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ARTICLES: J.S. Katz, R.J. Barohn, S. Kojan, G.I. Wolfe, S.P. Nations, D.S. Saperstein, and A.A. Amato Axonal multifocal motor neuropathy without conduction block or other features of demyelination Neurology 2002; 58: 615-620 [Abstract] [Full text] [PDF]

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Axonal multifocal motor neuropathy without conduction block or other features of demyelination

Ludovico Lispi, Simona Galgani, Manlio Giacanelli   (26 September 2002)

Reply to Weiss

Jon S Katz, Richard. Barohn, David Saperstein, Anthony Amato   (10 June 2002)

Axonal multifocal motor neuropathy

Michael D Weiss   (10 June 2002)

Reply to both Letters to the Editor

Jonathan S. Katz, Richard J. Barohn, David S. Saperstein, and Anthony A. Amato   (6 June 2002)

Axonal multifocal motor neuropathy without conduction block or other features of demyelination

Michael Donaghy, Amitabha Ghosh   (6 June 2002)

Axonal multifocal motor neuropathy without conduction block or other features of demyelination

Daniel L. Menkes   (6 June 2002)

Axonal multifocal motor neuropathy without conduction block or other features of demyelination 26 September 2002
Ludovico Lispi, Physician (Neurology) Neurological Department, San Camillo Hospital, Roma, Italy, Simona Galgani, Manlio Giacanelli Send Correspondence to journal: Re: Axonal multifocal motor neuropathy without conduction block or other features of demyelination llispi{at}scamilloforlanini.rm.it Ludovico Lispi, et al.	We read with interest the paper of Katz et al. [1] and we agree with the hypothesis of an axonal variant of MMN. We recently observed two patients with clinical and laboratory findings similar to these [2]. The first patient we studied was a 71 year-old who had, for four years, asymmetric weakness in the hands and-to a lesser extent-proximal arms with right predominance and slight muscular hypotrophy restrictly confined to individual nerves (right axillary, median bilateral). There were no sensory signs and no upper motor neuron involvement. The cervical spine MRI was normal and there were no anti-GM1, anti-MAG, or anti-sulfatide antibodies. The EMG showed normal sensory NCS, reduced CMAP and active or chronic denervation involving individual nerves. There were no CB or other features of demyelination. He was treated with IVIg without improvement. He remained stable at 3 years follow-up. The second patient studied was a 19-year-old who had been ill for 3 years with weakness and muscular hypotrophy in the right hand and forearm and with minimal involvement in the left. These were confined to individual nerves (radial bilateral, rigth ulanar). There were no sensory or upper motor neuron signs. Normal cervical spine MRI was performed in hyperflexion. No anti-GM1 antibodies were evident. The EMG showed reduced CMAP, active or chronic denervation involving individual nerves. Sensory NCS were normal and no CB or demyelinating features were detected. He was treated with IVIg with clinical and EMG improvement. Our data support the hypothesis of an axonal form of multifocal motor neuropathy and that patients with clinical features of MMN without evidence of demyelination and GM1 antibodies should receive an empiric treatment with immune modulating therapy. We would suggest performing a cervical MRI in hyperflexion especially in young men in which Hirayama disease should be excluded [3]. References: 1. Katz JS, Barohn RJ, et al. Axonal multifocal motor neuropathy without conduction block or other features of demyelination. Neurology 2002; 58; 615-620 2. Lispi L., Galgani S.,Giacanelli M. Multifocal motor neuropathy without demyelinating features: an axonal variant?. Neurol. Sci. 2001; 22; S122 3. Kohno M., Takahashi H., et al. "Disproportion theory" of the cervical spine and spinal cord in patients with juvenile cervical flexion myelopathy - a study comparing cervical MRIs with normal controls. Surg Neurol 1998;50;421-30.
Reply to Weiss 10 June 2002
Jon S Katz, neurologist Stanford University School of Medicine, Richard. Barohn, David Saperstein, Anthony Amato Send Correspondence to journal: Re: Reply to Weiss jskatz{at}stanford.edu Jon S Katz, et al.	We appreciate the comments from Dr. Weiss. Note that our manuscript specifically stated that we had no way of knowing whether our cases have a common pathogenesis. MAMA is not a disease; it is a set of cases with a common clinical/electrodiagnostic presentation, as defined in our methods. Our work begins to explore the utility of common laboratory studies and treatments in this defined population. There are no other clues, short of a response to therapy, that helps us determine what these cases have. We agree with the idea that PMA patients can appear to show little progression over relatively short periods of time. We point out that a multifocal clinical presentation, as opposed to a myotomal presentation, is still atypical of PMA, as PMA is classically defined. We discussed the differential diagnosis for our patients but we were not able to clearly place them in any currently defined "clinical basket." We also referenced the two papers you cite [2,3)]. Like our work, these suggested that similar patients may respond to immune modulating therapies. However, the clinical and electrodiagnostic parameters were not as clearly defined in those reports (only stating that there was "no conduction block" or that patients were weak distally versus proximally). Overall, we believe that there is a strong possibility that our current nomenclature does not address every known phenomenon that faces clinicians. Clearly, the prior notion that motor neuropathies must have demonstrable conduction block or specific antibodies has proven too narrow. However, this is troublesome for clinicians when deciding who to treat because the cases overlap with more common non-treatable degenerative disorders. We show that in this setting, antibodies against nerve antigens yield little in the way of useful information. We think it might be helpful to examine specific clinical patterns, as we wait for science to catch up.
Axonal multifocal motor neuropathy 10 June 2002
Michael D Weiss, physician (neurology) University of Washington Medical center Send Correspondence to journal: Re: Axonal multifocal motor neuropathy mdweiss{at}u.washington.edu Michael D Weiss	To the Editor: Katz et al. recently reported a multifocal acquired motor axonal neuropathy (MAMA) without conduction block or anti-GM1 antibodies in nine patients.[1] As three patients responded to either prednisone or intravenous immunoglobulin therapy (IVIG), they concluded that these patients had a distinct neuropathy syndrome that was likely immune-mediated. For the three patients who responded to immunotherapy, I would certainly concur that the underlying pathologic mechanism is inflammatory. However, it is misleading to suggest that all nine patients have the same disorder. While the authors indicate that multifocal motor neuropathy is distinguished from motor neuron disease by demonstration of conduction block or other signs of demyelination electrophysiologically, MAMA is not associated with any electrophysiologic signs that readily distinguish this condition from motor neuronopathy. Additionally, none of the IVIG or prednisone nonresponders in this series had anti-ganglioside antibodies to suggest a common immunologic pathogenesis for their condition. While all of the patients in the series remained stable or slowly progressed over the short observation period, their course is not distingushed from that of progressive muscular atrophy (PMA). PMA can advance at a slow pace, especially in younger patients and survival of greater than fifteen years is not uncommon. While I congratulate the authors on supplementing existing literature supporting the use of immunomodulatory therapy for a subset of patients with acquired motor axonopathy or neuronopathy [2,3], it is premature to conclude that all such patients have a similar pathogenic mechanism for their disease. Michael D. Weiss, MD, Seattle, WA References 1. Katz JS, Barohn RJ, Kojan S, et al. Axonal multifocal motor neuropathy without conduction block or other features of demyelination. Neurology 2002;58:615-620. 2. Pestronk A, Chaudhry V, Feldman EL, et al. Lower motor neuron syndromes defined by patterns of weakness, nerve conduction abnormalities, and high titers of antiglycolipid antibodies. Ann Neurol 1990;27:316-326. 3. Ellis CM, Leary S, Payan J, et al. Use of human intravenous immunoglobulin in lower motor neuron syndromes. J Neurol Neurosurg Psychiatry 1999;67:15-19.
Reply to both Letters to the Editor 6 June 2002
Jonathan S. Katz Palo Alto VA Medical Center and Stanford University, Richard J. Barohn, David S. Saperstein, and Anthony A. Amato Send Correspondence to journal: Re: Reply to both Letters to the Editor jskatz{at}stanford.edu Jonathan S. Katz, et al.	Our cases do not fit well into any currently defined clinical entity and therefore pose a diagnostic challenge. Even without full understanding of disease mechanisms, we believe there is still value in using empirical methods to show that these cases are different from other entities. As noted, we included patients with a multifocal phenotype, axonal electrodiagnostic features, and a response to therapy or lack of progression. These criteria distinguished our patients from other muscular atrophies that have overlapping clinical and electrodiagnostic findings. The different prognosis and potential for a response to therapy mandate that we not lump these cases together. In addition, we limited our focus to one clearly defined syndrome and we do not be advocate therapy for a less well-defined “patients who do not manifest a conduction block on NCS.” Using a similar argument, the use of the term MAMA separates our cases from “multifocal motor neuropathy (MMN) without conduction block.” Earlier reports on this topic do not explicitly describe a neuropathy that appears axonal on routine NCS, in that they do not exclude patients who have other demyelinating features such as slowing, temporal dispersion, or prolonged distal latencies. These can serve as additional clues for diagnosis of MMN [3]. Our suggestion that MAMA is probably a separate entity from MMN was based not only on the electrodiagnostic features, but also on the absence of anti-GM1 antibodies in all 9 of our patients. Assuming that the sensitivity for these antibodies in MMN is 40% and we had simply “missed” the conduction abnormalities because they were too proximal, the chance of finding no antibodies in our series would be 0.6 to the ninth power. This is only 1%. We found abnormalities of the CSF protein or paraspinous nerve roots in two of the nine patients but this only provides us with information about localization, not the type of lesion. We did root stimulation on two patients, including one of the three responders, and no block was present in either. We did not report on the root stimulation because we did not perform it routinely and there is only one report mentioning its utility in MMN [2]. The test is difficult to interpret in this setting because muscles are innervated by more than one root so that two or more nerve roots need to be simultaneously supramaximally stimulated. As a result, the significance of a "block," when found, becomes hard to interpret. Volume conduction between neighboring muscles that are differentially affected (median and ulnar innervated, for instance), a common feature of MMN, is another potential artifact that may mask CB. As we noted [1], it is possible that we failed to diagnose very proximal CB, but distinct pathophysiology should also be considered based on several of our findings. We appreciate the discussion by Drs Ghosh and Donaghy about the etiology of multifocal acquired motor axonopathy (MAMA). They accurately note that we observed weakness that exceeded the degree of atrophy in two of our nine patients, a feature suggesting CB was the underlying substrate of weakness. Note that as we prepared the manuscript we were concerned that the name MAMA too strongly implied that there is “no conduction block,” as opposed to the possibility that we could not demonstrate it with our techniques. However, our group agreed on the word “axonal” to emphasize the striking absence of any demyelinating abnormality in these patients on electrodiagnostic testing. This has not been previously reported and our primary intent was to alert clinicians to the existence of this clinical/electrophysiological syndrome. In our report we considered very distal axonal sprouting as a cause for potential cause for MAMA. Distal sprouting has been postulated as the cause of weakness in axonal forms of GBS. We noted that patients with AMAN recover at the same rate as those with demyelinating GBS. Unfortunately, this does not easily explain the lack of atrophy. We also considered that some of our patients could have an MMN “variant,” where we were simply not able to find CB because it was too proximal or too distal. However, this was unattractive because of the complete absence of any conduction abnormality at all in these patients, something that has not been clearly recorded in past MMN literature. In addition, our patients did not have anti-GM1 antibodies, were often younger, and were more likely to have weakness in proximal muscles than those with typical MMN. While a few of our patients certainly could have MMN, it is unlikely that all nine did. An activity dependent CB combined with some degree of superimposed axonal loss is a very attractive hypothesis to explain this clinical phenomenon. However, we note that atrophy was clearly associated with weakness in most of our cases. Indeed, the MAMA phenotype could well represent several diverse etiologies. While we can safely conclude that MAMA is immune mediated in the three treatment responders, and we believe that any of the above hypotheses might explain the rapid response to therapy. The target of an immune attack could also vary from case to case, being primarily directed against the structure of the axon in some and against the mechanisms that primarily impair conduction in others. We cannot even be certain this is an immune condition in patients who do not respond to therapy. We all agree that formal biological diagnostic criterion would be extremely valuable, but for now we still need to look closely for clinical clues just to decide in which patients with lower motor neuron syndromes is IVIg therapy worth attempting. We also should keep an open mind as to causation. References: 1 Katz JS, Barohn RJ, Kojan S et al. Axonal multifocal neuropathy without conduction block or other features of demyelination. Neurology 2002; 58:615-620. 2 Menkes DL, Hood DC, Ballesteros RA, Williams DA: Root stimulation improves the detection of acquired demyelinating polyneuropathies. Muscle Nerve 1998;21:298-308. 3.Katz JS, Wolfe GI, Bryan WW, Jackson CE, Amato AA, and Barohn RJ. Electrodiagnostic findings in multifocal motor neuropathy. Neurology 1997;48:700-707.
Axonal multifocal motor neuropathy without conduction block or other features of demyelination 6 June 2002
Michael Donaghy University of Oxford United Kingdom, Amitabha Ghosh Send Correspondence to journal: Re: Axonal multifocal motor neuropathy without conduction block or other features of demyelination joanna.wilkinson{at}clneuro.ox.ac.uk Michael Donaghy, et al.	We read with interest the recent article on an axonal variant of multifocal motor neuropathy (MMN) by Katz et al. [1] The authors described patients who they considered to have electrophysiological evidence of axonal damage but no overt conduction block (CB) or other features of demyelination. They proposed that the condition could be different from MMN. Of interest, were two instances of muscle wasting disproportionately less than the degree of weakness. Illustrated patient 8 was seen 5 years after the onset, but in spite of marked weakness of many muscles, muscle bulk was normal and grade 2 to 2+ reflexes were elicited. The abductor pollicis brevis on the right was moderately weak, but the amplitude of the distally evoked compound motor action potential (CMAP) was only slightly reduced. The authors mentioned other instances where the distal CMAP amplitudes were larger than would be expected for the degree of weakness. We interpret these features as reflecting undetected CB rather than primary chronic axonal loss. Current quantitative definitions for CB are still too restrictive, and in particular, they don’t establish the threshold for predicting IvIg responsiveness in MMN. Clinical weakness and fatigue could occur with much lesser degrees of conduction failure, particularly if proximally or diffusely located. Dynamic alterations to the level of CB are recognized. [2, 3] Conduction block undetected on routine neurophysiological examination may be precipitated by natural activity.[4] This has been attributed to membrane hyperpolarization due to an overactive Na+-K+ pump in demyelinated axons.[5] Recently a combined depolarization/hyperpolarization model has been proposed to explain the pathophysiology of MMN.[6] Impaired Na+-K+ pump activity causing depolarisation at the site of the lesion is hypothesised, with intracellular accumulation of Na+, which then diffuses along the axon to adjacent sites where the pump is still active, producing hyperpolarization at those sites. The high intracellular Na+ at the site of the lesion could reverse the action of the Na+-Ca++ exchanger, raising intracellular Ca++ levels, which, if persistent, could cause axonal degeneration. It is possible for CB, conduction slowing and axonal loss to coexist in variable proportions in a segment depending upon how individual fibres are involved. Electrophysiological proof for axonal damage could be found even when criteria for overt CB had not been met. Therefore, at least some of the patients described by Katz et al [1] could have had ‘typical’ MMN with CB, rather than a primary axonal variant. Routine electrophysiological tests do not analyse individual contributions made by CB, conduction slowing and axonal loss occurring in faster and slower conducting fibres. Until this is possible, we may never be able to estimate the minimum amount of CB needed to produce symptoms and should be guided by clinical clues. Three patients from this article improved within two weeks of IvIg infusion, a rapidity unlikely to be explicable by axonal regeneration but in keeping with reversal of CB. [1] Indeed, until formal biological diagnostic criteria for MMN with CB exist, we regard prompt response to IvIg as a practical diagnostic criterion to reveal CB, even if this has not been formally proven electrophysiologically. References: 1. Katz JS, Barohn RJ, Kojan S, Wolfe GI, Nations SP, Saperstein DS, et al. Axonal multifocal motor neuropathy without conduction block or other features of demyelination. Neurology 2002;58:615-620. 2. Cappellari A, Nobile-Orazio E, Meucci N, Levi Minzi G, Scarlato G, Barbieri S. Criteria for early detection of conduction block in multifocal motor neuropathy (MMN): a study based on control populations and follow-up of MMN patients. J Neurol 1997;244:625-630. 3. Kaji R, Bostock H, Kohara N, Murase N, Kimura J, Shibasaki H. Activity-dependent conduction block in multifocal motor neuropathy. Brain 2000;123:1602-1611. 4. Vagg R, Mogyoros I, Kiernan MC, Burke D. Activity-dependent hyperpolarization of human motor axons produced by natural activity. J Physiol 1998;507:919-925. 5. Bostock H, Grafe P. Activity-dependent excitability changes in normal and demyelinated rat spinal root axons. J Physiol 1985;365:239-257. 6. Kiernan MC, Guglielmi JM, Kaji R, Murray NM, Bostock H. Evidence for axonal membrane hyperpolarization in multifocal motor neuropathy with conduction block. Brain 2002;125:664-675.
Axonal multifocal motor neuropathy without conduction block or other features of demyelination 6 June 2002
Daniel L. Menkes UT Memphis College of Medicine Memphis TN Send Correspondence to journal: Re: Axonal multifocal motor neuropathy without conduction block or other features of demyelination dmenkes{at}utmem.edu Daniel L. Menkes	Katz et al. paper illustrates the important concept that not every immune mediated motor neuropathy demonstrates evidence of conduction block on routine nerve conduction studies, (NCS). [1] However, one should question whether they are justified in proposing different disease entities simply on the basis of electrophysiologic appearances. In fact, MAMA may have the same pathophysiology as multifocal neuropathy with conduction block. NCS detect myelin dysfunction when there is a significant change in waveforms across an affected nerve segment. In their study, root stimulation studies were not performed. Therefore, a proximal conduction block at nerve root level may have been overlooked and the response to treatment may have been misinterpreted. [2] Myelin dysfunction often results from an immune attack against nerve sites with a less robust blood nerve barrier; the proximal nerve roots and the distal segment of the axon. [3] Myelin dysfunction can occur at either site or both. The rate and degree of centripetal spread depends on the severity of the immune response. Those with greater degrees of centripetal spread will enter the nerve segments most often evaluated by routine NCS. Those with more indolent courses may not spread to these segments and thus overt evidence of myelin dysfunction may be missed. Katz et al. likely examined patients with an indolent disease course, (duration 3-19 years). These patients could be further subdivided into those with pure distal involvement, (treatment non-responders), and those with both proximal and distal involvement, (treatment responders). Consider a simple model of two independent nodes of Ranvier; one proximal, one distal. Failure at both nodes results in a markedly reduced probability of signal transmission success, (probability product rule). [4] Conversely, improvement at one site has a more significant impact when two nodes are affected. Evidence of radicular involvement was present in two responders; one had elevated CSF protein, the other, paraspinal fibrillation potentials. The third responder had neither of these parameters assessed. Had these abnormalities not been found, root stimulation studies might have demonstrated a proximal conduction block. Katz et al. should be commended for advocating empiric trials of therapy even in patients who do not manifest a conduction block on NCS. However, it may not be entirely appropriate to label these cases as a separate disease entity when they may merely reflect differences in anatomical locations and tempos of disease progression. While none of their patients demonstrated a conduction block, absence of evidence is not evidence of absence. References: 1 Katz JS, Barohn RJ, Kojan S et al. Axonal multifocal neuropathy without conduction block or other features of demyelination. Neurology 2002; 58:615-620. 2 Menkes DL, Hood DC, Ballesteros RA, Williams DA: Root stimulation improves the detection of acquired demyelinating polyneuropathies. Muscle Nerve 1998;21:298-308. 3 Kuwabara S, Ogawara K, Mizobuchi K, Koga M, Mori M, Hattori T, Yuki N. Isolated absence of F waves and proximal axonal dysfunction in Guillain-Barré syndrome with antiganglioside antibodies. J Neurol Neurosurg Psychiatry 2000; 68: 191-195. 4 Moore DS, McCabe GP. Introduction to the practice of statistics, 2nd Edition. New York: WH Freeman and Company, 1993.