Commentary: Managing clinicians’ assessmentBMJ 2009; 339 doi: https://doi.org/10.1136/bmj.b5177 (Published 10 December 2009) Cite this as: BMJ 2009;339:b5177
All rapid responses
Reinhard Reuß, Paulus S Rommer, Wolfgang Brück, Sven Jarius, Michael
Bolz, and Uwe K Zettl
We very much appreciate these interesting questions.
As for the histological description, there were numerous small
infarcts observable in the placenta.
AQP4 immunostaining showed a complete loss of immunoreactivity
compared to a normal placenta, in which AQP4 is ubiquitously expressed in
a cell-type-specific and stage-dependent manner with a decrease in the
syncytiotrophoblast from the first to the third trimester (then moderate)
and an increased expression in endothelial cells and villous stroma (then
There are two possible reasons for this. The cells originally
expressing AQP4 might have been destroyed by immunoreaction;2-4
alternatively, endocytosis and subsequent degradation of the water
channel, initiated by cross-linking of surface AQP4 by IgG, might have
C9neo deposits were seen in the perivascular space of placental blood
vessels. In particular, we observed onion bulb-like staining around
placental vessels. Additionally, the syncytiotrophoblast cell membrane was
The appropriate controls were performed (negative control with
omitting the first antibody; we also used several antibodies that
recognised the C9neo epitope). The control placenta shows no indications
It is still unclear whether this complement-activating antibody is
pathophysiologically relevant and able to initiate CNS lesions, but there
is increasing evidence that the anti-AQP4 ab is directly involved in the
autoimmune pathogenesis of neuromyelitis optica.5-7 Taking into account
the histologically observed similarity of lesions, anti-AQP4 ab may also
have caused the placental pathology found in our patient, yet this is
1. De Falco M, Cobellis L, Torella M, Acone G, Varano L, Sellitti A,
et al. Down-regulation of aquaporin 4 in human placenta throughout
pregnancy. In Vivo 2007;21:813-7.
2. Roemer SF, Parisi JE, Lennon VA, Benarroch EE, Lassmann H, Bruck
W, et al. Pattern-specific loss of aquaporin-4 immunoreactivity
distinguishes neuromyelitis optica from multiple sclerosis. Brain
3. Misu T, Fujihara K, Kakita A, Konno H, Nakamura M, Watanabe S, et
al. Loss of aquaporin 4 in lesions of neuromyelitis optica: distinction
from multiple sclerosis. Brain 2007;130:1224-34.
4. Hinson SR, Pittock SJ, Lucchinetti CF, Roemer SF, Fryer JP, Kryzer
TJ, et al. Pathogenic potential of IgG binding to water channel
extracellular domain in neuromyelitis optica. Neurology 2007;69:2221-31.
5. Jarius S, Paul F, Franciotta D, Waters P, Zipp F, Hohlfeld R, et
al. Mechanisms of Disease: aquaporin-4 antibodies in neuromyelitis optica.
Nat Clin Pract Neurol 2008;4:202-14.
6. Bradl M, Misu T, Takahashi T, Watanabe M, Mader S, Reindl M, et
al. Neuromyelitis optica: Pathogenicity of patient immunoglobulin in vivo.
Ann Neurol 2009;66:630-43.
7. Bennett JL, Lam C, Kalluri SR, Saikali P, Bautista K, Dupree C, et
al. Intrathecal pathogenic anti-aquaporin-4 antibodies in early
neuromyelitis optica. Ann Neurol 2009;66:617-29.
Competing interests: No competing interests
Presenting an interactive case report like this is very instructive
and appeals to several different specialities allowing wide discussion.
However, as your commentators have said these problems can be difficult
and require multidisciplinary input. After reading the report describing
the histology and seeing the figure (section of placenta illustrating C9
immunohistochemistry) I had some uncertainties about the description:
1. Histological Description:
The authors write "histological investigation of the placenta showed
multiple infarcts, mainly located in the maternal part of the placenta".
What does this mean? How much of the placenta was involved and what is
meant by the "maternal part"?
2. AQP4 immunostaining:
The authors write "AQP4 immunostaining showed a complete loss of
immunoreactivity" (in the context of maternal serum AQP4 antibodies).
Which cells were involved and what do the authors think is the likely
explanation for this finding (given that AQP4 is a transmembrane water
3. C9 immunostaining:
The authors write "diffuse, mainly perivascular, deposits of MAC of the
complement system were clearly detectable on syncytiotrophoblasts and to a
moderate degree in the perivasal layers of the fetal vessels". What does
this mean? (the syncytiotrophoblast is not vascular and I am not sure what
is meant by "perivasal" in relation to the fetal vessels).
Whenever immunohistochemistry is performed and interpreted it is necessary
to have appropriate controls. Non-specific staining is often difficult to
I would appreciate further clarity on the interpretation of the
histology and immunohistochemistry. However these questions are not
intended to detract from what is a fascinating clinical problem and
perhaps represents another example of a human channelopathy, aquaporin 4
(AQP4) channelopathy (?) in this case.
My final question for all of us: is this acquired or inherited, non-immune
-mediated or autoimmune? Thankfully, from the experience of the patient
and the authors, the pathology appears to be reversible.
Competing interests: No competing interests