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Pathological findings in a patient with amyotrophic lateral sclerosis and multifocal motor neuropathy with conduction block
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Journal of the Neurological Sciences 136 ( 1996) 64-70
Pathological findings in a patient with amyotrophic lateral sclerosis and multifocal motor neuropathy with conduction block Bastiaan Veugelers a, Paul Theys a, Martin Lammens b, Johan Van Hees a, Wim Robberecht a** ’ Department of Neurology, Universiry Hospital Gasthuisberg, Herestraat 49, 3000 Leaven, Be&an b Department of Pathology, University Hospital Gasthuisberg, Leuven, Belgium Received 31 May 1995; revised 25 August 1995; accepted 2 September 1995
Abstract We studied a 53-year-old woman with progressive weakness of the left arm, gradually spreading to the other limbs. Neurological examination revealed a motor neuron syndrome with paresis, fasciculations and atrophy. Electrophysiological studies showed multiple motor conduction blocks. The anti-GM1 IgM titer was elevated. The patient was thought to have a multifocal motor neuropathy. Despite intravenous cyclophosphamide treatment, however, she died with respiratory insufficiency. On postmortem examination, the brachial plexus showed patches of demyelination underlying different areas of motor conduction block. The spinal cord, however, revealed severe neuronal loss in the ventral horn and axonal loss in the corticospinal tract, indicative of amyotrophic lateral sclerosis. Demyelination of peripheral nerves could have been responsible for the other conduction blocks in this patient. The prominent degeneration of motor neurons, however, must also have played a role in the clinical picture. Some patients with the syndrome of a multifocal motor neuropathy may have MND rather than, or in addition to, a demyelinating peripheral motor neuropathy. Keywords: Motor neuropathy; Motor neuron disease; Amyotrophic
lateral sclerosis; Conduction block; Anti-GM1 antibodies
1. Introduction Multifocal motor neuropathy (MMN) is a rare disorder that can mimic motor neuron disease (Parry and Clark, 1988; Parry and Sumner, 1992). It is characterized clinically by progressive weakness and muscle atrophy, with no or only minor sensory changes. The diagnosis requires the identification of multifocal motor conduction blocks by electrophysiological study (Lange et al., 1992, 1993). The association of MMN with high titers of anti-GM, antibodies in many patients suggests an immunological abnormality in the pathogenesis (Pestronk et al., 1988, 1990; Feldman et al., 199 l), a hypothesis further supported by a favorable clinical response to treatment with immunosuppressive drugs or intravenous immunoglobulins (Feldman et al., 1991; Pestronk, 1991; Parry, 1993; Apostolski and Latov, 1993). The pathological basis of MMN has been documented only rarely so far, and in particular, very few data on the
’ Corresponding author. Fax: 32 16 34 42 85; Tel.: 32 16 34 42 80. 0022-510X/%/$15.00 0 19% Elsevier Science B.V. All rights reserved SSDI 0022-5 10X(95)00295-2
pathology of central nervous system motor neurons in MMN are available. Adams et al. (1993) reported one patient with a lower motor neuron syndrome with conduction block and high titers of anti-GM1 antibodies. These authors found pathological evidence for a proximal motor radiculoneuropathy with IgG and IgM deposits on nerve fibers. In addition, there was clear loss of spinal motor neurons, which was thought to be secondary to axonal damage. In this study we describe the pathological findings of the brachial plexus and spinal cord of a patient with a pure motor neuron syndrome and conduction blocks, suggesting MMN.
2. Case report An otherwise healthy 53-year-old woman was admitted because her left arm was weak. She related the onset of the weakness to minor trauma of the left shoulder. The weakness had been slowly progressive and confined to the left arm for 10 months. Two months before admission how-
B. Veugelers et al./Journal
of the Neurological
ever, the weakness spread to the other limbs. She had no paresthesiasor cramps. She reported no weight loss. Past medical history and family history were noncontributory. Neurological examination showed paralysis of the left arm. The right arm was graded 4/5 proximal, but intrinsic hand muscle strength was O/5. A diffuse 4/5 paresis of both legs was noted. There was atrophy of the muscles of the shoulder girdle, left arm, both hands, and the right leg. No fasciculations were seen. Hyporeflexia in the left arm was noted, but deep tendon reflexes were brisk in the other limbs. Hoffman-Triimner signs were absent. Plantar reflexes were normal. Cranial nerves were normal. Routine laboratory tests including spinal fluid analysis, immunoelectrophoresis and Borrelia serology were unremarkable. Anti-GM1 antibody titer (B.C. Jacobs, M.D., Rotterdam) was determined using an enzyme-linked immunosorbent assay and by thin layer chromatography, as extensively described (Jacobs et al., 1994). A clearly increased titer of 1:400 was found (normal < 1:lOO). The antibodies found were IgM proteins. MRI of the spinal cord was normal. A sural nerve biopsy was normal.
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Medelec). For each of the responses,the stimulus current that evoked the maximal response amplitude was clearly smaller than the maximal stimulus that could be generated by .the stimulator (100 mA). Amplitudes were measured from negative to positive maximum, and areas were measured by the computer program resident in the EMG machine. A reduction of amplitude and area of the CMAP by more than 50% without temporal dispersion was found in the right median, ulnar and left tibia1 nerves (Table 1 and Fig. l), indicating motor conduction blocks (Lange et al., 1992). Sensory nerve (median, ulnar and sural) action potentials and conduction velocity were normal. Electromyography showed positive sharp waves and fibrillation potentials in several muscles of the right arm and both legs. Polyphasic and desynchronized MUPs were obvious. In the same limbs, the recruitment pattern was reduced in all muscles examined.
2.1. Electrophysiology
Electrophysiological studies were performed using conventional equipment and standard methods. For motor conduction studies, electrical pulses were delivered using a constant voltage stimulator up to 250 V (Mystro MS 20,
2.2. Evolution
The patient was treated with cyclophosphamide, first intravenously, then orally. A total dose of 3 g/m* was administrated intravenously, followed by 100 mg orally daily. No other treatment was tried. Despite this treatment, the patient rapidly deteriorated for 6 weeks to complete tetraplegia and respiratory failure. Bulbar involvement was present but was not remarkable. The reflexes remained
Table 1 Amplitude, area and conduction velocity of motor nerves. The values indicating conduction block are in bold Site of stimulation
Amplitude
Area ( ~VS)
Negative phase duration (ms)
2 2.2 2.8 0.6
6.6 10.5 10.8 2.1
4 5.4 5.4 5.4
5.2 5.1 4.9 4 1
16 16.3 15 14.3 3.5
5 5.3 5.1 5.6 7
6 3.1
14.8 11
5.3 6.2
3.0 2 1.8
20 8.3 8
4.4 8.8 9.2
3.6 1.2
12 4
4.9 4.9
2.7 2.2 1.8
9.7 8 7
4.9 5.8 4.9
(mv) R median nerve wrist elbow axilla Erb’s point
Conduction velocity (m/s)
30
4.2
52.3
4.9
48
3.7
51.2
5.5
44.6
33.5
L peroneal nerve ankle below head fibula above head tibula
2.5
42.5 59.5
L tibia1 nerve ankle popliteal fossa
30.4
59.5 55.5
R peroneal nerve ankle below head fibula above head tibula
3.8
51
R tibia1 nerve ankle popliteal fossa
Latency of F-wave (ms)
42 47.8 45
R ulnar nerve wrist below elbow above elbow axilla Erb’s point
Terminal latency (ms)
45.5 72
66
B. Veugelers et al./Journal
of the Neurological
present and plantar reflexes remained in flexion. The duration of the illness was about 19 months. 2.3. Pathology
Macroscopic examination of the brachial plexus, spinal cord and brain did not show abnormalities. Both brachial plexus and the proximal median and ulnar nerves were examined. Paraffin-embedded sections were stained with hematoxylin and eosin for light microscopic examination. Immunohistochemical staining was done using antibodies to myelin basic protein (Dako) and neurofilaments (Sigma); the peroxidase anti-peroxidase method was used with diaminobenzidine as color reagent. Eponembedded sections were stained with paraphenylene diamine.
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On hematoxylin and eosin staining, no inflammatory changeswere found. Immunostaining using the anti-myelin basic protein antibodies and anti-neurofilament antibodies showed regions of demyelination with axonal sparing in the right proximal median nerve, immediately after its origin from the brachial plexus (Fig. 2). The ulnar part of the medial trunk of the right plexus, and the ulnar nerve 3 cm under its origin, showed similar patchesof demyelination. In the left median nerve, patchesof de- and remyelination were found 3 cm from its origin. In addition to the myelin changesdescribed, clear evidence of axonal degeneration was documented. Large axons with axonal sprouting were observed, and in the left brachial plexus, macrophagescontaining myelin debris were seen.Furthermore, as can be seenin Fig. 2, myelin ovoids were present. Routine examination of the cortex did not show any abnormalities. The spinal cord was examined at the cervical and thoracic level. The ventral spinal roots were atrophic. Hematoxylin and eosin stained sections showed severe motor neuron loss in the anterior horn, some of the remaining neurons showing chromatolysis (Fig. 3). Bunina bodies were present (Fig. 4) but axonal spheroidswere not evident. Gliosis was evident; no phagocytes were observed. No signs of inflammation were seen.Myelin staining of the spinal cord revealed pallor of the corticospinal tract (Fig. 5); the spinocerebellar tracts were not clearly affected. There was no evidence of demyeliniation in the ventral spinal roots. Examination of the brain stem showed loss of motor neurons and gliosis in the hypoglossal nucleus albeit less so than in the ventral horn of the spinal cord. The samebut milder abnormalities were found in the nucleus ambiguus. 3. Discussion
I
J 1 mv
2
mwe
d Fig. 1. Conduction block without dispersion in the right median (upper panel) and ulnar (lower panel) nerve, localized between the axilla and Erb’s point. Nerve stimulation for the median nerve (upper panel) is at the wrist (a), at the elbow (b), at the axilla (c) and at Erb’s point (d). The CMAP amplitude is larger in b than in a because of a Martin-Gnher anastomosis; the amplitude in c is larger than in b because of costimulation of the ulnar nerve. For the ulnar nerve (lower panel), nerve stimulation is distal form elbow (a), proximal form elbow (b), at the axilla (c) and at Erb’s point cd).
Our patient presented with a slowly progressive pure lower motor syndromein the upper extremity, which spread to involve the other extremities and then rapidly progressed to cause quadriplegia and to involve the respiratory muscles. Electrophysiological studies revealed multiple conduction blocks on motor nerves. To define this, we adhered to the definition suggestedbefore: a reduction of 50% or more of CMAP amplitude/area, not explained by temporal dispersion, implying that the potential’s duration should not increaseby more than 30% (Lange et al., 1993). In addition, an elevated titer of anti-GM1 antibodies was found. These findings suggestedthe diagnosis of MMN. Postmortem examination showed patchy demyelination to be the morphological substrateof conduction block. The reported pathological findings in patients with MMN have been rather consistent so far. In biopsies from motor nerves from the upper extremity, both Auer et al. (1989) and Kaji et al. (1993) demonstrated demyelination with onion bulb formation, bare axons and very thinly myelinated large axons. Our findings were similar to theirs but
B. Veugelers et al./Journal
of the Neurological
we did not find onion bulbs. In addition to these abnormalities, Bradley et al. (1988) described an inflammatory infiltrate in the brachial plexus. All three of these reports discussedbiopsy findings, and the central nervous system was not studied. Rowland et al. (1982) reported a patient with a syndrome of motor neuron disease. In the spinal cord, chromatolysis and other neuronal changes were attributed to retrograde degeneration. Both the cases of Bradley and Rowland showed diffuse slowing of motor conduction. Ghatak et al. (1986) described a patient with a lower motor neuron syndrome clinically and, at autopsy, showed both a demyelinating radiculopathy and anterior horn cell loss; he also had diffuse slowing of the motor nerve conduction without conduction block. Adams et al. (1993) described a patient rather similar to ours. Clear spinal motor neuron loss was documented in their case as well, and was thought to represent retrograde changes. There was no corticospinal axonal loss.
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Pathological examination of the spinal cord of our patient showed extensive motor neuron loss in the anterior horn and axonal loss in the corticospinal tracts, indicating that the disorder involved both the central and peripheral nervous systems.The findings suggestthat a motor neuron disease (MND) was the underlying disease and probably contributed more to the muscle weaknessthan the demyelination of peripheral nerves. Did this patient have MMN to begin with? It could be argued that the course was more rapid than expected in MMN and more like MND. However, subacute progression, evolution to quadriplegia, and respiratory involvement have all been described in MMN (Roth et al., 1986; Van den Bergh et al., 1989). Could the conduction block have been a erroneous diagnosis? Loss of CMAP area, probably due to phase cancellation, can erroneously suggest conduction block in MND (Lange et al., 1992, 1993). In such instanceshow-
Fig. 2. lmmunostaining using anti-MBP (upper panel) and anti-NF (lower panel) antibodies of longitudinal sections of the right median nerve, obtained at the origin in the plexus. Regions of demyelination with persistence of axons are indicated by arrows. Large arrow indicates myelin ovoids. Magnification 182X.
B. Veugelers et al./Journal
of the Neurological Sciences 136 (19%) 64-70
Fig. 3. H&E staining of spinal cord sections shows neuronal loss in the anterior horn. Remaining motor neurons show degenerative changes (arrows). Diffuse gliosis is evident. Magnification 350x.
ever, CMAP amplitude and area gradually fall over the length of the motor nerve, while our patient showed an abrupt loss of area. Conduction slowing was not present in our patient. This could be an argument against the presence of a genuine conduction block. However, the finding of focal demyelination underlying the area of conduction block strongly favors it to be a genuine abnormality. Furthermore, slowing seemsto be present in only 80% of
casesin the series of Lange et al. (19931, and is not to be expected if blocking is present in a subset of nerve fibers. The anti-GM1 antibody titer in our patient was clearly increased. High titers of these antibodies have been reported in patients with MMN (Pestronk et al., 1988, 1990). This finding suggestedthat MMN is an immunologically mediated condition, giving rise to successful treatment with immunosuppresants (Pestronk et al., 1988, 1990;
Fig. 4. H&E staining of motor neuron with 2 Bunina bodies (arrows). Magnification
1260x.
B. Veugelers et al. / Journal of the Neurological SciencesI36 (1596) 64-70
Fig. 5. Klbver-Banera section. Magnification
69
staining of transverse section of the thoracic spinal cord. Palor of the corticospinal tract is visible, most clearly on the left side of the 9.8 X .-
Pestronk, 1991; Feldman et al., 1991; Parry, 1993; Apostolski and Latov, 1993; Azulay et al., 1994). In low titers, the antibodies are present in a variety of conditions and need to be considered non-specific (Pestronk, 1991; Bansal et al., 1994). The pathophysiological role of these antibodies is still a matter of discussion, but there is evidence that they might induce demyeliniation and conduction block (Santoro et al., 1992; Uncini et al., 1993; Roberts et al., 1995). Anti-GM1 antibodies can be of the IgG or IgM class, as seen in our patient. The latter class may be more specific for MMN than the IgG class (Komberg and Pestronk, 1994). IgG anti-GM1 antibodies might actually play a pathogenic role in more acute axonal motor neuropathies such as the one associatedwith Campylubacter jejuni infections, resembling Guillain-Barre syndrome (Komberg et al., 1994; Komberg and Pestronk, 1994). Within the IgM class, further specification of the binding profile to antigens such as GMl, histone H3 and NP-9 has been suggestedto increase the significance of finding these antibodies in a patient with a motor neuron syndrome (Komberg and Pestronk, 1994). We could not perform these recently described tests in our patient. We thus believe that this patient fulfilled the diagnostic criteria for MMN, but that a MND was the underlying diseasewhich pathologically resembled classic ALS, with no inflammatory changesin the spinal cord, which would suggest a role for the anti-GM1 antibodies present (Corbo et al., 1992). The findings in our patient suggestthat some patients presenting with MMN may actually have MM). Rapid progression of the disease, as seen in our case and others (Roth et al., 1986; Van den Bergh et al., 1989) may indicate MND rather than MMN. The relationship between
MMN and MND, and the possible involvement of central motor structures id patients with conduction block requires further clarification. Acknowledgements
the authors are indebted to Mrs. L. Van Roey, L. D’olieslager and D. Kiraly for technical assistanceand Mr. A. Van Dormael for photography. W. Robberecht is a Clinical Investigator of the National Fund of Scientific Research,Belgium. References Adams, D., T. Kuntzer, A.J. Steck, A. Lobrinus, R.C. Janzer and F. Regli (1993) Motor conduction block and high titers of anti-GM1 ganghoside antibodies: pathological evidence of a motor neuropathy in a patient with lower motor neuron sydrome. J. Neurol. Neurosurg. Psychiatry, 56: 982-987. Apostolski, S. and N. Latov (1993) Clinical syndromes associated with anti-GM1 antibodies. Sem. Neurol., 13: 264-268. Auer, R.N., R.B. Bell and M.A. Lee (1989) Neuropathy with onion bulb formations and pure motor manifestations. Can. J. Neurol. Sci., 16: 194-197. Azulay J-P., 0. Blm, J. Pouget, J. Boucraut, F. Bill&Turc, G. Caries and G. Serratrice (1994) Intravenous immunoglobuhn treatment in patients with motor neuron syndromes associated with anti-GM1 antibodies: a double-blind, placebo-controlled study. Neurology, 44: 429-432. Bansal AS., B. Abdulkarim, R.A. Malik, P. Goulding, R.S.H. Pumphrey, A.J.M. Bouhon. P.L.J. Holt and P.B. Wilson (1994) IgM ganglioside GM1 antibodies in patients with autoimmune disease or neuropathy, and controls. J. Clin. Pathol., 47: 300-302.
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B. Veugelerset al./Journal of the Neurological Sciences136 (1996) 64-70
Bradley, W.G., R.K. Bemtet, P. Good and B. Little (1988) Proximal chronic inflammatory polyneuropathy with multifocal conduction block. Arch. Neurol., 45: 451-455. Corbo, M., A. Quattrini, A. Lugatesi, M. Santoro, N. Latov and A.P. Hays (1992) Patternsof reactivity of human anti-GM1 antibodies with spinal cord and motor neurons. Ann. Neural.. 32: 487-493. Feldman, E.L., M.B. Bromberg, J.W. Albers and A. Pestronk (1991) Immunosuppressivetreatment in multifocal motor neuropathy. Amt. Neurol., 30: 397-401. Ghatak, N.R.. W.W. Campbell, R.H. Lippman and M.G. Hadfield (1986) Anterior horn changes of motor neuron disease associated with demyelinating radiculopathy. J. Neuropathol.Exp. Neurol., 45: 385-395. Jacobs, B.C., H. Endtz and F.G.A. Van der Mech6 (1994) Serum anti-GQlb IgG antibodies recognize surfaceepitopes on Campylobacter jejuni form patients with Miller Fisher syndrome. Ann. Neurol., 37: 260-264. Kaji, R, 0. Nobuyuki. T. Teruyuki. T. Mezaki, T. Nishio, I. Akiguchi and J. Kimura (1993) Pathological findings at the site of conduction block in multifocal motor neuropathy. Ann. Neurol., 33: 152- 158. Komberg, A.J. and A. Pestronk(1994) The clinical and diagnostic role of anti-GM1 antibody testing. Muscle Nerve, 17: 100-104. Komberg, A.J., A. Pestronk, K. Bieser, T.W. Ho, G.M. McKahn, H.S. Wu and Z. Jiang (1994) The clinical correlates of high-titer IgG anti-GM1 antibodies. Ann. Neural., 35: 234-237. Lange, D.J., W. Trojaborg, N. Latov, A.P. Hays, D.S. Younger, A. Uncini, D.M. Blake, M. Hirano, S.M. Bums, R.E. Lovelace and L.P. Rowland (1992) Multifocal motor neuropathy with conduction block: is it a distinct clinical entity? Neurology, 42: 497-505. Lange, D.J., W. Trojaborg, T.D. McDonald and D.M. Blake. (1993) Persistent and ‘transient’ conduction block in motor neuron diseases. Muscle Nerve, 16: 896-903. Parry, G.J. (1993) Motor neuropathy with multifocal conduction block. Sem. Neurol., 13: 269-275. Parry, G.J. and S. Clark (1988) Multifocal acquired demyelinating neuropathy masquerading as motor neuron disease. Muscle Nerve, 11: 103-107.
Parry, G.J. and A.J. Sumner(19921Multifocal motor neuropathy.Neurol. Clin., lo: 671-684. Pestronk, A. (19911 Invited review: motor neuropathies, motor neuron disorders and antiglycolipid antibodies. Muscle Nerve, 14: 927-936. Pestronk, A., D.R. Comblath, A.A. Ilyas, H. Baba, R.H. Quarles, J.W. Gtifffm. K. Alderson and R.N. Adams (1988) A treatable multifocal motor neuropathy with antibodies to GM1 ganglioside. Ann. Neurol., 24: 73-78. Pesuonk, A., V. Chaudhry, E.L. Feldman, J.W. Gtiffm, D.R. Comblath, E..H. Denys. M. Glasberg. R.W. Kuncl, R.K. Ohrey and W.C. Yee (1990) Lower motor neuron syndromesdefined by patterns of weakness, nerve conduction abnormalities and high titers of antiglycolipid antibodies. Ann. Neurol., 27: 316-326. Roberts, M., HJ. Willison, A. Vincent, J. Newsomdavis (1995) Multifocal motor neuropathy human sera block distal motor nerve conduction in mice. Ann. Neurol., 38: 11l-l 18. Roth, R.G.. J. Rohr, M.R. Magisttis and F. Ochsner (1986) Motor neuropathy with proximal multifocal persistent conduction block, fasciculations, and myokymia. Eur. Neurol., 25: 416-423. Rowland, L.P., R. Defendini, W. Sherman, A. Hirano, M.R. Olarte, N. Latov, R.E. Lovelace, K. Inoue, E.F. Osserman(1982) Macroglobulinemia with peripheral neuropathy simulating motor neuron disease. Ann. Neurol., 11: 532-536. Santoro, M., A. Uncini. M. Corbo, S.M. Staugaitis, F.P. Thomas, A.P. Hays and N. Latov (19921Experimental conduction block induced by serum from a patient with anti-GM1 antibodies. Ann. Neural., 31: 385-390. Uncini, A., M. Santoro, M. Corbo, A. Lugaresi and N. Latov (1993) Conduction abnormalities induced by sera of patients with multifocal motor neuropathy and anti-GM1 antibodies. Muscle Nerve, 16: 610615. Van den Bergh, P., E.L. Logigian and J.J. Kelly Jr (1989) Motor neuropathy with multifocal conduction blocks. Muscle Nerve, 11: 26-3 1.
OF TNE
NEUROLOGICAL SCIENCES
EISEVIER
Journal of the Neurological Sciences 136 ( 1996) 64-70
Pathological findings in a patient with amyotrophic lateral sclerosis and multifocal motor neuropathy with conduction block Bastiaan Veugelers a, Paul Theys a, Martin Lammens b, Johan Van Hees a, Wim Robberecht a** ’ Department of Neurology, Universiry Hospital Gasthuisberg, Herestraat 49, 3000 Leaven, Be&an b Department of Pathology, University Hospital Gasthuisberg, Leuven, Belgium Received 31 May 1995; revised 25 August 1995; accepted 2 September 1995
Abstract We studied a 53-year-old woman with progressive weakness of the left arm, gradually spreading to the other limbs. Neurological examination revealed a motor neuron syndrome with paresis, fasciculations and atrophy. Electrophysiological studies showed multiple motor conduction blocks. The anti-GM1 IgM titer was elevated. The patient was thought to have a multifocal motor neuropathy. Despite intravenous cyclophosphamide treatment, however, she died with respiratory insufficiency. On postmortem examination, the brachial plexus showed patches of demyelination underlying different areas of motor conduction block. The spinal cord, however, revealed severe neuronal loss in the ventral horn and axonal loss in the corticospinal tract, indicative of amyotrophic lateral sclerosis. Demyelination of peripheral nerves could have been responsible for the other conduction blocks in this patient. The prominent degeneration of motor neurons, however, must also have played a role in the clinical picture. Some patients with the syndrome of a multifocal motor neuropathy may have MND rather than, or in addition to, a demyelinating peripheral motor neuropathy. Keywords: Motor neuropathy; Motor neuron disease; Amyotrophic
lateral sclerosis; Conduction block; Anti-GM1 antibodies
1. Introduction Multifocal motor neuropathy (MMN) is a rare disorder that can mimic motor neuron disease (Parry and Clark, 1988; Parry and Sumner, 1992). It is characterized clinically by progressive weakness and muscle atrophy, with no or only minor sensory changes. The diagnosis requires the identification of multifocal motor conduction blocks by electrophysiological study (Lange et al., 1992, 1993). The association of MMN with high titers of anti-GM, antibodies in many patients suggests an immunological abnormality in the pathogenesis (Pestronk et al., 1988, 1990; Feldman et al., 199 l), a hypothesis further supported by a favorable clinical response to treatment with immunosuppressive drugs or intravenous immunoglobulins (Feldman et al., 1991; Pestronk, 1991; Parry, 1993; Apostolski and Latov, 1993). The pathological basis of MMN has been documented only rarely so far, and in particular, very few data on the
’ Corresponding author. Fax: 32 16 34 42 85; Tel.: 32 16 34 42 80. 0022-510X/%/$15.00 0 19% Elsevier Science B.V. All rights reserved SSDI 0022-5 10X(95)00295-2
pathology of central nervous system motor neurons in MMN are available. Adams et al. (1993) reported one patient with a lower motor neuron syndrome with conduction block and high titers of anti-GM1 antibodies. These authors found pathological evidence for a proximal motor radiculoneuropathy with IgG and IgM deposits on nerve fibers. In addition, there was clear loss of spinal motor neurons, which was thought to be secondary to axonal damage. In this study we describe the pathological findings of the brachial plexus and spinal cord of a patient with a pure motor neuron syndrome and conduction blocks, suggesting MMN.
2. Case report An otherwise healthy 53-year-old woman was admitted because her left arm was weak. She related the onset of the weakness to minor trauma of the left shoulder. The weakness had been slowly progressive and confined to the left arm for 10 months. Two months before admission how-
B. Veugelers et al./Journal
of the Neurological
ever, the weakness spread to the other limbs. She had no paresthesiasor cramps. She reported no weight loss. Past medical history and family history were noncontributory. Neurological examination showed paralysis of the left arm. The right arm was graded 4/5 proximal, but intrinsic hand muscle strength was O/5. A diffuse 4/5 paresis of both legs was noted. There was atrophy of the muscles of the shoulder girdle, left arm, both hands, and the right leg. No fasciculations were seen. Hyporeflexia in the left arm was noted, but deep tendon reflexes were brisk in the other limbs. Hoffman-Triimner signs were absent. Plantar reflexes were normal. Cranial nerves were normal. Routine laboratory tests including spinal fluid analysis, immunoelectrophoresis and Borrelia serology were unremarkable. Anti-GM1 antibody titer (B.C. Jacobs, M.D., Rotterdam) was determined using an enzyme-linked immunosorbent assay and by thin layer chromatography, as extensively described (Jacobs et al., 1994). A clearly increased titer of 1:400 was found (normal < 1:lOO). The antibodies found were IgM proteins. MRI of the spinal cord was normal. A sural nerve biopsy was normal.
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65
Medelec). For each of the responses,the stimulus current that evoked the maximal response amplitude was clearly smaller than the maximal stimulus that could be generated by .the stimulator (100 mA). Amplitudes were measured from negative to positive maximum, and areas were measured by the computer program resident in the EMG machine. A reduction of amplitude and area of the CMAP by more than 50% without temporal dispersion was found in the right median, ulnar and left tibia1 nerves (Table 1 and Fig. l), indicating motor conduction blocks (Lange et al., 1992). Sensory nerve (median, ulnar and sural) action potentials and conduction velocity were normal. Electromyography showed positive sharp waves and fibrillation potentials in several muscles of the right arm and both legs. Polyphasic and desynchronized MUPs were obvious. In the same limbs, the recruitment pattern was reduced in all muscles examined.
2.1. Electrophysiology
Electrophysiological studies were performed using conventional equipment and standard methods. For motor conduction studies, electrical pulses were delivered using a constant voltage stimulator up to 250 V (Mystro MS 20,
2.2. Evolution
The patient was treated with cyclophosphamide, first intravenously, then orally. A total dose of 3 g/m* was administrated intravenously, followed by 100 mg orally daily. No other treatment was tried. Despite this treatment, the patient rapidly deteriorated for 6 weeks to complete tetraplegia and respiratory failure. Bulbar involvement was present but was not remarkable. The reflexes remained
Table 1 Amplitude, area and conduction velocity of motor nerves. The values indicating conduction block are in bold Site of stimulation
Amplitude
Area ( ~VS)
Negative phase duration (ms)
2 2.2 2.8 0.6
6.6 10.5 10.8 2.1
4 5.4 5.4 5.4
5.2 5.1 4.9 4 1
16 16.3 15 14.3 3.5
5 5.3 5.1 5.6 7
6 3.1
14.8 11
5.3 6.2
3.0 2 1.8
20 8.3 8
4.4 8.8 9.2
3.6 1.2
12 4
4.9 4.9
2.7 2.2 1.8
9.7 8 7
4.9 5.8 4.9
(mv) R median nerve wrist elbow axilla Erb’s point
Conduction velocity (m/s)
30
4.2
52.3
4.9
48
3.7
51.2
5.5
44.6
33.5
L peroneal nerve ankle below head fibula above head tibula
2.5
42.5 59.5
L tibia1 nerve ankle popliteal fossa
30.4
59.5 55.5
R peroneal nerve ankle below head fibula above head tibula
3.8
51
R tibia1 nerve ankle popliteal fossa
Latency of F-wave (ms)
42 47.8 45
R ulnar nerve wrist below elbow above elbow axilla Erb’s point
Terminal latency (ms)
45.5 72
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of the Neurological
present and plantar reflexes remained in flexion. The duration of the illness was about 19 months. 2.3. Pathology
Macroscopic examination of the brachial plexus, spinal cord and brain did not show abnormalities. Both brachial plexus and the proximal median and ulnar nerves were examined. Paraffin-embedded sections were stained with hematoxylin and eosin for light microscopic examination. Immunohistochemical staining was done using antibodies to myelin basic protein (Dako) and neurofilaments (Sigma); the peroxidase anti-peroxidase method was used with diaminobenzidine as color reagent. Eponembedded sections were stained with paraphenylene diamine.
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On hematoxylin and eosin staining, no inflammatory changeswere found. Immunostaining using the anti-myelin basic protein antibodies and anti-neurofilament antibodies showed regions of demyelination with axonal sparing in the right proximal median nerve, immediately after its origin from the brachial plexus (Fig. 2). The ulnar part of the medial trunk of the right plexus, and the ulnar nerve 3 cm under its origin, showed similar patchesof demyelination. In the left median nerve, patchesof de- and remyelination were found 3 cm from its origin. In addition to the myelin changesdescribed, clear evidence of axonal degeneration was documented. Large axons with axonal sprouting were observed, and in the left brachial plexus, macrophagescontaining myelin debris were seen.Furthermore, as can be seenin Fig. 2, myelin ovoids were present. Routine examination of the cortex did not show any abnormalities. The spinal cord was examined at the cervical and thoracic level. The ventral spinal roots were atrophic. Hematoxylin and eosin stained sections showed severe motor neuron loss in the anterior horn, some of the remaining neurons showing chromatolysis (Fig. 3). Bunina bodies were present (Fig. 4) but axonal spheroidswere not evident. Gliosis was evident; no phagocytes were observed. No signs of inflammation were seen.Myelin staining of the spinal cord revealed pallor of the corticospinal tract (Fig. 5); the spinocerebellar tracts were not clearly affected. There was no evidence of demyeliniation in the ventral spinal roots. Examination of the brain stem showed loss of motor neurons and gliosis in the hypoglossal nucleus albeit less so than in the ventral horn of the spinal cord. The samebut milder abnormalities were found in the nucleus ambiguus. 3. Discussion
I
J 1 mv
2
mwe
d Fig. 1. Conduction block without dispersion in the right median (upper panel) and ulnar (lower panel) nerve, localized between the axilla and Erb’s point. Nerve stimulation for the median nerve (upper panel) is at the wrist (a), at the elbow (b), at the axilla (c) and at Erb’s point (d). The CMAP amplitude is larger in b than in a because of a Martin-Gnher anastomosis; the amplitude in c is larger than in b because of costimulation of the ulnar nerve. For the ulnar nerve (lower panel), nerve stimulation is distal form elbow (a), proximal form elbow (b), at the axilla (c) and at Erb’s point cd).
Our patient presented with a slowly progressive pure lower motor syndromein the upper extremity, which spread to involve the other extremities and then rapidly progressed to cause quadriplegia and to involve the respiratory muscles. Electrophysiological studies revealed multiple conduction blocks on motor nerves. To define this, we adhered to the definition suggestedbefore: a reduction of 50% or more of CMAP amplitude/area, not explained by temporal dispersion, implying that the potential’s duration should not increaseby more than 30% (Lange et al., 1993). In addition, an elevated titer of anti-GM1 antibodies was found. These findings suggestedthe diagnosis of MMN. Postmortem examination showed patchy demyelination to be the morphological substrateof conduction block. The reported pathological findings in patients with MMN have been rather consistent so far. In biopsies from motor nerves from the upper extremity, both Auer et al. (1989) and Kaji et al. (1993) demonstrated demyelination with onion bulb formation, bare axons and very thinly myelinated large axons. Our findings were similar to theirs but
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we did not find onion bulbs. In addition to these abnormalities, Bradley et al. (1988) described an inflammatory infiltrate in the brachial plexus. All three of these reports discussedbiopsy findings, and the central nervous system was not studied. Rowland et al. (1982) reported a patient with a syndrome of motor neuron disease. In the spinal cord, chromatolysis and other neuronal changes were attributed to retrograde degeneration. Both the cases of Bradley and Rowland showed diffuse slowing of motor conduction. Ghatak et al. (1986) described a patient with a lower motor neuron syndrome clinically and, at autopsy, showed both a demyelinating radiculopathy and anterior horn cell loss; he also had diffuse slowing of the motor nerve conduction without conduction block. Adams et al. (1993) described a patient rather similar to ours. Clear spinal motor neuron loss was documented in their case as well, and was thought to represent retrograde changes. There was no corticospinal axonal loss.
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Pathological examination of the spinal cord of our patient showed extensive motor neuron loss in the anterior horn and axonal loss in the corticospinal tracts, indicating that the disorder involved both the central and peripheral nervous systems.The findings suggestthat a motor neuron disease (MND) was the underlying disease and probably contributed more to the muscle weaknessthan the demyelination of peripheral nerves. Did this patient have MMN to begin with? It could be argued that the course was more rapid than expected in MMN and more like MND. However, subacute progression, evolution to quadriplegia, and respiratory involvement have all been described in MMN (Roth et al., 1986; Van den Bergh et al., 1989). Could the conduction block have been a erroneous diagnosis? Loss of CMAP area, probably due to phase cancellation, can erroneously suggest conduction block in MND (Lange et al., 1992, 1993). In such instanceshow-
Fig. 2. lmmunostaining using anti-MBP (upper panel) and anti-NF (lower panel) antibodies of longitudinal sections of the right median nerve, obtained at the origin in the plexus. Regions of demyelination with persistence of axons are indicated by arrows. Large arrow indicates myelin ovoids. Magnification 182X.
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Fig. 3. H&E staining of spinal cord sections shows neuronal loss in the anterior horn. Remaining motor neurons show degenerative changes (arrows). Diffuse gliosis is evident. Magnification 350x.
ever, CMAP amplitude and area gradually fall over the length of the motor nerve, while our patient showed an abrupt loss of area. Conduction slowing was not present in our patient. This could be an argument against the presence of a genuine conduction block. However, the finding of focal demyelination underlying the area of conduction block strongly favors it to be a genuine abnormality. Furthermore, slowing seemsto be present in only 80% of
casesin the series of Lange et al. (19931, and is not to be expected if blocking is present in a subset of nerve fibers. The anti-GM1 antibody titer in our patient was clearly increased. High titers of these antibodies have been reported in patients with MMN (Pestronk et al., 1988, 1990). This finding suggestedthat MMN is an immunologically mediated condition, giving rise to successful treatment with immunosuppresants (Pestronk et al., 1988, 1990;
Fig. 4. H&E staining of motor neuron with 2 Bunina bodies (arrows). Magnification
1260x.
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Fig. 5. Klbver-Banera section. Magnification
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staining of transverse section of the thoracic spinal cord. Palor of the corticospinal tract is visible, most clearly on the left side of the 9.8 X .-
Pestronk, 1991; Feldman et al., 1991; Parry, 1993; Apostolski and Latov, 1993; Azulay et al., 1994). In low titers, the antibodies are present in a variety of conditions and need to be considered non-specific (Pestronk, 1991; Bansal et al., 1994). The pathophysiological role of these antibodies is still a matter of discussion, but there is evidence that they might induce demyeliniation and conduction block (Santoro et al., 1992; Uncini et al., 1993; Roberts et al., 1995). Anti-GM1 antibodies can be of the IgG or IgM class, as seen in our patient. The latter class may be more specific for MMN than the IgG class (Komberg and Pestronk, 1994). IgG anti-GM1 antibodies might actually play a pathogenic role in more acute axonal motor neuropathies such as the one associatedwith Campylubacter jejuni infections, resembling Guillain-Barre syndrome (Komberg et al., 1994; Komberg and Pestronk, 1994). Within the IgM class, further specification of the binding profile to antigens such as GMl, histone H3 and NP-9 has been suggestedto increase the significance of finding these antibodies in a patient with a motor neuron syndrome (Komberg and Pestronk, 1994). We could not perform these recently described tests in our patient. We thus believe that this patient fulfilled the diagnostic criteria for MMN, but that a MND was the underlying diseasewhich pathologically resembled classic ALS, with no inflammatory changesin the spinal cord, which would suggest a role for the anti-GM1 antibodies present (Corbo et al., 1992). The findings in our patient suggestthat some patients presenting with MMN may actually have MM). Rapid progression of the disease, as seen in our case and others (Roth et al., 1986; Van den Bergh et al., 1989) may indicate MND rather than MMN. The relationship between
MMN and MND, and the possible involvement of central motor structures id patients with conduction block requires further clarification. Acknowledgements
the authors are indebted to Mrs. L. Van Roey, L. D’olieslager and D. Kiraly for technical assistanceand Mr. A. Van Dormael for photography. W. Robberecht is a Clinical Investigator of the National Fund of Scientific Research,Belgium. References Adams, D., T. Kuntzer, A.J. Steck, A. Lobrinus, R.C. Janzer and F. Regli (1993) Motor conduction block and high titers of anti-GM1 ganghoside antibodies: pathological evidence of a motor neuropathy in a patient with lower motor neuron sydrome. J. Neurol. Neurosurg. Psychiatry, 56: 982-987. Apostolski, S. and N. Latov (1993) Clinical syndromes associated with anti-GM1 antibodies. Sem. Neurol., 13: 264-268. Auer, R.N., R.B. Bell and M.A. Lee (1989) Neuropathy with onion bulb formations and pure motor manifestations. Can. J. Neurol. Sci., 16: 194-197. Azulay J-P., 0. Blm, J. Pouget, J. Boucraut, F. Bill&Turc, G. Caries and G. Serratrice (1994) Intravenous immunoglobuhn treatment in patients with motor neuron syndromes associated with anti-GM1 antibodies: a double-blind, placebo-controlled study. Neurology, 44: 429-432. Bansal AS., B. Abdulkarim, R.A. Malik, P. Goulding, R.S.H. Pumphrey, A.J.M. Bouhon. P.L.J. Holt and P.B. Wilson (1994) IgM ganglioside GM1 antibodies in patients with autoimmune disease or neuropathy, and controls. J. Clin. Pathol., 47: 300-302.
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Bradley, W.G., R.K. Bemtet, P. Good and B. Little (1988) Proximal chronic inflammatory polyneuropathy with multifocal conduction block. Arch. Neurol., 45: 451-455. Corbo, M., A. Quattrini, A. Lugatesi, M. Santoro, N. Latov and A.P. Hays (1992) Patternsof reactivity of human anti-GM1 antibodies with spinal cord and motor neurons. Ann. Neural.. 32: 487-493. Feldman, E.L., M.B. Bromberg, J.W. Albers and A. Pestronk (1991) Immunosuppressivetreatment in multifocal motor neuropathy. Amt. Neurol., 30: 397-401. Ghatak, N.R.. W.W. Campbell, R.H. Lippman and M.G. Hadfield (1986) Anterior horn changes of motor neuron disease associated with demyelinating radiculopathy. J. Neuropathol.Exp. Neurol., 45: 385-395. Jacobs, B.C., H. Endtz and F.G.A. Van der Mech6 (1994) Serum anti-GQlb IgG antibodies recognize surfaceepitopes on Campylobacter jejuni form patients with Miller Fisher syndrome. Ann. Neurol., 37: 260-264. Kaji, R, 0. Nobuyuki. T. Teruyuki. T. Mezaki, T. Nishio, I. Akiguchi and J. Kimura (1993) Pathological findings at the site of conduction block in multifocal motor neuropathy. Ann. Neurol., 33: 152- 158. Komberg, A.J. and A. Pestronk(1994) The clinical and diagnostic role of anti-GM1 antibody testing. Muscle Nerve, 17: 100-104. Komberg, A.J., A. Pestronk, K. Bieser, T.W. Ho, G.M. McKahn, H.S. Wu and Z. Jiang (1994) The clinical correlates of high-titer IgG anti-GM1 antibodies. Ann. Neural., 35: 234-237. Lange, D.J., W. Trojaborg, N. Latov, A.P. Hays, D.S. Younger, A. Uncini, D.M. Blake, M. Hirano, S.M. Bums, R.E. Lovelace and L.P. Rowland (1992) Multifocal motor neuropathy with conduction block: is it a distinct clinical entity? Neurology, 42: 497-505. Lange, D.J., W. Trojaborg, T.D. McDonald and D.M. Blake. (1993) Persistent and ‘transient’ conduction block in motor neuron diseases. Muscle Nerve, 16: 896-903. Parry, G.J. (1993) Motor neuropathy with multifocal conduction block. Sem. Neurol., 13: 269-275. Parry, G.J. and S. Clark (1988) Multifocal acquired demyelinating neuropathy masquerading as motor neuron disease. Muscle Nerve, 11: 103-107.
Parry, G.J. and A.J. Sumner(19921Multifocal motor neuropathy.Neurol. Clin., lo: 671-684. Pestronk, A. (19911 Invited review: motor neuropathies, motor neuron disorders and antiglycolipid antibodies. Muscle Nerve, 14: 927-936. Pestronk, A., D.R. Comblath, A.A. Ilyas, H. Baba, R.H. Quarles, J.W. Gtifffm. K. Alderson and R.N. Adams (1988) A treatable multifocal motor neuropathy with antibodies to GM1 ganglioside. Ann. Neurol., 24: 73-78. Pesuonk, A., V. Chaudhry, E.L. Feldman, J.W. Gtiffm, D.R. Comblath, E..H. Denys. M. Glasberg. R.W. Kuncl, R.K. Ohrey and W.C. Yee (1990) Lower motor neuron syndromesdefined by patterns of weakness, nerve conduction abnormalities and high titers of antiglycolipid antibodies. Ann. Neurol., 27: 316-326. Roberts, M., HJ. Willison, A. Vincent, J. Newsomdavis (1995) Multifocal motor neuropathy human sera block distal motor nerve conduction in mice. Ann. Neurol., 38: 11l-l 18. Roth, R.G.. J. Rohr, M.R. Magisttis and F. Ochsner (1986) Motor neuropathy with proximal multifocal persistent conduction block, fasciculations, and myokymia. Eur. Neurol., 25: 416-423. Rowland, L.P., R. Defendini, W. Sherman, A. Hirano, M.R. Olarte, N. Latov, R.E. Lovelace, K. Inoue, E.F. Osserman(1982) Macroglobulinemia with peripheral neuropathy simulating motor neuron disease. Ann. Neurol., 11: 532-536. Santoro, M., A. Uncini. M. Corbo, S.M. Staugaitis, F.P. Thomas, A.P. Hays and N. Latov (19921Experimental conduction block induced by serum from a patient with anti-GM1 antibodies. Ann. Neural., 31: 385-390. Uncini, A., M. Santoro, M. Corbo, A. Lugaresi and N. Latov (1993) Conduction abnormalities induced by sera of patients with multifocal motor neuropathy and anti-GM1 antibodies. Muscle Nerve, 16: 610615. Van den Bergh, P., E.L. Logigian and J.J. Kelly Jr (1989) Motor neuropathy with multifocal conduction blocks. Muscle Nerve, 11: 26-3 1.