Norman Latov

Distal symmetric polyneuropathy: A definition for clinical research: Report of the American Academy of Neurology, the American Association of Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation

The objective of this report was to develop a case definition of distal symmetric polyneuropathy to standardize and facilitate clinical research and epidemiologic studies. A formalized consensus process was employed to reach agreement after a systematic review and classification of evidence from the literature. The literature indicates that symptoms alone have relatively poor diagnostic accuracy in predicting the presence of polyneuropathy; signs are better predictors of polyneuropathy than symptoms; and single abnormalities on examination are less sensitive than multiple abnormalities in predicting the presence of polyneuropathy. The combination of neuropathic symptoms, signs, and electrodiagnostic findings provides the most accurate diagnosis of distal symmetric polyneuropathy. A set of case definitions was rank ordered by likelihood of disease. The highest likelihood of polyneuropathy (useful for clinical trials) occurs with a combination of multiple symptoms, multiple signs, and abnormal electrodiagnostic studies. A modest likelihood of polyneuropathy (useful for field or epidemiologic studies) occurs with a combination of multiple symptoms and multiple signs when the results of electrodiagnostic studies are not available. A lower likelihood of polyneuropathy occurs when electrodiagnostic studies and signs are discordant. For research purposes, the best approach to defining distal symmetric polyneuropathy is a set of case definitions rank ordered by estimated likelihood of disease. The inclusion of this formalized case definition in clinical and epidemiologic research studies will ensure greater consistency of case selection.

Fibrillary astrocytes proliferate in response to brain injury: A study combining immunoperoxidase technique for glial fibrillary acidic protein and radioautography of tritiated thymidine☆

Abstract To determine whether fibrillary astrocytes proliferate in response to brain injury, cells identified as fibrillary astrocytes using immunoperoxidase technique for glial fibrillary acidic protein (GFAP) were examined for uptake of radiolabeled thymidine by autoradiography. In injured mouse brain, autoradiographic label was present over nuclei of immunoreactive fibrillary astrocytes in the lesion site 1 hr following injection of radiolabeled thymidine. The data suggest that fibrillary astrocytes which are sufficiently differentiated to accumulate GFAP retain the capacity to proliferate in response to injury.

Intravenous immune globulin (10% caprylate-chromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomised placebo-controlled trial

BACKGROUND Short-term studies suggest that intravenous immunoglobulin might reduce disability caused by chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) but long-term effects have not been shown. We aimed to establish whether 10% caprylate-chromatography purified immune globulin intravenous (IGIV-C) has short-term and long-term benefit in patients with CIDP. METHODS 117 patients with CIDP who met specific neurophysiological inflammatory neuropathy cause and treatment (INCAT) criteria participated in a randomised, double-blind, placebo-controlled, response-conditional crossover trial. IGIV-C (Gamunex) or placebo was given every 3 weeks for up to 24 weeks in an initial treatment period, and patients who did not show an improvement in INCAT disability score of 1 point or more received the alternate treatment in a crossover period. The primary outcome was the percentage of patients who had maintained an improvement from baseline in adjusted INCAT disability score of 1 point or more through to week 24. Patients who showed an improvement and completed 24 weeks of treatment were eligible to be randomly re-assigned in a blinded 24-week extension phase. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00220740. FINDINGS During the first period, 32 of 59 (54%) patients treated with IGIV-C and 12 of 58 (21%) patients who received placebo had an improvement in adjusted INCAT disability score that was maintained through to week 24 (treatment difference 33.5%, 95% CI 15.4-51.7; p=0.0002). Improvements from baseline to endpoint were also recorded for grip strength in the dominant hand (treatment difference 10.9 kPa, 4.6-17.2; p=0.0008) and the non-dominant hand (8.6 kPa, 2.6-14.6; p=0.005). Results were similar during the crossover period. During the extension phase, participants who continued to receive IGIV-C had a longer time to relapse than did patients treated with placebo (p=0.011). The incidence of serious adverse events per infusion was 0.8% (9/1096) with IGIV-C versus 1.9% (11/575) with placebo. The most common adverse events with IGIV-C were headache, pyrexia, and hypertension. INTERPRETATION This study, the largest reported trial of any CIDP treatment, shows the short-term and long-term efficacy and safety of IGIV-C and supports use of IGIV-C as a therapy for CIDP.

Myelin-Associated Glycoprotein Is the Antigen for a Monoclonal IgM in Polyneuropathy

Abstract: Recent studies show that IgM monoclonal antibody from patients with IgM paraproteinemia and peripheral neuropathy reacts with a protein component of human PNS myelin and an analogous component or components of human CNS myelin. We have now demonstrated that the antigen for this antibody is a specific glycoprotein component of myelin, referred to as myelin‐associated glycoprotein (MAG). Human PNS and CNS myelin proteins were separated by sodium dodecyl sulfate‐polyacrylamide gel electrophoresis on pore‐gradient slabs, and MAG was identified by the immuno‐electroblot procedure with rabbit anti‐MAG (rat). The identical band(s) were stained by an analogous procedure with patient serum as the first antibody. Human PNS MAG had an apparent molecular weight of 107,000. Human CNS MAG appeared as three bands: 113,000, 107,000, and 92,000. Passage of myelin proteins through a concanavalin A‐Sepharose column removed the staining component. Purified patient IgM, added to a lithium diiodosalicylate extract of myelin, immunoprecipitated MAG. This antibody also cross‐reacted with MAG from bovine CNS, but not from rabbit, rat, or mouse.

The spectrum of neurologic disease associated with anti‐GM1 antibodies

We compared anti-GM1 IgM antibody titers in patients with various neurologic diseases and in normal subjects. We found increased titers in patients with lower motor neuron disease, sensorimotor neuropathy, or motor neuropathy with or without multifocal conduction block. In patients with other diseases, titers are similar to those in normal individuals, suggesting that anti-GM1 antibody levels are not increased nonspecifically after neural injury or inflammatory diseases. Anti-GM1 antibodies in many of the patients occur as monoclonal gammopathies, predominantly of lambda light-chain type, but the antibodies are sometimes polyclonal with normal or increased serum IgM concentrations. Most of the anti-GM1 antibodies appear to react with the Gal(β1-3)GalNAc epitope which is shared with asialo-GM1 and GD1b, but in some patients the antibodies are more specific for GM1 and associated with motor neuropathy. Patients with motor or sensorimotor peripheral neuropathy or lower motor neuron disease should be tested for anti-GM1 antibodies or anti-Gal(β1-3)GalNAc antibodies, as therapeutic reduction in antibody concentrations was reported to result in clinical improvement in some patients.

Experimental demyelination of nerve induced by serum of patients with neuropathy and an anti‐MAG IgM M‐protein

Demyelination of feline sciatic nerve was induced by intraneural injection of serum from three patients with neuropathy and an IgM M-protein that reacted with myelin-associated glycoprotein (MAG). Demyelimtion exceeded that induced by serum from 18 other individuals, including six IgM M-proteins unreactive with MAG. The myelholytic effect required active hurnan complement and was abolished by exposure of serum to homogenate o human peripheral nerve that removed 90% of the M-protein. Immunofluorescence studies demonstrated deposition of the injected M-protein and complement on the surface of myelin sheaths, implying that the M-protein reacted with epitopes of myelin exposed to the extracellular space.

Gangliosides GM1 and GD1b are antigens for IgM M-protein in a patient with motor neuron disease

We studied a patient with an IgM M-protein and lower motor neuron disease to identify the antigens to which the M-protein bound. Gangliosides from peripheral nerve and spinal cord were separated by high-performance thin-layer chromatography and immunostained with the patients serum. The serum IgM immunostained two gangliosides identified as GM1 and GD1b, and immunostaining was specific for the M- protein light chain type. IgM-binding to the two gangliosides was detectable by ELISA at serum dilutions of greater than 1:10,000, and the M-protein was selectively immunoabsorbed by liposomes containing GM1 or GD1b. The IgM M-protein also bound to asialo-GM1, indicating reactivity to the galactosyl(beta 1-3)N-acetylgalactosaminyl moiety shared by GM1, GD1b, and asialo-GM1.

Practice Parameter: Evaluation of distal symmetric polyneuropathy: Role of autonomic testing, nerve biopsy, and skin biopsy (an evidence-based review) Report of the American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Academy of Physical Medicine and Rehabilitation

Background: Distal symmetric polyneuropathy (DSP) is the most common variety of neuropathy. Since the evaluation of this disorder is not standardized, the available literature was reviewed to provide evidence-based guidelines regarding the role of autonomic testing, nerve biopsy, and skin biopsy for the assessment of polyneuropathy. Methods: A literature review using MEDLINE, EMBASE, and Current Contents was performed to identify the best evidence regarding the evaluation of polyneuropathy published between 1980 and March 2007. Articles were classified according to a four-tiered level of evidence scheme and recommendations were based upon the level of evidence. Results and Recommendations: 1) Autonomic testing should be considered in the evaluation of patients with polyneuropathy to document autonomic nervous system dysfunction (Level B). Such testing should be considered especially for the evaluation of suspected autonomic neuropathy (Level B) and distal small fiber sensory polyneuropathy (SFSN) (Level C). A battery of validated tests is recommended to achieve the highest diagnostic accuracy (Level B). 2) Nerve biopsy is generally accepted as useful in the evaluation of certain neuropathies as in patients with suspected amyloid neuropathy, mononeuropathy multiplex due to vasculitis, or with atypical forms of chronic inflammatory demyelinating polyneuropathy (CIDP). However, the literature is insufficient to provide a recommendation regarding when a nerve biopsy may be useful in the evaluation of DSP (Level U). 3) Skin biopsy is a validated technique for determining intraepidermal nerve fiber density and may be considered for the diagnosis of DSP, particularly SFSN (Level C). There is a need for additional prospective studies to define more exact guidelines for the evaluation of polyneuropathy. AAN = American Academy of Neurology; AANEM = American Academy of Neuromuscular and Electrodiagnostic Medicine; AAPM&R = American Academy of Physical Medicine and Rehabilitation; ART = autonomic reflex testing; BRSI = baroreflex sensitivity index; CASS = composite autonomic scoring scale; CIDP = chronic inflammatory demyelinating polyneuropathy; DSFN = distal small fiber neuropathy; DSP = distal symmetric polyneuropathy; EDx = electrodiagnosis; EFNS = European Federation of Neurological Societies; HRV = heart rate variability; IAN = idiopathic autonomic neuropathy; IENF = intraepidermal nerve fibers; MSNA = muscle sympathetic nerve activity; NCSs = nerve conduction studies; PGP 9.5 = protein-gene-product 9.5; PN = peripheral neuropathy; PRT = blood pressure recovery time; QAE = quantitative autonomic examination; QSART = quantitative sudomotor axon reflex test; QSS = Quality Standards Subcommittee; QST = quantitative sensory testing; SFSN = small fiber sensory polyneuropathy; TST = thermoregulatory sweat testing.

Monoclonal IgM with unique specificity to gangliosides GM1 and GD1b and to lacto‐N ‐tetraose associated with human motor neuron disease

IgM lambda monoclonal antibodies in two patients with motor neuron disease showed the same unique antigenic specificity. They bound to gangliosides GM1 and GD1b and to lacto-N-tetraose-BSA. By immunofluorescence microscopy they bound to central and peripheral nerve tissue and to motor end-plates at the neuromuscular junction. Sera from control subjects did not contain antibodies of similar specificity. Monoclonal IgMs with the same unique specificity could be responsible for motor neuron disease in some patients with monoclonal gammopathies.

Practice parameter: the evaluation of distal symmetric polyneuropathy: the role of autonomic testing, nerve biopsy, and skin biopsy (an evidence-based review). Report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation.

Distal symmetric polyneuropathy (DSP) is the most common variety of neuropathy. Since the evaluation of this disorder is not standardized, the available literature was reviewed to provide evidence‐based guidelines regarding the role of autonomic testing, nerve biopsy and skin biopsy for the assessment of polyneuropathy.