Bone Marrow Transplantation (2015) 50, 1125–1126
© 2015 Macmillan Publishers Limited All rights reserved 0268-3369/15
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LETTER TO THE EDITOR
Late post-transplant anti-aquaporin-4 Ab-positive optic
neuritis in a patient with AML
Bone Marrow Transplantation (2015) 50, 1125–1126; doi:10.1038/
bmt.2015.84; published online 27 April 2015
Seropositivity for anti-aquaporin-4 Abs (AQP-4-IgG) marks severe
forms of optic neuritis (ON), which are part of the so-called
neuromyelitis optica spectrum disorders (NMOSD), and can
remain isolated or evolve into the complete phenotype of the
spectrum, namely, neuromyelitis optica (NMO).1,2 AQP-4-IgG play
a pivotal diagnostic role, as they are directly involved in the
pathogenetic mechanisms of NMOSD.3 The dysregulation of the
immune system that likely underlies the pathogenesis of NMOSD
also accounts for the frequent association of these disorders with
other organ- and non-organ specific autoimmune diseases.2
Allogeneic bone marrow transplantation (allo-BMT) after myeloablative conditioning is a current, effective treatment for many
hematologic malignancies. In post-transplant patients, neurologic
complications, which include posterior reversible encephalopathy,
seizures, encephalopathy, polyneuropathy and central nervous
system (CNS) infections, are described, but CNS immune-mediated
demyelinating diseases (IMDD), either primary4 or secondary to
chronic GvHD,5 are rare.
We report on a patient who developed AQP-4-IgG-associated
ON, after allo-BMT for AML.
In 2005, a 51-year-old Caucasian woman was diagnosed with
AML. In 2006, she underwent allo-BMT (the donor was the HLAmatched sister), followed by CR, without acute GvHD. Over the
following years, the patient began complaining of mild and diffuse
arthromyalgias, which promptly responded to low doses of
corticosteroids, but that tended to recur after gradual discontinuation of therapy. In September 2013, she developed sudden
bilateral visual loss until blindness in a few days. Past medical
history was remarkable only for hypothyroidism secondary to
post-BMT anti-TPO-seronegative Hashimoto thyroiditis (on
therapy with levothyroxine, 100 μg/day). Neurological examination was unremarkable, except for visual acuity of 0/10 and for
bilateral optic disc pallor. Visual evoked potentials were absent
bilaterally. Visual field testing disclosed bitemporal hemianopsia.
Brain magnetic resonance imaging (MRI) showed T2-weighted
rare tiny nonspecific subcortical lesions, and hyperintensity and
surrounding swelling in the optic chiasm, without gadolinium
enhancement (Figures 1a and b). Routine laboratory tests,
including extractable nuclear antigens antibodies, angiotensinconverting enzyme, neoplastic and paraneoplastic (onconeural
Abs) markers were negative or normal, except for a positive
antinuclear antibodies test (titer, 1:160; granular pattern). Cerebrospinal fluid (CSF) examination disclosed 39 lymphocytes/μL,
normal albumin quotient (index of blood–CSF barrier permeability). Oligoclonal IgG bands were negative. Immunophenotypic
analysis of the CSF and blood cells, and, soon after, of a bone
marrow biopsy excluded the recurrence of the myeloid leukemia.
The donor chimerism was complete. Extensive searches on blood,
serum and/or CSF for infective causes (HIV-1/2, Mycoplasma
pneumoniae, Mycobacteria, HSV-1/2, Varicella Zoster Virus, CMV,
EBV and Cryptococcus neoformans) performed by cultures,
serology and/or real-time PCR were negative. Due to the severity
of the ON, the patient’s serum was then tested for AQP-4-IgG
(indirect immunofluorescence on AQP-4-transfected cells;
Euroimmun, Germany), which resulted positive. Spinal cord MRI,
which was performed to exclude medullary lesions that can
associate with AQP-4-IgG,1,2 was normal. The patient was treated
with IV 6-methylprednisolone (1 g/day for 6 days), followed by oral
prednisone (100 mg/day), with slow subsequent tapering. After
3 months, her visual acuity was still 0/10 bilaterally, and she was
treated with four cycles of plasma exchange, without improvement. Then, in January 2014, rituximab (562 mg/week for 4 weeks)
was started to prevent new inflammatory events in the CNS.
Prednisone was tapered off. On the latest follow-up (May 2014),
Figure 1. Brain MRI. (a) Axial FLAIR (fluid-attenuated inversion recovery) image shows tiny hyperintense white matter lesions. (b) Coronal T2weighted image shows hyperintensity and enlargement of the optic chiasm (arrow).
Letter to the Editor
1126
the neurological findings were unchanged, the spinal cord MRI
was normal and the brain MRI showed residual atrophy of the
optic chiasm, and unchanged subcortical lesions (data not shown).
Controls for the hematological disease showed persistent CR.
Our patient developed AQP-4-IgG-associated ON as a likely late
complication of allo-BMT. The frequency of post-allo-BMT IMDD,
which include ON, is rare, 0.5%, in the largest series of patients
reported so far.4 Six of the seven patients were transplanted from
HLA-matched related donors, and the median time from
transplant to the onset of neurologic symptoms was 4 months.4
In another retrospective study on patients with severe autoimmune diseases, IMDD occurred up to 5 years after allo-BMT.6 In
our patient, the interval between allo-BMT and ON was 7 years.
Allo-BMT profoundly interferes with the immune system mechanisms that regulate the balance between tolerance and immunity,
and the development of autoreactive T lymphocytes in the
thymus, or the emergence of autoreactive B-cell clones can be
delayed throughout the long follow-up after transplantation.7
Indeed, our patient sequentially developed Hashimoto thyroiditis,
arthromyalgias, seropositivity for anti-nuclear Ab and eventually,
AQP-4-IgG-seropositive ON. It is likely that these autoimmune
phenomena followed a post-BMT failure of tolerance, within or
without a context of chronic GvHD. Otherwise, the possibility that
some pathogenic plasmablasts producing AQP-4-IgG survived the
transplantation to develop ON later cannot be excluded.
Regrettably, the patient’s sera obtained before the allo-BMT were
not available for determining AQP-4-IgG, and thus testing this
hypothesis. In this regard, the fact that the donor, the patient’s
healthy sister, was seronegative for AQP-4-IgG is an important
piece of information. Although within a different immunopathological context, Matiello et al.8 reported an NMO patient who
relapsed a few months after autologous BMT for Hodgkin
lymphoma, which could be due to either T or B cells in the graft,
or surviving autoreactive T or B cells within the patient. They
concluded that, contrary to what is expected, BMT could even
have favored the NMO relapse.8
CSF examination was remarkable for lymphocytic pleiocytosis,
which was compatible with AQP-4-IgG-associated ON.9 Oligoclonal IgG band negativity is commonly seen in NMOSD, whereas
CSF elevated total proteins or abnormal albumin quotient, which
was normal in our patient, are more frequently reported.9
In conclusion, the presence of AQP-4-IgG, and the negative
findings in both CSF and bone marrow cells for recurrence of the
myeloid leukemia, led to the diagnosis of AQP-4-IgG-associated
ON. This is the first case in the medical literature, as the previously
reported allo-BMT cases with ON or NMOSD, which included
longitudinally extensive transverse myelitis, were published in the
pre-AQP-4-IgG era, or no information on such Ab testing was
provided.4,6 AQP-4-IgG positivity has prognostic meaning, as it
predicts ON relapses, evolution to NMO and permanent neurological deficits.2 Therefore, our patient, who was blind after the first
attack of ON notwithstanding high-doses of corticosteroids (both
IV and oral), is on rituximab, a highly efficacious drug in NMOSD.10
Our case suggests that AQP-4-IgG-seropositive NMOSD, which
needs early diagnosis and appropriate therapies, may be late
Bone Marrow Transplantation (2015) 1125 – 1126
autoimmune complications in post-transplant hematology
patients.
Informed consents were obtained from the patient and her
sister.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
ACKNOWLEDGEMENTS
This work was supported by the Italian Ministry of Health, research grant RF 2011–
2012 no. 2534459.
L Diamanti1,2, D Franciotta2, G Berzero1,2, P Bini2, LM Farina2,
AA Colombo3, M Ceroni2,4 and E Marchioni2
1
Neuroscience Consortium, University of Pavia, Monza Policlinico and
Pavia Mondino, Pavia, Italy;
2
IRCCS, ‘C. Mondino’ National Neurological Institute, Pavia, Italy;
3
Transplantation Unit, Department of Hematology and Oncology,
IRCCS, Policlinico San Matteo, Pavia, Italy and
4
Department of Brain and Behavioral Sciences, University of Pavia,
Pavia, Italy
E-mail: [email protected]
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