The article by Roberts and colleagues on formaldehyde and ALS, is
important for its contribution to job related hazards of formaldehyde
exposure. One occupation that would be interesting to examine, is wood
working/carpentry using mainly plywood. At the core of its manufacture, is
formaldehyde. Plywood for indoor use generally uses urea-formaldehyde
glue, which has limited water resistance, while outdoor and marine-grade...
The article by Roberts and colleagues on formaldehyde and ALS, is
important for its contribution to job related hazards of formaldehyde
exposure. One occupation that would be interesting to examine, is wood
working/carpentry using mainly plywood. At the core of its manufacture, is
formaldehyde. Plywood for indoor use generally uses urea-formaldehyde
glue, which has limited water resistance, while outdoor and marine-grade
plywood are designed to withstand moisture, and use a water resistant
phenol-formaldehyde glue.. Working with plywood produces significant
amounts of fine dust containing formaldehyde as well as wood particles. If
adequate protection is not used, and ventilation poor, the results can
range from eye irritation to various forms of respiratory compromise.
Neurological effects are equally likely, especially after years of working
in similar dust/formaldehyde environments.
Anthony David's article on Paralympics and conversion disorder opens
an important and useful debate about the legitimacy of physical disability
when related to a functional (psychogenic) disorder and the extent to
which patients with these disorders should have access to the normal
rights of a disabled person(3). If functional disorders, and to be clear
we are talking here specifically about functional limb weakness, are...
Anthony David's article on Paralympics and conversion disorder opens
an important and useful debate about the legitimacy of physical disability
when related to a functional (psychogenic) disorder and the extent to
which patients with these disorders should have access to the normal
rights of a disabled person(3). If functional disorders, and to be clear
we are talking here specifically about functional limb weakness, are a
genuine cause of disability why would they be excluded from the
paralympics?
The article highlighted the important fact that conversion disorder
does not stand alone in being excluded from Paralympic classification and
that each sport has different rules(5). The classification itself however
is not based on disease categories but on impairments that are
quantifiable and permanent. As a result many disabling conditions do not
'fit'. As well as chronic pain and epilepsy, it is important we think to
highlight that other 'motor' neurological disorders including Parkinson's
disease are usually excluded so this is not an issue about having a
pathological disease to get you "entry to the club".
We recognise the need for fairness and agree there is an inherent
problem in allowing someone with functional limb weakness that, by
definition can transiently improve, in competing against athletes with
fixed deficits. Improvement in motor function in functional disorders
occurs when the patient is not attending to the limb and is often hard for
the person themselves to appreciate(6). Whether this is really an issue in
sports where the limb is not ostensibly being used anyway, such as
wheelchair sports is debatable, although we recognise there may be
advantages in terms of core stability or training for the patient with a
functional disorder and matching deficits could be difficult.
However, we don't agree that issues of 'secondary gain' should come
in to the discussion. "Secondary gain", the interpersonal or social
advantage that occurs secondary to illness which may unconsciously
perpetuate disability, is not specific to patients with functional
disorder but exists across the whole spectrum of disease. What differs is
our social response to it. In many situations we actively encourage it,
helping the patient solicit disability benefits or participation in
'positive' disability activities. But for some disorders we actively
discourage it believing it is not in the patients best interest to benefit
from being unwell- such considerations are almost always made in a
paternalistic fashion with little open discussion with patient about what
is in their interest. In fact decisions on secondary gain can quickly
become moral judgements and are prone to error, prejudice and social bias.
In a hypothetical future in which spinal cord injury could be cured
with regenerative medicine, would we ban all patients with potentially
curable conditions from taking part to make sure that they were all
correctly motivated to treatment? Patients with epilepsy sometimes refuse
surgery even when its offered(2) and experience the 'burden of normality'
that seizure freedom may bring(7). But we do not ban patients with
epilepsy from state related financial benefits if they refuse treatment.
The reality for many patients with functional motor disorders is that
their condition may not be reversible even if it retains the potential for
improvement. Patients may not even be a candidate for treatment, either
because of lack of success of previous treatment or poor availability of
adequate treatment. Furthermore, many well motivated patients do not
achieve improvement even with access to treatment(4). Is paralympic sport
a bad outcome in such circumstances?
Finally we dont agree that the DSM-5 definition of conversion
disorder (CD) which includes the criterion that "The symptom or deficit
causes significant distress, psychosocial impairment or warrants medical
evaluation" implies that 'the person with CD is barred from overcoming or
compensating for their predicament, or coping with it positively, e.g.
taking up competitive sports), without distress'(1)(3). The criterion is
worded with an 'or' to ensure that patients can receive this diagnosis who
are coping it with positively but still require medical evaluation to
determine why they have a motor symptom.
We can see the difficulties of classifying patients with functional
limb weakness for Paralympic sport but do not think issues of secondary
gain should be a factor in deciding eligibility.
1. American Psychiatric Association. Diagnostic and Statistical
Manual of Mental Disorders, Fifth Edition (DSM-5TM). Arlington, Virginia:
American Psychiatric Press, Inc.; 2013.
2. Anderson CT, Noble E, Mani R, Lawler K, Pollard JR. Epilepsy
Surgery: Factors That Affect Patient Decision-Making in Choosing or
Deferring a Procedure. Epilepsy Res Treat 2013; 2013:10.1155/2013/309284.
3. David AS. Paralympics and conversion disorder. J Neurol Neurosurg
Psychiatry 2015; :10.1136/jnnp - 2014-309957.
4. Gelauff J, Stone J, Edwards M, Carson A. The prognosis of
functional (psychogenic) motor symptoms: a systematic review. J Neurol
Neurosurg Psychiatry 2014; 85:220-6.
5. International Paralympic Committee. Athletics Classification
Rules and Regulations. www.paralympic.org 2014;
6. Pare?s I, Saifee T, Kassavetis P. Believing is perceiving: mismatch
between self-report and actigraphy in psychogenic tremor. Brain 2012;
135:117-23.
7. Wrench J, Wilson SJ, Bladin PF. Mood Disturbance before and after
Seizure Surgery: A Comparison of Temporal and Extratemporal Resections.
Epilepsia 2004; 45:534-43.
Dear Sirs,
Gold and colleagues recently found a significantly decreased risk of
developing multiple sclerosis (MS) after the onset of HIV infection in a
large cohort of national linked data set of English Hospital Episode
Statistics.(1) The possible causes of this negative association have been
hypothesized to be immunodeficiency and antiretroviral treatment (ART) as
MS is usually treated with immunosuppressive drugs and...
Dear Sirs,
Gold and colleagues recently found a significantly decreased risk of
developing multiple sclerosis (MS) after the onset of HIV infection in a
large cohort of national linked data set of English Hospital Episode
Statistics.(1) The possible causes of this negative association have been
hypothesized to be immunodeficiency and antiretroviral treatment (ART) as
MS is usually treated with immunosuppressive drugs and its pathogenesis
has been linked to human endogenous retroviruses. Since the ART might
improve HIV-related immunodeficiency being these two variables inversely
correlated, and reliable data on the ART could not be deduced with
certainty from the database of the study, this supposition leaves some
doubts. With this letter we want to discuss the supposed protective
mechanism of HIV against MS.
HIV is an immunodeficiency syndrome with progressive CD4+ T lymphocyte
loss leading to the development of opportunistic infections, cancers and
death especially in untreated patients. However, also autoimmune diseases
with rheumatological, haematological, endocrinological and neurological
manifestations have been already described in the early pre-ART era.(2)
Similarly to what was observed for MS,(1) clinical and serological
improvement of systemic lupus erythematosus during the onset of HIV has
been reported in some cases, therefore, a therapeutic effect of HIV on
autoimmune diseases was already hypothesized.(2) In the ART age, while
several autoimmune diseases have been shown to occur at a lower rate than
before in HIV patients, other ones (e.g. sarcoidosis) have contrariwise a
higher incidence.(2) Furthermore, some autoimmune manifestations may occur
contemporarily with the immune reconstitution inflammatory syndrome (IRIS)
associated with ART, making particularly difficult their diagnosis.(2)
Therefore, the hypothetical protective effect of HIV against MS could be
explained in part by a possibility of misdiagnosis of the latter, as
acknowledged by the authors themselves.(1) In effect, the authors excluded
from the analysis of the HIV cohort five people with prior MS and three
people with a simultaneous record of HIV and MS, whereas they included 7
new observed cases during the median follow-up period of 2454 days after
the diagnosis of HIV. Indeed, HIV infection might manifest with MS-like
clinical and radiological features and with presence of oligoclonal bands
in cerebrospinal fluid (CSF), as well as severe inflammatory demyelinating
lesions have been observed during IRIS after the onset of ART. Since the
diagnostic criteria of MS recommend the exclusion of other pathologies, it
is logical to assume that after being diagnosed with HIV the new
neurological manifestations are more readily attributed to the latter
omitting the diagnosis of MS.
In our opinion, the effect of HIV on MS is more correct to be defined as
subjugating rather than protective. However, we agree with the authors
that by studying the relationships between these two diseases we can
better understand the pathogenesis of MS due to its immunological
similarities with HIV.
Even if for a long time the role of CD4+ and CD8+ T lymphocytes has been
emphasized in both MS and HIV, more recently a dysregulation of the innate
immunity has been extensively demonstrated in HIV, MS and other autoimmune
disorders.(3,4) In particular the natural killer (NK) cells have been
demonstrated to be implicated in these pathologies influencing the
activity of other components of the innate and adaptive immune systems.(5)
NK cells foster anti-viral and anti-tumour immunity recognizing and
killing virally-infected or neoplastic cells.
A small RNA HIV-1 virus has developed specific strategies to evade control
of the NK cells.(3) A functional impairment of NK cell response and in
particular their decreased cytotoxic activity has been shown since the
early phases of HIV infection persisting during disease progression.(3)
HIV-infected individuals have shown progressive expansion of functionally
anergic NK cell subset, thus it has been hypothesized that these subjects
have an incomplete activation of NK cells due to chronic stimulation
leading to NK cell exhaustion and anergy.(3) These anergic NK cells,
accumulated during progressive HIV-1 infection, have not produced IFNgamma
and TNFalpha by a stimulation with MHC-devoid target cells, reducing a
consequent activation of antigen-presenting dendritic cells and components
of adaptive immunity.(3)
Interestingly, NK cells show similar alterations in both HIV infection and
autoimmune diseases, even if the latter are not generally considered as
infectious disorders.(4) Several studies have reported both a decreased
number of peripheral blood NK cells and an impairment of their
cytotoxicity in patients with different autoimmune diseases.(4) However,
more recent works have demonstrated accumulation of NK cells in target
tissues of several autoimmune diseases such as in pancreatic islets in
type I diabetes mellitus, hair follicles in alopecia areata, muscles in
juvenile dermatomyositis and synovia in rheumatoid arthritis, supporting
the possibility that a decrease of circulating NK cells in autoimmune
disorders is consequent to their trafficking to the affected tissues.(4)
The functional impairment of NK cells was found prevalently in the early
phase of autoimmune diseases and, even at the time of their diagnosis it
appears more likely that the NK defect is primary and not secondary to the
disease progression or to the treatments.(4) Moreover, the NK dysfunction
is present in active but not in quiescent phase, suggesting that NK cells
may be involved particularly in the initiation of the disease process.(4)
Finally, the same killer immunoglobulin-like receptor/HLA associations
fostering NK activation protect against the infections and predispose to
autoimmune diseases including MS.(4)
In MS, the NK cells might lyse directly oligodendrocytes, astrocytes,
microglia and activated T cells, thus having a probable immunoregulatory
role.(4) Moreover, transitory reductions of NK cytolytic activity, called
"valleys", have been demonstrated to precede radiological and clinical
relapses whereas the CD56bright NK cells, more efficient cytokine and
chemokine producers compared to the potent cytolytic CD56dim effectors,
have been shown a substantial enrichment in the CSF.(4)
Finally, NK cells show close modifications also during viral infections,
being their number and their cytotoxicity reduced in the peripheral blood
with a shift from CD56dim to CD56bright cells.(5)
Taken together, these features support the hypothesis that MS as well as
other autoimmune diseases may be an expression of latent, chronic
infections due to an inadequate immune response to pathogens. Such immune
reaction weakens further in HIV infection up to be completely subjugated
in the most severe HIV stages.
References
1. Gold J, Goldacre R, Maruszak H, Giovannoni G, Yeates D, Goldacre M. HIV
and lower risk of multiple sclerosis: beginning to unravel a mystery using
a record-linked database study. J Neurol Neurosurg Psychiatry. 2015
Jan;86(1):9-12. doi:10.1136/jnnp-2014-307932.
2. Stratton R, Slapak G, Mahungu T, Kinloch-de Loes S. Autoimmunity and
HIV. Curr Opin Infect Dis. 2009 Feb;22(1):49-56. doi:
10.1097/QCO.0b013e3283210006.
3. Altfeld M, Fadda L, Frleta D, Bhardwaj N. DCs and NK cells: critical
effectors in the immune response to HIV-1. Nat Rev Immunol. 2011
Mar;11(3):176-86. doi: 10.1038/nri2935.
4. Fogel LA, Yokoyama WM, French AR. Natural killer cells in human
autoimmune disorders. Arthritis Res Ther. 2013 Jul 11;15(4):216. doi:
10.1186/ar4232.
5. Mandal A, Viswanathan C. Natural killer cells: In health and disease.
Hematol Oncol Stem Cell Ther. 2014 Dec 27. pii: S1658-3876(14)00108-3.
doi:10.1016/j.hemonc.2014.11.006.
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
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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.
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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...
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