Journal of the Peripheral Nervous System 16:341–346 (2011)

CASE REPORT
Chronic motor axonal neuropathy

Nilo Riva1 , Francesca Gallia2 , Sandro Iannaccone3 , Massimo Corbo4 , Fabrizia Terenghi2 ,
Alberto Lazzerini5 , Federica Cerri1 , Giancarlo Comi1,6 , Angelo Quattrini1 ,
and Eduardo Nobile-Orazio2
1 Departmentof Neurology, INSPE and Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy; 2 2nd
Neurology, Department of Translational Medicine, Milan University IRCCS Humanitas Clinical Institute, Milan, Italy;
3
Department of Clinical Neurosciences, San Raffaele Turro Hospital, Milan, Italy; 4 NEuroMuscular Omnicentre (NEMO),
Niguarda Ca Granda Hospital, Milan, Italy; 5 Hand Surgery and Microsurgery Unit, IRCCS Humanitas Clinical Institute, Milan,
Italy; and 6 Università Vita e Salute San Raffaele Milan, Italy

Abstract The identification of a distinct subgroup of patients within the spectrum

of lower motor neuron syndromes (LMNS) is crucial as some are potentially treatable.
We describe the clinical and neuropathological characteristics of a patient presenting
with a rapidly progressive LMNS associated with high titers of anti-GM1 antibodies,
leading to respiratory failure within 10 months. Histopathological study of a biopsy of a
obturator nerve motor branch demonstrated a predominantly axonal motor neuropathy,
while electron microscopy analysis localized macrophages located within the periaxonal
space. Immunohistochemistry demonstrated deposits of complement activation products
(C3i) and immunoglobulins (IgM) on nerve fibers. The patient’s clinical, immunological and
pathological findings are consistent with a diagnosis of a chronic motor axonal neuropathy
(CMAN), likely of immune-mediated origin.

Key words: acute motor axonal neuropathy, amyotrophic lateral sclerosis, anti-GM1
antibodies, lower motor neuron disease, neuropathology, nerve biopsy, peripheral
neuropathy

Introduction differentiation among LMNS is relevant because some

Lower motor neuron syndromes (LMNS) comprise
diseases affecting primarily the motor axons of periph-
eral nerves (motor neuropathies, MN) and the lower
motor neurons. Amyotrophic lateral sclerosis (ALS)
is the most common and severe form of motor
neuron disease (MND), while progressive (spinal)
muscular atrophy (PMA) is the most common form
of lower MND. A substantial proportion of PMA
patients develop ALS or have an ‘‘ALS-like’’ dis-
ease course (Van den Berg-Vos et al., 2009). The
Address correspondence to: Nilo Riva, MD, PhD, Department
of Neurology, INSPE and Division of Neuroscience, San Raffaele
Scientific Institute, via Olgettina 48, 20132 Milan, Italy. Tel: +(39)-2-
26435094; Fax: +(39)-2-26433085; E-mail: riva.nilo@hsr.it
forms of MN, specifically multifocal motor neuropathy
(MMN), are treatable. After the identification of MMN,
attempts to identify other treatable subgroups of
LMNS patients have been performed, mainly based
on positive GM1 titres (Azulay et al., 1994; Tan et al.,
1994; Van Den Berg et al., 1997; Katz et al., 2002; Del-
mont et al., 2006). However, no consistent response
to immunotherapy has been found.
Case Report
A 50-year-old man noted five-month progressive
weakness in four limbs. No previous infections were
reported. Weakness first involved the upper right limb,
then soon afterwards the upper left limb. Walking
difficulties were noted for 1 month. Three monthly

© 2011 Peripheral Nerve Society 341

Riva et al. Journal of the Peripheral Nervous System 16:341–346 (2011)

courses of intravenous immunoglobulin therapy (2 g/kg unit potentials in all limb muscles tested but not in
body weight) had been administered, with subjective, paraspinal muscles and tongue.
partial benefit after the first course. However, weak- Motor biopsy of the obturator nerve was per-
ness progressed. Examination showed widespread formed, as described, after informed consent (Sup-
asymmetric muscular atrophy and weakness in the porting Information) (Corbo et al., 1997). Semithin
upper limbs, predominantly affecting shoulder and plastic sections showed moderate reduction of the
hand muscles and mild muscular atrophy and weak- myelinated fibers (fiber density: 4400/mm2 ), axonal
ness distally in the lower limbs. The patient was unable degeneration and endoneurial edema (Figs. 1A and
to walk on his heels and toes. Tendon reflexes were 1B). A moderate number of clusters of small myeli-
reduced or absent. There were no upper motor neuron nated fibers, indicating axonal regeneration (Figs. 1B
signs or fasciculations. Sensation and cranial nerves and 1C), was observed (cluster density: 28.3/mm2 ).
were normal. Routine laboratory investigations were Isolated thinly myelinated fibers (Figs. 1B and 1C)
unremarkable. High titers of IgM anti-GM1 antibodies and onion-bulb formations, suggesting recurrent de-
(1:5120) were detected (normal <1:640). CSF showed and re-myelination, were identified and subsequently
pleocytosis (9 cells/mm2 ) and a mild protein increase confirmed by electron microscope analysis (Fig. 1D).
(69.9 mg/dl). Spine MRI showed widespread enhance- The g -ratio was 0.65. Electron microscopy showed
ment of anterior leptomeninges and anterior roots up macrophages located in the periaxonal space, between
to the intervertebral foramina and spinal nerves, with- the adaxonal Schwann cell plasmalemma and the axon,
out volumetric increase. A full-body CT scan showed often appearing with a condensed axolemma (Figs. 1E
normal results. and 1F), consistent with a neuropathological diagnosis
Electroneurography was consistent with an axonal of definite MN (Riva et al., 2011).
motor neuropathy/neuronopathy, with slightly asym- Immunocytochemistry showed macrophage in-
metric reduction of compound motor action potential flammatory infiltrates (CD68+), predominantly in strict
(CMAP) amplitudes without conduction blocks or signs contact with axonal fibers (Fig. 1G). Some nerve fibers
of demyelination/temporal dispersion. Sensory con- were positive for immunofluorescence staining for
ductions were normal (Table 1). Electromyography the complement activation product C3i (Figs. 1H–1K)
revealed active denervation and neurogenic motor and for human-IgM, more prominently at nodes
of Ranvier (Figs. 1L–1N); control nerves from ALS
Table 1. Motor nerve conduction studies. patients resulted negative for the same reactions
Latency (data not shown). Indirect immunofluorescence on
Amplitude (ms)∗ or rat sciatic nerve sections with the patient’s serum
Stimulation Recording (mV) CV (m/s) showed immunostaining located at nodes of Ranvier,
Nerve site site (R/L) (R/L) as demonstrated by co-localization with contactin-
associated protein (Caspr), a paranodal marker
Median Wrist ADM 0.78/1.1 6.2/6.7 (Figs. 2A–2E) (Peles et al., 1997).
Elbow 0.59/1.1 51.9/52.0
A 3-day course of intravenous methylprednisolone
Axilla 0.32 47.2
ERB 0.23 44.1 (1 g/d) was interrupted because of worsening of
Ulnar Wrist APB 1.8/2.9 4.3/3.7 weakness. Four monthly additional courses of intra-
Below EL 1.3/2.4 52.4/54.5 venous immunoglobulin therapy were administered
Above EL 1.1 46.1 with only a minimal, subjective transitory response, fol-
Axilla 0.9 46.2 lowed by further disease progression to severe tetra-
Radial Forearm EIP 3.2 3.3
paresis. Nine months after onset, plasma-exchange
Below SG 2.8 50.2
Above SG 2.5 49.1 was tried, without any benefits. Cyclophosphamide
Musculo- Axilla BB 8.6 3.2 (100 mg/m2 monthly) was started, but progression
cutaneous ERB 7.3 52 continued. Repeated neurophysiologic examination
Tibial Ankle AH 3.3/1.5 5.6/7.1 confirmed preserved normal sensory conductions and
PF 1.9/0.85 45.2/53.8 widespread muscle denervation, including paraspinal
Peroneal Ankle EDB 1.3/1.6 10.3/5.9 muscles. Respiratory failure developed 10 months
Below FH 1.2/1.6 44.0/42.5
after onset. The patients died 15 months after onset.
Above FH 1.2/1.4 50.0/42.0

Complete results of neurophysiological studies shown in Table S1.

ADM, abductor digiti minimi; APB, abductor pollicis brevis; AH,
abductor hallucis; BB, biceps brachii; CV, conduction velocity; EL, Discussion
elbow; EIP, extensor indicis proprius; ERB, ERB point; EDB, extensor
digitorum brevis; FH, fibular head; L, left; NR, not recordable; PF, This patient presented a rapidly progressive LMNS.
popliteal fossa; R, right; SG, spiral groove.
∗ Significantly high titers of anti-GM1 IgM antibodies
Terminal latency.

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Riva et al. Journal of the Peripheral Nervous System 16:341–346 (2011)

Figure 1. Motor nerve biopsy findings. (A–C) Transverse semithin sections: focal reduction of myelinated nerve fibers and
endoneurial edema (A*); clusters of small myelinated fibers (arrows, B and C) indicating axonal regeneration and thinly
myelinated nerve fibers (arrowheads, B and C), indicating re-myelination. (D–F) Electron microscopy analysis showing onion-
bulb formation (D, ax = axon) and macrophages (mf, E and F) into the periaxonal space (E, ax = axon). Immunohistochemistry
studies on transverse (G–K) and longitudinal (L–N) motor nerve biopsy sections: (G) paraffin section immunostained with the
macrophage marker CD68 showing a positive cell in the axon of a large motor nerve fiber (arrow); (H–K) Immunohistochemistry
using anti-C3i (H–K green, to recognize complement activation), anti-NF antibody (K, red, to recognize axons), anti-IgM antibody
(L, green) to detect human auto-antibodies. Motor nerve fibers are positive for C3i (H and I, arrow) but some large fibers had
no detectable staining (I); higher magnification (J) shows signal co-localization (arrow) within the myelin sheath of a large fiber
(arrowhead). C3i signal (K, green, arrow) is in contact with the axon (K, red, arrowhead), suggesting complement activation
at the node of Ranvier. In longitudinal sections, positive staining for anti-human IgM (L, green, arrow) localized on large
myelinated fibers (M, arrow) and IgM localized at the node (N, arrow). Bars: (A) 70 mm; (B) 25 mm; (C, G–H, L and M) 10 mm;
(D and E, J and K, N) 5 mm; (F) 2 mm.

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Figure 2. Double labeling of longitudinal sections of rat nerve with patient’s serum (anti-IgM, green) and anti-Caspr (red),
which identifies paranodal domains in longitudinal section. IgM binds the nodal gap (arrow, A) and is distributed along the outer
surface of paranodal myelin; Caspr is seen in the paranodes (arrowhead, B). Merge (in D–E) confirms the IgM localization at
the node of Ranvier (arrows). Bars: (A–D) 3 mm; (E) 1 mm.

led to a diagnosis of immune-mediated MN. The
patient, however, did not respond to intravenous
immunoglobulin therapy, which is typically effective
in MMN (van Schaik et al., 2010), but also in some
patients with a similar clinical presentation associated
with pure axonal electrophysiological findings, referred
to as multifocal acquired motor axonopathy (MAMA)
(Katz et al., 2002; Delmont et al., 2006). Moreover,
MMN or MAMA, unlike our patient, typically presents
with a relatively indolent disease progression (Nobile-
Orazio et al., 2005; Cats et al., 2010). The alternative
diagnosis of lower MND was therefore considered.
Anti-IgM antibodies are not only important for the
diagnosis of MMN, but are also believed to play a rel-
evant role in the disease pathogenesis (Nobile-Orazio
et al., 2002; Taylor and Willison, 2005). The pathologic

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Riva et al.
basis of MMN is not fully characterized, therefore
a direct comparison with the present case is not
possible. Previous pathological reports of two single
cases have shown segmental demyelination and re-
myelination of motor axons (Auer et al., 1989; Kaji
et al., 1993). A subsequent study, performed in more
chronic MMN cases, showed focal reduction of myeli-
nated nerve fibers, involving primarily large fibers,
signs of re-myelination and axonal regeneration (Tay-
lor et al., 2004). Similar findings were observed in our
patient’s motor biopsy, supporting a diagnosis of MN,
predominant axonal. The density of clusters of small
myelinated fibers, indicating axonal regeneration after
axonal injury (28.3/mm2 ) was at the lower half of the
MN range (a value >22.4/mm2 supports a diagnosis of
MN), which was consistent with the poor prognosis of
the patient (Riva et al., 2011). Therefore our patient’s
neuropathy could also be interpreted as previously not
identified extreme within the spectrum of MMN. How-
ever, in the present case, nerve conduction studies
could not demonstrate conduction blocks, while elec-
tron microscopy studies demonstrated macrophages
located within the periaxonal space, between the adax-
onal Schwann cell plasmalemma and a condensed-
appearing axon. These pathological features resemble
the pattern described for acute motor axonal neu-
ropathy (AMAN), the axonal variant of Guillain-Barré
syndrome (McKhann et al., 1993; Griffin et al., 1995).
Such distribution has never been observed in ALS
motor nerves, in which, instead, some macrophages
can be detected in the endoneurial space, similar to the
physiological response following Wallerian degenera-
tion (Stoll and Muller, 1999). Moreover, differentiating
this case from the classical AMAN pattern, minor signs
of myelin damage, such as thin myelinated axons and
chronic re-myelination, were also observed, even if
we cannot exclude that they might be secondary to
axonal damage. Pathology typical of primary inflam-
matory demyelinating neuropathies was not observed
(Quattrini et al., 2003).
Direct and indirect immunocytochemistry demon-
strated IgM and C3i bound to the axolemma of motor
fibers, at nodes of Ranvier. Although such findings
might be epiphenomena to axonal degeneration, they
were not observed in control nerves from ALS patients,
and are similar to what has previously been described
in AMAN (Griffin et al., 1995; Hafer-Macko et al., 1996).
These results suggest an immune-mediated disor-
der whose target epitopes might be constituents of
motor fiber axolemma. It is therefore possible that
macrophages, attracted to the affected nodes by
chemotropic complement products, dissected through
the Schwann cell basal lamina into the internodal peri-
axonal spaces, leading to axonal degeneration.
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Journal of the Peripheral Nervous System 16:341–346 (2011)
The association between lower MND and anti-
GM1 IgM antibodies is well known, but the patho-
genetic role of this finding is poorly understood
(Sanders et al., 1993; Tan et al., 1994; Van den Berg
et al., 1997). In this case, the morphologic character-
istics of motor nerve biopsy were consistent with a
diagnosis of chronic motor axonal neuropathy, prob-
ably immune-mediated. The alternative diagnosis of
MND is not completely excluded, as autopsy was
not performed. This hypothesis would imply a promi-
nent involvement of the inflammatory response in
MND pathogenesis, or at least in a subgroup of MND
patients, which, if recently conjectured, has however
not yet been clearly demonstrated (Lincecum et al.,
2010; Devigili et al., 2011).
Our patient only marginally and transiently
responded to intravenous immunoglobulin but not
to cyclophosphamide while steroids were associated
with clinical worsening, as reported in MMN patients
(Van Asseldonk et al., 2005). In spite of that, this form
of neuropathy could theoretically explain at least part of
the patients presenting with the unusual association
between lower MND and anti-GM1 IgM antibodies.
This case supports the need for a better clinical and
pathological distinction between lower MND and MN
in order to identify patients that might respond to more
effective and earlier instituted therapies.
Acknowledgements
The authors thank E. Peles (Weizman Institute,
Rehovot, Israel) for anti-Caspr antibody.
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Supporting Information
Additional Supporting Information may be found in the online
version of this article:
Appendix S1. Morphological and Electrophysiological Studies.
Table S1. Neurophysiological evaluation results.
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