Mutant small heat shock protein B3 causes motor neuropathy: utility of a candidate gene approach.

OBJECTIVE: Idiopathic peripheral neuropathy is common and likely due to genetic factors that are not detectable using standard linkage analysis. We initiated a candidate gene approach to study the genetic influence of the small heat shock protein (sHSP) gene family on an axonal motor and motor/sensory neuropathy patient population. METHODS: The promoter region and all exonic and intronic sequences of the 10 sHSP genes (HSPB1-HSPB10) were screened in a cohort of presumed nonacquired, axonal motor and motor/sensory neuropathy patients seen at the Ohio State University Neuromuscular Clinic. RESULTS: A missense mutation in the gene encoding small heat shock protein B3 (HSPB3, also called HSP27, protein 3) was discovered in 2 siblings with an asymmetric axonal motor neuropathy. Electrophysiologic studies revealed an axonal, predominantly motor, length-dependent neuropathy. The mutation, HSPB3(R7S), is located in the N-terminal domain and involves the loss of a conserved arginine. CONCLUSIONS: The discovery of an HSPB3 mutation associated with an axonal motor neuropathy using a candidate gene approach supports the notion that the small heat shock protein gene family coordinately plays an important role in motor neuron viability.

NT-3 promotes nerve regeneration and sensory improvement in CMT1A mouse models and in patients.

BACKGROUND: Xenografts from patients with Charcot-Marie-Tooth type 1A (CMT1A) have shown delayed myelination and impaired regeneration of nude mice axons passing through the grafted segments. Neurotrophin-3 (NT-3), an important component of the Schwann cell (SC) autocrine survival loop, could correct these deficiencies. OBJECTIVE: To assess the efficacy of NT-3 treatment in preclinical studies using animal models of CMT1A and to conduct a double-blind, placebo-controlled, randomized, pilot clinical study to assess the efficacy of subcutaneously administered NT-3 in patients with CMT1A. METHODS: Nude mice harboring CMT1A xenografts and Trembler(J) mice with a peripheral myelin protein 22-point mutation were treated with NT-3, and the myelinated fiber (MF) and SC numbers were quantitated. Eight patients received either placebo (n = 4) or 150 microg/kg NT-3 (n = 4) three times a week for 6 months. MF regeneration in sural nerve biopsies before and after treatment served as the primary outcome measure. Additional endpoint measures included the Mayo Clinic Neuropathy Impairment Score (NIS), electrophysiologic measurements, quantitative muscle testing, and pegboard performance. RESULTS: The NT-3 treatment augmented axonal regeneration in both animal models. For CMT1A patients, changes in the NT-3 group were different from those observed in the placebo group for the mean number of small MFs within regeneration units (p = 0.0001), solitary MFs, (p = 0.0002), and NIS (p = 0.0041). Significant improvements in these variables were detected in the NT-3 group but not in the placebo group. Pegboard performance was significantly worsened in the placebo group. NT-3 was well tolerated. CONCLUSION: Neurotrophin-3 augments nerve regeneration in animal models for CMT1A and may benefit patients clinically, but these results need further confirmation.

Autonomic impairment in painful neuropathy.

OBJECTIVES: 1) To determine the degree and distribution and quantitate the severity of autonomic impairment in painful neuropathy (PN). 2) To assess the role of autonomic testing in evaluating PN. METHODS: The authors studied 92 patients with PN (60 women and 32 men, age 56.9 +/- 12.4 years) using: 1) autonomic reflex testing (ART), Quantitative Sudomotor Axon Reflex Test (QSART), cardiac-vagal, head-up tilt, and surface skin temperature; 2) autonomic symptoms questionnaire; 3) nerve conduction (NCS) and laboratory studies; 4) quantitative sensory testing; 5) skin biopsy; and 6) Composite Autonomic Symptoms Score (CASS) scale to grade ART results from 0 (normal) to 10 (autonomic failure). RESULTS: Autonomic involvement in PN had characteristic features. Main symptoms were pain, secretory and skin vasomotor signs, hypertension, and impotence. ART results were abnormal in 86 (93.5%) (CASS < 4), QSART in 67 (72.8%), cardiac-vagal index in 58 (63%), skin temperature in 51 (55.4%), orthostatic hypertension in 39 (42.3%), and family history of PN in 26 (21%) of patients. Group 1 (abnormal NCS) (n = 45) had more severe ART and sensory abnormalities than the Group 2 (normal NCS) (n = 47): 1) CASS 2.0 +/- 0.96 vs 1.55 +/- 0.88 (p < 0.01), cardiac-vagal index (p < 0.02), skin temperature (p < 0.02), hypertension (p < 0.03), cooling (p < 0.002), and vibration (p < 0.0005) thresholds. CONCLUSIONS: Autonomic symptoms in painful neuropathy are predominantly cholinergic and form a unique constellation of features that are distinct from other autonomic neuropathies.

Randomized controlled trial of IVIg in untreated chronic inflammatory demyelinating polyradiculoneuropathy.

OBJECTIVE: To determine the efficacy of IV immunoglobulin (IVIg) given patients with untreated chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). METHODS: A randomized, double-blind, multicenter, investigator-initiated study compared IVIg (Aventis Behring LLC, King of Prussia, PA) with placebo (5% albumin). On days 1, 2, and 21, IVIg (1 g/kg) or placebo was given. The primary outcome measure was the change in muscle strength from baseline to day 42, using the average muscle score (AMS). Secondary outcome measures included change from baseline AMS at days 10 and 21, the Hughes' functional disability scale, forced vital capacity (FVC), and nerve conduction studies (NCS) of four motor nerves (median, ulnar, peroneal, and tibial). RESULTS: The patients (n = 33) were randomized. Of these, 30 (14 women, 16 men, aged 54 +/- 20 years, range 13 to 82) received IVIg and 23 were given placebo (12 women, 11 men, aged 50 +/- 18 years, range 23 to 73). Baseline AMS values of the groups were similar (IVIg 7.06 +/- 1.31 versus placebo 7.28 +/- 1.18, p = 0.53). There were two dropouts in placebo group and one in the IVIg group. Mean AMS improved at day 42 comparing IVIg with placebo (0.63 versus -0.1, p = 0.006). Improved strength was seen by day 10. The placebo group lost strength over this same interval. In the IVIg, 11 subjects improved by the functional disability scale; none worsened. This differed (p = 0.019) from those in the placebo-treated group (two improved, two got worse, remainder unchanged). Forced vital capacity did not improve with IVIg treatment. IVIg improved ulnar motor distal latency (p = 0.005), tibial distal compound muscle amplitude (p = 0.003), and peroneal nerve conduction velocity (p = 0.03). CONCLUSIONS: IVIg improves strength in patients with untreated CIDP by day 10 with continued benefit through day 42; more than one third improve by at least a functional grade on a disability scale. This study provides data supporting IVIg as the initial treatment for CIDP.

Painful sensory neuropathy: prospective evaluation using skin biopsy.

OBJECTIVE: In patients presenting with painful, burning feet with minimal signs of neuropathy, the following questions were addressed: 1) How many of these patients have a peripheral neuropathy? 2) What is the role of skin biopsy in establishing a diagnosis of neuropathy? 3) What conditions are associated with the neuropathy? and 4) What laboratory studies are useful in this patient population? METHODS: A total of 117 consecutive patients referred for evaluation were prospectively studied. All underwent nerve conduction studies (NCS) and a battery of blood tests, including antinerve antibodies. If NCS were normal, a punch biopsy of the skin of the distal leg was performed to ascertain the intraepidermal nerve fiber (IENF) density. In a subset of 32 patients, the sensitivity of skin biopsy was compared to quantitative sudomotor axon test (QSART) and quantitative sensory tests (QST). RESULTS: Three groups emerged. Group 1, with abnormal NCS (n = 60, 34 F/26 M, mean age 60 +/- 14 years), represented 51% of the cohort. The majority had neuropathies of undetermined cause, but 18 (30%) had associated conditions. Group 2, with normal NCS and reduced IENF density (n = 44, 29 F/15 M, mean age 57 +/- 14 years), represented 38% of the cohort. Three in this group had associated conditions. Group 3, with normal NCS and IENF density (n = 13, 6 F/7 M, mean age 53 +/- 13 years), represented 11% of the cohort; most had no diagnoses but two had MS. In a comparative subset analysis, skin biopsy was more sensitive than QSART or QST in diagnosing a neuropathy. CONCLUSIONS: Patients presenting with painful feet are heterogeneous, consisting of both large and small fiber sensory neuropathies. In rare cases, a central cause for pain can be found. Over one-third of patients required a skin biopsy to diagnose a small fiber sensory neuropathy. A limited battery of blood tests facilitated diagnosis, but serum antinerve antibodies were not helpful.

Inter- and intraexaminer reliability of nerve conduction measurements in patients with diabetic neuropathy.

We determined the inter- and intraexaminer reliability of nerve conduction measurements in six patients with diabetic peripheral neuropathy. Each patient was examined by six electromyographers on two separate occasions at least 1 week apart. We obtained attributes of nerve conduction at each examination and analyzed the data by analysis of variance. Intraexaminer reliability was high for 11 of 12 measurements, and interexaminer reliability was high for eight of twelve. Three of the four measurements that varied between examiners were either sensory or motor amplitudes, attributes frequently used to measure disease progression or to assess the result of therapeutic intervention. Our results suggest that longitudinal nerve conduction measurements used to assess worsening or improvement over time should optimally be performed by a single examiner to minimize the degree of variability associated with different examiners.

Multifocal motor neuropathy: electrodiagnostic features.

Diagnosis of multifocal motor neuropathy (MMN), a syndrome characterized by progressive asymmetric weakness with intact sensation, is important because the disorder often responds to treatment. Multifocal partial motor conduction block (PMCB) has been emphasized as a cardinal feature in the diagnosis of this syndrome, but detailed nerve conduction studies are not available. Nine patients, ages 28-58, had chronic, progressive, asymmetric, predominantly distal limb weakness for 5-18 years. Sensation was normal and reflexes were reduced asymmetrically. Although all 9 demonstrated PMCB localized to short nerve segments, additional features of multifocal motor demyelination were present, including temporal dispersion (5 patients), segmentally reduced motor nerve conduction velocity (7 patients), prolonged distal motor latency (4 patients), and prolonged F-wave latency (9 patients). The strength of all patients improved after treatment with human immune globulin. A reduction in the degree of PMCB or an increase in the distal motor amplitude or both accompanied the clinical improvement. These studies suggest that patients with MMN demonstrate widespread evidence of motor demyelination in addition to the well-described PMCB, and that reduction of PMCB accounts for the increase in strength following therapy.

Gangliosides elicit a T-cell independent antibody response.

Antibodies to glycolipids have recently been found to be elevated in a substantial proportion of patients with motor neuron diseases, various neuropathies and classical ALS. Several features of these antibody responses suggest that they may be produced by a T-cell independent B lymphocyte response: (1) antibodies are predominantly of IgM class; (2) antibodies against gangliosides are directed against the carbohydrate component of the gangliosides; and (3) antiganglioside antibodies are difficult to suppress. In this study we have asked whether gangliosides can induce T-independent responses, in T-cell deficient and T-cell competent mice. Homozygous nude mice (nu/nu), which lack T-cells, and heterozygous controls (nu/+) with intact T-cells, were immunized and rechallenged with the ganglioside GM1 in liposomes. Antibodies were measured by an ELISA method. Both nude mice and controls produced high titers of IgM class antibodies to the ganglioside GM1. The antibody titers peaked by 7 days after each immunization and declined by 14 days. The maximum titer rose progressively after each immunization. No significant amount of IgG antibody to GM1 was produced by either nu/nu or nu/+ mice, even after repeated immunization. These results suggest that gangliosides elicit prominent T-cell-independent antibody responses. The implications of these findings for neurologic disorders associated with anti-ganglioside antibodies are discussed.

Multifocal motor neuropathy: response to human immune globulin.

Multifocal motor neuropathy (MMN) is a progressive disorder producing asymmetrical weakness and muscle wasting. Case reports suggest that patients with MMN improve after cyclophosphamide therapy, but not after prednisone or plasmapheresis. Because MMN is likely to be immune mediated, we investigated the therapeutic response to human immune globulin (HIG) in an open, uncontrolled trial. Nine patients, ages 28 to 58 years, had chronic, progressive, asymmetrical, predominantly distal, limb weakness for 5 to 18 years. Sensation was normal, and reflexes were reduced asymmetrically. All had physiological evidence of multifocal motor demyelination with partial motor conduction block, and 7 had elevated serum titers of anti-GM1 IgM antibody. All patients were treated with HIG, 1.6 to 2.4 gm/kg, given intravenously over 3 to 5 days. Strength improved in all patients 3 to 10 days after treatment, with improvement peaking at 2 weeks and lasting for an average of 2 months. The range of functional improvement varied from dramatic to mild. The degree of partial motor conduction block was reduced, at least partially, in 7 of 8 patients. The serum anti-GM1 antibody titers did not change. Repeated courses of HIG resulted in similar improvements. We conclude that HIG may be an effective therapy for patients with MMN.

Chronic demyelinating polyneuropathy associated with eosinophilia-myalgia syndrome.

Eosinophilia-myalgia syndrome (EMS) is a newly described syndrome associated with use of L-tryptophan. A neuropathy with features of axonal degeneration has also been described in conjunction with EMS. Demyelinating polyneuropathy is not a well recognised association of the syndrome. The two patients with EMS reported presented with profound weakness and sensory loss and were found to have clinical, electrophysiological and pathological evidence of a chronic demyelinating polyneuropathy. The concurrence of this neuropathy with EMS, as well as several other features of their illness, is suggestive of an immune mediated mechanism in the pathophysiology of EMS.

Inter- and intra-examiner reliability of nerve conduction measurements in normal subjects.

Nerve conduction studies are widely employed in evaluating patients with peripheral nerve disease and are often used serially to measure disease progression or to assess a therapeutic intervention. We determined the inter- and intra-examiner reliability of electrophysiological data by performing serial nerve conduction studies on 7 normal subjects. A high degree of intra-examiner reliability was present, but significant inter-examiner differences were found. Our results suggest that if nerve conduction studies are to be used longitudinally, they should optimally be performed by a single examiner to minimize the degree of variability associated with different examiners.

Olivopontocerebellar atrophy with retinal degeneration. A clinical and ocular histopathologic study.

The ocular histopathologic and electron microscopic findings were determined in eyes obtained at autopsy from twins with dominant olivopontocerebellar atrophy (OPCA) and retinal degeneration (OPCA type III). On light microscopy, a retinal degeneration that involved primarily the photoreceptor layer was present and appeared to start in the macular area and spread to involve the peripheral fundus. The retinal pigment epithelium was variably hypopigmented and hyperpigmented. On electron microscopy, osmiophilic, multimembranous, and complex lipofuscin inclusions were present in conjunctival cells, keratocytes, lens epithelium, iris and ciliary body fibrocytes, occasional outer retinal cells, and retinal pigment epithelial cells. The twins' father and an older sister were also affected and had classic neurologic and ophthalmologic abnormalities. The similarities were noted between the clinical and ultrastructural findings between OPCA type III and the neuronal ceroid lipofuscinoses.