We thank Dr Aboul-Enein for asking us to discuss in more details some results of the study published recently by Reuter et al that provides the prevalence of cognitive impairment in patients with early multiple sclerosis explored after a clinical isolated syndrome and 5 years later. This study demonstrates that the proportion of patients suffering from cognitive impairment almost doubles between baseline (29%) and five years (54%)...
We thank Dr Aboul-Enein for asking us to discuss in more details some results of the study published recently by Reuter et al that provides the prevalence of cognitive impairment in patients with early multiple sclerosis explored after a clinical isolated syndrome and 5 years later. This study demonstrates that the proportion of patients suffering from cognitive impairment almost doubles between baseline (29%) and five years (54%). We are surprised by the comments edited by Dr Aboul-Enein that never address the essence of our study. Nevertheless, we agree to clarify the points highlighted by the author.
As noticed by the author, the population of MS patients was largely similar to the population explored in the spectroscopic study published recently in Journal of Neurology (Zaaraoui et al, J of Neurol 2010) and that aimed to assess the functional counterpart of early metabolic changes in multiple sclerosis. According to the different scientific goals of these studies, the populations of controls explored are totally different. Actually, in the study published in Journal of Neurology Neurosurgery and Psychiatry (JNNP), we included only controls that were explored in term of cognition at two time points (n=13) in order to take into account the test retest effect. In contrast, only controls that were explored in term of magnetic resonance spectroscopy were included (n=24) in the study published in Journal of Neurology. The slight variation of the prevalence of cognitive impairment at baseline in these two studies (22% versus 29%) noticed by the author is due to different controls' populations.
The author has misinterpreted one result obtained in the spectroscopic study published in Journal of Neurology. Actually, the percentage of 39% represents the proportion of patients for whom the degree of cognitive impairment increased during the follow-up and not the proportion of patients suffering from cognitive impairment at five years. This approach selected for the spectroscopic study enables to assess the potential association between metabolic changes and cognitive evolution during the five-year follow-up.
The author suggests that side effects related to disease modifying therapy (DMT) may significantly alter cognitive functioning. According to the small number of patients receiving DMT and the different DMT molecules prescribed, this hypothesis cannot be verified.
Finally, the author has misunderstood the methodological approach used to classify each patient as cognitively preserved or impaired based on the methodology developed in the study published by Camp et al in 2005 (Camp et al, Brain 2005). Using this method, the percentage of patients with impaired cognitive functions was obtained. It is noteworthy to mention that figure 1 displays a demographic representation of the prevalence of cognitive impairment in the population and not the display of performances.
We hope that we have clarified all the issues pointed out by the author.
The synthesis of epidemiological studies of the natural history of
treated and untreated epilepsy proposed in 2004 by Kwan and Sander(1)
separates people with epilepsy into 3 prognostic groups. However, further
interpretation of available evidence suggest that this prognostic groups
could be further subdivided:
Group 1 is the group of patients who would enter remission with or
without an...
The synthesis of epidemiological studies of the natural history of
treated and untreated epilepsy proposed in 2004 by Kwan and Sander(1)
separates people with epilepsy into 3 prognostic groups. However, further
interpretation of available evidence suggest that this prognostic groups
could be further subdivided:
Group 1 is the group of patients who would enter remission with or
without antiepileptic drug (AED) therapy, those who would automatically
achieve remission even if they did not have access to AEDs.
Sub-Group 1A therefore will represent those with immediate
spontaneous remission. They will not have a third seizure, i.e. upon
starting AED or being recruited into a cohort, they enter remission
immediately, and will not relapse after complete AED withdrawal. In a New
York childhood first seizure cohort, Shinnar et al(2) reported that out of
182 children who had a second seizure, 28% did not have a third seizure
(second recurrence) at 5 years follow up, meaning they could be
effectively considered as having entered into immediate remission.
Hauser et al(3) reported that 27% did not have a second recurrence
after 4 years of follow up in an all age cohort in Minnesota. Treatment
did not influence the rate of second recurrence in both studies, although
for Hauser et al(3) the risk of additional seizures in those with two
previous seizures is greater than the risk of adverse effects of
antiepileptic drugs. Neither study investigated the subset of these
patients who are successfully taken off antiepileptic drugs. Hence the
proportion of patients within IA may be less than they have reported.
Sub-Group 1B represents those who although do not enter remission
immediately, ultimately do so, and who alongside those who enter immediate
remission, will remain in remission on antiepileptic drug withdrawal.
There is however no study from which an estimate of the proportion of
patients who will be in this group could be derived. It does however
fulfil an important conceptual role within the range of temporal
prognostic epilepsy.
Notwithstanding their original eligibility into any of the Sub-Groups
of Group 1, those who cannot be successfully weaned off antiepileptic
drugs belong in Group 2. Those within Sub-Group 2A are patients whose
epilepsy alongside the whole of Group 1 did run a remitting course only
that they could not be taken off AED. Those in Sub-Group 2B arrived in
remission after a remitting-relapsing course. People in Sub-Group 2B made
up 20% of the Finnish cohort.(4)
Group 3 comprises those patients who will not enter terminal
remission either because after a remitting-relapsing course they do not
achieve terminal remission (14% of Sillanpaa et al's Finnish childhood
cohort) (4) or because they continue to have seizures from diagnosis in
spite of AEDs i.e. they never experience remission. Within this group will
be those (Sub-Group 3A) who will continue to have seizures, not frequent
or debilitating enough to be described as intractable and those (Sub-Group
3B) who will fulfil the definition of medically intractable seizures: 10%
in Berg et al's prospective population based cohort.(5)
Further subdivision of 3B would give us the two categories of those
whose seizures will remit on non-pharmacological intervention, and those
who will never achieve remission no matter the intervention. Sub-Group 3A
will also have a sub-population of those who ran a remitting-relapsing
course within it. Therefore the whole of Sub-Group 2B and part of Sub-
Group 3A is made of patients running a remitting-relapsing course, which
also indicates that the boundary between Sub-Group 2B and Sub-Group 3A
will be a potential area of cross-over activity.
One group that may exist but is not covered here is that of patients
who initially enter immediate remission and then go on to have a remitting
-relapsing course, but are eventually successfully weaned off AEDs.
However, evidence from Sillanpaa et al(4) suggest that it is unlikely that
such individuals exist. They show that the number of years before entering
5-year remission is an independent predictor of relapse. Therefore there
is a low probability that a patient with immediate remission will go on to
have a remitting-relapsing course, and if they do, it may be ill advised
to wean them off AEDs.
References
1. Kwan P, Sander JW. The natural history of epilepsy: an
epidemiological view. Journal of Neurology, Neurosurgery & Psychiatry.
2004 Oct;75(10):1376-81.
2. Shinnar S, Berg AT, O'Dell C, Newstein D, Moshe SL, Hauser WA.
Predictors of multiple seizures in a cohort of children prospectively
followed from the time of their first unprovoked seizure. Annals of
Neurology. 2000 Aug;48(2):140-7.
3. Hauser WA, Rich SS, Lee JR, Annegers JF, Anderson VE. Risk of
recurrent seizures after two unprovoked seizures. New England Journal of
Medicine. 1998 Feb 12;338(7):429-34.
4. Sillanpaa M, Schmidt D, Sillanpaa M, Schmidt D. Natural history of
treated childhood-onset epilepsy: prospective, long-term population-based
study. Brain. 2006 Mar;129(Pt 3):617-24.
5. Berg AT, Shinnar S, Levy SR, Testa FM, Smith-Rapaport S, Beckerman
B. Early development of intractable epilepsy in children: A prospective
study. Neurology. 2001;56(11):1445-52.
Dear Sir,
We have read with great interest the article by Reuter et al. entitled
'Frequency of cognitive
impairment dramatically increases during the first 5 years of multiple
sclerosis'
1
, which
seems related to another recent published article.
1,2
Whether steadily ongoing, but clinically
silent axonal changes occur in all MS patients and MS subtypes, and if so,
progressive axonal
changes occur already at...
Dear Sir,
We have read with great interest the article by Reuter et al. entitled
'Frequency of cognitive
impairment dramatically increases during the first 5 years of multiple
sclerosis'
1
, which
seems related to another recent published article.
1,2
Whether steadily ongoing, but clinically
silent axonal changes occur in all MS patients and MS subtypes, and if so,
progressive axonal
changes occur already at the earliest disease stages is still under
intense discussion, and of
most importance to MS patients, neurologists and researchers.
3-8
The demographics, clinical and MRI data were very similar in both
papers.
1,2
For
example, the baseline T2 lesion load (T2LL) reported here, was 2.825
(mean, n=24)
1
vs. 2.9
(mean, n=23) reported elsewhere
2
etc., all suggestive that at least 23 of the included MS
patients were the same in both studies(?). The used neuropsychological
assessment (NpA)
was identically described in both publications.
2
However, the numbers of the included MS
patients (n=23 vs. n=24) and controls (n=13 vs. n=24) and the numbers of
'cognitive
impaired' MS patients differed (baseline, 29% [7 out of 24] of the
patients vs. 22% [5 out of
23] of the patients and at year 5, 54% of the patients [13 out of 24] vs.
39% of the patients [9
out of 23]).
1,2
How can these differences be explained? Additionally, NpA consisted of a
plenty of exertive and time consuming tests and was described as
'exhaustive'. Were the tests
performed in one or multiple sessions? Had disease modifying drugs or
their side effects an
influence on NpA testing? Figure 1 might be misleading. Bar charts with
'the % of the
patients with cognitive impairment' can never replace the detailed
information of scatter plots
providing single values of patients and controls. Moreover, a regression
plot with T2LL (as
independent variable?) and cognitive impairment index (CII) would have
been preferred by
some reviewer and the readers to avoid any confusion or over-
interpretation. The T2LL was
found increased from 3cm? (mean) at baseline to 4.5cm? (mean) 5 years
later. Were the T2LL
and the CII correlated weakly or moderately?
Competing Interest: None
declared.
References:
1. Reuter F, Zaaraoui W, Crespy L, et al. Frequency of cognitive
impairment
dramatically increases during the first 5 years of multiple sclerosis. J
Neurol
Neurosurg Psychiatry doi:10.1136/jnnp.2010.213744
2. Zaaraoui W, Reuter F, Rico A, et al. Occurrence of neuronal dysfunction
during the
first 5 years of multiple sclerosis is associated with cognitive
deterioration. Journal of
Neurology doi: 10.1007/s00415-010-5845-4
3. Kirov II, Patil V, Babb JS, et al. MR spectroscopy indicates diffuse
multiple sclerosis
activity during remission. J Neurol Neurosurg Psychiatry 2009;80:1330-6.
4. Aboul-Enein F, Krss?k M, H?ftberger R, et al. Reduced NAA-levels in the
NAWM
of patients with MS is a feature of progression. A study with quantitative
magnetic
resonance spectroscopy at 3 Tesla. PLoS One 2010;5(7):e11625.
5. Aboul-Enein F, Krss?k M, H?ftberger R, et al. Diffuse white matter
damage is absent
in neuromyelitis optica. AJNR Am J Neuroradiol 2010;31:76-9.
6. Serbecic N, Aboul-Enein F, Beutelspacher SC, et al. Heterogeneous
pattern of retinal
nerve fiber layer in multiple sclerosis. High resolution optical coherence
tomography:
potential and limitations. PLoS One. 2010;5(11):e13877.
7. Serbecic N, Beutelspacher SC, Aboul-Enein FC, et al. Reproducibility of
highresolution optical coherence tomography measurements of the nerve
fibre layer with
the new Heidelberg Spectralis optical coherence tomography. Br J
Ophthalmol
doi:10.1136/bjo.2010.186221
8. Gilmore CP, Cottrell DA, Scolding NJ, et al. A window of opportunity
for no
treatment in early multiple sclerosis? Mult Scler 2010;16:756-9.
We appreciate the comment regarding our study on ulcerated plaque
in the aortic arch.
As the commenter pointed, vascular neurologists might have
believed that the aortic plaque configuration was as important as the
plaque
thickness when aortogenic embolism was assessed. Our study could identify
a strong association between ulcerated plaque and recent multiple brain
infarction, which was possibly caused by rec...
We appreciate the comment regarding our study on ulcerated plaque
in the aortic arch.
As the commenter pointed, vascular neurologists might have
believed that the aortic plaque configuration was as important as the
plaque
thickness when aortogenic embolism was assessed. Our study could identify
a strong association between ulcerated plaque and recent multiple brain
infarction, which was possibly caused by recent plaque rupture.
Moreover, the aortic plaque tissue quality may be as important as
the plaque configuration to detect vulnerable plaque before plaque
rupture,
as mentioned about coronary artery and carotid artery. A study with
repeated
aortic MRI,enhanced CT and TOE examination may be required to solve this
problem.
I read the article by Alonso on smoking and risk of amyotrophic
lateral sclerosis (ALS) with interest (1)
While the meta-analysis may not support a strong association with smoking
and ALS, there may be a relationship with the combination of smoking and
exercise.
Smoking increases carbon monoxide (CO) levels (2) and cyanide (3) in the
blood.
Cyanide binds with cytochrome oxidase in the mitochondria, and CO
interferes wi...
I read the article by Alonso on smoking and risk of amyotrophic
lateral sclerosis (ALS) with interest (1)
While the meta-analysis may not support a strong association with smoking
and ALS, there may be a relationship with the combination of smoking and
exercise.
Smoking increases carbon monoxide (CO) levels (2) and cyanide (3) in the
blood.
Cyanide binds with cytochrome oxidase in the mitochondria, and CO
interferes with the mitochondrial respiratory chain as well.
Mitochondria are also dynamically involved with exercise, with alteration
in mitochondrial network function induced by exercise (4).
Mitochrondrial protein composition is altered by ALS linked mutant
superoxide dismutase-1 (5), indicating a target organelle in ALS is the
mitochondria.
The interactions of smoking products such as CO and cyanide, causing
reduced oxygen availability from formation of carboxyhaemoglobin, causing
oxygen starvation of tissues, and poisoning of mitochondrial respiratory
chain function through interactions with CO and cyanide, when combined
with the increased oxygenation/reduction demands of exercise all may
interact on mitochrondrial genesis and energy production in the motor
neuron, to produce neurodegeneration and development of ALS in
susceptible individuals.
References:
1. Alonso A, Logroscino G, Hernan M. Smoking and the risk of amyotrophic
lateral sclerosis: a systematic review and meta-analysis. J Neurol
Neurosurg Psychiatry 2010;81: 1249-1252.
2. Klausen K, Anderson C, Nandrup S. Acute effects of cigarette smoking
and inhalation of carbon monoxide during maximal exercise. Eur J Appl
Physiol Occup Physiol 1983; 51: 371-379.
3. Lundquiest P. Rosling H, Sorbo B, Tibbling L. Cyanide
concentrations in blood after cigarette smoking, as determined by a
sensitive fluorimetric method. Clin Chem 1987; 33: 1228-1230
4. Bo H, Zhang Y, Ji LL Redefining the role of mitochondria in
exercise: a dynamic remodeling. Ann N Y Acad Sci 2010; 1201: 121-128
5. Li Q, Vande Velde C, Israelson A, Xie J, Bailey AO, Dong MQ. Et
al. ALS-linked mutant superoxide dismutase 1 (SOD1) alters mitochondrial
protein composition and decreased protein import Proc Natl Acad Sci USA
2010; 107: 21146-21151. Epub 2010 Nov 15.
We read with great interest the article about non-paraneoplastic
limbic encephalitis (LE) associated with NMDAR and VGKC antibodies by
Pellkofer et al (1).
In the analysis of National Hospital Discharge data, the cause of
encephalitis was unknown in 60% of cases (2). We have similar experience
in children. Recently, we found about one third of those unknown childhood
non-paraneoplastic encephalitides had positi...
We read with great interest the article about non-paraneoplastic
limbic encephalitis (LE) associated with NMDAR and VGKC antibodies by
Pellkofer et al (1).
In the analysis of National Hospital Discharge data, the cause of
encephalitis was unknown in 60% of cases (2). We have similar experience
in children. Recently, we found about one third of those unknown childhood
non-paraneoplastic encephalitides had positive anti-amphiphysin antibody
that only reported in paraneoplastic LE in adults (3).
We consider that, with wide screening for all immune biomarkers, more
and more autoimmune encephalitis may explain those unknown etiologies of
encephalitides. However, a more sensitive and easy-assessed biomarker
should be found to start early immunotherapy for improving their outcome.4
REFERENCES
1. Pellkofer HL, Kuempfel T, Jacobson L, Angela Vincent A, Derfuss T. Non-
paraneoplastic limbic encephalitis associated with NMDAR and VGKC
antibodies. J. Neurol. Neurosurg. Psychiatry 2010 81:1407-1408
2. Lewis P, Glaser CA. Encephalitis. Pediatr Rev 2005;26 : 353-63
3. Pittock SJ, Lucchinetti CF, Parisi JE, et al. Amphiphysin autoimmunity:
paraneoplastic accompaniments. Ann Neurol. 2005;58:96-107.
4. Florance-Ryan N, Dalmau J. Update on anti-N-methyl-D-aspartate receptor
encephalitis in children and adolescents. Curr Opin Pediatr. 2010;22:739-
44.
We read with great interest the article by Nolte et al. on the
spinocerebellar ataxia type 17 (SCA17) associated with a trinucleotide
repeats (TNR) number of 42.[1] The authors examined 285 patients with
ataxia, and found eight cases of SCA17. Of those, four patients had 42
TNR, which is one codon less than the generally accepted threshold of 43.
They contended that the definition of TNR for pathological SCA17 should be...
We read with great interest the article by Nolte et al. on the
spinocerebellar ataxia type 17 (SCA17) associated with a trinucleotide
repeats (TNR) number of 42.[1] The authors examined 285 patients with
ataxia, and found eight cases of SCA17. Of those, four patients had 42
TNR, which is one codon less than the generally accepted threshold of 43.
They contended that the definition of TNR for pathological SCA17 should be
lowered to 42.
Our data are in line with the results reported by Nolte et al., and
support their conclusion that a TNR number of 42 might be a cutoff point
for the lowest range of abnormal expansion.[2] We screened 1155
parkinsonian patients to investigate the role of SCA17 in parkinsonism.
Ten patients were identified to have pathologic expansions ranged from 43
to 46, using 42 repeats as an upper normal limit. Among 400 normal control
subjects, we found one individual with a TNR of 44, another with 43, and
two with 42. Dopamine transporter imaging was performed in these subjects,
as well as in two control subjects who had a TNR of 41. 99mTc-TRODAT-1
SPECT showed that striatal DAT binding was decreased not only in the
control subjects with TNR numbers of 44 or 43, but in ones with 42
repeats. Striatal DAT binding was normal in the two control subjects with
41 repeats. Our data showed that both control subjects with a TNR of 42 as
well as ones with 44 or 43 repeats have subclinical nigrostriatal damage,
and ones with 41 repeats does not have nigrostriatal damage. We suggested
that a TNR as low as 42 repeats be a susceptibility gene for parkinsonism
related to SCA17.
The gap between normal and pathologic expansion in SCA17 is very
narrow. In general, expansions of 42 repeats or less are accepted to be in
the range of normal expansion. Our data, together with the results
reported by Nolte et al., indicate that the TNR number of 42 can cause the
SCA17 phenotype, whether it is parkinsonism or ataxia. The uncertainty
regarding the precise cutoff point may be due to reduced penetrance or
variable expressivity in low range expansions. In conclusion, the
definition of at least 43 TNR for pathological SCA17 should be lowered to
42.
References
[1] Nolte D, Sobanski E, Wissen A, Regula JU, Lichy C, Muller U.
Spinocerebellar ataxia type 17 associated with an expansion of 42
glutamine residues in TATA-box binding protein gene. J Neurol Neurosurg
Psychiatry 2010;81(12):1396-1399.
[2] Kim JY, Kim SY, Kim JM, Kim YK, Yoon KY, Kim JY, Lee BC, Kim JS, Paek
SH, Park SS, Kim SE, Jeon BS. Spinocerebellar ataxia type 17 mutation as a
causative and susceptibility gene in parkinsonism. Neurology
2009;72(16):1385-1389.
We agree that genetic studies have so far explained only a small
fraction of the heritability of ALS (1,2), and this is true in many other
diseases as well (3). Epigenetic factors are almost certainly part of the
answer, but there are also several other possibilities. We are only just
developing the tools to look for disease-associated rare variants on a
large scale. In addition, we do not understa...
We agree that genetic studies have so far explained only a small
fraction of the heritability of ALS (1,2), and this is true in many other
diseases as well (3). Epigenetic factors are almost certainly part of the
answer, but there are also several other possibilities. We are only just
developing the tools to look for disease-associated rare variants on a
large scale. In addition, we do not understand the genetic code for most
of the genome since we can only reliably translate the 1% that is exonic
sequence (4). This means much variation cannot be interpreted even though
it is very likely to contribute to disease and the associated genetic
variants may be weak correlates of the larger effect true causal variant.
We do not routinely search for interaction between genes or genes and
environment and there is no easy method to interpret the actions of
multiple gene variants acting in concert. Furthermore, the three
dimensional nature of the genome is not considered but may have a role to
play in disease if variants in physical proximity interact through protein
binding or other mechanisms.
As genetic, statistical and computing technologies advance, we expect
our current linear and simple view of the genome to be transformed and far
more of the so-called missing heritability explained.
(1) Al-Chalabi A, Fang F, Leigh PN, et al. An estimate of
amytotrophic lateral sclerosis heritability using twin data. J Neurol
Neurosurg Psychiatry 2010;81:1324-1326
(2) Shatunov A, Mok K, Newhouse S, et al. Chromosome 9p21 in sporadic
amyotrophic lateral sclerosis in the UK and seven other countries: a
genome-wide association study. Lancet Neurol 2010;9,986-994
(3) Manolio TA, Collins FS, Cox NJ, et al. Finding the missing
heritability of complex diseases. Nature 2009;461,747-753
(4) Taft RJ, Pheasant M, and Mattick JS. The relationship between non
-protein-coding DNA and eukaryotic complexity. Bioessays 2007;29:288-299
The twin studies show conclusively the limits of classical genetics
in the studies of the etiology and pathogenesis of the ALS (1).
It has been suggested that a susceptibility or familial factor could
play a role. In this case, they may be mediated by epigenetic mechanisms
which control the activity and expression of the genome (2).
The incorrectly coded polypeptides could lead to...
The twin studies show conclusively the limits of classical genetics
in the studies of the etiology and pathogenesis of the ALS (1).
It has been suggested that a susceptibility or familial factor could
play a role. In this case, they may be mediated by epigenetic mechanisms
which control the activity and expression of the genome (2).
The incorrectly coded polypeptides could lead to a gain of function
of an enzyme or to aberrant tertiary structures of protein species (3).
This sequence of events could also shed light on familial cases as
family members often are exposed to similar environment or other exogenous
factors.
1 Al-Chalabi A, Fang F, Leigh PN, et al. An estimate of amytotrophic
lateral sclerosis heritability using twin data. J Neurol Neurosurg
Psychiatry 2010; 81: 1324-1326
2 Stauffer BL, DeSouza CA. Epigenetics: an emerging player in health
and disease. J appl Physiol 2010; 109: 230-231
3 Palo J, Savolainen H, Kivalo E. Comparison between the proteins of
human brain myelin in subacute sclerosing panencephalitis, amyotrophic
lateral sclerosis and malignant diseases. J neurol Sci 1973; 18: 175-181
The twin studies show conclusively the limits of classical genetics
in the studies of the etiology and pathogenesis of the ALS (1).
It has been suggested that a susceptibility or familial factor could
play a role. In this case, they may be mediated by epigenetic mechanisms
which control the activity and expression of the genome (2).
The incorrectly coded polypeptides could lead to...
The twin studies show conclusively the limits of classical genetics
in the studies of the etiology and pathogenesis of the ALS (1).
It has been suggested that a susceptibility or familial factor could
play a role. In this case, they may be mediated by epigenetic mechanisms
which control the activity and expression of the genome (2).
The incorrectly coded polypeptides could lead to a gain of function
of an enzyme or to aberrant tertiary structures of protein species (3).
This sequence of events could also shed light on familial cases as
family members often are exposed to similar environment or other exogenous
factors.
1 Al-Chalabi A, Fang F, Leigh PN, et al. An estimate of amytotrophic
lateral sclerosis heritability using twin data. J Neurol Neurosurg
Psychiatry 2010; 81: 1324-1326
2 Stauffer BL, DeSouza CA. Epigenetics: an emerging player in health
and disease. J appl Physiol 2010; 109: 230-231
3 Palo J, Savolainen H, Kivalo E. Comparison between the proteins of
human brain myelin in subacute sclerosing panencephalitis, amyotrophic
lateral sclerosis and malignant diseases. J neurol Sci 1973; 18: 175-181
Dear editor,
The synthesis of epidemiological studies of the natural history of treated and untreated epilepsy proposed in 2004 by Kwan and Sander(1) separates people with epilepsy into 3 prognostic groups. However, further interpretation of available evidence suggest that this prognostic groups could be further subdivided:
Group 1 is the group of patients who would enter remission with or without an...
Dear Sir, We have read with great interest the article by Reuter et al. entitled 'Frequency of cognitive impairment dramatically increases during the first 5 years of multiple sclerosis' 1 , which seems related to another recent published article. 1,2
Whether steadily ongoing, but clinically silent axonal changes occur in all MS patients and MS subtypes, and if so, progressive axonal changes occur already at...
We appreciate the comment regarding our study on ulcerated plaque in the aortic arch.
As the commenter pointed, vascular neurologists might have believed that the aortic plaque configuration was as important as the plaque thickness when aortogenic embolism was assessed. Our study could identify a strong association between ulcerated plaque and recent multiple brain infarction, which was possibly caused by rec...
I read the article by Alonso on smoking and risk of amyotrophic lateral sclerosis (ALS) with interest (1) While the meta-analysis may not support a strong association with smoking and ALS, there may be a relationship with the combination of smoking and exercise. Smoking increases carbon monoxide (CO) levels (2) and cyanide (3) in the blood. Cyanide binds with cytochrome oxidase in the mitochondria, and CO interferes wi...
We read with great interest the article about non-paraneoplastic limbic encephalitis (LE) associated with NMDAR and VGKC antibodies by Pellkofer et al (1).
In the analysis of National Hospital Discharge data, the cause of encephalitis was unknown in 60% of cases (2). We have similar experience in children. Recently, we found about one third of those unknown childhood non-paraneoplastic encephalitides had positi...
We read with great interest the article by Nolte et al. on the spinocerebellar ataxia type 17 (SCA17) associated with a trinucleotide repeats (TNR) number of 42.[1] The authors examined 285 patients with ataxia, and found eight cases of SCA17. Of those, four patients had 42 TNR, which is one codon less than the generally accepted threshold of 43. They contended that the definition of TNR for pathological SCA17 should be...
Dear Editor,
We agree that genetic studies have so far explained only a small fraction of the heritability of ALS (1,2), and this is true in many other diseases as well (3). Epigenetic factors are almost certainly part of the answer, but there are also several other possibilities. We are only just developing the tools to look for disease-associated rare variants on a large scale. In addition, we do not understa...
Dear Editor,
The twin studies show conclusively the limits of classical genetics in the studies of the etiology and pathogenesis of the ALS (1).
It has been suggested that a susceptibility or familial factor could play a role. In this case, they may be mediated by epigenetic mechanisms which control the activity and expression of the genome (2).
The incorrectly coded polypeptides could lead to...
Dear Editor,
The twin studies show conclusively the limits of classical genetics in the studies of the etiology and pathogenesis of the ALS (1).
It has been suggested that a susceptibility or familial factor could play a role. In this case, they may be mediated by epigenetic mechanisms which control the activity and expression of the genome (2).
The incorrectly coded polypeptides could lead to...
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