Journal of Neuropathology and Experimental Neurology
Copyright q 2004 by the American Association of Neuropathologists
Vol. 63, No. 2
February, 2004
pp. 129 137
Multifocal Motor Neuropathy: Pathologic Alterations at the Site of Conduction Block
BRUCE V. TAYLOR, MD, P. JAMES B. DYCK, MD, JANEAN ENGELSTAD, HT, GREGORY GRUENER, MD,
IAN GRANT, MD, AND PETER J. DYCK, MD
Abstract. The pathologic changes of nerves in multifocal motor neuropathy (MMN), a rare neuropathy with selective focal
conduction block of motor fibers in mixed nerves, remain essentially unstudied. Fascicular nerve biopsy of 8 forearm or arm
nerves in 7 patients with typical MMN was undertaken for diagnostic reasons at the site of the conduction block. Abnormalities
were seen in 7 of 8 nerves, including a varying degree of multifocal fiber degeneration and loss, an altered fiber size
distribution with fewer large fibers, an increased frequency of remyelinated fiber profiles, and frequent and prominent regenerating fiber clusters. Small epineurial perivascular inflammatory infiltrates were observed in 2 nerves. We did not observe
overt segmental demyelination or onion bulb formation. We hypothesize that an antibody-mediated attack directed against
components of axolemma at nodes of Ranvier could cause conduction block, transitory paranodal demyelination and remyelination, and axonal degeneration and regeneration. Alternatively, the antibody attack could be directed at components of
paranodal myelin. We favor the first hypothesis because in nerves studied by us, axonal pathological alteration predominated
over myelin pathology. Irrespective of which mechanism is involved, we conclude that the unequivocal multifocal fiber
degeneration and loss and regenerative clusters at sites of conduction block explains the observed clinical muscle weakness
and atrophy and alterations of motor unit potentials. The occurrence of conduction block and multifocal fiber degeneration
and regeneration at the same sites suggests that the processes of conduction block and fiber degeneration and regeneration
are linked. Finding discrete multifocal fiber degeneration may also provide an explanation for why the functional abnormalities
remain unchanged over long periods of time at discrete proximal to distal levels of nerve and may emphasize a need for
early intervention (assuming that efficacious treatment is available).
Key Words:
Axonal degeneration; Multifocal motor neuropathy; Nerve fiber degeneration; Regenerating nerve clusters.
INTRODUCTION
Multifocal motor neuropathy with persistent conduction
block (MMN-PCB, or simply MMN) is a rare neuropathy
clinically characterized by multiple pure motor mononeuropathies and electrophysiologically by persistent motor
conduction block. It has a predilection for the upper limbs,
particularly the forearm segments of mixed nerves, and often results in asymmetrical painless wasting and weakness
of the hands. Sensory or autonomic nerve involvement and
upper motor neuron signs or symptoms are atypical of the
disorder (1).
The regions of focal motor conduction block of limb
nerves are not at common compression sites and these sites
do not change over long periods of time. Sensory fibers
remain unblocked. The exact criteria for conduction block
are somewhat controversial but there is agreement on general principles (2). We have proposed diagnostic criteria,
From Peripheral Neuropathy Research Center (PJBD, JE, PJD), Department of Neurology, Mayo Clinic and Mayo Foundation, Rochester,
Minnesota. This report was initiated while Drs. Taylor, Gruener, and
Grant were visiting clinicians or peripheral nerve fellows in the Peripheral Neuropathy Research Center, Department of Neurology, Mayo
Clinic and Mayo Foundation, Rochester, Minnesota. Their present affiliations are Department of Neurology (GG), Loyola University Chicago, Maywood, Illinois; Department of Neurology (BVT), Royal Hobart Hospital, Hobart Tasmania, Australia; Division of Neurology (IG),
QE II Health Sciences Center, Halifax, Nova Scotia, Canada.
Correspondence to: Peter J. Dyck, MD, Mayo Clinic, 200 First Street
SW, Rochester, MN 55905. E-mail: [email protected]
Supported in part by grants obtained from the National Institute of
Neurological Diseases and Stroke (NINDS 36797) and Mayo Foundation.
which we use for the identification of our cases (1). However, lesser degrees or no conduction block could conceivably occur in a subset of patients with the same disorder
(3–5).
The pathologic changes underlying the muscle weakness and atrophy and motor unit potential change and the
conduction block have been studied in only a few patients, presumably because nerve tissue at sites of conduction block was not available for study. The presence
of conduction block in motor fibers and the other clinical
and electromyographic findings have been taken by some
authors as evidence of demyelination with secondary axonal degeneration resulting in denervation and atrophy
(6, 7). Other authors have speculated that a functional
block at nodes of Ranvier results in block of saltatory
conduction (8). This finding has been supported by recent
work suggesting that the axon distal to the site of conduction block in MMN is hyperpolarized with similar
electrical properties to that seen in ischemic axons and
consistent with dysfunction of the voltage gated Na1/K1
channels (9).
It is generally felt that MMN is an autoimmune disorder based on the response to immunomodulating therapy (10–14) and an association with high titers of antiganglioside antibodies in a proportion of cases (15–17).
Two previous pathological studies of individual cases
of MMN have been reported. Auer et al (18) reported a
patient with onion bulbs and pure motor manifestations.
Clinically, their patient probably had MMN. They biopsied a proximal ulnar nerve and reported finding a chronic demyelinating process and onion bulbs. We note that
129
130
TAYLOR ET AL
frank demyelination was not seen and that a regenerative
cluster is shown in one of their figures. The MMN case
of Kaji et al is informative in that focal segmental demyelination and remyelination and onion bulbs are illustrated (19). Neither of these reports provides an explanation for the obvious muscle weakness and atrophy and
motor unit potential changes that are characteristic of
many chronic cases. Corse et al have reported minor
changes in the sural nerves of patients with MMN, but
since the sural nerve is not known to be affected in
MMN, pathological inferences to MMN may not be justified (20).
The present report focuses on the pathologic alterations
in fascicular biopsy specimens of forearm or arm nerves
at the site of conduction block of a series of patients with
well-documented typical MMN.
MATERIALS AND METHODS
All patients met our previously published clinical and electrophysiological criteria for MMN (1). The clinical features of
patients 2 through 6 have been included in previous reports (1).
Fascicular biopsies of forearm or arm nerves were obtained at
sites of conduction block for diagnostic and treatment considerations to ascertain whether a treatable pathologic alteration
(e.g. inflammatory demyelination, necrotizing vasculitis, granuloma, a constrictive lesion, or tumor) was present. We submitted and obtained permission from the Institutional Review
Board and from the patient to study the dossier medical records
and tissues for research purposes.
Before biopsy the anatomical location of the nerve and the
site of the lower edge of the conduction block was determined
and marked on the skin. After surgical exposure of the nerve
the epineurium was slit longitudinally to expose individual or
small groups of fascicles. Intraoperatively, sutures were used to
lightly elevate fascicles from the nerve bed so that individual
or small groups of fascicles could be stimulated by microelectrodes to identify fascicles with motor fibers and the distal site
of conduction block. Such fascicles, or preferably 2 to 3 fascicles (so as to have some intervening epineurial tissue), were
biopsied from a point approximately 2.5 cm above, to about
2.5 cm below the distal edge of conduction block. The procedures we use for nerve fixation, histological processing, and
evaluation have been described (21). As for all nerve biopsies,
we maintained the proximal to distal identity of tissue blocks
and the proximal to distal orientation of individual blocks. In
all cases where sufficient tissue was available, teased fibers and
epoxy sections (for light and electron microscopy) were prepared from tissue blocks at several levels to assess proximal to
distal changes.
Our interactive system for nerve morphometry (ISNM) was
used for morphometric studies of all fascicles and of sections
of proximal to distal blocks to assess for proximal to distal
changes and to determine fiber density, fiber size distribution,
number of regenerating clusters, and number of degenerating
nerve fiber profiles. The approaches used in the development
of ISNM have been extensively described and validated and
extensively employed in experimental and clinical studies (21–
25).
J Neuropathol Exp Neurol, Vol 63, February, 2004
Systematic sampling is used both for study of teased fibers
and morphometric assessment so as to avoid biased selection
of fibers or frames for analysis. For teased fibers, the fascicular
endoneurium is divided into 50 strands of nerve tissue and
small strands of endoneurial tissue are teased from the right
hand side of each of these 50 strands, whether the tissue contains fibers or not. By this approach we avoid selecting strands
of tissue with large-diameter fibers. Likewise in morphometric
assessment, the transverse fascicular area is subdivided into
rectangular frames. We begin by determining the frequency of
frames to be evaluated (e.g. 1 in 3 frames). Then we traverse
the endoneurial area in an x and y direction. The first frame to
be evaluated is chosen by chance and thereafter every third
frame (partial or whole) is evaluated. This approach ensures
systematic sampling of the entire cross-sectional endoneurium.
No control biopsy tissue obtained at biopsy and processed
by the same techniques was available for comparison. However,
the histological features of paraffin sections and morphometry
of myelinated fibers in semithin epoxy sections of 2 ulnar forearm nerves, taken within 6 hours of death from patients without
neurologic disease, were studied for comparative purposes.
RESULTS
The demographic, clinical, and electrophysiological
features of the 7 patients are given in Table 1. These
features are typical for patients with MMN (21, 26). The
major pathologic findings were a marked reduction of the
numbers of myelinated fibers (Fig. 1) in transverse sections of nerve, focal, and multifocal regions. These regions were almost devoid of large fibers with mostly
small fibers remaining. In some sections there appeared
to be an increased number of intermediate-sized fibers
with thin myelin. By electron microscopy many of the
small fibers were in regenerative clusters (Fig. 2), showing increased frequency of degenerating axons and small
perivascular lymphocyte infiltrates (Fig. 3). Paranodal or
internodal demyelination (absent myelin) or onion bulb
formations were not seen. These changes are described
in more detail below.
Teased Fibers
Examination of teased nerve fiber preparations from
all nerves and in 5 nerves from at least 2 levels of the
same nerve revealed a low rate of axonal degeneration
(median 4%, range 1%–10%) of classifiable fibers. Although we only have anecdotal information about the frequency of axonal degeneration from mixed nerves of the
upper limbs in controls, we judge the frequency to be
increased in some of the nerves. Teased fibers with unequivocal de- and remyelination were infrequent and
probably not more frequent than in controls. A proximal
to distal gradient of teased fiber change was not observed.
Paraffin and Epoxy Sections
Light microscopy of transverse and longitudinal paraffin sections revealed no major alterations of nerve architecture. The most striking abnormality found in epoxy
CONDUCTION BLOCK ALTERATIONS IN MULTIFOCAL MOTOR NEUROPATHY
131
TABLE 1
Clinical Electrophysiological and Demographic Features of 7 MMN Cases
Case
Sex
1
2
3
4
5
6
7
F
M
M
M
M
F
F
Age at time
of biopsy
51
29
29
48
47
64
51
years
years
years
years
years
years
years
Sites of definite
conduction blocks
RU, LP
LU, LM
LU, LP, LT
RM, LR, LM
LU, LMC
RM, LM, RU, RP
RM, RMC, LM, LU
Disease
duration
6
5
2
6
22
3
20
Years
Years
Years
Years
Years
Years
Years
NIS at time
of biopsy
Response to
therapy
Atypical features
24.5
29
5.5
19
127.5
20.5
39
Uncertain
Marked
Moderate
Marked
Mild
Marked
Moderate
None
None
Type 1 DM 23 years
None
None
None
No
All conduction blocks were graded as definite according to the criteria of Taylor et al (1). Disease duration is the time from
symptom onset to biopsy. All nerve conduction studies and determination of sites of definite block were performed just prior to
biopsy. Abbreviations: RU, right ulnar; LU, left ulnar; LM, left median; RM, right median; LMC, left musculocutaneous; RMC,
right musculocutaneous; LR, left radial; RP, right peroneal; LP, left peroneal; LT, left tibial; NIS, neuropathy impairment score;
DM, diabetes mellitus.
semithin transverse sections was a reduction in fiber density, which was distributed multifocally among and within fascicles in the nerve of case 5 (Fig. 1). These regions
of fiber decrease were also characterized by a remarkable
alteration of fiber size (fewer large-diameter fibers and
increased numbers of small- and intermediate-diameter
fibers). When these regions of decreased fiber density
were viewed under light and electron microscopes, the
decrease in large fibers was evident but many of the small
fibers (;2–4 mm in diameter) were clustered close together in a pattern of regenerating nerve sprouts (Fig. 2).
In a few cases, they were surrounded by a common basement membrane, although in other cases the basement
membrane had disappeared but the close apposition of
fibers appeared to have been retained. There were transverse profiles of single, small- and intermediate-diameter
myelinated fibers that could have represented remyelinated segments. No unequivocally demyelinated profiles
or onion bulbs (indicators of myelin remodeling) were
seen. Apart from the small inflammatory collections seen
in paraffin sections, no obvious interstitial pathologic abnormality explained this fiber decrease. We did not find
evidence other than multifocal fiber loss that could be
interpreted to be from ischemia. For example, we did not
find perineurial necrosis, necrotizing vasculitis, bleeding,
injury neuroma, neovascularization, or accumulation of
axonal organelles). Most nerves (7 of 8) showed changes
similar to, but less pronounced, than those described in
case 5 (Fig. 1). Cases 1, 4R, 5, and 6 showed the most
prominent abnormalities, with increased numbers of regenerating clusters, more small- and intermediate-sized
fibers, and few large fibers. Some of the intermediatesized myelinated fibers had thin myelin (Fig. 4, left middle panel). The nerve of case 2 and 7 were relatively
normal.
Small perivascular lymphocytic infiltrates were observed in case 1 and 2 (Fig. 3). In case 1, it was seen in
the outer layers of the perineurium. In case 2, it was also
in the perineurium and extended into the endoneurium.
Paraffin sections were reacted for common leukocyte antigen (CD 45) and for macrophages (CD 68), but affected
areas did not show additional inflammatory infiltrates to
those already described.
Morphometry
The studies are summarized in Table 2 and illustrated
in Figure 4. Direct comparison with normative data was
not possible because nerve taken at biopsy were unavailable for comparison. The 2 postmortem nerves assessed
demonstrated no active fiber de- or regeneration and no
focal fiber density decrease (Table 2).
Similar to the light microscopy findings, morphometry
demonstrated abnormalities in 7 of 8 nerves studied, with
relative decrease of large myelinated fibers and relative
increase in the number of small fibers. In the more severely affected nerves there was an increase in the index
of dispersion among frames consistent with multifocal
fiber loss (Table 2). The fiber density in case 6 and case
4R may be increased due to the large numbers of regenerating clusters (groups of small, thinly myelinated fibers). Case 7 demonstrated changes only on nerve morphometry with an altered size distribution, increased
index of dispersion, and increased numbers of regenerating fiber clusters. The relative decrease of large myelinated fibers and relative increase of small fibers is illustrated in Figure 4. Plots of the relationship of axon
diameter to myelin thickness revealed differences among
nerves. Whereas case 2 had many large fibers with thick
myelin, the more severely affected nerves (case 4R, case
6, and case 5) demonstrated smaller axons with thinner
myelin. A definitive electron microscopic study of axon
diameter (from area) on number of myelin lamellae was
not possible because only necropsy forearm control
nerves were available for study.
J Neuropathol Exp Neurol, Vol 63, February, 2004
132
J Neuropathol Exp Neurol, Vol 63, February, 2004
TAYLOR ET AL
CONDUCTION BLOCK ALTERATIONS IN MULTIFOCAL MOTOR NEUROPATHY
133
←
Fig. 1. Transverse sections of a fascicular biopsy of ulnar nerve from case 5 showing striking foci of myelinated fiber decrease
(upper frames). The rectangles in upper frames are shown at greater magnification in lower frames. In addition to decreased
density of myelinated fibers, there is a striking alteration of size distribution (fewer large fibers) and prominent regenerating
clusters (arrowhead).
Electron Microscopy
Electron microscopy of regions of large myelinated fiber decrease (e.g. case 5) demonstrated the presence of
unmyelinated fibers, stacks of Schwann cell processes,
and regenerating clusters of small, thinly myelinated fibers (Fig. 4). There were no intracellular inclusions seen
and no abnormal organelles seen within Schwann cell
nuclei or axons. The myelin sheaths of unaffected myelinated fibers appeared morphometrically normal with no
alteration in spacing of lamellae.
DISCUSSION
The findings presented here are of importance because
they focus on the pathological alterations at or near the
most common sites of conduction block in forearm or
arm nerves of patients with MMN. The principle findings
of our studies are somewhat at variance with these earlier
findings, but the differences may be explained by differences in the acuteness of the pathologic lesions—our cases perhaps being more chronic. Unlike the findings of
earlier investigators of single cases, we found focal and
multifocal regions of fiber decrease (especially of large
fibers), an altered size distribution, regenerating fiber
clusters, and a low frequency of fiber degeneration. The
decrease in fiber density (especially of large fibers) in
focal or multifocal regions, alteration in size distribution,
the presence of regenerating clusters, and low-grade axonal degeneration was seen to varying degrees in 7 of 8
nerves. Although we did not find paranodal or internodal
segmental demyelination or onion bulbs, some intermediate-sized fibers with thin myelin were seen, perhaps
indicative of previous remyelination.
Our results provide an improved understanding of the
clinically observed muscle atrophy and fibrillation and
motor unit potential change in MMN. Degeneration of
motor axons of limb nerves appears to account for these
clinical and electrophysiologic changes. This conclusion
is inferred from intraoperative electrophysiologic recordings, showing that fascicles that were biopsied contained
motor fibers and demonstrated conduction block. The biopsied fascicles appeared to have an increased frequency
Fig. 2. Low-power scanning electron micrograph of an area of nerve with decreased density of myelinated fibers (case 5).
The clusters of closely applied small myelinated fibers are indicative of there being regenerating fibers. The significance of this
finding is discussed in the text.
J Neuropathol Exp Neurol, Vol 63, February, 2004
134
J Neuropathol Exp Neurol, Vol 63, February, 2004
TAYLOR ET AL
CONDUCTION BLOCK ALTERATIONS IN MULTIFOCAL MOTOR NEUROPATHY
135
←
Fig. 3. Upper panel: Transverse paraffin section stained with hematoxylin and eosin to show a minute perivascular inflammatory cell infiltrate near the inner aspect of the perineurium (case 2). Lower panel: Transverse epoxy section stained with
methylene blue and showing a small perivascular inflammatory cell infiltrate just outside the perineurium (case 1). The significance
is unclear but may be in keeping with an autoimmune process. The findings are discussed in text.
Fig. 4. Representative sections from nerves of patients with multifocal motor neuropathy. The panels on the left show less
severe changes than those shown in Figure 1. The panels on the right show no change. Although the density of fibers (left) is
probably normal, there is a marked alteration of the diameter distribution (more small- and intermediate-sized fibers and few
large fibers). The nerve shown on the right appears to have a normal distribution of fiber diameters. The nerve shown on the
right was from case 2, the one on the left from case 6.
J Neuropathol Exp Neurol, Vol 63, February, 2004
136
TAYLOR ET AL
TABLE 2
Interactive System for Nerve Morphometry Results for 8 MMN Nerves and 2 Control Ulnar Nerves of Forearm
Obtained at Necropsy
Nerve and
level (L)
Number of
fascicles
Index of
dispersion
Density
MF/mm2
Clusters mm2
DPs mm2
MF diameter
Control 1
Control 2
Case 1
Case 2 L1
L2
L3
Case 3
Case 4 L1
Right L2
Case 4 L1
Left L2
Case 5
Case 6 L1
L2
L3
Case 7
6
2
1
1
1
1
1
2
3
2
1
3
2
1
1
5
1.41
1.85
1.38
1.35
1.10
1.24
1.66
1.60
2.82
1.67
0.76
3.20
4.63
1.44
2.12
2.72
7003
8727
8795
7177
7323
7787
9342
10,635
10,663
7851
7910
4933
11,893
10,334
9623
8095
0
0
164
0
4
0
9
192
229
14
74
128
159
53
0
28
0
0
300
4
4
20
85
26
13
19
30
123
208
67
121
0
6.390
6.351
4.644
9.044
9.416
7.775
6.059
4.848
5.696
8.060
7.380
6.037
4.837
6.029
5.584
5.375
* Median values.
Clusters are groups of small thinly myelinated fibers presumably originally contained in a common basement membrane
remaining after degeneration of a myelinated fiber. All densities are per mm2 of endoneurium. Abbreviations: MF, myelinated
fiber; DP, degenerating profile (nerve fiber undergoing active degeneration).
of degenerating fibers and, perhaps more dramatically,
had multifocal regions of fiber decrease with many regenerating sprouts in them. Our histologic studies, therefore, provide unequivocal evidence of a multifocal process affecting motor fibers of limb nerves resulting in
fiber degeneration. In addition, abortive nerve regeneration was prominent in these regions of fiber loss.
The issue of whether any of these regenerated sprouts
can or do regrow and re-innervate muscle target remains
unclear, although the alteration of motor unit potential
suggests that some do. Although there is information on
the characteristic features of regenerative sprouts, little is
known about the time course of development and disappearance of regenerative nerve clusters. It is assumed
that some regenerating axons re-innervate previously denervated muscle.
The degree of focal fiber loss and regenerative sprouting may also provide an explanation for why patients
with MMN tend to be refractory to treatment. In our experience, despite intensive treatment with intravenous
gamma globulin or cyclophosphamide for long periods
of time, patients with this disease may show only partial
improvement, being left with considerable clinical deficit.
Our studies provide unequivocal evidence that the
pathologic lesions of forearm nerves are focal and multifocal and are at fixed proximal to distal levels of nerve.
Finding discrete regions of fiber decrease, altered size
distribution, and regenerative clusters suggests that these
foci are near the proximal level of the lesions because if
they were not, a greater spread of pathologic abnormalities would have been seen. It is further noted that these
J Neuropathol Exp Neurol, Vol 63, February, 2004
foci occur in the general region of conduction block, providing a linkage between conduction block and fiber degeneration and regeneration (see below). Conduction
block may be an earlier and milder alteration than the
obvious axonal degeneration, fiber loss, and regenerative
sprouting we have observed here. Apart from the known
selective vulnerability of motor fibers (i.e. the mid-forearm location of many of the lesions), the reason for sites
of involvement remains unexplained.
Can the findings of conduction block, segmental demyelination, and remyelination by Auer et al (18) and
Kaji et al (19) be reconciled with our studies showing
multifocal fiber loss and abortive regeneration? We hypothesize that an antibody-mediated attack directed
against components of the axolemma of nodes of Ranvier,
if mild, could explain the conduction block and, if more
severe, could induce transitory demyelination (and varying degrees of remyelination) and axonal degeneration
(and regeneration, perhaps mainly abortive). Alternatively, an attack on components of paranodal myelin could
also explain both segmental demyelination and axonal
degeneration and regeneration. We favor the first hypothesis because anti-ganglioside antibodies are thought to be
directed at components of axolemma and because we
found prominent fiber loss and abortive regeneration
without finding overt segmental demyelination or onion
bulbs.
The small inflammatory infiltrates seen in 2 cases are
of unclear pathological significance but may suggest an
inflammatory or immune component. Although we accept Kaji et al’s evidence for the occurrence of segmental
CONDUCTION BLOCK ALTERATIONS IN MULTIFOCAL MOTOR NEUROPATHY
demyelination and remyelination in MMN, it appears that
it is not a prominent feature in chronic cases.
A physiological block of motor axons based on an antibody-mediated blockade or damage of Na1, K1 channels at the nodes of Ranvier could explain conduction
block in MMN. Takigawa et al (8) demonstrated alterations in K1 currents at nodes of Ranvier using a voltage
clamp technique of isolated single myelinated rat nerve
fibers using anti-ganglioside (GM1) antibodies and complement. They concluded that anti-GM1 antibodies may
be able to uncover potassium channels in the paranodal
regions, while GM1 antibodies in the presence of complement may form antibody complexes that block sodium
channels and disrupt the membrane at the nodes of Ranvier. The findings by Kiernan (9) of hyperpolarization of
the axon distal to the site of conduction block in MMN
patients are also supportive of a functional block. According to his view, functional conduction block, if more
severe or prolonged, could cause axonal degeneration.
The fact that others (18, 19), and now we, have shown
morphologic changes at sites of conduction block suggests that more than a functional block develops.
An antibody-mediated channelopathy could explain the
initial response to therapy seen with immunomodulating
therapy, particularly IVIg, where neutralization of neuromuscular blocking antibodies by IVIg has been demonstrated in GBS, and a similar mechanism may be operative in MMN (27). The subsequent pathologic
alteration of fibers (segmental remodeling and axonal degeneration and regeneration) could then explain the decreasing responses to treatment with time with the development of irreversible muscle atrophy.
The pathologic changes we have described have therapeutic implications. Our findings suggest that functional
alterations precede fiber degeneration and faulty regeneration. Therefore, if available, early and adequate treatment would be preferable to delayed treatment.
REFERENCES
1. Taylor BV, Wright RA, Harper CM, Dyck PJ. Natural history of 46
patients with multifocal motor neuropathy with conduction block.
Muscle Nerve 2000;23:900–908
2. Olney RK. Consensus criteria for the diagnosis of partial motor
conduction block. Muscle Nerve 1999;22(Suppl 8):S225–S229
3. 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:
625–30
4. Felice KJ, Goldstein JM. Monofocal motor neuropathy: Improvement with intravenous immunoglobulin. Muscle Nerve 2002;25:
674–78
5. Pakiam AS, Parry GJ. Multifocal motor neuropathy without overt
conduction block. Muscle Nerve 1998;21:243–45
6. Katz JS, Wolfe GI, Bryan WW, Jackson CE, Amato AA, Barohn
RJ. Electrophysiological findings in multifocal motor neuropathy.
Neurology 1997;48:700–707
137
7. Chaudhry V. Multifocal motor neuropathy. Seminars in Neurology
1998;18:73–81
8. Takigawa T, Yasuda H, Kikkawa R, Shigeta Y, Saida T, Kitasato
H. Antibodies against GM1 ganglioside affect K1 and Na1 currents in isolated rat myelinated nerve fibers. Ann Neurol 1995;37:
436–42
9. Kiernan MC, Guglielmi JM, Kaji R, Murray NM, Bostock H. Evidence for axonal membrane hyperpolarization in multifocal motor
neuropathy with conduction block. Brain 2002;125:664–75
10. Azulay JP, Rihet R, Pougert J, et al. Long-term follow-up of multifocal motor neuropathy with conduction block under treatment. J
Neurol Neurosurg Psychiatry 1997;62:391–94
11. Leger JM, Chassande B, Musset L, Meininger V, Bouche P, Baumann N. Intravenous immunoglobulin therapy in multifocal motor
neuropathy: A double-blind, placebo-controlled study. Brain 2001;
124:145–53
12. Carpo M, Allaria S, Scarlato G, Nobile-Orazio E. Marginally improved detection of GM1 antibodies by Covalink ELISA in multifocal motor neuropathy. Neurology 1999;53:2206–7
13. Van den Berg LH, Franssen H, Wokke JHJ. The long-term effect
of intravenous immunoglobulin treatment in multifocal motor neuropathy. Brain 1998;121:421–28
14. Federico P, Zochodne DW, Hahn AF, Brown WF, Feasby TE. Multifocal motor neuropathy improved by IVIg: Randomized, doubleblind, placebo-controlled study. Neurology 2000;55:1256–62
15. Pestronk A, Choksi R. Multifocal motor neuropathy. Serum IgM
anti-GM1 ganglioside antibodies in most patients detected suing
covalent linkage of GM1 to ELISA plates. Neurology 1997;49:
1289–92
16. Taylor BV, Gross L, Windebank AJ. The sensitivity and specificity
of anti-GM1 antibody testing. Neurology 1996;47:951–55
17. Willison HJ. Antiglycolipid antibodies in peripheral neuropathy:
Fact or fiction. J Neurol Neurosurg Psychiatry 1994;57:1383–87
18. Auer RN, Bell RB, Lee MA. Neuropathy with onion bulb formations and pure motor manifestations. Can J Neurol Sci 1989;16:
194–97
19. Kaji R, Oka N, Tsuji T, et al. Pathological findings at the site of
conduction block in multifocal motor neuropathy. Ann Neurol
1993;33:152–58
20. Chaudhry V, Corse A, Cornblath D, et al. Maintenance immune
globulin therapy for multifocal motor neuropathy: Results of longterm follow-up. Ann Neurol 1996;40:513–14
21. Dyck PJ, Giannini C, Lais A. Pathologic alterations of nerves. In:
Dyck PJ, Thomas PK, Low PA, Griffin JW, Poduslo JF, eds. Peripheral neuropathy, 3rd ed. Philadelphia: W.B. Saunders, 1993:
514–95
22. Karnes J, Robb R, O’Brien PC, Lambert EH, Dyck PJ. Computerized image recognition for morphometry of nerve attribute of
shape of sampled transverse sections of myelinated fibers which
best estimates their average diameter. J Neurol Sci 1977;34:43–51
23. Zimmerman IR, Karnes JL, O’Brien PC, Dyck PJ. Imaging system for
nerve and fiber tract morphometry: Components, approaches, performance, and results. J Neuropathol Exp Neurol 1980;39:409–19
24. Dyck PJ, Karnes J. Morphometry of neuron columns and fiber
tracts in neurobiology and pathology using computer imaging.
Trends Neurosci 1981;4:138–41
25. Dyck PJ, Dyck PJB, Giannini C, Sahenk Z, Windebank AJ, Engelstad J. Peripheral Nerves. In: Graham DI, Lantos PL, eds. Greenfield’s neuropathology. London: Arnold Publishing, 2002: 551–675
26. Nobile-Orazio E. Multifocal motor neuropathy. J Neuroimmunol
2001;115:4–18
27. Buchwald B, Ahangari R, Weishaupt A, Toyka KV. Intravenous
immunoglobulins neutralize blocking antibodies in Guillain Barre
Syndrome. Ann Neurol 2002;51:673–80
Received July 10, 2003
Revision received October 14, 2003
Accepted October 16, 2003
J Neuropathol Exp Neurol, Vol 63, February, 2004