Patterns of sensory nerve conduction abnormalities in demyelinating and axonal peripheral nerve disorders

The pattern of an abnormal median-normal sural (AMNS) sensory response is associated with acute and chronic inflammatory demyelinating polyradiculoneuropathy (AIDP and CIDP) and considered unusual in other types of neuropathy, although specificity and sensitivity of this pattern have not been evaluated. We compared sensory responses (patterns and absolute values) in patients with AIDP, CIDP, diabetic polyneuropathy (DP), and motor neuron disease (MND). Using strict criteria, the AMNS pattern occurred more frequently in recent onset AIDP (39%) compared with CIDP (28%), DP (14%–23%), or MND (22%) patients. This pattern was found in 3% of control subjects. The extreme pattern of an absent median-present sural response occurred only in AIDP and CIDP patients and in no other groups. Abnormalities of both nerves were more common in long-standing polyneuropathies such as CIDP and DP compared with AIDP or MND. Median nerve amplitudes were reduced significantly in AIDP, CIDP, and DP patients compared with MND patients, whereas sural nerve amplitudes were significantly reduced only in DP and CIDP patients. These findings may reflect early distal nerve involvement particularly in AIDP patients which is highlighted by differences in median and sural nerve recording electrode placement. We conclude that, in the appropriate clinical setting, the AMNS pattern, an absent median-present sural response pattern, or a reduced median amplitude compared with the sural amplitude supports a diagnosis of a primary demyelinating polyneuropathy. © 1993 John Wiley & Sons, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/50157/1/880160304_ftp.pd

Polyneuropathy associated with IgA monoclonal gammopathy of undetermined significance

Although polyneuropathies associated with IgM and IgG monoclonal gammopathies have been well described, polyneuropathy with IgA monoclonal gammopathy of undetermined significance (MGUS) is less commonly seen and has not been well studies. We reviewed the clinical and electrodiagnostic features of 5 such patients, and the sural nerve biopsy findings in 4 of them. One patient was diabetic, while 4 were free of other diagnoses commonly associated with neuropathy. Clinical presentations were varied. Electrodiagnostic and histological studies ranged from primary demyelination to primary axon loss to a mixed axonal/demyelinating picture. Three patients who were treated appeared to respond to prednisone or intravenous gamma globulin, despite clear clinical, electrodiagnostic, and histological differences. We conclude that the polyneuropathy associated with IgA MGUS is heterogeneous, similar to that in IgM and IgG MGUS. A trial of immunomodulating therapy appears to be warranted in such patients if the neuropathy is sufficiently servere. © 1993 John Wiley & Sons, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/50156/1/880160113_ftp.pd

Preservation of physical dimensions in a model of reactive synaptogenesis in the red nucleus

Collateral sprouting of cerebral cortical fibers in the red nucleus following destruction of the interpositus nucleus may be effective in restoring activity of rubral neurons. Shrinkage of the deafferented red nucleus was measured to estimate its effect on recording neural activity and its contribution as a stimulus for sprouting. The results suggest that rubral morphology is preserved during the early time course of collateral sprouting when electrophysiological changes are evident.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25091/1/0000522.pd

Evidence for reactive synaptogenesis in the ventrolateral thalamus and red nucleus of the rat: changes in high affinity glutamate uptake and numbers of corticofugal fiber terminals

High affinity glutamate uptake into corticofugal fiber terminals was measured in the ventrolateral thalamus and red nucleus at varying time intervals after lesions were made by kainic acid in the contralateral interpositus nucleus of the cerebellum in rats. Under similar conditions the density of cortical fiber terminals was estimated using the Fink-Heimer impregnation technique. 1. Glutamate uptake steadily increased in the ventrolateral thalamus up to 60 days after lesions in the contralateral cerebellum. 2. Similar changes were noted in the red nucleus. 3. The changes were dependent on the integrity of corticofugal fibers to the thalamus and red nucleus. 4. No changes in uptake of gammaaminobutyric acid were noted. 5. Saturation curves for glutamate uptake suggested a change in the maximal number of transport sites. 6. Fink-Heimer degeneration studies showed an increase in cortical terminals in the ipsilateral ventrolateral thalamus and in both rostral and caudal regions of the red nucleus following lesions in the contralateral interpositus nucleus. The data are consistent with an increase in the number of cortical fiber terminals in reaction to loss of cerebellar input to the ventrolateral thalamus and red nucleus. This study correlates anatomical and biochemical evidence for collateral sprouting in a model based on electrophysiologic data in the red nucleus and extends the model to include the thalamus.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46558/1/221_2004_Article_BF00247028.pd

Prognosis in long-term immunosuppressive treatment of refractory chronic inflammatory demyelinating polyradiculoneuropathy

Treatment of chronic inflammatory demyelinating polyneuropathy (CIDP) frequently includes use of immunosuppressive agents. Controlled treatment trials demonstrating efficacy are available only for prednisone and therapeutic plasma exchange (TPE). When these fail to achieve lasting clinical improvement after reduction or cessation of therapy, subsequent regimens are empiric, often leading to prolonged immunosuppression. It is not possible to predict who will respond to which agent and when. Administered individually, immunosuppressive agents may pose an acceptable risk, but cumulative effects of multiple agents in refractory patients may suppress the immune system and contribute to increased morbidity and mortality. Treatment difficulties with refractory CIDP patients have not been emphasized, and long-term effects of immunosuppression have focused on the risk of malignancy. In reviewing our clinical experience treating over 100 CIDP patients we identified approximately 20 patients who could be considered refractory to multiple immunosuppressive therapies and dependent upon long-term intermittent TPE. Two of these patients exemplify the morbidity associated with CIDP and its associated treatment. Our review of the clinical course of these patients raised issues about the use of multiple immunosuppressive agents, long-term goals, and long-term prognosis in CIDP.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30273/1/0000674.pd

Low diagnostic yield of sural nerve biopsy in patients with peripheral neuropathy and primary amyloidosis

Patients with primary amyloidosis may develop peripheral neuropathy as an early feature. Sural nerve biopsy is reported to be a sensitive method for diagnosing amyloidosis in such patients. We identified nine patients, ultimately diagnosed as having amyloidosis, who were referred for peripheral neuropathy of undetermined etiology. In six, a sural nerve biopsy demonstrated no amyloid. Subsequent examination of other tissue or of the contralateral sural nerve eventually resulted in the correct diagnosis. We conclude that sural nerve biopsy may be less sensitive than previously believed for the diagnosis of amyloidosis in patients with peripheral neuropathy secondary to amyloid. When the clinical suspicion of amyloidosis is high, a nondiagnostic sural nerve biopsy should not discourage the performance of further investigative studies.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30401/1/0000021.pd

Phase II Open Label Study of Valproic Acid in Spinal Muscular Atrophy

UNLABELLED:Preliminary in vitro and in vivo studies with valproic acid (VPA) in cell lines and patients with spinal muscular atrophy (SMA) demonstrate increased expression of SMN, supporting the possibility of therapeutic benefit. We performed an open label trial of VPA in 42 subjects with SMA to assess safety and explore potential outcome measures to help guide design of future controlled clinical trials. Subjects included 2 SMA type I ages 2-3 years, 29 SMA type II ages 2-14 years and 11 type III ages 2-31 years, recruited from a natural history study. VPA was well-tolerated and without evident hepatotoxicity. Carnitine depletion was frequent and temporally associated with increased weakness in two subjects. Exploratory outcome measures included assessment of gross motor function via the modified Hammersmith Functional Motor Scale (MHFMS), electrophysiologic measures of innervation including maximum ulnar compound muscle action potential (CMAP) amplitudes and motor unit number estimation (MUNE), body composition and bone density via dual-energy X-ray absorptiometry (DEXA), and quantitative blood SMN mRNA levels. Clear decline in motor function occurred in several subjects in association with weight gain; mean fat mass increased without a corresponding increase in lean mass. We observed an increased mean score on the MHFMS scale in 27 subjects with SMA type II (p<or=0.001); however, significant improvement was almost entirely restricted to participants <5 years of age. Full length SMN levels were unchanged and Delta7SMN levels were significantly reduced for 2 of 3 treatment visits. In contrast, bone mineral density (p<or=0.0036) and maximum ulnar CMAP scores (p<or=0.0001) increased significantly. CONCLUSIONS:While VPA appears safe and well-tolerated in this initial pilot trial, these data suggest that weight gain and carnitine depletion are likely to be significant confounding factors in clinical trials. This study highlights potential strengths and limitations of various candidate outcome measures and underscores the need for additional controlled clinical trials with VPA targeting more restricted cohorts of subjects. TRIAL REGISTRATION:ClinicalTrials.gov

SMA CARNI-VAL Trial Part I: Double-Blind, Randomized, Placebo-Controlled Trial of L-Carnitine and Valproic Acid in Spinal Muscular Atrophy

Valproic acid (VPA) has demonstrated potential as a therapeutic candidate for spinal muscular atrophy (SMA) in vitro and in vivo.Two cohorts of subjects were enrolled in the SMA CARNIVAL TRIAL, a non-ambulatory group of "sitters" (cohort 1) and an ambulatory group of "walkers" (cohort 2). Here, we present results for cohort 1: a multicenter phase II randomized double-blind intention-to-treat protocol in non-ambulatory SMA subjects 2-8 years of age. Sixty-one subjects were randomized 1:1 to placebo or treatment for the first six months; all received active treatment the subsequent six months. The primary outcome was change in the modified Hammersmith Functional Motor Scale (MHFMS) score following six months of treatment. Secondary outcomes included safety and adverse event data, and change in MHFMS score for twelve versus six months of active treatment, body composition, quantitative SMN mRNA levels, maximum ulnar CMAP amplitudes, myometry and PFT measures.At 6 months, there was no difference in change from the baseline MHFMS score between treatment and placebo groups (difference = 0.643, 95% CI = -1.22-2.51). Adverse events occurred in >80% of subjects and were more common in the treatment group. Excessive weight gain was the most frequent drug-related adverse event, and increased fat mass was negatively related to change in MHFMS values (p = 0.0409). Post-hoc analysis found that children ages two to three years that received 12 months treatment, when adjusted for baseline weight, had significantly improved MHFMS scores (p = 0.03) compared to those who received placebo the first six months. A linear regression analysis limited to the influence of age demonstrates young age as a significant factor in improved MHFMS scores (p = 0.007).This study demonstrated no benefit from six months treatment with VPA and L-carnitine in a young non-ambulatory cohort of subjects with SMA. Weight gain, age and treatment duration were significant confounding variables that should be considered in the design of future trials.Clinicaltrials.gov NCT00227266

Distinct Patterns of DNA Damage Response and Apoptosis Correlate with Jak/Stat and PI3Kinase Response Profiles in Human Acute Myelogenous Leukemia

BACKGROUND:Single cell network profiling (SCNP) utilizing flow cytometry measures alterations in intracellular signaling responses. Here SCNP was used to characterize Acute Myeloid Leukemia (AML) disease subtypes based on survival, DNA damage response and apoptosis pathways. METHODOLOGY AND PRINCIPAL FINDINGS:Thirty four diagnostic non-M3 AML samples from patients with known clinical outcome were treated with a panel of myeloid growth factors and cytokines, as well as with apoptosis-inducing agents. Analysis of induced Jak/Stat and PI3K pathway responses in blasts from individual patient samples identified subgroups with distinct signaling profiles that were not seen in the absence of a modulator. In vitro exposure of patient samples to etoposide, a DNA damaging agent, revealed three distinct "DNA damage response (DDR)/apoptosis" profiles: 1) AML blasts with a defective DDR and failure to undergo apoptosis; 2) AML blasts with proficient DDR and failure to undergo apoptosis; 3) AML blasts with proficiency in both DDR and apoptosis pathways. Notably, AML samples from clinical responders fell within the "DDR/apoptosis" proficient profile and, as well, had low PI3K and Jak/Stat signaling responses. In contrast, samples from clinical non responders had variable signaling profiles often with in vitro apoptotic failure and elevated PI3K pathway activity. Individual patient samples often harbored multiple, distinct, leukemia-associated cell populations identifiable by their surface marker expression, functional performance of signaling pathway in the face of cytokine or growth factor stimulation, as well as their response to apoptosis-inducing agents. CONCLUSIONS AND SIGNIFICANCE:Characterizing and tracking changes in intracellular pathway profiles in cell subpopulations both at baseline and under therapeutic pressure will likely have important clinical applications, potentially informing the selection of beneficial targeted agents, used either alone or in combination with chemotherapy