Introduction
Monoclonal gammopathy of unknown significance (MGUS)
is an asymptomatic plasma cell dyscrasia, which is characterized by
the presence of M-protein in individuals lacking evidence of
multiple myeloma (1).
Numerous studies have found underlying pathological
associations between neuropathies and MGUS. Peripheral neuropathies
have been found in 8–36% of patients with MGUS (2) and in 50% of patients with
immunoglobulin M (IgM)-MGUS (3).
These patients showed a slowly progressive, sensory motor
demyelinating neuropathy with antibodies and T-cell infiltration in
the nerve lesions (4,5).
In the present study, a patient with IgG-MGUS, with
motor neuron disorder as the main complaint, mimicking amyotrophic
lateral sclerosis (ALS), is reported. The response of the patient
to chemotherapy and autologous stem cell transplantation (ASCT) is
presented.
Case report
A 47-year-old Chinese female was admitted to the
General Hospital of Jinan Military District (Jinan, China) due to a
10-month history of muscle weakness and progressive muscle wasting
of the limbs and a 3-month history of slurred speech and
involuntary muscle twitching. The therapy protocols described in
this study were approved by Ethics Committee, Institute of the
General Hospital of Jinnan Military. The patient’s legal guardian
signed written informed consent before the therapy.
The neurological examination revealed atrophy in the
left first dorsal interossei (DI) muscle and left thenar muscle.
Fasciculation was observed in the left first DI, left biceps and
lingual muscle. The results from the strength tests, presented as
Medical Research Council grades (6) were as follows: 5-/5 for the left
extensor carpi radialis longus and 4/5 for the left infraspinatus.
Diminished grip strength of the left hand was observed (4/5);
however, normal strength (5/5) was found for the right arm and
bilateral lower extremities. The deep tendon reflexes were 3/4 in
the left brachioradialis, biceps and triceps, and 2/4 for others.
The Hoffmann and Babinski signs were negative. The sensory
examination was intact and no coordination deficits or cranial
nerve deficits were observed in the patient.
An electrodiagnostic study revealed low amplitudes
in the compound muscle action potentials of the left upper
extremity motor nerve, with intact sensory nerve action potential
responses. There was no evidence of any abnormal temporal
dispersion or conduction block in multiple nerves tested. There
were 1–2+ fibrillation potentials and positive sharp waves in the
left tibialis anterior and first dorsal interosseous muscles.
Magnetic resonance imaging examination revealed Wallerian
degeneration of the bilateral thalamus, the midbrain, the lateral
cerebral ventricle and the centrum ovale. The patient showed
clinically possible amyotrophic lateral sclerosis (ALS). However,
an exact diagnosis that would account for the clinical condition
was not identified.
Further laboratory investigations revealed elevated
IgG 2,500 mg/dl (normal, 751–1,560 mg/dl) and κ light chain 2,990
mg/dl (normal, 629–1,350 mg/dl) levels in the serum. The level of
IgG in the cerebrospinal fluid (CSF) was also elevated 52.8 mg/l
(normal, 0–34 mg/l) and CSF-restricted IgG oligoclonal bands were
positive. Immunofixation electrophoresis of serum and CSF showed
the same positive IgG protein. The myelin-basic-protein antibody
(MBP.Ab) level was 1.203 μg/l in the serum (normal, <0.650 μg/l)
and 1.411 μg/l in the CSF (normal, <0.750 μg/l); and the
myelin-oligodendrocyte-glycoprotein antibody (MOG.Ab) level was
1.484 μg/l in the serum (normal, <0.560 μg/l) and 1.424 μg/l in
the CSF (normal, <0.640 μg/l). The increased levels of
antibodies indicated an association between neuropathy and
IgG-MGUS. Bence-Jones protein was not detected and proteinuria was
2.5 g/day. B12 deficiency and hyperparathyroidism were excluded.
The results from 99mTc methyl diphosphonate (MDP) bone
scintigraphy and fludeoxyglucose positron emission
tomography-computed tomography demonstrated that there was no
positive manifestation. Bone marrow (BM) examination revealed 5%
atypical plasma cells, which were found to express surface cluster
of differentiation (CD)38, CD34, CD117, human leukocyte antigen
(HLA)-DR, CD33, CD19 and CD13. The chromosomal constitution was 46,
XX. Fluorescence in situ hybridization analyses of p53, RB1,
1q21, D135319 and IGH gene rearrangements were negative.
The patient showed no signs of end-organ damage, the
serum M-protein level of the patient was 2.5 g/dl (normal, <3
g/dl) and the clonal plasma cell population in the BM was 5%
(normal, <10%); in combination, these results support the
diagnosis of MGUS. Chemotherapy with vascular-targeted photodynamic
therapy (VTP) and bortezomib, plus dexamethasone and thalidomide,
was administered due to the worsened motor neuron damage caused by
M-protein. Following two cycles of chemotherapy, the serum IgG
levels were reduced and the percentage of atypical cells decreased
to 0.7%. Dexamethasone (5 mg) and cytarabine (50 mg) treatment was
then administered by intrathecal injection. The levels of IgG in
the CSF were found to decrease significantly. The patient was
administered cyclophosphamide (2 g/m2, 2 days) as
mobilization chemotherapy, followed by ASCT; the conditioning
treatment consisted of 900 cGy total body irradiation (TBI) and
melphalan 140 mg/m2. Three months following ASCT, the
atrophy in the left first DI and left thenar muscles was
persistent. The results from the strength tests were 4-/5 for the
biceps and 4-/5 for the triceps. The wrist extensors on the left
side were weakened with an inability to extend the fingers. In
addition, fasciculation in the upper extremity muscles was observed
with a scattered distribution, predominantly proximally. Serum IgG
and κ light chain test results remained positive (Fig 1). Thus, oral treatment of the
patient with thalidomide was resumed. During the 24-month
follow-up, the patient’s ALS mimicking symptoms did not appear to
be aggravated, and the results from the strength tests were 4-/5-
for the biceps and 4-/5- for the triceps. Cranial nerve deficits
were observed, and the patient exhibited mild dysarthria and
dysphasia.
Discussion
The prudent management strategy of MGUS is ‘watch
and wait’. At present, there are no standard treatments. Patients
with MGUS with clinical features of ALS are rare. In the present
case, serum-IgG and CSF-IgG levels were elevated, and
immunofixation electrophoresis of immunoglobulin showed that serum
and CSF IgG were homologous. This result indicates that the IgG in
the CSF may not be endogenous; it may originate from M-protein in
the serum that passed through the damaged blood-brain barrier
(BBB). The elevated levels of MBP.Ab and MOG.Ab are also indicative
of damage of the CNS.
The serum levels of IgG and the plasma cell levels
were reduced following chemotherapy; however, the IgG levels in the
CSF remained high. This may be due to the chemotherapy administered
not being able to penetrate the BBB, or slow attenuation of IgG in
the CSF Following the intrathecal injection of dexamethasone and
cytarabine, the IgG levels in the CSF decreased significantly. The
symptoms of lingual muscle fasciculation and slurred speech were
ameliorated. TBI was used in the conditioning regimen, which may
have helped to eliminate autoimmune damage of the motor neurons
caused by M-protein. However, there were no significant
improvements in neuronal symptoms following ASCT. The patient did
not benefit from single ASCT. This may be as a result of the
malignant clones not being completely cleansed, or the nervous
system damage being irreversible. Patients with multiple myeloma
who achieve complete remission (CR) with conventional chemotherapy
and do not receive transplantation have the same prolonged
progression-free survival and overall survival as those attaining
CR following ASCT (7).
Conservative chemotherapy or double ASCT may be used for the
patient as a follow-up treatment.
MGUS mimicking ALS is extremely rare. The ALS
symptoms of the patient in the present study aggravated quickly.
Although the therapies did not achieve the expected effect, they
delayed the deterioration of the disease. These observations may be
of use for the treatment of MGUS in the future.
Acknowledgements
This work was supported by the China Postdoctoral
Science Foundation (20090451567).
References
|
1
|
Kyle RA and Rajkumar SV: Multiple myeloma.
N Engl J Med. 351:1860–1873. 2004. View Article : Google Scholar
|
|
2
|
Vrethem M, Cruz M, Wen-Xin H, Malm C,
Holmgren H and Ernerudh J: Clinical, neurophysiological and
immunological evidence of polyneuropathy in patients with
monoclonal gammopathies. J Neurol Sci. 114:193–199. 1993.
View Article : Google Scholar : PubMed/NCBI
|
|
3
|
Kyle RA, Therneau TM, Rajkumar SV, Larson
DR, Plevak MF, Offord JR, Dispenzieri A, Katzmann JA and Melton LJ
III: Prevalence of monoclonal gammopathy of undetermined
significance. N Engl J Med. 354:1362–1369. 2006. View Article : Google Scholar : PubMed/NCBI
|
|
4
|
Gosselin S, Kyle RA and Dyck PJ:
Neuropathy associated with monoclonal gammopathies of undetermined
significance. Ann Neurol. 30:54–61. 1991. View Article : Google Scholar : PubMed/NCBI
|
|
5
|
Solders G, Nennesmo I, Ernerudh J, Cruz M
and Vrethem M: Lymphocytes in sural nerve biopsies from patients
with plasma cell dyscrasia and polyneuropathy. J Peripher Nerv
Syst. 4:91–98. 1999.PubMed/NCBI
|
|
6
|
Dyck PJ, Boes CJ, Mulder D, Millikan C,
Windebank AJ, Dyck PJ and Espinosa R: History of standard scoring,
notation, and summation of neuromuscular signs. A current survey
and recommendation. J Peripher Nerv Syst. 10:158–173. 2005.
View Article : Google Scholar : PubMed/NCBI
|
|
7
|
Alexanian R, Weber D, Giralt S, Dimopoulos
M, Delasalle K, Smith T and Champlin R: Impact of complete
remission with intensive therapy in patients with responsive
multiple myeloma. Bone Marrow Transplant. 27:1037–1043. 2001.
View Article : Google Scholar : PubMed/NCBI
|
