Surgeons, Urologist
7 years of experience

Accepting new patients
Uconn Medical Group
1115 West St
Southington, CT 06489
800-535-6232
Locations and availability (4)

Education ?

Medical School Score Rankings
Thomas Jefferson University (2003)
  • Currently 3 of 4 apples
Top 50%

Awards & Distinctions ?

Awards  
Alpha Omega Alpha Honor Society
Hobart Amory Hare Honor Society
Endourology Annual Essay Contest, 2nd Prize
American Urological Association Best Poster: Stone Disease

Affiliations ?

Dr. Lambert is affiliated with 8 hospitals.

Hospital Affilations

Score

Rankings

  • University of Connecticut Health Center
    263 Farmington Ave, Farmington, CT 06032
    • Currently 3 of 4 crosses
    Top 50%
  • Hahnemann University Hospital
    230 N Broad St, Philadelphia, PA 19102
    • Currently 2 of 4 crosses
  • Mount Sinai Rehabilitation Hospital
    490 Blue Hills Ave, Hartford, CT 06112
    • Currently 2 of 4 crosses
  • Roxborough Memorial Hospital
    5800 Ridge Ave, Philadelphia, PA 19128
    • Currently 2 of 4 crosses
  • Mercy Fitzgerald Hospital
    1400 Lansdowne Ave, Darby, PA 19023
    • Currently 2 of 4 crosses
  • St Francis Hospital & Medical Center
    Urology
    114 Woodland St, Hartford, CT 06105
    • Currently 1 of 4 crosses
  • HttpWww.Mercyhealth.OrgFitzgerald
  • University of Penn Med Center-Presb Med Group
  • Publications & Research

    Dr. Lambert has contributed to 127 publications.
    Title Analysis of 24-hour Urine Parameters As It Relates to Age of Onset of Cystine Stone Formation.
    Date November 2010
    Journal Journal of Endourology / Endourological Society
    Excerpt

    Cystinuria is an inherited disorder characterized by the impaired reabsorption of the dibasic amino acid, cystine, in the proximal tubule of the nephron. Cystine stones most frequently occur in the first through third decades of life with a decreased incidence in old age. We hypothesize that patients presenting with first stone event at an older age would have more favorable 24-hour urine parameters compared with those patients who present early.

    Title A Sealed Bladder Cuff Technique During Laparoscopic Nephroureterectomy Utilizing the Ligasure Electrosurgical Device: Laboratory and Clinical Experience.
    Date June 2010
    Journal Journal of Endourology / Endourological Society
    Excerpt

    Laparoscopic nephroureterectomy (LNU) is a safe, minimally invasive approach for management of upper tract urothelial tumors. Controversy exists over the optimal technique for the distal ureter and bladder cuff (DUBC) excision. We examined the novel technique of using the LigaSure bipolar electrosurgical device in laboratory investigations and during clinical LNU to manage the DUBC.

    Title Effect of Escalating Versus Fixed Voltage Treatment on Stone Comminution and Renal Injury During Extracorporeal Shock Wave Lithotripsy: a Prospective Randomized Trial.
    Date February 2010
    Journal The Journal of Urology
    Excerpt

    ESWL is a minimally invasive, efficacious therapy for most renal stones. However, an optimal voltage treatment protocol ensuring effective stone comminution while minimizing tissue injury is not well established. We performed a prospective, randomized trial of the stone-free rate and renoprotective effect of an escalating vs a fixed voltage treatment strategy during ESWL.

    Title Comparison of the Histologic Accuracy of Needle Biopsy Before and After Renal Cryoablation: Laboratory and Initial Clinical Experience.
    Date January 2008
    Journal Urology
    Excerpt

    OBJECTIVES: To minimize the risk of needle biopsy, including tumor seeding and hemorrhage, we examined the feasibility of needle biopsy after renal cryoablation. METHODS: Four cryolesions were created bilaterally on normal porcine renal tissue with an 8-minute double-freeze cycle using a single 17-gauge cryoprobe. Biopsies were obtained with a 16G biopsy needle before and after cryoablation under direct vision. Each biopsy specimen was evaluated for the number of glomeruli and arterioles. We used a two-sample t-test to analyze the data. Subsequently, 10 patients with small renal masses underwent laparoscopic cryoablation using a standard double freeze-thaw cycle. We used an 18G biopsy needle to sample the renal mass with a single core taken before and after cryoablation. A blinded pathologist evaluated the specimens for the histologic accuracy of the two sampling techniques. We used chi-square statistic to determine an association between the diagnostic quality of the core specimens. RESULTS: Two hundred biopsies were obtained from porcine renal tissue. The average number of glomeruli for the pre- and postcryoablation sample was 9.6, and 7.8, respectively (P = 0.04). The average number of arterioles for the pre- and postcryoablation group was 2.3 and 1.9, respectively (P = 0.04). During clinical application, seven of 10 precryoablation and seven of 10 postcryoablation biopsies were diagnostic (P = 0.639). Histopathology was established in all 10 cases. There was no significant bleeding from any needle biopsy. CONCLUSIONS: The porcine model established the feasibility of histologic diagnosis after cryoablation. Our preliminary clinical experience demonstrates that postcryoablation biopsy has similar diagnostic yields to precryoablation biopsy.

    Title Prognostic Risk Stratification and Clinical Outcomes in Patients Undergoing Surgical Treatment for Renal Cell Carcinoma with Vascular Tumor Thrombus.
    Date August 2007
    Journal Urology
    Excerpt

    OBJECTIVES: Approximately 4% to 10% of patients with renal cell carcinoma (RCC) present with vascular tumor thrombus. Often, these patients also present with metastatic disease. This study examined the clinical outcome and morbidity of patients with RCC and vascular tumor thrombus treated with aggressive surgical therapy. METHODS: From 1989 to 2006, 118 patients were identified with Stage pT3b or pT3c RCC who had undergone radical nephrectomy and thrombectomy. Disease-specific survival (DSS) and overall survival were measured by Kaplan-Meier statistics with the log-rank test to assess differences in survival stratified by the clinical and pathologic variables. Cox regression techniques were used to identify significant predictors of DSS. RESULTS: The median follow-up was 18 months (range 1 month to 13.55 years). Tumor thrombus was at the level of the renal vein in 67 patients (56.8%), the infradiaphragmatic inferior vena cava in 39 (33%), and the supradiaphragmatic inferior vena cava in 12 patients (10%). Of the 118 patients, 42 (35.6%) presented with metastasis. The median tumor size was 8.2 cm. The 5-year overall survival rate was 40.7%. The 5-year DSS rate was 60.3% in those without metastasis and 10% in those with metastasis (P <0.001). The level of tumor thrombus did not significantly affect survival (P = 0.85). When the patients without metastasis were analyzed separately, nodal positivity (P = 0.03) and a tumor diameter greater than 7 cm (P = 0.05) were significant predictors of DSS. CONCLUSIONS: Our results support the role of radical nephrectomy and thrombectomy in patients with RCC and vascular tumor thrombus. The absence of significant morbidity makes aggressive radical surgery feasible in the patients with tumor thrombus and metastatic disease. The current TNM staging system may need to be revised, given the evidence that the level of tumor thrombus invasion does not affect the survival outcomes.

    Title Focal Cryosurgery: Encouraging Health Outcomes for Unifocal Prostate Cancer.
    Date August 2007
    Journal Urology
    Excerpt

    OBJECTIVES: Owing to the ability to better detect small-volume tumors, we have seen an increasing population of men with low-risk unifocal prostate cancer. We report our safety and efficacy experience of focal cryoablation of the prostate to maintain potency and preserve genitourinary function in men with localized, unifocal disease. METHODS: From June 2002 to December 2005, 25 patients with primary unifocal prostate cancer were treated with focal cryoablation of the prostate. The patients were followed up with physical examinations, morbidity questionnaires, and prostate-specific antigen (PSA) determinations every 3 months for the first year and every 6 to 12 months thereafter. Patients with a PSA nadir greater than 1.0 ng/mL or a nadir plus 2 ng/mL underwent repeat biopsy to assess for cancer recurrence. RESULTS: The median age was 68 years (range 48 to 78). The median preoperative PSA level was 6.0 ng/mL, and the postoperative PSA nadir was 2.4 ng/mL. The median follow-up was 28 months. Seventeen patients remained potent. No patients reported worsened lower urinary tract symptoms, incontinence, rectal pain, perineal discomfort, or fistula formation. The median PSA nadir was 2.4 ng/mL, and 40% of patients had a PSA nadir of less than 1.0 ng/mL. Of the 25 patients, 21 (84%) had not experienced biochemical failure, defined as a greater than 50% PSA nadir reduction. Seven patients underwent repeat biopsy, and prostate cancer was detected in the contralateral gland in 2 patients and in the area of previous cryosurgery in 1 patient. CONCLUSIONS: Focal cryoablation of the prostate has exhibited minimal morbidity and promising efficacy in our 3-year observation. Longer follow-up is necessary to determine its role in the treatment of patients with low-risk unifocal prostate cancer.

    Title The Increasing Use of Intravesical Therapies for Stage T1 Bladder Cancer Coincides with Decreasing Survival After Cystectomy.
    Date August 2007
    Journal Bju International
    Excerpt

    OBJECTIVE: Intravesical therapy (IVT), chemo and immunotherapy, has made conservative, bladder-sparing strategies a viable option for managing patients with high grade T1 bladder cancer. However, many of these patients will have recurrence and occasionally progression, questioning delayed intervention. This study examines the patterns of use of IVT in high-grade T1 bladder cancer and the subsequent impact on survival for patients ultimately proceeding to radical cystectomy (RC). PATIENTS AND METHODS: Between 1990 and 2005, 104 patients were identified with T1 high-grade transitional cell carcinoma (TCC) and who underwent RC. Patients were divided into two groups; those having RC before 1998 (median year of surgery) and those after 1998. Trends in time from diagnosis to RC, courses of IVT, recurrence and pathological stage were analysed using two-sample t-tests with 95% confidence intervals. Kaplan-Meier analysis was used to determine the disease-free and overall survival rates. RESULTS: Before 1998, 28 of 38 patients (74%) proceeded directly to RC with no IVT, vs 20 of 47 (43%) after 1998 (P = 0.004). The mean number of IVT courses per patient was 0.53 before 1998 and 1.2 afterward (P = 0.016). Patients who had RC before 1998 had a 69.7% disease-free survival at 5 years, vs 39.6% for those after 1998 (P = 0.05). CONCLUSION: In the past 15 years, our experience indicates that patients having RC for T1 high-grade TCC after 1998 were more likely to receive IVT. These same patients had a worsening disease-free survival. In very few other cancers has disease-free survival decreased over time. We postulate that the decrease in survival might be related to an increased use of IVT.

    Title Hair Cells in the Inner Ear of the Pirouette and Shaker 2 Mutant Mice.
    Date June 2001
    Journal Journal of Neurocytology
    Excerpt

    The shaker 2 (sh2) and pirouette (pi) mouse mutants display severe inner ear dysfunction that involves both auditory and vestibular manifestation. Pathology of the stereocilia of hair cells has been found in both mutants. This study was designed to further our knowledge of the pathological characteristics of the inner ear sensory epithelia in both the sh2 and pi strains. Measurements of auditory brainstem responses indicated that both mutants were profoundly deaf. The morphological assays were specifically designed to characterize a pathological actin bundle that is found in both the inner hair cells and the vestibular hair cells in all five vestibular organs in these two mutants. Using light microscope analysis of phalloidin-stained specimens, these actin bundles could first be detected on postnatal day 3. As the cochleae matured, each inner hair cell and type I vestibular hair cell contained a bundle that spans from the region of the cuticular plate to the basal end of the cell, then extends along with cytoplasm and membrane, towards the basement membrane. Abnormal contact with the basement membrane was found in vestibular hair cells. Based on the shape of the cellular extension and the actin bundle that supports it, we propose to name these extensions "cytocauds." The data suggest that the cytocauds in type I vestibular hair cells and inner hair cells are associated with a failure to differentiate and detach from the basement membrane.

    Title The Role of Preoperative Radial Artery Ultrasound and Digital Plethysmography Prior to Coronary Artery Bypass Grafting.
    Date May 2001
    Journal European Journal of Cardio-thoracic Surgery : Official Journal of the European Association for Cardio-thoracic Surgery
    Excerpt

    OBJECTIVE: Doppler ultrasound and digital plethysmography are used at our institution to determine the suitability of the radial artery for harvest prior to coronary artery bypass grafting (CABG). The purpose of this study is to determine the value of this preoperative evaluation. METHODS: A retrospective analysis of non-invasive radial artery testing was performed on 187 CABG patients. Criteria used to exclude radial arteries from harvest were anatomic abnormalities (size<2 mm, diffuse calcifications), and perfusion deficits during radial artery occlusion (>40% reduction in digital pressure, non-reversal of radial artery flow, or minimal increase in ulnar velocity). A questionnaire was used to determine the incidence of postoperative hand ischemia or rehabilitation. RESULTS: In 187 patients, 346 arms were evaluated. Ninety-four arms (27.1%) were excluded for harvesting. Anatomical abnormalities included size<2 mm (1.5%), diffuse calcifications (8.7%), congenital anomalies (2.3%), and radial artery occlusion (0.3%). Circulatory abnormalities included non-reversal of flow (7.2%), abnormal digital pressures (5.5%), and inappropriate increase in ulnar velocity (1.7%). A total of 116 radial arteries were harvested. There were no episodes of hand ischemia. No patient required hand rehabilitation. CONCLUSIONS Doppler ultrasound and digital plethysmography identifies both perfusion (14.5%) and anatomical (12.7%) abnormalities that may make the radial artery less suitable as a bypass conduit.

    Title Contractile Smooth Muscle Cell Apoptosis Early After Saphenous Vein Grafting.
    Date November 2000
    Journal The Annals of Thoracic Surgery
    Excerpt

    BACKGROUND: The media of saphenous veins is composed of two cell populations: smooth muscle (SMC) and non-smooth muscle (NSMC) cells. Previous studies demonstrate a loss of SMCs by 3 days after grafting, despite an increase in cell proliferation. The purpose of this study is to determine the rates of apoptotic cell death versus cell proliferation for the two major cell populations of the media. METHODS: Veins (six/time point) were examined at 0.5, 1, 2, 4, 8, 24, and 48 hours after grafting in crossbred pigs. Terminal transferase-mediated dUTP nick end labeling (TUNEL) and proliferating cell nuclear antigen (PCNA) stains were used to assess apoptosis and proliferation. Apoptosis was also corroborated with confocal and electron microscopy. RESULTS: Apoptosis was high in both cell populations: at 8 hours, SMC and NSMC apoptosis peaked at 14.5% +/- 3.5% and 49.9% +/- 7.8%, respectively. In contrast, cell proliferation was different between the two populations. SMC proliferation was low at all time points, whereas NSMC proliferation rose to 22% +/- 5.4% by 48 hours. CONCLUSIONS: Medial SMCs are removed through apoptosis and appear to be replaced by fibrous tissue (NSMCs) early after vein grafting. This reciprocal change between the medial SMC and NSMC populations may contribute to late vein graft degeneration.

    Title A 17-mer Self-peptide of Acetylcholine Receptor Binds to B Cell Mhc Class Ii, Activates Helper T Cells, and Stimulates Autoantibody Production and Electrophysiologic Signs of Myasthenia Gravis.
    Date August 1997
    Journal Journal of Immunology (baltimore, Md. : 1950)
    Excerpt

    We have identified in an extracellular segment of the alpha1 subunit of nicotinic acetylcholine receptor (AChR) of homologous muscle a 17-residue autoantigen that, without conjugation to a carrier, activates Th lymphocytes and induces production of autoantibodies that cause electrophysiologic signs of experimental autoimmune myasthenia gravis. A panel of overlapping synthetic peptides revealed two T cell epitopes, one encompassed by residues 121-136 and the other by 129-145. Residues 129 (glutamic acid) and 130 (isoleucine) were implicated in a pathogenic B cell epitope. Peptide 129-145 (Glu-Ile-Ile-Val-Thr-His-Phe-Pro-Phe-Asp-Glu-Gln-Asn-Cys-Ser-Met-Lys, a conserved sequence in rat and human AChR) induced autoantibody production in 76% of rats. All seropositive rats had evidence of experimental autoimmune myasthenia gravis; five of five tested had electrophysiologic signs, and all had loss of immunochemically measured autologous muscle AChR. Analogues of 129-145, with single residues substituted by alanine, revealed phenylalanine 135, phenylalanine 137, and glutamic acid 139 as most important determinants of Ag/MHC-II/TCR interactions; phenylalanine 137 is critical for T cell activation. B cells were the major MHC-II-positive cell type to which the self-peptide 129-145 bound in a population of nonimmune splenic cells. More efficient processing and presentation of the Th cell epitope by an expanded population of immune B cells selected by specifically binding another epitope of the same peptide would greatly amplify the production of autoantibodies. Peptide autoantigens of this type could plausibly perpetuate the autoantibody response in myasthenia gravis, and are a rational target for strategies aimed at Ag-specific therapeutic intervention.

    Title A Transgenic Mouse Model of the Slow-channel Syndrome.
    Date February 1996
    Journal Muscle & Nerve
    Excerpt

    To investigate the effect of acetylcholine receptor (AChR) mutations on neuromuscular transmission and to develop a model for the human neuromuscular disease, the slow-channel syndrome, we generated transgenic mice with abnormal AChRs using a delta subunit with a mutation in the ion channel domain. In three transgenic lines, nerve-evoked end-plate currents and spontaneous miniature end-plate currents (MEPCs) had prolonged decay phases and MEPC amplitudes were reduced by 33%. Single nerve stimuli elicited repetitive compound muscle action potentials in vivo. Transgenic mice were abnormally sensitive to the neuromuscular blocker, curare. These observations demonstrate that we can predictably alter AChR function, synaptic responses, and muscle fiber excitation in vivo by overexpressing subunits containing well-defined mutations. Furthermore these data support the hypothesis that the electrophysiological findings in the neuromuscular disorder, the slow-channel syndrome, are due to mutant AChRs.

    Title Calcium-channel Antibodies in the Lambert-eaton Syndrome and Other Paraneoplastic Syndromes.
    Date June 1995
    Journal The New England Journal of Medicine
    Excerpt

    BACKGROUND. Voltage-gated calcium channels in small-cell lung carcinomas may initiate autoimmunity in the paraneoplastic neuromuscular disorder Lambert-Eaton syndrome. The calcium-channel subtype that is responsible is not known. METHODS. We compared the effects of antagonists of L-type, N-type, and P/Q-type neuronal calcium channels on the depolarization-dependent influx of calcium-45 in cultured carcinoma cells. Serum samples from patients with various disorders were tested for reactivity with P/Q-type channels solubilized from carcinoma and cerebellar membranes and N-type channels from cerebral cortex. RESULTS. P/Q-type calcium-channel antagonists were the most potent inhibitors of depolarization-induced 45Ca influx in cultured small-cell carcinoma cell lines. Anti-P/Q-type calcium-channel antibodies were found in serum from all 32 patients with Lambert-Eaton syndrome and a diagnosis of cancer and in 91 percent of the 33 patients with Lambert-Eaton syndrome without cancer. Anti-N-type calcium-channel antibodies were found in 49 percent of the 65 patients with the Lambert-Eaton Syndrome. Lower titers of anti-P/Q-type and anti-N-type calcium-channel antibodies were found in 54 percent of 70 patients with a paraneoplastic encephalomyeloneuropathic complication of lung, ovarian, or breast carcinoma, 24 percent of 90 patients with cancer but no evident neurologic complications, 23 percent of 78 patients with sporadic amyotrophic lateral sclerosis, and less than 3 percent of 69 patients with myasthenia gravis, epilepsy, or scleroderma. CONCLUSIONS. The high frequency of P/Q-type calcium-channel antibodies found in patients with Lambert-Eaton syndrome implies that antibodies of this specificity have a role in the presynaptic pathophysiology of this disorder.

    Title End-plate Acetylcholinesterase Deficiency Associated with Small Nerve Terminals and Reduced Acetylcholine Release. A New Syndrome.
    Date September 1992
    Journal International Journal of Neurology
    Title Muscle Acetylcholine Receptors Complexed with Autologous Igg Reflect Seropositivity but Not Necessarily in Vivo Binding.
    Date March 1992
    Journal Neurology
    Excerpt

    The diagnosis of acquired myasthenia gravis (MG) in apparently seronegative individuals is aided by finding immunoglobulin complexed to acetylcholine receptors (AChR) and a reduction in the number of binding sites for alpha-bungarotoxin (alpha-BTx) in nerve-muscle biopsies. In this study, we found that anti-AChR antibodies in extracellular fluids can complex with cytoplasmic epitopes of AChR in the process of muscle extraction. When normal muscle was briefly exposed to antibodies (greater than or equal to 0.3 nmol/l) in the initial step of tissue homogenization (before detergent extraction), membranous AChR became complexed with IgG. This was so even with a nonmyasthenogenic monoclonal antibody specific for the alpha-subunit's presumptive cytoplasmic segment 366-389. We also found that antibodies reactive with AChR's alpha-BTx binding region can significantly lower apparent yields of alpha-BTx binding sites extracted from muscle. Thus, the finding of IgG complexed to AChR extracted from biopsied muscle does not necessarily reflect in vivo binding but, nevertheless, is a sensitive indicator of AChR seropositivity in patients suspected to have MG.

    Title Recombinant Human Acetylcholine Receptor Alpha-subunit Induces Chronic Experimental Autoimmune Myasthenia Gravis.
    Date April 1991
    Journal Journal of Immunology (baltimore, Md. : 1950)
    Excerpt

    A synthetic gene encoding the 210 N-terminal residues of the alpha-subunit of the nicotinic acetylcholine receptor (AChR) of human skeletal muscle was cloned into an inducible expression plasmid to produce a fusion protein in high yield in Escherichia coli. Like native human AChR, the recombinant human alpha 1-210 protein induced AChR-binding, AChR-modulating, and AChR-blocking autoantibodies in rats when injected once intradermally as an emulsion in CFA, with Bordetella pertussis vaccine as supplementary adjuvant. The minimum dose of recombinant protein required to induce biochemical signs of experimental autoimmune myasthenia gravis (EAMG) with 100% incidence was 2.2 micrograms. With 6.6 to 22 micrograms, serum levels of autoantibodies were persistent, and clinically apparent EAMG lasted more than a month. Clinical, electrophysiological, and biochemical indices of EAMG induced by doses of 66 micrograms or more were more uniformly severe and persistent, with 33% fatality. Rats receiving a control extract of E. coli containing plasmid without the alpha 1-210 codon insert, with adjuvants, did not develop autoantibodies or signs of EAMG. This highly reproducible new model of EAMG induced by a recombinant human autoantigen should be valuable for testing Ag-specific immunotherapeutic strategies that might be applicable to treating acquired myasthenia gravis in humans.

    Title Twitch Response in a Myopathy with Impaired Relaxation but No Myotonia.
    Date July 1990
    Journal Muscle & Nerve
    Excerpt

    A patient with slow muscle relaxation but without accompanying motor unit or myotonic electrical activity had a unique staircase twitch response to repeated nerve stimulation. During 1-Hz stimulation, twitches recorded by measurement of the ankle dorsiflexor group displayed progressively increasing relaxation times with successive stimuli (37% increase) unlike the progressively decreasing relaxation time of the normal response (12-37% decrease). The response may be diagnostic of this unusual myopathy; the test methods are noninvasive and easily tolerated.

    Title Autoantibodies Bind Solubilized Calcium Channel-omega-conotoxin Complexes from Small Cell Lung Carcinoma: a Diagnostic Aid for Lambert-eaton Myasthenic Syndrome.
    Date February 1990
    Journal Mayo Clinic Proceedings. Mayo Clinic
    Excerpt

    Serum autoantibodies found by radioimmunoassay in 27 of 52 patients with the Lambert-Eaton myasthenic syndrome (LES) bound specifically to a soluble omega-conotoxin binding component of a voltage-gated Ca2+ channel (VGCC) complex extracted from small cell lung carcinoma (SCC). These antibodies were not found in 43 control patients with other neurologic diseases, including myasthenia gravis, peripheral neuropathies, and amyotrophic lateral sclerosis, or in 9 patients with endocrine autoimmunity, but they were found in 2 of 21 control patients with SCC without a history of LES, 1 of whom had severe autonomic neuropathy. Seropositivity was more frequent in patients with LES who had evidence of a primary lung cancer (76%) than in those with other neoplasms or without evidence of cancer (30%). Antigens extracted from SCC tumor lines derived from patients with and without LES and from a human neuroblastoma line yielded results that were highly correlated. A control extract of colonic carcinoma (derived from a patient with LES) yielded negative results. The data implicate a tumor-associated VGCC as the autoimmunizing stimulus in a subset of patients with LES and provide the first direct evidence that the VGCC complex in SCC is a target for some LES antibodies. The serologic test described should be a useful aid in diagnosing LES.

    Title Longitudinal Study of Neuropathic Deficits and Nerve Conduction Abnormalities in Hereditary Motor and Sensory Neuropathy Type 1.
    Date November 1989
    Journal Neurology
    Excerpt

    We measured neuropathic deficit (neurologic disability score [NDS]) and attributes of nerve conduction in hereditary motor and sensory neuropathy (HMSN 1) in cross-sectional evaluation of 69 patients and in longitudinal evaluation over approximately 15 years in 31 of them. Neuropathic deficit worsened by 0.6 NDS point per year in patients 5 to 14 years old at first evaluation, by 1.1 points in patients 15 to 39 years old, and by 0.9 point in patients 40 or more years old. Neuropathic deficit was greater in HMSN 1b (the disorder linked to Duffy) than in HMSN 1a (not linked to Duffy). Nerve conduction attributes changed significantly depending on attribute studied, age, and nerve. In patients evaluated serially, ulnar conduction velocity (CV) increased by a few meters per second in patients who were 5 to 14 or 15 to 39 years old at first examination, but decreased in patients who were older. In serial measurements, peroneal nerve amplitude decreased in all 3 age groups. We found an association between CV and amplitude or NDS at first and last examinations, suggesting an association between severity of the CV abnormality and neuropathic deficit. The severity of the CV abnormality in the young appears to predict later neurologic abnormality.

    Title Ankle Dorsiflexor Twitch Properties in Malignant Hyperthermia.
    Date May 1989
    Journal Muscle & Nerve
    Excerpt

    A noninvasive method to diagnose malignant hyperthermia (MH) was sought. To this end, in vivo isometric twitch properties of the ankle dorsiflexor muscles were studied in three groups: (1) MH-susceptible patients (n = 12), (2) relatives (n = 12) of MH-susceptible patients who were judged to be MH resistant, and (3) a group of normal volunteers (n = 42) chosen from the community. Twitch properties were studied under resting state conditions and with 1 or 2 Hz stimulation to produce the negative staircase twitch response. There was a high degree of overlap between the ranges of the measured twitch parameters of all groups. Thus, the techniques presented in this study have no value in diagnosing susceptibility to MH. Several physiological features of human isometric twitch properties were demonstrated: (1) slowing of twitch speed with advancing age, (2) strong positive correlation between body weight and twitch torque, and (3) a negative staircase response typical of that described in other mammalian twitch studies.

    Title Selected Igg Rapidly Induces Lambert-eaton Myasthenic Syndrome in Mice: Complement Independence and Emg Abnormalities.
    Date March 1989
    Journal Muscle & Nerve
    Excerpt

    Antibodies in individual patients with the Lambert-Eaton myasthenic syndrome (LES) differ in their reactivity with mouse motor nerve terminals. Of 26 LES patients' sera injected a single time into mice, 3 caused a highly significant reduction in stimulus-dependent quantal release (m) of acetylcholine (ACh) (to 6, 33, and 42 quanta per impulse at 1 Hz, respectively; mean for 10 control sera, 100 quanta at 1 Hz). The most potent serum (LES-A) was fully effective in mice deficient in complement component C5 and in mice depleted of complement components C3----C9 by cobra venom factor. A single i.v. injection of serum reduced m in direct proportion to log dose. Responses to K+ depolarization and increasing concentrations of Ca2+ were like those observed in human LES. With LES-A serum, or its IgG, m was reduced near maximally in 1 day and plateaued in 3-4 days. Recovery began after day 8; m was in the normal range by day 20-30. Electromyographic (EMG) abnormalities were not seen until m fell below 40 quanta per impulse at 1 Hz. Below 10 quanta, clinical signs of weakness appeared, and the EMG abnormalities were those classically associated with LES: a marked reduction of compound muscle action potential to a single nerve stimulus in rested muscle, a further decrement during stimulation at slow rates, but marked facilitation during rapid repetitive stimulation.

    Title Synthetic Peptide of Human Acetylcholine Receptor Alpha-subunit Sequence 125-147 (methionine 144), a More Potent Autoantigen Than Its Norleucine 144 Analog.
    Date February 1989
    Journal Annals of the New York Academy of Sciences
    Title Voltage-dependent Ca2+ Channels in Small Cell Carcinomas Are Blocked by Autoantibodies from Patients with Lambert-eaton Myasthenic Syndrome.
    Date February 1989
    Journal Annals of the New York Academy of Sciences
    Title Assessment of Nerve Regeneration and Adaptation After Median Nerve Reconnection and Digital Neurovascular Flap Transfer.
    Date October 1988
    Journal Neurology
    Excerpt

    Six patients with median nerve severance (five sutured) were studied after an interval of 1.8 to 35 years to assess residual neurologic deficit, misdirected axonal regrowth, and adaptation to faulty reinnervation. Mild motor impairment was confirmed by the smaller thenar muscle action potentials and isometric muscle twitches from supramaximal stimulation of the median nerve. Sensory impairment was supported by the increased thresholds of vibratory (p = 0.003) and touch-pressure (p = 0.004) detection thresholds of the pulp of index fingers and decreased amplitudes of sensory nerve action potentials. A tactile hemidigit localization test revealed that localization was not significantly different from that on the contralateral side but perceptual territory was increased. This increase is best explained by misdirected axon regrowth without CNS adaptation. Long-standing faculty tactile digit localization in neurovascular skin flaps from finger to thumb also was demonstrated--further evidence that CNS adaptation is imperfect when sensory nerves to digits are relocated.

    Title Antagonism of Voltage-gated Calcium Channels in Small Cell Carcinomas of Patients with and Without Lambert-eaton Myasthenic Syndrome by Autoantibodies Omega-conotoxin and Adenosine.
    Date September 1988
    Journal Cancer Research
    Excerpt

    The Lambert-Eaton myasthenic syndrome (LES) is an autoimmune presynaptic disorder of peripheral cholinergic neurotransmission in which there is often an associated small cell lung carcinoma (SCC). SCC lines established from patients with and without LES exhibit a Ca2+ influx response to depolarization by K+ that is consistent with the presence of voltage-gated Ca2+ channels. Autoantibodies antagonistic to SCC Ca2+ channel activity were found exclusively in patients with LES, independent of cancer status. Depolarization-induced uptake of 45Ca2+ by SCC lines was reduced maximally after 3-4 days of exposure to serum immunoglobulins from 14 of 19 LES patients, while 53 control immunoglobulins (including patients with SCC, other tumors, other paraneoplastic syndromes, and other neurological and autoimmune diseases) were without effect. The snail neurotoxin omega-conotoxin of subtype GVIA, which is a specific antagonist of presynaptic Ca2+ channels, inhibited K+-stimulated Ca2+ uptake in a dose-dependent manner that was essentially irreversible. Adenosine, reported to be a specific antagonist of neuronal Ca2+ channels, also impaired voltage-stimulated Ca2+ influx in SCC. Use of LES patients' IgG and omega-conotoxin in further studies of SCC may facilitate identification and purification of the LES antigen(s) and yield a quantitative serological test for diagnosing this autoimmune paraneoplastic syndrome.

    Title Definition of Myasthenogenic Sites of the Human Acetylcholine Receptor Using Synthetic Peptides.
    Date January 1988
    Journal Annals of the New York Academy of Sciences
    Excerpt

    Experimental autoimmune myasthenia gravis (EAMG) and antibodies that modulate AChRs from cultured human muscle are induced by a disulfide-looped peptide comprising the human acetylcholine receptor (AChR) alpha-subunit residues 125-147 (H alpha 125-147). To delineate the essential antigenic requirements for induction of EAMG by this peptide, a series of peptides was synthesized: (a) a nonlooped analog (Cys 128 replaced by Ser) stimulated modulating autoantibodies, induced EAMG, and bound antibodies induced by native AChR; (b) H alpha 131-147, a heptadecylpeptide shorter by 6 N-terminal residues, induced modulating antibodies, EAMG, and T cells that responded to H alpha 125-147, but not to H alpha 137-147; (c) H alpha 137-147, an undecapeptide shorter than H alpha 125-147 by 12 N-terminal residues, did not stimulate T cells or induce antibody production, but it bound antibodies generated by the longer peptides. Thus, when coupled to an epitope that could stimulate helper T cells, the region 137-147 was able to stimulate B cells. This study has defined a myasthenogenic region of the human AChR's alpha-subunit, 17 amino acids long, that contains several distinct epitopes, including at least one N-terminal site inducing T-cell responses (region 131-136) and two possibly overlapping sites that induce antibodies (regions 131-136 and 137-147). Further definition of antigenic sites inducing helper and suppressor T-cell responses and stimulating production of autoantibodies to AChR is essential to the goal of antigen-specific immunotherapy for myasthenia gravis.

    Title Myasthenogenicity of Human Acetylcholine Receptor Synthetic Alpha-subunit Peptide 125-147 Does Not Require Intramolecular Disulfide Cyclization.
    Date November 1987
    Journal Journal of Immunology (baltimore, Md. : 1950)
    Excerpt

    This study reports the synthesis of a disulfide-looped peptide corresponding to residues 125-147 (Cys 128-Cys 142) of the nicotinic acetylcholine receptor (AChR) of human skeletal muscle, H alpha 125-147 (Lys-Ser-Tyr-Cys-Glu-Ile-Ile-Val-Thr-His-Phe-Pro-Phe-Asp-Glu-Gln- Asn-Cys-Ser-Nle-Lys Leu-Gly), and a nondisulfide-looped analogue, H alpha 125-147(S) (Lys-Ser-Tyr-Ser-Glu-Ile-Ile-Val-Thr-His-Phe-Pro-Phe-Asp-Glu- Gln-Asn-Cys-Ser-Nle-Lys-Leu-Gly), in which the amino acid Cys 128 was replaced with serine. Both peptides induced antigen-specific helper T cell responses, as evidenced in vitro by lymph node cell proliferation and in vivo by production of anti-AChR antibodies. Rats immunized with 100 micrograms of either synthetic peptide, without conjugation to a carrier, produced anti-peptide antibodies which bound to native AChR in immunoprecipitation assays and induced modulation of membrane-bound AChR from cultured human myotubes. Both peptides also induced electrophysiologic and biochemical signs of experimental autoimmune myasthenia gravis. Thus, region 125-147 of the AChR alpha-subunit is at least partly exposed extracellularly in human muscle and contains one or more autoantigenic sites capable of stimulating T cells and B cells. Disulfide-linkage between residues Cys 128 and Cys 142 is not essential for myasthenogenicity.

    Title Congenital Myasthenic Syndromes.
    Date November 1987
    Journal Electroencephalography and Clinical Neurophysiology. Supplement
    Title Synaptic Vesicle Abnormality in Familial Infantile Myasthenia.
    Date March 1987
    Journal Neurology
    Excerpt

    In familial infantile myasthenia (FIM) the miniature end-plate potential (MEPP) amplitude is normal in rested muscle, but stimulation in vitro at 10 Hz decreases it abnormally, and neuromuscular transmission fails in a few minutes. In search of a morphologic correlate of the transmission failure, we analyzed the densities and diameters of synaptic vesicles in deep and superficial regions of nerve terminals in external intercostal muscles of three FIM patients and three nonweak controls before and after 10-Hz stimulation for 10 minutes. The densities of superficial or deep synaptic vesicles before or after stimulation in FIM were not significantly different from the corresponding control values. The diameters of superficial and deep synaptic vesicles before stimulation were significantly smaller in the three FIM patients than in the three controls. Stimulation in the FIM patients reduced the MEPP amplitude by 51 to 75%, but increased the vesicle diameter in two patients and did not change the vesicle diameter in one patient. Stimulation in the controls reduced the MEPP amplitude by only 16 to 34%, decreased the vesicle diameter in two, and did not change the vesicle diameter in one. Stimulation after treatment with 1 mg/dl hemicholinium markedly reduced the MEPP amplitude in the controls, had no further effect on the transmission defect in FIM, and had no consistent effect on vesicle diameter in FIM or controls. We conclude that synaptic vesicles are abnormally small in rested muscle in FIM, but vesicle size cannot be reliably correlated with the MEPP amplitude in FIM or controls.

    Title The Exercise Test in Periodic Paralysis.
    Date January 1987
    Journal Muscle & Nerve
    Excerpt

    Of 21 patients with clinically definite hypokalemic, hyperkalemic, or normokalemic periodic paralysis, 15 (71%) had a greater than normal increase in compound muscle action potential amplitude during 2-5 minutes of intermittent strong voluntary contraction of the muscle. This increase was followed by a progressive decline in amplitude, which was greater than in a control population and which was most rapid during the first 20 minutes after exercise. The amplitude often decreased to a level below the preexercise level. A similar response was seen in six of nine patients with periodic paralysis secondary to disorders such as thyrotoxicosis. This test may have value in the identification of patients with periodic paralysis.

    Title Region of Peptide 125-147 of Acetylcholine Receptor Alpha Subunit is Exposed at Neuromuscular Junction and Induces Experimental Autoimmune Myasthenia Gravis, T-cell Immunity, and Modulating Autoantibodies.
    Date February 1986
    Journal Proceedings of the National Academy of Sciences of the United States of America
    Excerpt

    A major antigenic region of native nicotinic acetylcholine receptors (AcChoR) has been identified by using a synthetic disulfide-looped peptide corresponding to alpha-subunit residues 125-147 of Torpedo electric organ AcChoR: Lys-Ser-Tyr-Cys-Glu-Ile-Ile-Val-Thr-His-Phe- Pro-Phe-Asp-Gln-Gln-Asn-Cys-Thr-Met-Lys-Leu-Gly. The peptide bound 26-56% of polyclonal antibodies induced in rat, rabbit, and dog by immunization with native AcChoR. Rats inoculated with 50 micrograms of unconjugated peptide developed helper T-cell responses, delayed hypersensitivity, and antibodies to native AcChoR. Anti-peptide antibodies were more reactive with native than denatured AcChoR and bound to the alpha subunit. Some reacted exclusively with mammalian muscle AcChoR, some induced modulation of AcChoR on cultured myotubes, but none inhibited binding of alpha-bungarotoxin to solubilized or membrane-associated AcChoR. Repeated immunization induced experimental autoimmune myasthenia gravis: clinical signs in one rat and electrophysiologic and/or biochemical signs in 10 of 11 rats. Thus, at least part of the corresponding region of the mammalian AcChoR alpha subunit is extracellular at the neuromuscular junction and a potential target for pathogenic autoantibodies in patients with acquired myasthenia gravis.

    Title Congenital Canine Myasthenia Gravis: I. Deficient Junctional Acetylcholine Receptors.
    Date November 1985
    Journal Muscle & Nerve
    Excerpt

    The neuromuscular junction was studied during growth in two breeds of dog with a congenital familial form of myasthenia gravis (CMG): the Jack Russell terrier and the springer spaniel. Light microscopy revealed no difference in endplate size or nerve terminal morphology in age-matched CMG dogs and unaffected littermates. At all ages there was in individual muscle fibers of CMG dogs an approximately 75% lower postsynaptic membrane density of acetylcholine receptors (AChR). There was no evidence that this abnormality had an autoimmune basis. Measurements of miniature endplate potential amplitude in relation to fiber diameter revealed that the low density of AChR in the postsynaptic membrane of CMG dogs remained constant and did not change with the marked progression of muscle weakness during growth. Antigenic determinants of AChR were deficient in CMG muscle to the same extent as alpha-bungarotoxin (alpha BT) binding sites. Thus, a low density of AChR in the muscle's postsynaptic membrane appears to be the principal abnormality of CMG. The data suggest that the normal increase in number of acetylcholine (ACh) quanta released by nerve impulse may not fully compensate for the reduction in depolarization produced by a single quantum as the muscle fiber diameter increases. This could cause progression of weakness during growth. In addition to being a useful animal model of a rare form of CMG that resembles one form of human CMG, canine CMG offers a unique model for investigating events of synaptogenesis at the neuromuscular junction.

    Title Congenital Canine Myasthenia Gravis: Ii. Acetylcholine Receptor Metabolism.
    Date November 1985
    Journal Muscle & Nerve
    Excerpt

    Acetylcholine receptor (AChR) metabolism was studied in muscle from juvenile and adult dogs with congenital myasthenia gravis (CMG) and their unaffected littermates. Although the amount of AChR in the junctional region of innervated CMG muscle fibers was 25% of normal, or less, denervation of CMG fibers resulted in the appearance of AChR in extrajunctional membranes at as high a concentration as in denervated normal fibers. The rate of degradation of junctional AChR in CMG fibers explanted to organ culture did not differ significantly from normal. In monolayer cultures derived from enzyme-dissociated CMG muscle, myotubes of normal morphology developed, and the synthesis and degradation of AChR did not differ from normal. Addition of sera from dogs with the acquired autoimmune form of MG accelerated the degradation of AChR on cultured myotubes, but CMG dog sera were without effect. These data suggest that the low junctional membrane density of AChR in CMG does not reflect a primary inability of muscle to synthesize AChR, nor an accelerated degradation of AChR in the postsynaptic membrane, but rather a low insertion rate of AChR in the postsynaptic membrane.

    Title Acetylcholine Receptors in Small Cell Carcinomas.
    Date July 1985
    Journal Journal of Neurochemistry
    Excerpt

    The presence of muscarinic and nicotinic acetylcholine receptors (m- and nAChR, respectively) in small cell carcinomas (SCC) of the lung was assessed by measurement of specific binding of (-)[3H]quinuclidinyl benzilate ([3H]QNB) and 125I-alpha-bungarotoxin, respectively. Of five SCC studied, four were originally derived from patients with the Lambert-Eaton myasthenic syndrome, an autoimmune disease of neuromuscular transmission, and one was from a patient without evidence of neurological disease. There was no evidence of nAChR, but all tumors bound (-)[3H]QNB in a saturable and specific manner. Dissociation constants derived from saturation isotherms ranged between 35.4 and 181.7 fmol/mg protein (mean values for the five SCC). Competition studies revealed a pharmacological profile consistent with previous descriptions of mAChR. Competition by pirenzepine revealed only one class of binding sites, that with a relatively low affinity for pirenzepine. In the presence of the guanine nucleotide analogue 5'-guanylyl imidodiphosphate, a decrease in affinity of the mAChR of SCC for oxotremorine was observed, with an increase in the pseudo-Hill coefficient, but there was no change in the binding of atropine. The expression on SCC of mAChR, apparently of the M2 subclass, represents yet another neural differentiation marker of SCC. It is noteworthy that the expression of this marker is not restricted to patients with an autoimmune paraneoplastic syndrome involving cholinergic neurons.

    Title Hereditary Form of Sustained Muscle Activity of Peripheral Nerve Origin Causing Generalized Myokymia and Muscle Stiffness.
    Date May 1984
    Journal Annals of Neurology
    Excerpt

    Six patients in two unrelated families had a hereditary form of sustained muscle activity of peripheral nerve origin. Although varying in severity among affected family members, the disease was manifested clinically as generalized myokymia and muscle stiffness. Motor and sensory nerve conduction velocities and results of nerve biopsy were normal. Repetitive after-discharges followed each motor nerve stimulus. Needle electrode examination demonstrated spontaneous recurrent bursts of motor unit activity. The burst activity of a motor unit occurred rhythmically (0.5 to 4 bursts per second) and independently of the activity of other units. Within a burst, the firing rate was high (150 to 300 Hz). The clinical and electromyographic abnormalities improved considerably after treatment with carbamazepine or phenytoin.

    Title Linkage Evidence for Genetic Heterogeneity Among Kinships with Hereditary Motor and Sensory Neuropathy, Type I.
    Date August 1983
    Journal Mayo Clinic Proceedings. Mayo Clinic
    Excerpt

    Previous reports have shown linkage of hereditary motor and sensory neuropathy, type I (HMSN I), a dominantly inherited hypertrophic neuropathy, to the locus for the Duffy blood group on the long arm of chromosome 1. Two kinships that were extensively studied and reported almost 20 years ago and used to show heterogeneity among kinships with peroneal muscular atrophy and to characterize HMSN I were investigated for linkage to various blood erythrocyte and lymphocyte (HLA) antigens. Strong evidence against linkage to the Duffy blood group locus was found for one kinship, whereas suggestive evidence for linkage was found for the other. These data imply that HMSN I is heterogeneous--that is, caused by different genetic mechanisms. The HMSN I that is not linked to the Duffy locus might be identified as HMSN IA, and the HMSN I that is linked to the Duffy locus might be designated as HMSN IB. HMSN IA was not linked to other blood types or HLA antigens. In addition, no evidence for linkage to blood types and HLA was found for spastic paraplegia with peroneal muscular atrophy and sensory loss (HMSN V).

    Title Not 'indifference to Pain' but Varieties of Hereditary Sensory and Autonomic Neuropathy.
    Date July 1983
    Journal Brain : a Journal of Neurology
    Excerpt

    Three children, from different kinships, with generalized insensitivity to pain, showed unusual manifestations of congenital, presumably inherited, sensory and autonomic neuropathy. The first child appeared to have a syndrome resembling those previously described as congenital indifference to pain, congenital universal loss of pain sensation from infancy without other apparent neurological deficit. Unlike most types of hereditary sensory and autonomic neuropathies (types I, II, III), but like type IV, she had normal sensory nerve action potentials. Abnormalities of sudomotor function and of somatosensory evoked potentials were demonstrated. A severe decrease in the number of sural nerve A delta fibres and a small reduction in C fibres were demonstrated morphometrically. An abnormality of C fibres was confirmed by a marked reduction in nerve dopamine-beta-hydroxylase activity. The plasma and CSF concentrations of beta endorphins, substance P and several other neuropeptides and hormones were normal. Unequivocal evidence of a neuropathic lesion is provided by this patient; her disorder may be identified as the fifth type of hereditary sensory and autonomic neuropathy. The second patient had a congenital pansensory neuropathy and progressive retinitis pigmentosa. Whether the disorder is inherited and, if so, whether the retinitis pigmentosa results from the same or from a second genetic abnormality, is unclear. The third case has, in addition to what is usually seen in hereditary sensory and autonomic neuropathy, type II, an unusually severe kinaesthetic difficulty in oral food handling. The sural nerves of the second and third patients had fibre composition characteristic of hereditary sensory and autonomic neuropathy, type II, few or no myelinated fibres and reduced numbers of unmyelinated fibres.

    Title Autoimmunity in the Lambert-eaton Myasthenic Syndrome.
    Date June 1983
    Journal Muscle & Nerve
    Excerpt

    Sera from 64 patients with the Lambert-Eaton myasthenic syndrome (LES) were tested for evidence of autoimmunity to a variety of tissue antigens. One or more organ-specific autoantibodies (thyroid, gastric, and/or skeletal muscle) were found in 29 patients (45%). Of 46 patients without evidence of tumor, autoantibodies were found in 24 (52%), and of 18 patients with tumor, autoantibodies were found in 5 (28%). In an age-matched group of 40 patients with miscellaneous neurologic diseases, 7 (17%) had one or more organ-specific autoantibodies, and in a control group of 47 patients with myasthenia gravis the combined prevalence of thyroid and gastric antibodies was 47%, comparable to that found in LES patients. The prevalence of non-organ-specific autoantibodies (for example, rheumatoid factor and/or antinuclear antibodies) was not significantly elevated in LES. These data clearly justify consideration of LES without tumor as an organ-specific autoimmune disease. If LES with tumor does prove to have an autoimmune basis, the mechanism may involve an antigen common to cholinergic neurons and oat cell carcinoma, both of which are neuroectoderm derivatives.

    Title Neuromuscular Transmission in Nude Mice Bearing Oat Cell Tumors from Lambert-eaton Myasthenic Syndrome.
    Date June 1983
    Journal Muscle & Nerve
    Excerpt

    Metastatic oat cell tumors from 3 patients with the Lambert-Eaton myasthenic syndrome were successfully transplanted to athymic nude mice, and serially passaged by subcutaneous inoculation. Mice bearing large tumors which maintained the characteristics of each patient's tumor had no evidence of muscle weakness. Intracellular microelectrode studies of end-plate potentials in the diaphragms of the mice revealed no evidence of a defect of neuromuscular transmission.

    Title Congenital Myasthenia Gravis in 13 Smooth Fox Terriers.
    Date June 1983
    Journal Journal of the American Veterinary Medical Association
    Excerpt

    In 13 Smooth Fox Terriers with a congenital form of myasthenia gravis, clinical signs included intermittent, progressive muscle weakness that became more pronounced with exercise; muscle wasting; megaesophagus; and aspiration pneumonia. Neurologic abnormalities were apparent only during periods of weakness and included inability to retract the fore- and hindlimbs from painful stimuli. A decrement of the compound muscle action potential was evident during repetitive supramaximal nerve stimulation. Intravenous injection of a short-acting cholinesterase inhibitor evoked immediate improvement of clinical and electromyographic signs. Intracellular microelectrode studies of a biopsied external intercostal muscle revealed reduced amplitude of miniature end-plate potentials, as occurs in acquired myasthenia gravis. However, in contrast to acquired myasthenia gravis, antibodies directed against acetylcholine receptors were not demonstrable in serum and were not bound to acetylcholine receptors in muscle. Despite lack of complexing with immunoglobulin, the amount of acetylcholine receptor protein in biopsied external intercostal muscles from 9 affected pups was less than 25% of the amount in 5 unaffected littermates. The latter finding accounted for the reduction in amplitude of miniature end-plate potential and the failure of neuromuscular transmission. Treatment with a long-acting cholinesterase inhibitor in 6 cases resulted in temporary improvement in muscle strength.

    Title Acute Panautonomic Neuropathy.
    Date May 1983
    Journal Annals of Neurology
    Excerpt

    Two patients with acute panautonomic neuropathy had severe impairment of sympathetic and parasympathetic function of acute onset. Autonomic tests suggesting a postganglionic lesion and direct evidence of loss of unmyelinated and small myelinated fibers on nerve biopsy were found in Patient 1. There was a selective loss of small myelinated and unmyelinated nerve fibers; C potential was absent in the in vitro compound action potential; dopamine-beta-hydroxylase activity was unmeasurable. No definite abnormalities were found on the nerve biopsy of Patient 2. The acute panautonomic neuropathies appear to comprise a spectrum of somatic and autonomic involvement.

    Title Failure to Induce Malignant Hyperthermia in Myotonic Goats.
    Date March 1983
    Journal British Journal of Anaesthesia
    Excerpt

    Six goats with myotonia congenita were exposed for 1 h to 1% halothane and a single injection of suxamethonium i.v. in an attempt to induce malignant hyperthermia. No evidence of malignant hyperthermia occurred. Suxamethonium did produce a myotonic response in each goat, lasting 10-20s, which was accompanied by a transient increase in aerobic metabolism as indicated by a decrease in PvO2 from 6.6 to 5.7 kPa, an increase in PaCO2 from 5.1 to 6.1 kPa and an increase in PVCO2 from 5.5 to 6.3 kPa. There was no evidence of any metabolic acidosis since the transient changes in pH and buffer base were consistent with the increase in carbon dioxide tension. It is concluded that in goats myotonia congenita does not predispose to susceptibility to malignant hyperthermia.

    Title Myasthenia Gravis in Two Cats.
    Date March 1983
    Journal Journal of the American Veterinary Medical Association
    Excerpt

    A case of the autoimmune form of myasthenia gravis and a case of what is probably a congenital form of myasthenia gravis were diagnosed in 2 unrelated cats. Neuromuscular weakness exacerbated by exercise was a prominent feature in both cats. Weakness was eliminated temporarily by administration of anticholinesterase drugs. Serum autoantibodies to acetylcholine receptors of skeletal muscle were present in the 1st cat and were not detected in the 2nd cat. A characteristic decrement in the amplitude of the compound muscle action potential during repetitive stimulation of the motor nerve was elicited in the 2nd cat. There was marked electromyographic improvement in response to anticholinesterase drugs. Electromyography was not performed in the 1st cat.

    Title End-plate Acetylcholinesterase Deficiency Associated with Small Nerve Terminals and Reduced Acetylcholine Release. A New Syndrome.
    Date February 1983
    Journal International Journal of Neurology
    Title A Newly Recognized Congenital Myasthenic Syndrome Attributed to a Prolonged Open Time of the Acetylcholine-induced Ion Channel.
    Date October 1982
    Journal Annals of Neurology
    Excerpt

    Five familial cases (in two families) and one sporadic case of a new congenital myasthenic syndrome were investigated. Symptoms arise in infancy or later life. Typically, one finds selective involvement of cervical, scapular, and finger extensor muscles, ophthalmoparesis, and variable involvement of other muscles. There is a repetitive muscle action potential to single nerve stimulus in all muscles and a decremental response at 2 to 3 Hz stimulation in clinical affected muscles. Microelectrode studies reveal markedly prolonged end-plate potential (epp), miniature end-plate potential (mepp), and miniature end-plate current; normal quantum content of the epp; and a smaller than normal or low-normal mepp amplitude. Light microscopy demonstrates predominance of type I fibers, small groups of atrophic fibers, tubular aggregates and vacuoles near end-plates, abnormal end-plate configuration, and nonspecific myopathic changes. Abundant acetylcholinesterase activity is present at all end-plates, and the activity and kinetic properties of this enzyme in muscle are normal. Calcium accumulated at the end-plate in one patient. Quantitative electron microscopy shows decrease in the size of nerve terminals, increase in the density of synaptic vesicles, and reduction in the length of postsynaptic membranes. There is focal degeneration of junctional folds with corresponding loss of acetylcholine receptor, most marked in cases with the lowest mepp amplitude. There are no immune complexes at the end-plate. Fiber regions near end-plates display dilation, proliferation, and degeneration of the sarcoplasmic reticulum; nuclear, mitochondrial, and myofibrillar degeneration; and vacuoles resembling those found in periodic paralysis. A prolonged open time of the acetylcholine-induced ion channel is considered to be the basic abnormality and may account for the physiological, morphological, and clinical alterations.

    Title Prednisone-responsive Hereditary Motor and Sensory Neuropathy.
    Date June 1982
    Journal Mayo Clinic Proceedings. Mayo Clinic
    Excerpt

    Neurologic improvement with use of prednisone, in some cases on several occasions, was demonstrated in seven patients who had a chronic progressive polyradiculoneuropathy with nerve conduction velocity and electromyographic findings consistent with segmental demyelination and axonal degeneration and increases protein concentration in the cerebrospinal fluid. These patients seemed to have the progressive form of chronic inflammatory-demyelinating polyradiculoneuropathy and, in addition, had clinical features of hereditary motor and sensory neuropathy including pes cavus and hammer toes. On systematic examination, bony abnormalities or asymptomatic neuropathy typical of subclinical inherited neuropathy was discovered among their kin. There patients might therefore be identified as having inflammatory-demyelinating hereditary motor and sensory neuropathy. These cases may represent a chance association of chronic inflammatory-demyelinating polyradiculoneuropathy and hereditary motor and sensory neuropathy, a causally linked association of these disorders, or a prednisone-responsive inherited neuropathy only. We wish to draw attention to this treatable neuropathy and to raise the question of whether environmental factors play role in the expression of dominantly inherited mutant genes.

    Title Monoclonal Autoantibodies to Acetylcholine Receptors: Evidence for a Dominant Idiotype and Requirement of Complement for Pathogenicity.
    Date June 1982
    Journal Annals of the New York Academy of Sciences
    Excerpt

    An antigenic determinant of mammalian muscle acetylcholine receptors (AChR) remote from the ACh-binding site and exposed extracellularly at the neuromuscular junction has been defined by monoclonal autoantibodies (McAb's). The determinant is a dominant antigen in the rat's autoimmune response to AChR. It was defined by four IgG McAb's (from two individual donor rats) which shared a common idiotype (Id) complementary to the AChR determinant. These four McAb's bound to AChR in vivo and induced experimental autoimmune myasthenia gravis (EAMG). They also bound to nonjunctional AChR on living myotubes in culture at 37 degrees and caused loss of alpha-bungarotoxin (alpha-BT) binding sites. The McAb's did not inhibit binding of alpha-BT to solubilized AChR or to nonjunctional AChR in membranes of muscle cells held at 4 degrees C. Impairment of neuromuscular transmission by the McAb's required activation of complement via the classical pathway. In the absence of C3 leads to C9, or in isolated deficiency of C4, binding of McAb's to at least 62% of AChR for 72 hours in vivo did not alter miniature endplate potentials (MEPPs) or EPPs or reduce the muscle's content of AChR. The common Id was detectable in sera of rats immunized with AChR of either Torpedo, eel or syngeneic muscle. Anti-Id antibodies raised against 3 of the McAb's inhibited in vitro binding of each of the 4 McAb's to AChR; absorption of one anti-Id by a second McAb removed inhibitory activity for all McAb's. However, when rats with high titers of anti-Id were challenged by immunization with torpedo AChR, the severity of EAMG was undiminished despite a continuing excess of anti-Id antibodies. Success of the anti-Id approach to therapy of myasthenia gravis may require definition of several antigenic determinants of human muscle AChR with which patients' auto-antibodies interact in vivo.

    Title Recently Recognized Congenital Myasthenic Syndromes: (a) End-plate Acetylcholine (ach) Esterase Deficiency (b) Putative Abnormality of the Ach Induced Ion Channel (c) Putative Defect of Ach Resynthesis or Mobilization - Clinical Features, Ultrastructure and Cytochemistry.
    Date June 1982
    Journal Annals of the New York Academy of Sciences
    Title Genetic Control of Autoimmunity to Acetylcholine Receptors: Role of Ia Molecules.
    Date June 1982
    Journal Annals of the New York Academy of Sciences
    Excerpt

    Evidence that human susceptibility to myasthenia gravis (MG) might be determined genetically is suggested by clinical surveys showing an association of MG with an increased frequency of certain histocompatibility antigens. We have studied the experimental autoimmune model of MG in mice to investigate whether or not major histocompatibility complex (MHC) gene products play a role in determining susceptibility to EAMG. When MHC congenic and recombinant strains of mice were inoculated with Torpedo acetylcholine receptor (AChR) and adjuvants, the magnitude of autoantibody responses to muscle AChR and of the defect of neuromuscular transmission (i.e., reduction in MEPP amplitude) closely paralleled in vitro lymphocyte proliferative responses to torpedo AChR. Reduction in MEPP amplitude correlated strikingly with the degree to which autologous muscle AChR was complexed with antibody. Lymphocyte responses to Torpedo AChR, antibody responses to mouse muscle AChR, and susceptibility to EAMG are controlled by gene(s) at the I-A subregion of the H-2 complex. Backcross studies confirmed that lymphocyte proliferative responses to AChR are controlled by a Mendelian dominant gene linked to H-2, probably at the I-A subregion. Mutation at the I-A subregion in the B6 strain, which resulted in structural alteration of the Ia molecule, converted high responsiveness to low responsiveness. Lymphocyte responses were eliminated by blocking Ia antigens on lymph node cell surfaces with specific anti-I-A alloantisera. Cellular immune responses to AChR are dependent on Lyt 1+23- cells and adherent cells. These data implicate a macrophage-associated Ia molecular in induction of autoimmune responses to AChR, probably in the presentation of AChR to helper (Lyt 1+23-) T-lymphocytes, which thereby help B-lymphocytes to differentiate into anti-AChR antibody forming cells.

    Title Clinical and Electrophysiological Characteristics of the Experimental Neuropathy Caused by P-bromophenylacetylurea.
    Date May 1982
    Journal Experimental Neurology
    Title Intensive Evaluation of Referred Unclassified Neuropathies Yields Improved Diagnosis.
    Date December 1981
    Journal Annals of Neurology
    Excerpt

    Intensive evaluation of 205 cases of undiagnosed neuropathy in a center with special approaches and facilities permitted classification of 76% of the patients. Inherited disorders accounted for 42% of the series, 21% of the patients were shown to have inflammatory-demyelinating polyradiculoneuropathy, and 13% had neuropathies associated with other disorders. A considerable improvement in diagnosis was possible from evaluation of the kin of the patients with undiagnosed neuropathy. Analysis of the frequency and type of various sensory symptoms also was helpful in distinguishing between acquired and inherited neuropathies.

    Title Multisystem Neuronal Degeneration, Hepatosplenomegaly, and Adrenocortical Deficiency Associated with Reduced Tissue Arachidonic Acid.
    Date October 1981
    Journal Neurology
    Title Acute Hyperosmolar Hyperglycemia Causes Axonal Shrinkage and Reduced Nerve Conduction Velocity.
    Date April 1981
    Journal Experimental Neurology
    Title Structural and Biochemical Effects of Essential Fatty Acid Deficiency on Peripheral Nerve.
    Date March 1981
    Journal Journal of Neuropathology and Experimental Neurology
    Excerpt

    The effect of postweaning essential fatty acid (EFA) deficiency on the peripheral nerve was studied in groups of rats. At 325 days, the characteristic biochemical changes of EFA deficiency were present in isolated peripheral myelin, although to a lesser degree than reported in non-neural tissues. There was no significant difference between control and deficient groups in number or size distributions of myelinated fibers (MFs) in muscle and sensory nerves, in the incidence of teased fiber abnormalities, in rates of axonal transport of dopamine-beta-hydroxylase and acetylcholinesterase, or in conduction velocity and compound action potentials of peripheral nerve in vivo or in vitro. Four weeks after a standard sciatic crush injury, the median MF diameter in regenerated peroneal nerves was significantly smaller in EFA-deficient rats than in control rats, but this difference was no longer significant at 18 weeks. At 18 weeks, EFA-deficient and control regenerated nerves showed similar myelin periodicity and relationship of axonal area to number of myelin lamellae. We conclude that acquired EFA deficiency in the rat leads to biochemically abnormal peripheral myelin, but that this state is unaccompanied by clinical, physiological, or morphological evidence of neuropathy.

    Title Interstitial Hyperosmolarity May Cause Axis Cylinder Shrinkage in Streptozotocin Diabetic Nerve.
    Date March 1981
    Journal Journal of Neuropathology and Experimental Neurology
    Excerpt

    Maximal conduction velocity values of nerves of diabetic rats 20 weeks after streptozotocin intoxication were found to be intermediate between those of onset-control and those of end-control groups. The abnormality of conduction velocity of the streptozotocin group might therefore be attributed to a failure of maturation. Detailed electron microscopic morphometry of myelinated fibers (MFs) indicates that more than lack of maturation is involved. Whereas the number of lamellae and the perimeter of axis cylinders of myelinated fibers of the three study groups suggested that growth continues, cross-sectional area of the axis cylinders of the streptozotocin group was smaller than those of either control group. Scored evaluation of fiber shape and the measured index of circularity, which related perimeter and transverse axis cylinder area, also indicated that a selective shrinkage of axis cylinders had occurred. This selective alteration in size and shape of axis cylinders is identical to that described after hyperosmolar fixation. Compared with that of controls, the serum of streptozotocin rats is hyperosmolar. It would seem reasonable to attribute the axis cylinder changes to shrinkage. Whether an additional maturational effect is operative as well cannot be resolved from our data.

    Title Multiple Endocrine Neoplasia, Type 2b: Phenotype Recognition; Neurological Features and Their Pathological Basis.
    Date March 1981
    Journal Annals of Neurology
    Excerpt

    Sixteen patients affected with multiple endocrine neoplasia, type 2b (MEN 2b), were evaluated by clinical, neurological, nerve conduction and electromyographic, and postmortem examinations. Eight of the 11 patients examined clinically had symptoms: 5, neurogenic constipation; 1, failing vision due to hypertrophied corneal nerves; 1, neuromuscular symptoms and pes cavus; and 1, facial disfigurement. Expression of the dominantly inherited MEN 2b gene is more variable than previously known. When neuromuscular findings are present alone, the features may be those of peroneal muscular atrophy. Because 10 of the 11 patients had sufficiently full expression of the dominantly inherited gene--"Marfanlike" body build, full and fleshy lips, whitish yellow nodules (neuromas) on the tip and edges of the tongue, pes cavus, or peroneal muscular atrophy--the presence of MEN 2b was recognized and a search for the usually associated medullary thyroid carcinoma was instigated. In addition to the recognized involvement of autonomic nerves, we have confirmed that somatic motor and senory neurons may be involved. Findings at postmortem evaluation indicate that symptoms can be attributed to neuroma formation: a characteristic adventitious plaque of tissue composed of hyperplastic, interlacing bands of Schwann cells and myelinated fibers overlay the posterior columns of the spinal cord.

    Title Investigations of 3 Cases of a Newly Recognized Familial, Congenital Myasthenic Syndrome.
    Date February 1981
    Journal Transactions of the American Neurological Association
    Title Nitrous Oxide Neurotoxicity Studies in Man and Rat.
    Date December 1980
    Journal Anesthesiology
    Excerpt

    To assess the effects of chronic exposure to low levels of nitrous oxide on neural function of man, the authors evaluated the neurologic condition, motor and sensory nerve conduction, and computerized tests of sensation of approximately half of the dentists in Rochester, Minnesota. Results of scored tests of neural function were not significantly different for dentists who used nitrous oxide extensively in their practices and dentists who did not. To assess the effects of chronic exposure to high levels of nitrous oxide on neural function and structure of experimental animals, groups of rats were exposed to 70 per cent N2O in 30 per cent oxygen for four hours, five days a week, for six months. Rats exposed to N2O and control rats showed no difference in well-being, in caudal nerve conduction, in axonal content and transport of acetylcholinesterase and dopamine-beta-hydroxylase, or in number and size distribution and pathologic abnormality of teased myelinated fibers. Although these results indicate a lack of peripheral nerve neurotoxicity of N2O in the rat, one cannot assume a similar lack of neurotoxicity in man with heavy exposures.

    Title Myasthenia Gravis Induced by Monoclonal Antibodies to Acetylcholine Receptors.
    Date July 1980
    Journal Nature
    Title Ultrastructural Localization of the Terminal and Lytic Ninth Complement Component (c9) at the Motor End-plate in Myasthenia Gravis.
    Date July 1980
    Journal Journal of Neuropathology and Experimental Neurology
    Excerpt

    The terminal and lytic complement component (C9) was localized at the motor end-plate in acquired autoimmune myasthenia gravis (MG) by the immunoperoxidase method, with adequate preservation of fine structure and negligible background staining. C9 was localized on short segments of the postsynaptic membrane on degenerated fragments of the junctional folds shed into the synaptic space, and on disintegrating junctional folds. An inverse relationship was noted between the structural integrity of the junctional folds and the abundance of C9 at a given end-plate region. Destruction of junctional folds by complement may induce relocation of the nerve terminal and increased spatial separation of end-plate regions on the muscle fiber. Destruction of junctional folds by the complement membrane attack complex is a cause of the acetylcholine receptor deficiency at the MG end-plate, but antibody-dependent modulation of the receptor may also contribute to deficiency of the receptor. In certain disorders other than autoimmune MG, pathological mechanisms other than complement-mediated lysis may affect the structural integrity of the postsynaptic region.

    Title Comparison of Symptoms, Chemistry, and Nerve Function to Assess Hemodialysis Adequacy.
    Date December 1979
    Journal Proceedings of the Clinical Dialysis and Transplant Forum
    Title Comparison of Symptoms, Chemistry, and Nerve Function to Assess Adequacy of Hemodialysis.
    Date November 1979
    Journal Neurology
    Title Structure-function Correlations in Myasthenia Gravis and a New Myasthenic Syndrome.
    Date July 1979
    Journal Electroencephalography and Clinical Neurophysiology. Supplement
    Excerpt

    The physiologic hallmark of MG is the small amplitude of the mepp. This can be correlated with a deficiency of postsynaptic AChR. The AChR deficiency is caused by antiAChR antibodies. Antibody dependent, complement mediated lysis of the postsynaptic membrane contributes significantly to the AChR deficiency. The abundance of immune complexes localized at the end-plate correlates with the amount of AChR remaining at the end-plate and with the mepp amplitude. The physiologic hallmarks of the new myasthenic syndrome are a small quantum content of the end-plate potential due to a decreased store of immediately releasable quanta, repetitive response of the muscle to a single nerve stimulus and refractoriness to anticholinesterase drugs. The findings are explained by a marked decrease of the size of the nerve terminal and by the total absence of AChE from the end-plate.

    Title Passively Transferred Experimental Autoimmune Myasthenia Gravis. Sequential and Quantitative Study of the Motor End-plate Fine Structure and Ultrastructural Localization of Immune Complexes (igg and C3), and of the Acetylcholine Receptor.
    Date June 1979
    Journal Neurology
    Excerpt

    Experimental autoimmune myasthenia gravis (EAMG) was passively transferred with immunoglobulin from rats with chronic EAMG to normal recipients. IgG and C3 were localized on terminal expansions of junctional folds of end-plates by 6 hours. Segments of folds rich in acetylcholine receptor (AChR) and coated with IgG and C3 were shed into the synaptic space by 24 hours, resulting in AChR deficiency of the postsynaptic membrane. Many sensitized postsynaptic regions were destroyed by macrophages by day 2, but effective nerve-muscle contacts were reestablished by day 5. On day 10, end-plates were still structurally abnormal and showed AChR deficiency, but the animals were clinically recovered. On day 54, postsynaptic regions were still reduced in size, with slight reduction of postsynaptic AChR. Throughout the study, the miniature end-plate potential amplitude tended to vary directly with morphometric estimates of the abundance of the postsynaptic membrane reacting for AChR. Complement-mediated injury to the junctional folds and opsonization of the postsynaptic region can explain the morphologic changes. It is not yet known why phagocytic invasion of the end-plate occurs in acute EAMG and in passively transferred EAMG induced by chronic EAMG immuglobulin, but not in chronic EAMG and only rarely in the human disease.

    Title A New Myasthenic Syndrome with End-plate Acetylcholinesterase Deficiency, Small Nerve Terminals, and Reduced Acetylcholine Release.
    Date January 1979
    Journal Annals of Neurology
    Excerpt

    A new myasthenic syndrome is described in a patient whose symptoms began soon after birth and included generalized weakness increased by exertion, easy fatigability, hyporeflexia, and refractoriness to anticholinesterase drugs. Electromyography showed a decremental response at all frequencies of stimulation and a repetitive response to single nerve stimulation. Miniature end-plate potentials (mepps) were of normal amplitude but of decreased frequency. The mepp duration and half-decay time were prolonged, and prostigmine was without any addtitional effect. The quantum content of the end-plate potential was decreased due to a reduced store of quanta immediately available for release, but the probability of release was normal. Quantitative electron microscopy demonstrated a 3-fold to 4-fold decrease of nerve terminal size and reduced postsynaptic membrane density. The postsynaptic folds showed focal degeneration, and many were distended by labyrinthine membranous networks that communicated with the synaptic space. Degenerating nuclei were found in the junctional sarcoplasm. The ultrastructural localization of the acetylcholine receptor protein was normal. Acetylcholinesterase (AChE) was absent from the motor end-plates by histochemical and electron cytochemical criteria. Biochemical studies indicated total absence of the end-plate-specific 16 S species of AChE and marked decrease in total muscle AChE. A congenital defect in the molecular assembly of AChE or in its attachment to the postsynaptic membrane might represent the basic abnormality and condition the morphological and physiological alterations.

    Title Acetylcholine Release in Diaphragm of Rats with Chronic Experimental Autoimmune Myasthenia Gravis.
    Date December 1978
    Journal Annals of Neurology
    Excerpt

    Recent evidence indicates that in chronic experimental autoimmune myasthenia gravis (EAMG) and in human myasthenia gravis, the defect of neuromuscular transmission results from immune-mediated destruction of post-synaptic membrane at the neuromuscular junction, with a reduction in the density of acetylcholine (ACh) receptors and decreased sensitivity to ACh released by nerve impulses. In the present study, the amount of ACh released by nerve impulse in rats with chronic EAMG and control rats of the same age, weight, and sex was compared. Phrenic nerve-hemidiaphragm preparations were stimulated in vitro, and the amount of ACh released was measured by bioassay. Despite a marked reduction in the amplitude of miniature end-plate potentials in chronic EAMG, ACh output at rest and during stimulation was not different from that of control rats. These data support the concept that the defect of neuromuscular transmission is due to a reduction of postsynaptic sensitivity to ACh.

    Title Ultrastructural Localization of Immune Complexes (igg and C3) at the End-plate in Experimental Autoimmune Myasthenia Gravis.
    Date May 1978
    Journal Journal of Neuropathology and Experimental Neurology
    Excerpt

    Rats immunized with purified torpedo acetylcholine receptor (AChR) plus adjuvants developed chronic experimental autoimmune myasthenia gravis (EAMG) after day 28. Forelimb muscles from EAMG rats 29 to 103 days after immunization and from control animals were used for the ultrastructural localization of IgG and C3. IgG was demonstrated with rabbit anti-rat IgG followed by treatment with peroxidase-labeled staphylococcal protein A; and C3 with peroxidase-labeled rabbit anti-rat C3, or with unlabeled rabbit anti-rat C3 followed by peroxidase-labeled protein A. In EAMG rats both IgG and C3 were localized on the terminal expansions of the junctional folds, where AChR is known to be located, and on detached, degenerated parts of the folds in the synaptic space. Background staining was negligible. The findings provide unambiguous evidence for a destructive autoimmune reaction involving the postsynaptic membrane in EAMG, implicate the complement system in this reaction and show that detachment of the tips of the junctional folds is one way by which immune complexes, and AChR, are eliminated from the postsynaptic membrane. The immuno-electron microscopic findings in chronic EAMG closely resemble those described in human myasthenia gravis.

    Title Content of Acetylcholine Receptor and Antibodies Bound to Receptor in Myasthenia Gravis, Experimental Autoimmune Myasthenia Gravis, and Eaton-lambert Syndrome.
    Date March 1978
    Journal Neurology
    Title Sensory Nerve Conduction Velocity in Children Using Cerebral Evoked Potentials.
    Date February 1978
    Journal Archives of Physical Medicine and Rehabilitation
    Excerpt

    Sensory nerve conduction velocity was measured in 16 healthy volunteers from 3 to 16 years of age by using evoked cortical potentials. Using the latencies to the peaks of the 2nd and 3rd components (N1 and P2) of the average evoked response, conduction velocities for the wrist-to-elbow segment of the median nerve were found to have a range of 58 to 74 meters/second (m/s). Mean values using N1 and P2 were not significantly different. Conduction velocities in the same children obtained by stimulation of the median nerve at the elbow and wrist while recording the digital nerve action potential from the index finger had a range of 58 to 70 m/s. Mean values determined using cortical and digital potentials were not significantly different. In individual subjects, values obtained with the two techniques differed by 0 to 9 m/s using the N1 peak and 0 to 11 m/s using the P2 peak of the of the cortical potential. Reliable conduction velocity measurements for sensory nerves can be obtained in children using evoked cortical potentials with relatively simple methods. This technique has been successful when conventional methods did not detect peripheral sensory responses.

    Title Computerized Image Recognition for Morphometry of Nerve Attribute of Shape of Sampled Transverse Sections of Myelinated Fibers Which Best Estimates Their Average Diameter.
    Date December 1977
    Journal Journal of the Neurological Sciences
    Excerpt

    A computerized image recognition method was used to measure various attributes of shape of cross-sections of myelinated nerve fibers. Measurements were made at intervals over 1/2 internode of each fiber on 20 fibers from each of 4 sural nerves from rats. Diameters were computed in 6 different ways from the computer measurements and compared for bias, precision, and accuracy between sections and to the diameter of an idealized cylinder reconstructed for each fiber from multiple actual cross sections. The diameter computed from cross-sectional areas of transversely sectioned myelinated fibers, converted into a circle, showed the highest precision, greatest accuracy and least bias. Fibers were classified by shape and the frequency was determined in defined regions (I1 = paranodal, I3= nuclear and I2=region between I1 and I3) of the 1/2 internode. A crenated shape is highly characteristic of the I1 region. The boomerang shape was found most frequently in I3 whereas the circular shape was found most frequently in I2. Epileptical and boomerang shapes of myelinated fibers within fascicles which have been orientated carefully to obtain transverse sections, are not due to obliquity of section. Therefore, using the minor axis to determine the diameter of such profiles, as we had done previously in our laboratory, is in error. We conclude from these studies, that in carefully orientated transverse sections of nerve trucks, the diameter calculated from measurement of area converted to a circular shape is the best among the various estimates of myelinated fiber diameter and is the most suitable one for use in computerized image recognition systems for nerve morphometry. It seems reasonable to extrapolate this general conclusion to myelinated fibers of man.

    Title Duchenne Dystrophy: Ultrastructural Localization of the Acetylcholine Receptor and Intracellular Microelectrode Studies of Neuromuscular Transmission.
    Date September 1977
    Journal Neurology
    Excerpt

    Despite focal degeneration and simplification of the postsynaptic region in Duchenne dystrophy, the postsynaptic acetylcholine receptor (AChR) is preserved. This is in contrast to myasthenia gravis where similar postsynaptic alterations are invariably associated with a marked decrease in AChR. There is no extrajunctional spread of AChR in Duchenne dystrophy. The amplitude and frequency of miniature end-plate potentials and the number of transmitter quanta released by nerve impulse are normal but the resting membrane potential is lower than normal. The findings indicate that the release and the postsynaptic responsiveness to acetylcholine are intact in Duchenne dystrophy.

    Title A New Myasthenic Syndrome with End-plate Acetyl Cholinesterase (ache) Deficiency, Small Nerve Terminals, and Reduced Acetylcholine Release.
    Date August 1977
    Journal Transactions of the American Neurological Association
    Title Lead Neuropathy. 1) Morphometry, Nerve Conduction, and Choline Acetyltransferase Transport: New Finding of Endoneurial Edema Associated with Segmental Demyelination.
    Date June 1977
    Journal Journal of Neuropathology and Experimental Neurology
    Excerpt

    Morphometric and pathologic studies along the length of the peripheral nervous system were obtained in groups of rats fed 4% lead carbonate for 3 and 6 months and in match-fed controls. The number and diameter histograms of L6 cytons of spinal ganglia and of myelinated fibers of proximal and distal portions of peroneal and sural nerve were not significantly different from the control groups. On the other hand, segmental demyelination occurred approximately as frequently in proximal as in distal parts of nerves. At 3 months approximately 1/3 of teased myelinated fibers showed changes of segmental demyelination (Condition C), or of remyelination after segmental demyelination (Condition F) or of both segmental demyelination and of remyelination (Condition D), while at 6 months more than 4/5ths of fibers showed these changes. As expected, regression lines of axonal area on number of lamellae of myelin, were less steep in nerves of rats fed on lead for 6 months as compared to controls. Axonal transport of choline acetyltransferase in lead neuropathy did not differ from that in control rats. As expected from the studies of others, conduction velocity of myelinated fibers of caudal nerve were low. A new finding was the often quite striking increase of transverse fascicular area of peripheral nerves. This was due to edema which appeared to develop at about the time of onset os segmental demyelination. Although the edema may be an epiphenomenon, it could be an important observation bearing on the development of lead neuropathy. It would be important to know next whether or not the blood nerve barrier is altered in lead neuropathy.

    Title Immune Complexes (igg and C3) at the Motor End-plate in Myasthenia Gravis: Ultrastructural and Light Microscopic Localization and Electrophysiologic Correlations.
    Date June 1977
    Journal Mayo Clinic Proceedings. Mayo Clinic
    Excerpt

    Although there is strong evidence that myasthenia gravis (MG) is caused by an autoimmune reaction to the nicotinic postsynaptic acetylcholine receptor (AChR) protein, immune complexes have never been directly demonstrated at the end-plate by immunocyto-chemistry or immunoelectron microscopy. Staphylococcal protein A (which binds to the Fc region of human IgG subclasses 1, 2, and 4) and rabbit anti-human C3 conjugated with peroxidase were used for the ultrastructural (5 patients) and light microscopic (12 patients) localization of IgG and C3, respectively, at MG end-plates. Both IgG and C3 were localized on segments of the postsynaptic membrance and fragments of degenerating junctional folds in the synaptic space. In nonmyasthenic control patients no immune complexes were evident at the end-plate. As judged by morphometric analysis of electron micrographs, the immune complexes were more abundant in the less severely affected MG patients than in the more severely affected ones. A linear correlation was demonstrated between the length of the postsynaptic membrance binding immune complexes and the amplitude of the miniature end-plate potential. The less intense reaction for immune complexes in the more severely affected MG patients can be attributed to the smaller quantity of AChR remaining at their end-plates. The findings provide unambiguous evidence for a destructive auto-immune reaction involving the postsynaptic membrance in MG. Immunopharmacologic blockade of AChR and IgG-induced modulation of AChR may also contribute to the AChR deficiency at the MG end-plates.

    Title Ultrastructural Localization of the Acetylcholine Receptor in Myasthenia Gravis and in Its Experimental Autoimmune Model.
    Date May 1977
    Journal Neurology
    Excerpt

    Peroxidase-conjugated alpha-bungarotoxin (P-BGT) was used for the ultrastructural localization of the acetylcholine receptor in end-plates in external intercostal muscles of four patients with myasthenia gravis, in forelimb digit extensor muscles of rats with advanced chronic experimental autoimmune myasthenia gravis, and in suitable human and rat controls. In control end-plates, the previously reported localization of acetylcholine receptor on the terminal expansions of the postsynaptic folds and, in traces, on the presynaptic membrane was confirmed. By contrast, in myasthenia gravis some postsynaptic regions bound no P-BGT; in other regions, the folds displayed only faint traces of the reaction product, or only some segments of the postsynaptic membrane showed the reaction product; finally, in some regions there was no apparent decrease in reaction product. In general, those postsynaptic regions showing the greatest decrease in P-BGT binding were also the simplest or showed the most degenerative changes, and the presynaptic staining was decreased in proportion to the decrease in the adjacent postsynaptic P-BGT binding. In the experimental animals, the abnormalities in the amount and distribution of the acetylcholine receptor were essentially like those in the more severely affected patients. Morphometric estimates of the postsynaptic acetylcholine receptor surface correlated well with the patients' clinical status and linearly with the miniature end-plate potential amplitude.

    Title Experimental Autoimmune Myasthenia Gravis: a Sequential and Quantitative Study of the Neuromuscular Junction Ultrastructure and Electrophysiologic Correlations.
    Date October 1976
    Journal Journal of Neuropathology and Experimental Neurology
    Excerpt

    Neuromuscular junction ultrastructure in rat forelimb digit extensor muscle was sequentially and quantitatively investigated in experimental autoimmune myasthenia gravis (EAMG). Experimental animals were immunized with highly purified eel electroplax acetylcholine receptor protein plus complete Freund's adjuvant and B pertussis vaccine; control animals received only adjuvant and vaccine. During the first 7 days (latent period) after immunization end-plate structure and neuromuscular transmission remained normal in the experimental group. Between day 7 and 11 (acute phase) mononuclear cells infiltrated those regions of muscle where the end-plates were located and there was intense degeneration of the postsynaptic regions with splitting away of abnormal junctional folds from the underlying muscle fibers. Macrophages entered the gaps thus formed and removed the degenerating folds by phagocytosis. The nerve terminals were displaced from their usual location but maintained their structural integrity. Neuromuscular transmission was blocked in many muscle fibers. Miniature end-plate potentias (MEPPs), detectable in only a few fibers, were of abnormally low amplitude. After day 11 (chronic phase) the nerve terminals returned to the highly simplified postsynaptic folds became reconstituted and again degenerated. Immature junctions with poorly differentiated postsynaptic regions and nerve sprouts near end-plates were also observed. In two animals relapsing during the chronic phase degeneration of the postsynaptic folds was more intense than in the other chronic-phase animals. The posysynaptic membrane length and length per unit area and the MEPP amplitudes were significantly decreased in all chronic phase animals and the decreases were greater in the relapsing than in the non-lapsing animals. Minor morphometric alterations were also observed in the nerve terminals. These might have been secondary to the postsynaptic changes. The postsynaptic region is the primary target of the autoimmune reaction in EAMG. The ultrastructural, morphometric and electrophysiological abnormalities of the end-plate in chronic EAMG resemble those which have been observed in human myasthenia gravis.

    Title Pathological Mechanisms in Experimental Autoimmune Myasthenia Gravis. Ii. Passive Transfer of Experimental Autoimmune Myasthenia Gravis in Rats with Anti-acetylcholine Recepotr Antibodies.
    Date October 1976
    Journal The Journal of Experimental Medicine
    Excerpt

    Passive transfer of experimental autoimmune myasthenia gravis (EAMG) was achieved using the gamma globulin fraction and purified IgG from sera of rats immunized with Electrophus electricus (eel) acetylcholine receptor (AChR). This demonstrates the critical role of anti-AChR antibodies in impairing neuromuscular transmission in EAMG. Passive transfer of anti-AChR antibodies from rats with chronic EAMG induced signs of the acute phase of EAMG in normal recipient rats, including invasion of the motor end-plate region by mononuclear inflammatory cells. Clinical, eletrophysiological, histological, and biochemical signs of acute EAMG were observed by 24 h after antibody transfer. Recipient rats developed profound weakness and fatigability, and the posture characteristic of EAMG. Striking weight loss was attributable to dehydration. Recipient rats showed large decreases in amplitude of muscle responses to motor nerve stimulation, and repetitive nerve stimulation induced characteristic decrementing responses. End-plate potentials were not detectable in many muscle fibers, and the amplitudes of miniature end-plate potentials were reduced in the others. Passively transferred EAMG more severely affected the forearm muscles than diaphragm muscles, though neuromuscular transmission was impaired and curare sensitivity was increased in both muscles. Some AChR extracted from the muscles of rats with passively transferred EAMG was found to be complexed with antibody, and the total yield of AChR per rat was decreased. The quantitative decrease in AChR approximately paralleled in time the course of clinical and electrophysiological signs. The amount of AChR increased to normal levels and beyond at the time neuromuscular transmission was improving. The excess of AChR extractable from muscle as the serum antibody level decreased probably represented extrajunctional receptors formed in response to functional denervation caused by phagocytosis of the postsynaptic membrane by macrophages. The amount of antibody required to passively transfer EAMG was less than required to bind all AChR molecules in a rat's musculature. The effectiveness of samll amounts of antibody was probably amplified by the activation of complement and by the destruction of large areas of postsynaptic membrane by phagocytic cells. A self-sustaining autoimmune response to AChR was not provoked in animals with passively transferred EAMG.

    Title Alternate-day Prednisone: Preliminary Report of a Double-blind Controlled Study.
    Date October 1976
    Journal Annals of the New York Academy of Sciences
    Excerpt

    Thirteen patients with moderately severe myasthenia gravis participated in a double-blind study using either 100 mg of prednisone or an equivalen numbder of placebo tablets on alternate days. Anticholinesterase therapy was continued on a demand basis. At the end of 6 months the code was broken. Seven patients were on placebo and three of these had improved to such a degree that steroid therapy was not indicated. Four of these patients ultimately were started on prednisone and improved. Of the six patients on prednisone, three showed no improvement and three were improved. At the end of 2 years, the seven patients still taking prednisone were on maintenance dosage of this drug. Three of this group had experienced relapses when the dosage was cut to 15 to 25 mg on alternate days, and they again improved when the prednisone dosage was increased. No statistical evaluation is possible because of the small number of patients. It can be stated that seven patients improved with steroid therapy. Conversely, not all patients treated with alternate-day prednisone improved. Finally, any evaluation of treatment of myasthenia gravis must take into consideration the potential for spontaneous improvement, as demonstrated by three of the patients treated with placebo.

    Title Experimental Autoimmune Myasthenia: Clinical, Neurophysiologic, and Pharmacologic Aspects.
    Date October 1976
    Journal Annals of the New York Academy of Sciences
    Title End-plate Potentials in Experimental Autoimmune Myasthenia Gravis in Rats.
    Date October 1976
    Journal Annals of the New York Academy of Sciences
    Excerpt

    Rats inoculated once with nicotinic acetylcholine receptor and adjuvants had two episodes of weakness, the first being acute and transient, starting on day 8, and remitting in a few days, the second, chronic, progressive, and appearing after day 20. In the acute phase, the compound action potential and twitch evoked in weak forelimb muscles by maximal nerve stimulus were greatly reduced. Nerve action potentials were normal, however, and the muscle responded to direct electrical stimulation. Using intracellular microelectrodes, miniature end-plate potentials were difficult to find and often were low in amplitude. Many fibers were functionally denervated; no action potential or end-plate potential was evoked by nerve stimulus, although the muscle fiber responded to direct stimulation. In fibers with EEPs the number of acetylcholine quanta released by nerve impulse, the store of quanta readily available for release and the mobilization rate were low. The diaphragm was similarly, but less severely affected. Recovery from the acute phase occurred in a few days with restoration of the response of forelimb muscle to nerve stimulus, even though MEPP amplitude remained low. In the chronic phase, in both forelimb muscle and diaphragm, MEPP were more easily found, but in all rats MEPP amplitude was below normal whether or not there was weakness or a decrement in the EMG. The number of quanta released by nerve stimulus, the store, and the mobilization rate of quanta were normal in all animals. The titer of antibodies ot syngeneic acetylcholine receptor was elevated in all chronic phase animals. The chronic phase is like myasthenia gravis, but rats with MEPP amplitudes as low as those in patients with MG frequently were not weak, because the number of ACh quanta released per nerve impulse is greater in the rat than in man.

    Title Pain in Peripheral Neuropathy Related to Rate and Kind of Fiber Degeneration.
    Date July 1976
    Journal Neurology
    Excerpt

    In a series of 72 patients with disease of peripheral neurons, neuropathic painfulness of the foot was found to be related to the rate and kind of nerve fiber degeneration. Patients with acute breakdown of myelinated fibers (either by wallerian or axonal degeneration) tend to have pain more often and to a greater degree than do patients with more chronic forms of nerve fiber degeneration. Neuropathic painfulness was not found to be related simply to the ratio of remaining large and small fibers after nerve fiber degeneration. These studies do not fit the expectation of the proponents of the gate theory of pain.

    Title Uremic Neuropathy. Iii. Controlled Study of Restricted Protein and Fluid Diet and Infrequent Hemodialysis Versus Conventional Hemodialysis Treatment.
    Date February 1976
    Journal Mayo Clinic Proceedings. Mayo Clinic
    Excerpt

    The effect of a treatment schedule of restricted protein and fluid intake and of infrequent hemodialysis (schedule 1) as compared to a conventional hemodialysis treatment schedule (schedule 2) on the presence and severity of peripheral neuropathy has been studied in a small group of patients using a crossover design. Using the neurologic evaluation and quantitative assessment of cutaneous sensation and of nerve conduction as indices of peripheral nerve function, we have not demonstrated any worsening of peripheral nerve function from markedly curtailing the frequency of hemodialysis and modifying the diet. Because of the small size of the study, the preponderance of patients receiving the test treatment schedule first, and the possibility that nerve function slowly worsens with time, it is not possible to say with certainty that the test or the control treatment schedule might adversely affect peripheral nerve function. If such an effect is present it would appear to be small.

    Title Detection and Evaluation of Uremic Peripheral Neuropathy in Patients on Hemodialysis.
    Date December 1975
    Journal Kidney International. Supplement
    Title Experimental Facial Nerve Paralysis: Influence of Decompression.
    Date December 1974
    Journal The Annals of Otology, Rhinology, and Laryngology
    Title Motor End-plate Fine Structure in Acrylamide Dying-back Neuropathy: a Sequential Morphometric Study.
    Date November 1974
    Journal Neurology
    Title The Response of Denervated Skeletal Muscle to Succinylcholine.
    Date June 1974
    Journal Anesthesiology
    Title Study of Long-term Anticholinesterase Therapy. Effects on Neuromuscular Transmission and on Motor End-plate Fine Structure.
    Date January 1974
    Journal Neurology
    Title Hereditary Sensory Neuropathy, Type Ii. Clinical, Electrophysiologic, Histologic, and Biochemical Studies of a Quebec Kinship.
    Date August 1973
    Journal Archives of Neurology
    Title Age Changes in Conduction Velocity of Unmyelinated Fibers.
    Date August 1973
    Journal The Journal of Comparative Neurology
    Title Conduction in Regenerating Unmyelinated Fibres.
    Date May 1973
    Journal Brain : a Journal of Neurology
    Title The Spectrum and Diagnosis of Acid Maltase Deficiency.
    Date April 1973
    Journal Neurology
    Title Conduction in Unmyelinated Fibres in Experimental Neuropathy.
    Date August 1972
    Journal Journal of Neurology, Neurosurgery, and Psychiatry
    Title Histometric Study of Neuromuscular Junction Ultrastructure. I. Myasthenia Gravis.
    Date April 1972
    Journal Neurology
    Title Quantal Components of End-plate Potentials in the Myasthenic Syndrome.
    Date February 1972
    Journal Annals of the New York Academy of Sciences
    Title Acid Maltase Deficiency: Comparison of Infantile, Childhood, and Adult Types.
    Date October 1971
    Journal Neurology
    Title Segmental Demyelination Secondary to Axonal Degeneration in Uremic Neuropathy.
    Date August 1971
    Journal Mayo Clinic Proceedings. Mayo Clinic
    Title Severe Hypomyelination and Marked Abnormality of Conduction in Dejerine-sottas Hypertrophic Neuropathy: Myelin Thickness and Compound Action Potential of Sural Nerve in Vitro.
    Date August 1971
    Journal Mayo Clinic Proceedings. Mayo Clinic
    Title Polyneuropathy Associated with Hypothyroidism.
    Date December 1970
    Journal Journal of Neuropathology and Experimental Neurology
    Title Polyneuropathy Associated with Hypothyroidism: Electrophysiologic, Quantitative Histologic and Teased Fiber, and Electron Microscopic Study of Nerve Biopsies.
    Date April 1970
    Journal Transactions of the American Neurological Association
    Title Use of Intracardiac A-v Nodal Potentials in Producing Complete Heart Block in Dogs.
    Date February 1970
    Journal Journal of Applied Physiology
    Title The Accessory Deep Peroneal Nerve. A Common Variation in Innervation of Extensor Digitorum Brevis.
    Date January 1970
    Journal Neurology
    Title Calcium Activation of Electrically Inexcitable Muscle Fibers in Primary Hypokalemic Periodic Paralysis.
    Date October 1969
    Journal Neurology
    Title Terminology of Electromyography.
    Date September 1969
    Journal Electroencephalography and Clinical Neurophysiology
    Title Dissociated Sensation in Amylidosis. Compound Action Potential, Quantitative Histologic and Teased-fiber, and Electron Microscopic Studies of Sural Nerve Biopsies.
    Date June 1969
    Journal Archives of Neurology
    Title Thymoma with Myopathy. Report of a Case.
    Date May 1969
    Journal Minnesota Medicine
    Title Dissociated Sensation in Amyloidosis: Compound Action Potentials; Quantitative Histologic and Teased Fibers; and Electron Microscopic Studies of Sural Nerve Biopsies.
    Date April 1969
    Journal Transactions of the American Neurological Association
    Title Detailed Analysis of Neuromuscular Transmission in a Patient with the Myasthenic Syndrome Sometimes Associated with Bronchogenic Carcinoma.
    Date April 1969
    Journal Mayo Clinic Proceedings. Mayo Clinic
    Title Course of Dermatomyositis-polymyositis: Comparison of Untreated and Cortisone-treated Patients.
    Date April 1969
    Journal Mayo Clinic Proceedings. Mayo Clinic
    Title "mouth-to-lung Airway" for Cardiac Resuscitation.
    Date January 1969
    Journal Lancet
    Title Compound Action Potentials of Human Sural Nerve Biopsies.
    Date December 1968
    Journal Electroencephalography and Clinical Neurophysiology
    Title Polyphastic Motor Unit Action Potentials.
    Date December 1968
    Journal Electroencephalography and Clinical Neurophysiology
    Title Small Cell Carcinoma of Lung. Observations on Four Patients Including One with a Myasthenic Syndrome.
    Date October 1968
    Journal Archives of Internal Medicine
    Title Lower Motor and Primary Sensory Neuron Diseases with Peroneal Muscular Atrophy. I. Neurologic, Genetic, and Electrophysiologic Findings in Hereditary Polyneuropathies.
    Date July 1968
    Journal Archives of Neurology
    Title Lower Motor and Primary Sensory Neuron Diseases with Peroneal Muscular Atrophy. Ii. Neurologic, Genetic, and Electrophysiologic Findings in Various Neuronal Degenerations.
    Date July 1968
    Journal Archives of Neurology
    Title Effects of Calcium on Isolated Muscle Fibers in Primary Hypokalemic Periodic Paralysis.
    Date June 1968
    Journal Neurology
    Title The Relation Between Twitch Tension and Action Potential in Plasmocid Myopathy in the Rat.
    Date June 1968
    Journal Neurology
    Title Electrodiagnostic Aspects of the Carpal Tunnel Syndrome.
    Date August 1967
    Journal Archives of Neurology
    Title Facial Myokymia Affecting the Electroencephalogram.
    Date June 1967
    Journal Mayo Clinic Proceedings. Mayo Clinic
    Title The Neuropathy of Sulfatide Lipidosis (metachromatic Leukodystrophy).
    Date April 1967
    Journal Neurology
    Title Shivering and Heat Production in Men Exposed to Intense Cold.
    Date April 1967
    Journal Journal of Applied Physiology
    Title Experience with a Combined Hemodialysis-renal Transplantation Program: Neurologic Aspects.
    Date February 1967
    Journal Mayo Clinic Proceedings. Mayo Clinic
    Title Defects of Neuromuscular Transmission in Syndromes Other Than Myasthenia Gravis.
    Date October 1966
    Journal Annals of the New York Academy of Sciences
    Title Laboratory Tests in Polymyositis.
    Date July 1966
    Journal Archives of Internal Medicine
    Title Long-term Results of Operation for Carpal Tunnel Syndrome.
    Date May 1966
    Journal Mayo Clinic Proceedings. Mayo Clinic
    Title A Kinship with the Roussy-levy Syndrome.
    Date December 1965
    Journal Archives of Neurology
    Title A Kinship of the Roussy-levy Syndrome: a Clinical and Electrophysiological Study.
    Date November 1965
    Journal Transactions of the American Neurological Association
    Title Fast Motor Systems in Man: Physiopathology of the Sonomotor Response.
    Date November 1965
    Journal Transactions of the American Neurological Association

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