Hatano and colleagues recently published a paper of considerable
interest, investigating possible metabolic pathways associated with
Parkinson's disease (PD) by using metabolomic technologies [1]. Their
results on redox homeostasis deserve to be further discussed, since
oxidative stress is possibly involved in PD risk and progression. In
particular, authors found bilirubin, a strong natural antioxidant, to be
significan...
Hatano and colleagues recently published a paper of considerable
interest, investigating possible metabolic pathways associated with
Parkinson's disease (PD) by using metabolomic technologies [1]. Their
results on redox homeostasis deserve to be further discussed, since
oxidative stress is possibly involved in PD risk and progression. In
particular, authors found bilirubin, a strong natural antioxidant, to be
significantly reduced in patients with PD, as compared to controls [1].
However, there are different studies reporting conflicting results on
bilirubin metabolism in PD.
From a pathophysiological perspective, the production of bilirubin and,
subsequently, its plasma levels are mainly related to heme-oxigenase (HO)
activity [2-3]. The up-regulation of the HO-bilirubin pathway is an early
response to oxidative stress within dopaminergic cells and, accordingly,
cytoplasmatic Lewy bodies of PD patients display intense peripheral HO
staining [2]. In line with this, Scigliano and colleagues previously
reported increased total bilirubin levels in PD [4], and, similarly, we
recently confirmed this result in our population of newly-diagnosed, drug-
na?ve PD subjects [5]. These findings are supported by the hypothesis that
HO up-regulation within the substantia nigra is an adaptive response to
increased oxidative stress, occurring since the early phases of PD, and is
subsequently responsible for systemic bilirubin increase [2-3].
On the other hand, Hatano and colleagues reported reduced bilirubin levels
in PD, compared to controls, possibly as a consequence of increased
oxidative stress [1], whereas Qin and colleagues found no difference in
total bilirubin concentrations between PD cases and controls [6].
These discordant results can be explained by the presence of confounding
factors affecting bilirubin levels and/or by bilirubin variations during
the course of the disease. Among possible confounding factors, for
instance, we must report the presence of HO polymorphisms, which probably
modify bilirubin levels in PD cohorts with different genetic background
[7]. There are also several comorbidities affecting bilirubin that are
difficult to exclude completely in clinical practice, in particular for
studies with small sample size [5]. Finally, it is possible to hypothesize
a variability of bilirubin levels during the course of PD. Considering
different studies that have been conducted so far, it can be hypothesized
an increase in bilirubin levels in the early phases of PD, with subsequent
gradual decrease during the course of the disease, due to progressive
reduction of the antioxidant reserve [1,4-5]. However, since bilirubin
increase is generally considered a marker of improved health outcomes in
the general population [2-3], PD patients presenting higher bilirubin
levels in both early and late phases of PD are conceivably those with
better response to the increased oxidative stress and, thus, are expected
to have better motor performances, as described by Hirano and colleagues,
and in our population [1,5]. As a future perspective, considering that all
previous studies presented a cross-sectional design [1,4-6], further
investigations should be conducted with a longitudinal design in order to
specifically investigate the modifications of bilirubin levels during the
course of the disease in relation to dopaminergic treatments, disease
progression and/or PD-related pathological changes [2-3].
In conclusion, the HO-bilirubin pathway seems to be affected by various
factors and, thus, appears a dynamic antioxidant mechanism with a
significant role in PD. In particular, we thank Hatano and colleagues for
their contribution in this field, and strongly encourage further studies
investigating variations in bilirubin levels during the course of PD with
subsequent health outcomes.
References
1. Hatano T, Saiki S, Okusumi A, et al. Identification of novel biomarkers
for Parkinson's disease by metabolomic technologies. J Neurol Neurosurg
Psychiatry 2015.
2. Schipper HM, Song W, Zukor H, et al. Heme oxygenase-1 and
neurodegeneration: expanding frontiers of engagement. J Neurochem
2009;110(2):469-485.
3. McCarty MF. Serum bilirubin may serve as a marker for increased heme
oxygenase activity and inducibility in tissues - A rationale for the
versatile health protection associated with elevated plasma bilirubin. Med
Hypotheses 2013;81(4):607-610.
4. Scigliano G, Girotti F, Soliveri P, et al. Increased plasma bilirubin
in Parkinson patients on L-dopa: evidence against the free radical
hypothesis? Ital J Neurol Sci 1997;18(2), 69-72.?
5. Moccia M, Picillo M, Erro R, et al. Increased bilirubin levels in de
novo Parkinson's disease. Eur J Neurol 2015.
6. Qin XL, Zhang QS, Sun L, et al. Lower Serum Bilirubin and Uric Acid
Concentrations in Patients with Parkinson's Disease in China. Cell Biochem
Biophys 2014.
7. Ayuso P, Mart?nez C, Pastor P, et al. An association study between Heme
oxygenase-1 genetic variants and Parkinson's disease. Front Cell Neurosci
2014;8:298.
As a research intern aspiring to be a neurologist, I found Dr. Mathew
et al. article highly interesting and thought provoking [1]. Multiple
sclerosis is a complex neurological condition to manage, given its
numerous phenotypes.
It was very interesting to note that the authors found similar
imaging features on conventional MR brain scan in patients with multiple
sclerosis (MS)-like disease in association with LH...
As a research intern aspiring to be a neurologist, I found Dr. Mathew
et al. article highly interesting and thought provoking [1]. Multiple
sclerosis is a complex neurological condition to manage, given its
numerous phenotypes.
It was very interesting to note that the authors found similar
imaging features on conventional MR brain scan in patients with multiple
sclerosis (MS)-like disease in association with LHON (LMS) as well as
multiple sclerosis (MS) and hypothesized that mitochondrial dysfunction
could be a common pathophysiological pathway in the formation of white
matter lesions in these disorders [1].
Diffusion tensor MR imaging (DT MRI) has shown to be useful in
detecting micro-structural alterations in white matter and grey matter in
MS, in seemingly "normal -appearing white matter and gray matter" on
conventional MR images [2,3]. Recent studies also indicate that DT MRI may
demonstrate characteristic features in LHON such as decreased fractional
anisotropy (FA) and an increased mean diffusivity and radial diffusivity,
affecting exclusively the optic tracts and optic radiations, and in some
patients the acoustic radiations [4,5]. In that regard, it would be
useful to know if DT MRI could further identify any specific micro-
structural alteration that are common in these two conditions, which may
indeed act as a biomarker, and perhaps fuel future research in genotype-
phenotype correlation utilizing advanced MRI techniques including DT MRI
and functional MRI techniques.
References
1. Matthews L, Enzinger C, Fazekas F et al. MRI in Leber's hereditary
optic neuropathy: the relationship to multiple sclerosis. J Neurol
Neurosurg Psychiatry. 2015 May; 86(5):537-42
2. Fox RJ. Picturing multiple sclerosis: conventional and diffusion
tensor imaging. Semin Neurol. 2008 Sep; 28(4):453-66
3. Goldberg-Zimring D, Mewes AU, Maddah M, Warfield SK. Diffusion
tensor magnetic resonance imaging in multiple sclerosis. J Neuroimaging.
2005;15(4 Suppl):68S-81S.
4. Milesi J, Rocca MA, Bianchi-Marzoli S et al. Patterns of white
matter diffusivity abnormalities in Leber's hereditary optic neuropathy: a
tract-based spatial statistics study. J Neurol. 2012 Sep; 259(9):1801-7
5. Manners DN, Rizzo G, La Morgia C et al. Diffusion Tensor Imaging
Mapping of Brain White Matter Pathology in Mitochondrial Optic
Neuropathies. AJNR Am J Neuroradiol. 2015 Mar 19.
Thank you for your enthusiasm for our study, and for your questions.
In our opinion, an extensive neuropsychological test battery is
mandatory for diagnosis of probable AD dementia. An MMSE score alone is
not sufficient for the assessment of cognitive impairment.
We used MMSE as indicator for disease severity, within our sample of
already diagnosed probable AD patients. It is an interesting suggestion t...
Thank you for your enthusiasm for our study, and for your questions.
In our opinion, an extensive neuropsychological test battery is
mandatory for diagnosis of probable AD dementia. An MMSE score alone is
not sufficient for the assessment of cognitive impairment.
We used MMSE as indicator for disease severity, within our sample of
already diagnosed probable AD patients. It is an interesting suggestion to
use the MoCA for this purpose, because this test focuses more on several
non-memory domains. However, we preferred MMSE because it is commonly used
and easy to interpret.
Mean age of the patients in our cohort was 69+/-9 years old (shown in
table 1). Mean ages per cluster are given in table 4.
We thank Drs. Yuki and Wong for their interest in our paper. We agree
that the finding that anti-CNTN1 autoantibodies in patients are mostly of
the IgG4 subtype is important for our understanding of the pathophysiology
of anti-CNTN1-associated neuropathy. However, in the study by Miura as
well as in our study, IgG2 and IgG3 autoantibodies were detected in some
patients (1, 2). The two patients from our study with predomina...
We thank Drs. Yuki and Wong for their interest in our paper. We agree
that the finding that anti-CNTN1 autoantibodies in patients are mostly of
the IgG4 subtype is important for our understanding of the pathophysiology
of anti-CNTN1-associated neuropathy. However, in the study by Miura as
well as in our study, IgG2 and IgG3 autoantibodies were detected in some
patients (1, 2). The two patients from our study with predominance of IgG3
autoantibodies were tested in the acute phase of disease (1). It would be
of interest to learn if the samples of the patients with IgG2/IgG3
autoantibodies from Miura's study might also have been taken at the
beginning of disease, as this might suggest a switch of IgG subclasses
during the course of disease.
As pointed out by Yuki and Wong, the study by Miura et al. provides
additional findings shedding further light on the pathogenicity of anti-
CNTN1 IgG4 autoantibodies (2). Although fulfilling clinical and
electrophysiological criteria of chronic inflammatory demyelinating
polyneuropathy (CIDP), neuropathy with anti-CNTN1 autoantibodies more and
more evolves to be an independent disease differing from classical CIDP.
Yuki and Wong addressed the binding of sera of patients with anti-CNTN1
IgG4 autoantibodies to dorsal root ganglia (DRG), a finding that was first
described in the study by Miura et al. (2). This raises the question if
anti-CNTN1-IgG4-associated neuropathy should be categorized as a
ganglionopathy rather than a neuropathy or paranodopathy. Indeed, several
studies provide evidence that binding of anti-CNTN1 autoantibodies is not
restricted to the paranodes but can also be found on hippocampal neurons,
in the cerebellum and DRG, presumably correlating with clinical symptoms
like tremor or sensory ataxia (1-3). Nevertheless, in our opinion, anti-
CNTN1-IgG4-associated neuropathy should be considered a paranodopathy as
there is ample evidence that the paranodes are the major site of action in
this disease: Neuropathic symptoms are the first and predominant symptoms
in all patients described so far (1, 3). Morphological analysis of
paranodes shows severe destruction of paranodal architecture as a
correlate of impaired nerve conduction (1). Electrophysiological studies
showing conduction block, prolonged distal motor latency and slowing of
nerve conduction velocities are well in line with the concept of
paranodopathy (4). Distal onset of sensory symptoms further strengthens
this notion and argues against a ganglionopathy as a major cause of
sensory loss. Damage to DRG might contribute to sensory ataxia, especially
in truncal forms as decribed by Miura et al. (2), but all in all the
clinical and electrophysiological phenotype of these patients suggests to
consider anti-CNTN1-IgG4-associated disease a paranodopathy (or
paranodopathy plus). Further studies are needed to 1) elucidate the
pathogenesis of this disease on the molecular level and to 2) better
characterize the clinical phenotype in a larger cohort of patients.
1. Doppler K, Appeltshauser L, Wilhelmi K, et al. Destruction of
paranodal architecture in inflammatory neuropathy with anti-contactin-1
autoantibodies. J Neurol Neurosurg Psychiatry 2015.
2. Miura Y, Devaux JJ, Fukami Y, et al. Contactin 1 IgG4 associates to
chronic inflammatory demyelinating polyneuropathy with sensory ataxia.
Brain 2015.
3. Querol L, Nogales-Gadea G, Rojas-Garcia R, et al. Antibodies to
contactin-1 in chronic inflammatory demyelinating polyneuropathy. Ann
Neurol 2013;73:370-380.
4. Uncini A, Susuki K, Yuki N. Nodo-paranodopathy: beyond the
demyelinating and axonal classification in anti-ganglioside antibody-
mediated neuropathies. Clin Neurophysiol 2013;124:1928-1934.
We would like to draw attention to one important point in regard to
hyperammonaemic encephalopathy which was not mentioned in the recent
excellent article by Sutter and Kaplan discussing the imaging features of
encephalopathy.
The cases of hyperammonaemic encephalopathy with neuroimaging
features number less than 10 in the reported literature. As the authors
stated they can develop cortical signal abnormalitie...
We would like to draw attention to one important point in regard to
hyperammonaemic encephalopathy which was not mentioned in the recent
excellent article by Sutter and Kaplan discussing the imaging features of
encephalopathy.
The cases of hyperammonaemic encephalopathy with neuroimaging
features number less than 10 in the reported literature. As the authors
stated they can develop cortical signal abnormalities.
However having recently had experience with three cases of
hyperammonaemia we noted despite the very diffuse cortical signal change,
the signal change didn't involve the perirolandic cortex, in each of the
three cases. This was noted in all but one of the reported cases in the
literature.
It is worth drawing attention to this, as this radiological feature
may be a feature which is quite specific to hyperammonaemia. Clearly this
is observation is based on a very small number of patients, but is worth
bearing in mind when assessing patients with cortical signal change, which
may spare the perirolandic cortex.
As an explanation for this process, it is possible that this is
related to cortical cytoarchitecture (perineuronal nets-abundent in
perirolandic cortex [1])/receptor characteristics leading to a
differential sensitivity to the toxic insult of elevated ammonia.
Reference:
[1] Karaarslan E, Arslan A. Perirolandic cortex of the normal brain.
Low signal intensity on turbo FLAIR MR images. Radiology. 2003;227:538-541
We read with interest the recent article published by Scheltens et.
al. [1] The article helped us in understanding greater insights about AD
dementia. As rightly stated by the authors that one magic bullet will
never be found, but different therapeutic agents may benefit different
subgroups of patients. The identification and importance of cognitive AD
subtypes for making differentiated diagnoses will also help in the fu...
We read with interest the recent article published by Scheltens et.
al. [1] The article helped us in understanding greater insights about AD
dementia. As rightly stated by the authors that one magic bullet will
never be found, but different therapeutic agents may benefit different
subgroups of patients. The identification and importance of cognitive AD
subtypes for making differentiated diagnoses will also help in the further
cognitive rehabilitation of AD patients. Out of the three clusters
classified by the authors, one was the memory indifferent group wherein
all patients were diagnosed with probable AD with a MMSE score with mean
14. The review suggests how an MMSE score is not supportive of AD
diagnosis. [2][3] We would like to know the view of the authors on how
memory indifferent group a MMSE score. As the neuropsychological test
battery used by the institute is dynamic, the use of MMSE in future can be
avoided as it is not a sensitive measure for diagnosis of AD. There are
other available measures which are found to be more sensitive than MMSE
for cognitive screening like MoCA. [4][5]Attention is one of the cognitive
domains that are found to be impaired in people suffering from AD. [6]
It's intriguing to know from the results of the paper which show how
attention is comparatively less affected in these patients. Lastly, we
would like to know the age of the patients as the article talks about the
younger patients who were six times more likely to be classified in MOD-
VISP, three times likely to be classified in SEV-DIFF and two times likely
to be classifies in MILD-EXE. The information about the different age
ranges would provide a better insight. We would like to thank the authors
for carrying out this research as it provides greater understanding of the
AD.
1. Scheltens, N. M., Galindo-Garre, F., Pijnenburg, Y. A., van der
Vlies, A. E., Smits, L. L., Koene, T., & van der Flier, W. M. (2015).
The identification of cognitive subtypes in Alzheimer's disease dementia
using latent class analysis. Journal of Neurology, Neurosurgery &
Psychiatry, jnnp-2014.
2. Roselli, F., Tartaglione, B., Federico, F., Lepore, V., Defazio, G.,
& Livrea, P. (2009). Rate of MMSE score change in Alzheimer's disease:
influence of education and vascular risk factors. Clinical neurology and
neurosurgery, 111(4), 327-330.
3. Galasko, D., Klauber, M. R., Hofstetter, C. R., Salmon, D. P., Lasker,
B., & Thal, L. J. (1990). The Mini-Mental State Examination in the
early diagnosis of Alzheimer's disease. Archives of Neurology, 47(1), 49-
52.
4. Neufang, S., Akhrif, A., Riedl, V., F?rstl, H., Kurz, A., Zimmer, C.,
& Wohlschl?ger, A. M. (2011). Disconnection of frontal and parietal
areas contributes to impaired attention in very early Alzheimer's disease.
Journal of Alzheimer's Disease, 25(2), 309-321.
5. Pendlebury, S. T., Markwick, A., de Jager, C. A., Zamboni, G., Wilcock,
G. K., & Rothwell, P. M. (2011). Differences in cognitive profile
between TIA, stroke and elderly memory research subjects: a comparison of
the MMSE and MoCA. Cerebrovascular diseases (Basel, Switzerland), 34(1),
48-54.
6. Larner, A. J. (2012). Screening utility of the Montreal Cognitive
Assessment (MoCA): in place of-or as well as-the MMSE?. International
Psychogeriatrics, 24(3), 391.
7. Calderon, J., Perry, R. J., Erzinclioglu, S. W., Berrios, G. E.,
Dening, T., & Hodges, J. R. (2001). Perception, attention, and working
memory are disproportionately impaired in dementia with Lewy bodies
compared with Alzheimer's disease. Journal of Neurology, Neurosurgery
& Psychiatry, 70(2), 157-164.
At paranodes of both central and peripheral nerves, neurofascin-155
(NF155) is expressed by the terminal loops of myelin and associates with
the axonal cell adhesion molecules contactin-1 and contactin-associated
protein-1. They are important in maintaining the integrity of axo-glial
junction and forming barrier against lateral diffusion of nodal channels.
Human IgG antibodies consist of four subclasses (IgG1-4) with dif...
At paranodes of both central and peripheral nerves, neurofascin-155
(NF155) is expressed by the terminal loops of myelin and associates with
the axonal cell adhesion molecules contactin-1 and contactin-associated
protein-1. They are important in maintaining the integrity of axo-glial
junction and forming barrier against lateral diffusion of nodal channels.
Human IgG antibodies consist of four subclasses (IgG1-4) with different
structural and functional characteristics. IgG4 are generally believed to
be non-inflammatory antibodies because of their inability to activate
complement. IgG4 autoantibodies to NF155 and CNTN1 were identified in
patients with chronic inflammatory demyelinating polyneuropathy (CIDP)
sharing common clinical features, including subacute symptom onset and
poor response to intravenous immunoglobulins (IVIG) (1, 2). Anti-contactin
-1 IgG4 autoantibodies appear to affect paranodal structure both in vivo
and in vitro (1, 3), suggesting that they are pathogenic.
Anti-NF155 antibodies were reported by a single Japanese group in a
proportion of patients with combined central and peripheral demyelination
(CCPD) (4, 5). It is unclear whether their autoantibodies belong to the
IgG4 subclass, but we have identified three Japanese patients with CCPD
presenting with anti-NF155 IgG4 antibodies (Miura and Yuki, unpublished
results). Whereas their CCPD patients responded to IVIG, our patients did
not always respond to IVIG (Fukami and Yuki, unpublished results). One
possible explanation is that the IgG subclasses were different in these
two cohorts. Our patients showed anti-NF155 IgG4 antibodies, which had a
low affinity for Fc receptors and complement, and did not activate
complement in vitro (Miura and Yuki, unpublished results). By contrast,
the IgG subclass has not been examined in their studies. It is thus
important to know whether the autoantibodies identified in their study
belong to the IgG4 subclass, and the reason why there is discrepancy in
the response to IVIG treatment between their study and ours if both
patients demonstrated anti-NF155 IgG4 antibodies.
Referemces
1. Doppler K, Appeltshauser L, Wilhelmi K, Villmann C, Dib-Hajj SD, Waxman
SG, et al. Destruction of paranodal architecture in inflammatory
neuropathy with anti-contactin-1 autoantibodies. J Neurol Neurosurg
Psychiatry. 2015 Feb 18. pii: jnnp-2014-309916. doi: 10.1136/jnnp-2014-
309916.
2. Querol L, Nogales-Gadea G, Rojas-Garcia R, Diaz-Manera J, Pardo J,
Ortega-Moreno A, et al. Neurofascin IgG4 antibodies in CIDP associate with
disabling tremor and poor response to IVIg. Neurology. 2014;82:879-86.
3. Labasque M, Hivert B, Nogales-Gadea G, Querol L, Illa I, Faivre-
Sarrailh C. Specific contactin N-glycans are implicated in neurofascin
binding and autoimmune targeting in peripheral neuropathies. J Biol Chem.
2014;289:7907-18.
4. Kawamura N, Yamasaki R, Yonekawa T, Matsushita T, Kusunoki S, Nagayama
S, et al. Anti-neurofascin antibody in patients with combined central and
peripheral demyelination. Neurology. 2013;81:714-22.
5. Ogata H, Matsuse D, Yamasaki R, Kawamura N, Matsushita T, Yonekawa T,
et al. A nationwide survey of combined central and peripheral
demyelination in Japan. J Neurol Neurosurg Psychiatry. 2015 Feb 11. pii:
jnnp-2014-309831. doi: 10.1136/jnnp-2014-309831.
With interest, we read an excellent paper written by a German group,
in which four patients with chronic inflammatory demyelinating
polyneuropathy (CIDP) carried IgG autoantibodies against contactin-1
(CNTN1) expressed at the paranodes in the peripheral nerves.[1] Human IgG
antibodies consist of four subclasses (IgG1-4) with different structural
and functional characteristics. IgG4 are generally believed to be non-
infla...
With interest, we read an excellent paper written by a German group,
in which four patients with chronic inflammatory demyelinating
polyneuropathy (CIDP) carried IgG autoantibodies against contactin-1
(CNTN1) expressed at the paranodes in the peripheral nerves.[1] Human IgG
antibodies consist of four subclasses (IgG1-4) with different structural
and functional characteristics. IgG4 are generally believed to be non-
inflammatory antibodies because they poorly bind to complement and Fc
receptors Three of their patients had anti-CNTN1 IgG4 and sera from these
three patients bound the paranodes in the mouse teased nerve fibers. On
the other hand, the remaining patient with no anti-CNTN1 IgG4 antibodies
in the serum did not bind the paranodes.
In a large cohort of Japanese patients with CIDP (n = 533) and
Guillain-Barre syndrome (GBS) (n = 200), our group identified anti-CNTN1
IgG antibodies in 16 sera from patients with CIDP and five with GBS.[2]
IgG4 antibodies to CNTN1 were identified in 13 of 16 patients with CIDP,
but none of those with GBS. IgG2 antibodies to CNTN1 were identified in
three patients with CIDP and in five patients with GBS. We also blindly
tested the sera on mouse teased fibers. Of interest, all the IgG4-positive
CIDP sera strongly reacted against the paranodal domains but not for the
IgG2-positive sera from patients with CIDP or GBS. These results are in
line with those of the German group,[1] suggesting that only the IgG4
antibodies are pathogenic.
We further tested whether these sera activate the complement pathway
in vitro.[2] None of the sera with anti-CNTN1 IgG4 antibodies induced the
deposition of activated C3 components on enzyme-linked immunosorbent assay
plates. These results support that anti-CNTN1 IgG4 antibodies do not fix
complement.
The German group found out a typical clinical picture among the CIDP
patients with anti-CNTN1 antibodies, namely acute onset of disease and
severe motor symptoms, with three out of four patients manifesting action
tremor.[1] However, in our cohort we found out that presence of anti-CNTN1
IgG4 antibodies was significantly associated with the clinical sign of
sensory ataxia.[2] CNTN1 was widely expressed in large dorsal root
ganglion neurons. Similarly, CIDP sera with anti-CNTN1 IgG4 antibodies
stained large neurons in dorsal root ganglion sections and co-localized
with CNTN1 staining in the soma and at the paranodes of sensory axons.
These results support that the anti-CNTN1 autoantibodies induce the
development of sensory ataxia. Nonetheless, the clinical feature of our
patients contrasted with previous studies where none of the three German
patients and only one of four Spanish patients with anti-CNTN1 IgG4
antibodies showed sensory ataxia.[1,3] The reason for this discrepancy is
unclear, but this discrepancy should motivate international study groups
to investigate the clinical feature of the anti-CNTN1 IgG4 antibodies
among different countries, and their underlying mechanism.
References
1. Doppler K, Appeltshauser L, Wilhelmi K, et al. Destruction of paranodal
architecture in inflammatory neuropathy with anti-contactin-1
autoantibodies. J Neurol Neurosurg Psychiatry 2015 Feb 18. pii:jnnp-2014-
309916. doi: 10.1136/jnnp-2014-309916.
2. Miura Y, Devaux N, Fukami Y, et al. Contactin 1 IgG4 associated to
chronic inflammatory demyelinating polyneuropathy with sensory ataxia.
Brain 2015 Mar 25. pii: awv054.
3. Querol L, Nogales-Gadea G, Rojas-Garcia R, et al. Antibodies to
contactin-1 in chronic inflammatory demyelinating polyneuropathy. Ann
Neurol 2013;73:370-80.
In peripheral nerves, the domain organization of myelinated axons
depends on specific axoglial contacts between the axonal membrane and
Schwann cells at nodes, paranodes and juxtaparanodes. The term nodo-
paranodopathy was originally proposed to characterize neuropathies with
anti-ganglioside antibodies by a common pathological continuum starting
with dysfunction/disruption at the nodes of Ranvier, a transitory nerve
fai...
In peripheral nerves, the domain organization of myelinated axons
depends on specific axoglial contacts between the axonal membrane and
Schwann cells at nodes, paranodes and juxtaparanodes. The term nodo-
paranodopathy was originally proposed to characterize neuropathies with
anti-ganglioside antibodies by a common pathological continuum starting
with dysfunction/disruption at the nodes of Ranvier, a transitory nerve
failure and resulting in axonal degeneration.[1] Uncini and Kuwabara[2]
extended the concept to include neuropathies of different etiology
(dysimmune, inflammatory, ischemic, nutritional and toxic) in which the
involvement of the nodal region is determinant. As the pathogenic
mechanisms are mainly focused on the node, the authors proposed to
classify these neuropathies as nodopathies. We agree with the change from
nodo-paranodopathy to "nodopathy" because the latter term is simple and
easy to be kept in mind. However, as recently suggested by Doppler and
colleagues, a new term "paranodopathy" should be used to define
neuropathies associated with autoantibodies to paranodal cell adhesion
molecules.[3]
Cell adhesion molecules at the nodes and paranodes dictate the
formation of the nodes of Ranvier and enable the rapid saltatory
propagation. At paranodes, contactin-associated protein-1 associates with
contactin-1 (CNTN1) on the axonal membrane and this complex interacts with
a glial partner expressed by the terminal loops of myelin, neurofascin-155
(NF155). This ternary complex of glycoproteins is required for the
formation and stability of the septate-like junctions which form an
insulating barrier at paranodes. IgG4 autoantibodies to NF155 and CNTN1
have been documented in patients with chronic inflammatory demyelinating
polyneuropathy, sharing common clinical features, including subacute
symptom onset and poor response to intravenous immunoglobulin.[3-5] When
introducing the term nodopathy/paranodopathy, Uncini and colleagues[1]
referred to patients with anti-ganglioside antibodies and conduction
block, but nearly normal nerve conduction velocities. In contrast, both
anti-CNTN1 and anti-NF155-mediated neuropathies are associated with a
reduction of nerve conduction velocity.[3-5] The loss of paranodal
axoglial junctions and the elongation of the nodal gap in these patients
indicate that autoantibodies against CNTN1 could lead to paranode
disruption and result in slow nerve conduction or conduction block.[3] We
agree with the new concept proposed by Doppler and colleagues[3] that
anti-CNTN1 and anti-NF155-mediated paranodopathies are a new subgroup of
autoimmune peripheral neuropathy with distinct clinical phenotypes and
damage to the paranodes.
References
1. Uncini A, Susuki K, Yuki N. Nodo-paranodopathy: beyond the
demyelinating and axonal classification in anti-ganglioside antibody-
mediated neuropathies. Clin Neurophysiol 2013;124:1298-34.
2. Uncini A, Kuwabara S. Nodopathies of the peripheral nerve: an emerging
concept. J Neurol Neurosurg Psychiatry 2015 Feb 19. pii: jnnp-2014-310097.
doi: 10.1136/jnnp-2014-310097.
3. Doppler K, Appeltshauser L, Wilhelmi K, et al. Destruction of paranodal
architecture in inflammatory neuropathy with anti-contactin-1
autoantibodies. J Neurol Neurosurg Psychiatry 2015 Feb 18. pii: jnnp-2014-
309916. doi: 10.1136/jnnp-2014-309916.
4. Querol L, Nogales-Gadea G, Rojas-Garcia R, et al. Neurofascin IgG4
antibodies in CIDP associate with disabling tremor and poor response to
IVIg. Neurology 2014;82:879-86.
5. Miura Y, Devaux N, Fukami Y, et al. Contactin 1 IgG4 associated to
chronic inflammatory demyelinating polyneuropathy with sensory ataxia.
Brain 2015 Mar 25. pii: awv054.
We read with great interest the recent study by Maia et al., which
reports retrospectively central nervous system (CNS) involvement in
patients with familial amyloid polyneuropathy associated with Val30Met
mutation (ATTR Val30Met FAP)1. This complication was observed in 31% of
ATTR Val30Met FAP patients with long survival due to liver transplantation
(LT). CNS disorders occurred on average 14.6 years after the onset of TT...
We read with great interest the recent study by Maia et al., which
reports retrospectively central nervous system (CNS) involvement in
patients with familial amyloid polyneuropathy associated with Val30Met
mutation (ATTR Val30Met FAP)1. This complication was observed in 31% of
ATTR Val30Met FAP patients with long survival due to liver transplantation
(LT). CNS disorders occurred on average 14.6 years after the onset of TTR-
FAP, which is beyond the average life expectancy (11 years) of non-
transplanted patients2. The CNS symptoms were classified as negative
(ischemia and aura) or positive (epileptic seizures). Magnetic resonance
imaging (MRI) could not be performed in their population of patients;
however, amyloid deposition from the meninges to the brain parenchyma was
proposed as the neuropathological hallmark of those clinical
manifestations, mainly based on historical necropsy studies1.
Indeed, LT does not preclude amyloid production by the retinal pigment and
choroid plexus, thus ocular and CNS involvement many years after LT is not
an unexpected observation3. Moreover, atypical cases ATTR Val30Met FAP
presenting with early CNS manifestations have been described4.
In our center, a similar experience with de novo CNS dysfunction in
long survivors with ATTR Val30Met FAP has been identified. From 83
patients with a disease duration longer than 10 years (mean 15.6, SD 5.1),
in whom 91.5% (76/83) were submitted to LT (mean duration after LT of 10.8
years), 16.9% (14/83) had some CNS manifestation.
The mean interval between disease presentation and CNS manifestation was
16.9 years (SD 5.5). In the group of affected patients, 64% (9/14) had a
transitory ischemic accident-like episode, 7% (1/14) ischemic stroke, 7%
(1/14) brain hematoma, 42.8% (6/14) epileptic seizures, 7% (1/14) a
psychosis-like event and 92.8% (13/14) cognitive impairment (11 with
mild cognitive impairment criteria and 2 with minor cognitive impairment)
although no patients had criteria for dementia. Our patients underwent
brain CT scan, EEG, neurovascular workup (blood tests, EKG, transcranial
doppler, carotid ultrasound and echocardiogram) and formal
neuropsychological evaluation including Mini Mental State Examination
(MMSE), tests of attention, memory and executive functions. Brain MRI
(without gadolinium) was performed in two patients with seizures, which
excluded ischemic or hemorrhagic lesions. Neuropsychological assessments
disclosed attention and initiative deficits as the most critical findings,
suggesting dysexecutive (frontal) involvement. A 40 year-old male, in whom
LT was performed at the age of 26 (three years after the disease onset),
had an acute right parieto-occipital hematoma, two years after his initial
symptoms of epileptic seizures. During surgical decompression, a cerebral
biopsy was done that showed TTR amyloid deposition in meningeal vessels
and cerebral parenchyma with no beta A4 amyloid deposition (Figure 1).
This observation was in agreement with the neuropathological findings
described by Maia et al1.
In general, our results support the detailed report by Maia et al1. In our
population, seizures were somewhat more frequent, and MRI could be
performed in two of those patients, excluding vascular changes.
Furthermore, neuropsychological testing disclosed mild executive
impairment in almost all patients, which raises the hypothesis of a
predominant frontal amyloid deposition. Many questions remain open and
should be addressed in future studies, in particular the risk of dementia
and seizures in this group of patients. This has critical implications
regarding medical decision towards LT in TTR-FAP patients.
REFERENCES
1. Maia LF, Magalh?es R, Freitas J et al. CNS involvement in V30M
transthyretin amyloidosis: clinical, neuropathological and biochemical
findings. J Neurol Neurosurg Psychiatry 2015; 86:159-67.
2. Coutinho P, Martins da Silva, A, Lopes Lima J, Resende Barbosa A. Forty
years of experience with type I amyloid neuropathy. Review of 483 cases.
In: Glenner G, Costa P and de Freitas A. (eds). Amyloid and Amyloidosis
1980. Amsterdam: Execerpta Medica, pp. 88-98.
3. Sandgren O, Kjellgren D, Suhr O. Ocular manifestations in liver
transplant recipients with familial amyloid polyneuropathy. Acta
Ophthalmol 2008; 86:520-524.
4. Herrick MK, DeBruyne K, Horoupian DS, Skare J, Vanefsky MA, Ong T.
Massive leptomeningeal amyloidosis associated with a Val30Met
transthyretin gene. Neurology 1996; 47:988-992.
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Thank you for your enthusiasm for our study, and for your questions.
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We read with great interest the recent study by Maia et al., which reports retrospectively central nervous system (CNS) involvement in patients with familial amyloid polyneuropathy associated with Val30Met mutation (ATTR Val30Met FAP)1. This complication was observed in 31% of ATTR Val30Met FAP patients with long survival due to liver transplantation (LT). CNS disorders occurred on average 14.6 years after the onset of TT...
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