapy. RESULTS: The mean Neuropathy Impairment Score improved significantly from baseline (mean [SD], 61.5 [26.0] points) to the end of the fourth week (33 [29.6] points; P<.00l). This clinically significant improvement occurred in 21 (80.8%) of the 26 patients. Conduction block occurred in 11 (42.3%) of the 26 patients; improvement in the Neuropathy Impairment Score was more frequent in patients who had a conduction block (11 of 11 patients) than in those who did not (10/15 [66.7%]; P =.03). Adverse reactions to IVIG included reversible renal dysfunction in 3 patients, flulike symptoms in 5, headache in 5, and chest pain and shortness of breath in 1. CONCLUSION: Although IVIG therapy seemed to improve DM-CIDP in this uncontrolled trial, a controlled trial is required for confirmation of our findings.

Demyelinating neuropathy in diabetes mellitus.

BACKGROUND: Recent studies have reported that patients with diabetes mellitus (DM) have a predisposition to develop chronic inflammatory demyelinating polyneuropathy (CIDP). OBJECTIVES: To determine whether patients with DM have a polyneuropathy fulfilling electrophysiologic criteria for CIDP, and whether CIDP is more frequent in patients with type 1 than in patients with type 2 DM. METHODS: We prospectively studied the frequency of electrophysiologic changes meeting the criteria for CIDP in patients with DM seen in our electrophysiology laboratory during a 51-month period (period 1). To evaluate the relationship between DM and CIDP, we prospectively determined during a 14-month period (period 2) the frequency of DM in patients seen in our electrophysiology laboratory with other neuromuscular diseases, and the frequency of idiopathic CIDP. RESULTS: During period 1, 120 patients with DM met the electrophysiologic criteria for CIDP (DM-CIDP). The most frequent clinical features of DM-CIDP were those of a predominantly large-fiber sensorimotor neuropathy, with recent motor deterioration and a moderately increased cerebrospinal fluid protein concentration. Twenty-six of the 120 patients were given intravenous immunoglobulin (400 mg/kg per day for 5 days), and 21 patients (80.8%) had significant improvement in the neurologic deficit at the end of 4 weeks of therapy. The DM-CIDP occurred equally in type 1 and type 2 DM. During period 2, 1127 patients were seen. Of these, 189 (16.8%) had DM with various neurologic disorders, including 32 patients (16.9%) with DM-CIDP. Among the remaining 938 patients without DM, 17 (1.8%) had idiopathic CIDP. The odds of occurrence of DM-CIDP was 11 times higher among diabetic than nondiabetic patients (P<.001). CONCLUSIONS: Demyelinating neuropathy meeting the electrophysiologic criteria for CIDP occurred in both types of DM, and its occurrence was significantly higher in diabetic than in nondiabetic patients.

Diffusion tensor imaging of basal ganglia and thalamus in amyotrophic lateral sclerosis.

PURPOSE: To assess the involvement of basal ganglia and thalamus in patients with amyotrophic lateral sclerosis (ALS) using diffusion tensor imaging (DTI) method. METHODS: Fourteen definite-ALS patients and 12 age-matched controls underwent whole brain DTI on a 3T scanner. Mean-diffusivity (MD) and fractional anisotropy (FA) were obtained bilaterally from the basal ganglia and thalamus in the regions-of-interest (ROIs). RESULTS: The MD was significantly higher (P < .02) in basal ganglia and thalamus in patients with ALS compared with controls. Correspondingly, the FA was significantly lower (P < .02) in these structures, except in caudate (P = .04) and putamen (P = .06) in patients compared with controls. There were mild to strong correlations (r = .3-.7) between the DTI measures of basal ganglia and finger-tap, foot-tap, and lip-and-tongue movement rate. CONCLUSIONS: The increased MD in basal ganglia and thalamus and decreased FA in globus pallidus and thalamus are indicative of neuronal loss or dysfunction in these structures.

Comprehensive evaluation of corticospinal tract metabolites in amyotrophic lateral sclerosis using whole-brain 1H MR spectroscopy.

Changes in the distribution of the proton magnetic resonance spectroscopy (MRS) observed metabolites N-acetyl aspartate (NAA), total-choline (Cho), and total-creatine (Cre) in the entire intracranial corticospinal tract (CST) including the primary motor cortex were evaluated in patients with amyotrophic lateral sclerosis (ALS). The study included 38 sporadic definite-ALS subjects and 70 age-matched control subjects. All received whole-brain MR imaging and spectroscopic imaging scans at 3T and clinical neurological assessments including percentage maximum forced vital capacity (FVC) and upper motor neuron (UMN) function. Differences in each individual metabolite and its ratio distributions were evaluated in the entire intracranial CST and in five segments along the length of the CST (at the levels of precentral gyrus (PCG), centrum semiovale (CS), corona radiata (CR), posterior limb of internal capsule (PLIC) and cerebral peduncle (CP)). Major findings included significantly decreased NAA and increased Cho and Cho/NAA in the entire intracranial CST, with the largest differences for Cho/NAA in all the groups. Significant correlations between Cho/NAA in the entire intracranial CST and the right finger tap rate were noted. Of the ten bilateral CST segments, significantly decreased NAA in 4 segments, increased Cho in 5 segments and increased Cho/NAA in all the segments were found. Significant left versus right CST asymmetries were found only in ALS for Cho/NAA in the CS. Among the significant correlations found between Cho/NAA and the clinical assessments included the left-PCG versus FVC and right finger tap rate, left -CR versus FVC and right finger tap rate, and left PLIC versus FVC and right foot tap rate. These results demonstrate that a significant and bilaterally asymmetric alteration of metabolites occurs along the length of the entire intracranial CST in ALS, and the MRS metrics in the segments correlate with measures of disease severity and UMN function.

Chronic inflammatory demyelinating polyradiculoneuropathy associated with multiple sclerosis.

OBJECTIVE: To describe temporal profile of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) in patients with definite, relapsing multiple sclerosis (MS). BACKGROUND: Peripheral demyelinating neuropathy has been rarely reported in association with central nervous system demyelinating disorder indistinguishable from MS. METHODS: In addition to usual diagnostic studies for CIDP and MS in all 5 patients, we studied proximal segments of nerves using deep tendon reflex latency measurements of biceps reflex, patellar reflex, and ankle reflex. RESULTS: All patients with MS subsequently (4-22 years) developed definite CIDP. Two of these patients developed multiple cranial nerve and spinal root enhancement on subsequent imaging without new intraparenchymal enhancement after a diagnosis of CIDP. The deep tendon reflex latencies were prolonged at more than 2 sites in all patients. Cerebral spinal fluid protein increased (70 +/- 19 to 144.8 +/- 17.4 mg/dL, P = 0.0001) at time of diagnosis of CIDP. Clinical improvement was observed in all patients after intravenous immunoglobulin therapy. CONCLUSIONS: When patients with MS develop CIDP, manifestations of central and peripheral disease involvement seem to respond to intravenous immunoglobulin. These cases suggest that there may be common antigenic targets in central and peripheral nervous system in this subset of patients.

Diagnostic role of deep tendon reflex latency measurement in small-fiber neuropathy.

Small-fiber neuropathy (SFN) is diagnosed on the basis of clinical features and specialized tests of small-fiber function because standard nerve conduction studies are normal. Thus, the objective of this study was to determine the value of deep tendon reflex (DTR) latency measurement in the diagnosis of SFN in patients with preserved DTR on clinical examination. We prospectively examined electromyographic reflexes from the biceps brachii [biceps brachii reflex (BR)], patellar [patellar reflex (PR)], and ankle [ankle reflex (AR)] using a manually operated electronic reflex hammer attached to electromyography machine and recorded by means of surface electrodes in 18 patients with SFN and 38 controls. Intra- and inter-evaluator reliability was good (intraclass correlation coefficient: 0.80-0.91, p < 0.01). In controls, the latencies at all sites were correlated to the height (R= 0.6, p < 0.01). Compared with controls, in patients with SFN, the mean latency in milliseconds was prolonged at all sites (BR: 12.8 +/- 1.6 vs. 8.9 +/- 1.9, p < 0.01; PR: 23.0 +/- 5.8 vs. 17.4 +/- 2.4, p < 0.01; and AR: 34.5 +/- 4.8 vs. 30.0 +/- 2.4, p < 0.01). The sensitivity [61.1% (95% CI: 51-94.9)] and specificity [92% (95% CI: 73-97.3)] of BR latency were roughly equal to those of PR and AR. We conclude that DTR latencies were significantly abnormal in the majority of the patients with SFN, suggestive of subclinical involvement of large myelinated fibers. DTR latency measurement is a reproducible, valuable, sensitive tool in the evaluation of mild subclinical involvement of large fibers.

Chronic inflammatory demyelinating polyradiculoneuropathy in diabetes mellitus.

There is a higher incidence of demyelinating peripheral neuropathy responsive to immunomodulating treatment in patients with diabetes mellitus. The diagnosis is often overlooked and the patients are given the label of "diabetic neuropathy." Progressive symmetric or asymmetric motor deficit, progressive sensory neuropathy in spite of optimal diabetic control, and unusually high cerebrospinal fluid protein level in "diabetic neuropathy" should alert the clinician to the possibility of an underlying treatable demyelinating peripheral neuropathy masquerading as "diabetic neuropathy."