The role of inflammation in the etiopathogenesis of Alzheimer’s disease (AD) has been exhaustively analyzed by several authors, with a special focus on cytokines such as Tumor Necrosis Factor alpha (TNF-alpha), Interleukin-1 and Interleukink-6, demonstrated to be evidently connected with the neuroinflammatory processes; an augmented production of these cytokines have been revealed in AD subjects while a def...
The role of inflammation in the etiopathogenesis of Alzheimer’s disease (AD) has been exhaustively analyzed by several authors, with a special focus on cytokines such as Tumor Necrosis Factor alpha (TNF-alpha), Interleukin-1 and Interleukink-6, demonstrated to be evidently connected with the neuroinflammatory processes; an augmented production of these cytokines have been revealed in AD subjects while a deficiency have been shown in the late phase of the disorder (1).
Polymorphisms of genes encoding for cytokines have also been associated to AD (2). Recently Bossù et al. (3) demonstrated that Interleukin 18 promoter polymorphisms are involved in the prediction of the risk and outcome of AD.
In our case-control study we analyzed IL-18 gene promoter polymorphisms in AD patients and healthy controls in order to verify the involvement of these genetic variations in the onset of AD.
A hundred and eleven AD patients ( 79 F/ 32 M, mean age 79.47± SD 6.30) and 111 non-demented sex- and age- matched healthy controls (HC, 76 F/35 M, mean age 79.98± SD 6.36) were enrolled for this study.
All patients were Caucasian, living in Northern Italy and selected from a larger ambulatory population attended to at the Geriatric Department of the Ospedale Maggiore IRCCS, University of Milan, Italy. There were no significant differences between the groups in age or education level. Diagnosis of probable AD was performed according to standard clinical procedures and following the DMS IV and NINCDS-ADRDA criteria. The cognitive and functional performances were assessed using mini-mental state evaluation (MMSE), activities of daily living (ADL), instrumental activities of daily living (IADL) as well as an extensive neuropshycological evaluation. Every subject had undergone a recent brain magnetic resonance imaging (MRI)/computed tomography (CT) scan. Criteria for the diagnosis of normal cognition were as follows: (a) no active neurological or psychiatric disorders; (b) any ongoing medical problems or related treatments not interfering with cognitive function; (c) a normal neurological exam; (d) no psychoactive medications; (e) independently functioning community dwellers. In order to minimize the risk of possible inflammatory processes, all subjects selected showed no clinical signs of inflammation (e.g. normal body temperature, no concomitant inflammatory condition) and normal blood chemistry levels (red blood cell sedimentation rate, albumin, transferrin and C reactive protein plasma levels).
Genomic DNA was extracted by using the GenomePrep kit (GE Healthcare). Amplification of IL-18 promoter region was performed by using primers (Primer Reverse 5’- GGGCAATGGAAGTCGAAATAAAGT -3’ Primer Forward 5’- GAAAGTTTTAACACTGGAAACTGCAA -3’ ) designed using the software Primer Express 2.0 (Applied Biosystems, Foster City, CA) according to the human sequences available in GenBank.
PCR reactions were carried out in a GeneAmp 9700 Thermal cycler (Applied Biosystems, Foster City, CA) using PCR buffer 1X, 1 unit of Taq Gold, 0.2mM dNTPs and MgCl2 2 mM). The cycling was performed with an initial denaturation for 10 min at 95°C, followed by 40 cycles at 95°C for 20 s, at the annealing temperature of 60°C for 30 s and 72°C for 30 s with a final extension to 72°C for 7 min. DNA sequencing of PCR products was performed using the BigDye Terminator Cycle Sequencing Ready Reaction Kit 2.0 (Applied Biosystems, Foster City, CA). DNA sequences were run on an automated ABI Prism 3100 Genetic Analyser (Applied Biosystems, Foster City, CA). Sequences were handled using SeqScape 1.0 Software.
ApoE genotypes were determined by PCR amplification of a 234 base-pair fragment of exon 4 of the ApoE gene followed by digestion using Cfo1, according to standard protocols. Restriction patterns were revealed by 2% agarose gel electrophoresis.
Allele and genotype frequencies were calculated by direct gene counting and the differences were analyzed using the exact Fisher test; a p value less than 0.05 was considered statistically significant. Haplotype frequencies were calculated using the software Arlequin 3.01 (http://cmpg.unibe.ch/software/arlequin3/).
Three polymorphisms have been studied in the promoter region of the IL-18 gene at position -137 (G/C), - 607 (C/A) and -656 (G/T). Allelic and genotype frequencies of IL-18 promoter polymorphisms as well as haplotypes distribution in AD patients and controls are reported in Table 1. The distribution of the allelic and genotype frequencies of -137 (G/C), - 607 (C/A) and -656 (G/T) IL-18 promoter polymorphisms was in Hardy-Weimberg equilibrium in AD patients and controls.
No significant difference was detected for the three IL-18 SNPs between AD patients and controls. The haplotypes distribution also did not show any difference within AD subjects and controls.
We also performed ApoE genotyping and we evidenced, as expected, that the presence of the ApoE4 in the total AD patient population was significantly higher than in the control population (27% vs. 14% chi-sq=5.53 p=0.0188). However no significant association among ApoE variant alleles and the three studied polymorphisms was found in healthy controls as well as in AD patients (p=n.s. for all comparison).
Our results are not in agreement with those obtained by Bossù et al. (3), who demonstrated an association between two IL-18 polymorphisms (-137 G/C and -607 C/A) and the suceptibility and clinical outcome of AD.
In our study we analyzed the two functional IL-18 polymorphisms (-137 G/C and -607 C/A) and an additional polymorphisms at position -656: no association with AD was found.
Even if we do believe that the innate immune system - and more specifically cytokines - can play a role in the etiopathogenesis of AD having been widely demonstrated a chronic inflammatory response in AD brains, our negative results simply indicate that the association of IL-18 promoter polymorphisms with AD is not so strong, being AD a multifactorial disease.
Finally, as disaccording findings concerning the IL-18 production have been obtained by different authors in AD patients (4,5) it is not surprising that also the distribution of IL-18 functional polymorphisms could vary in different populations.
We do think, as also stated by Bossù et al. that further studies performed on larger Italian AD patients cohorts could contribute to clarify the role of IL-18 in AD.
Ludovica Segat
Michele Milanese
Beatrice Arosio
Sergio Crovella
References
1) Sala G, Galimberti G, Canevari C, Raggi ME, Isella V, Facheris M, Appollonio I, Ferrarese C. Peripheral cytokine release in Alzheimer patients: correlation with disease severity. Neurobiol Aging. 2003 Nov;24(7):909-14.
2) Yucesoy B, Peila R, White LR, Wu KM, Johnson VJ, Kashon ML, Luster MI, Launer LJ. Association of interleukin-1 gene polymorphisms with dementia in a community-based sample: the Honolulu-Asia Aging Study. Neurobiol Aging. 2006 Feb;27(2):211-7.
3) Bossu P, Ciaramella A, Moro ML, Bellincampi L, Bernardini S, Federici G, Trequattrini A, Macciardi F, Spoletini I, Di Iulio F, Caltagirone C, Spalletta G. Interleukin-18 gene polymorphisms predict risk and outcome of Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2007 Feb 13; [Epub ahead of print].
4) Lindberg C, Chromek M, Ahrengart L, Brauner A, Schultzberg M, Garlind A. Soluble interleukin-1 receptor type II, IL-18 and caspase-1 in mild cognitive impairment and severe Alzheimer's disease. Neurochem Int. 2005 Jun;46(7):551-7.
5) Malaguarnera L, Motta M, Di Rosa M, Anzaldi M, Malaguarnera M. Interleukin-18 and transforming growth factor-beta 1 plasma levels in Alzheimer's disease and vascular dementia. Neuropathology. 2006 Aug;26(4):307-1
Table 1: Allele, genotype and haplotype frequencies of IL-18 polymorphisms in Alzheimer’s disease subjects (AD) an healthy controls (HC).
We would like to share several observations that we made on Ammirati
et al. recently published meta-analysis. The authors reviewed the
available English-language literature from 1990 to the present, comparing
microsurgery versus endoscopy for treatment of pituitary adenomas, and
conducted a systematic review and meta-analysis of the data obtained. The
authors concluded that the two treatment methods produced similar out...
We would like to share several observations that we made on Ammirati
et al. recently published meta-analysis. The authors reviewed the
available English-language literature from 1990 to the present, comparing
microsurgery versus endoscopy for treatment of pituitary adenomas, and
conducted a systematic review and meta-analysis of the data obtained. The
authors concluded that the two treatment methods produced similar outcomes
for all of the variables analyzed, except for a statistically significant
higher rate of vascular complications with endoscopy. We want to point out
that endoscopy-assisted studies were included in the microsurgery cohort,
including most notably a study by Mortini et al.1 involving 1140 patients,
which represented 32.4% of all of the microsurgery cases and thus was
weighted heavily in the analysis. The use of intraoperative endoscopy
after microscopic resection provides the advantages of endoscopic
procedures, such as better visualization of structures and of lateral and
suprasellar limits, as well as differentiation between normal and diseased
tissue. Inclusion of these patients introduces significant bias, strongly
favoring microsurgery by giving it the advantages of endoscopy, and
complicating a comparison between the two methods. Additionally, the
variety of complications that were grouped together as vascular
complications was highly heterogeneous, encompassing carotid lesions,
lesions in less important vessels like the sphenopalatine artery,
intracranial or sellar hemorrhages, ischemic infarcts, and cavernous sinus
bleeding. While all of these complications are of a vascular nature, their
characteristics and the resulting morbidity/mortality can be quite
different. The limitations of microsurgery for treatment of significant
invasions into the cavernous sinus are well known. Thus, when approaching
an invasive cavernous sinus adenoma endoscopically for treatment, as in
the study by Zhang et al.2, consideration of vascular complications from
cavernous sinus bleeding is not comparable to microsurgical approach cases
where there was no initial intention to treat invasive cavernous sinus
tumors. Moreover, based on available data, we can only be certain that
57,6% (2027/3518) of the microscopic patients were macroadenomas, whereas
77% (1453/1887) of the cases were macroadenomas in the endoscopic cohort.
This heterogeneous distribution of patients for something as fundamental
as differentiation between micro and macroadenomas could have influenced
the meta-analysis results, especially the observed rates of complete
resection, vascular complications and csf leak. It is also worth noting
that of the 22 microsurgery studies included, only 12 had data on vascular
complications, whereas 17/24 endoscopic studies had such data. Meta-
analysis variable data are collected more frequently, in general, in
endoscopic studies than in microsurgery studies.As for the meta-analysis
methodology, depending on the heterogeneity between studies, fixed effect
models or randomized models were applied. Randomized models provide more
conservative estimates than fixed effect models, and therefore are more
apt to miss existing differences. These methods were used to compare rates
of diabetes insipidus, hypopituitarism, and complete resection. All
trended toward favoring the endoscopy group, but without statistical
significance. Death rates for the microsurgery and endoscopy cohorts were
0.23% and 0.49%, csf leak 6.34 vs 7%, meningitis 2,08 vs 1.11%, vascular
complication 0.5 vs 1.58%, visual loss 0.60 vs 0.72%, diabetes insipidus
temporary 10.23 vs 9.10% and permanent 4.25 vs 2.31%, hypopituitarism
11,64 vs 8.51%, nerve injury 0.53 vs 0.28% and complete resection 64.44 vs
68.77% respectively. When we evaluated surgeons with more than 500
microsurgeries from the study by Ciric et al.3, the death rate was 0.2%,
csf leak 1.5%, meningitis 0.5%, vascular complication (carotid artery
injury + hemorrhage residual tumor) 1.2%, visual loss 0.5%, diabetes
insipidus 7.6%, hypopituitarism 7.2%. Thus, with respect to vascular
complications, death, diabetes insipidus, and hypopituitarism, the
microsurgery group turned out to be a select group of patients with
results superior to those obtained by highly experienced microsurgery
specialists. This result could be due to many reasons, such as those
suggested above, including: a series of patients with a high incidence of
microadenomas; inclusion of endoscopy-assisted cases in the microsurgery
group; the long tradition and evolution of microsurgery since the 1950s
versus the recent history of purely endoscopic techniques (first series
reported in 1997); and the significant experience of microscopic surgeons
whose numerous studies populated the meta-analysis. There were two
microsurgery studies, which described sets of 1140 and 638 patients;
meanwhile, eight microsurgery studies described the treatment of only
functional tumors, and six of the reviewed studies included more than 50
acromegalies or Cushing's syndrome cases, implying that the surgeons in
question treated a significant number of adenomas. On the other hand, only
one endoscopic study had more than 200 patients. If we compare the group
of surgeons with less than 200 microscopic surgeries from the study by
Ciric et al. (results: death rate 1.2%, csf leak 4.2%, meningitis 1.9%,
vascular complication 4.2%, visual loss 2.4%, diabetes insipidus 19%,
hypopituitarism 20,6%), with the metaanalisis endoscopic group, results
strongly favor endoscopy. Nevertheless, the rates of complete resection,
hypopituitarism, diabetes insipidus, meningitis, and nerve damage were all
better for patients treated purely endoscopically, although without
statistical significance. The authors of the review study criticize prior
meta-analyses for being biased toward endoscopy based solely on the
argument of fewer included patients; but they did not take into account
their own inclusion criteria, which were more restrictive, considering
only studies comparing both techniques, but not those using endoscopy-
assisted microsurgery or those without complete outcomes that would enable
better data ?interpretation and more solid and reliable results. In short,
reading this study in isolation can lead to erroneous conclusions given
the aforementioned biases and limitations.
Reference
1. Ciric I, Ragin A, Baumgartner C, et al. Complications of
transsphenoidal surgery: results of a national survey, review of the
literature, and personal experience. Neurosurgery 1997;40:225-37.
2. Mortini P, Losa M, Barzaghi R, et al. Results of transsphenoidal
surgery in a large series of patients with pituitary adenoma. Neurosurgery
2005;56:1222-33.
3. Zhang X, Fei Z, Zhang W, et al. Endoscopic endonasal
transsphenoidal surgery for invasive pituitary adenoma. J Clin Neurosci
2008;15:241-5.
It is interesting to note that, Figure 3 Shows that Mean Memory
factor score for Neurofibrillary tangles(NFT) score-5 is 40.1,30.3 and
13.0 for plaques in CA1, plaques in subiculum and plaques in entorhinal
cortex respectively which is less compared to the memory scores of higher
NFT scores like 5 to 15 and >15. But this can be cautiously
interpreted as memory scoring is not directly related t...
It is interesting to note that, Figure 3 Shows that Mean Memory
factor score for Neurofibrillary tangles(NFT) score-5 is 40.1,30.3 and
13.0 for plaques in CA1, plaques in subiculum and plaques in entorhinal
cortex respectively which is less compared to the memory scores of higher
NFT scores like 5 to 15 and >15. But this can be cautiously
interpreted as memory scoring is not directly related the Plaques density
in the specific anatomical regions because of uneven distribution of data.
Also with similar observational results were present as shown for
Neurophil Threads(NT) in CA1, Subiculum and entorhinal cortex for severity
scoring. This may be going in contrast with the authors opinion “..
amyloid plaques in either region of the hippocampal formation,
particularly in the entorhinal cortex, were associated with memory
function in cross sectional and longitudinal analyses.”
It is not clear whether the dominant or non-dominant cerebral lobe is
evaluated for histopathological sections. This may be one of the major
limiting point because the pathogenesis, interpretation of cognitive
function results and progression of the cognitive decline are cerebral
hemispheres specific.
It is also interesting to note the important observation by the
authors that, the analyses relating Braak stage or counts of plaques, NFT
and NT in the frontal and parietal lobes with cognitive performance, none
of the neuropathological measures was associated with memory or any other
cognitive domain.
We would like to contribute on the article entitled “Radiological findings in individuals at high risk of schizophrenia and patients with first episode psychosis” by Borgwardt et al. [1] and on a letter by the
same group [2], in which they comment on our own paper investigating this issue [3]. The authors highlight that they have found [1] a lower prevalence of cavum septum pellucidum (CSP) both in su...
We would like to contribute on the article entitled “Radiological findings in individuals at high risk of schizophrenia and patients with first episode psychosis” by Borgwardt et al. [1] and on a letter by the
same group [2], in which they comment on our own paper investigating this issue [3]. The authors highlight that they have found [1] a lower prevalence of cavum septum pellucidum (CSP) both in subjects with first-episode schizophrenia (3.3%) and individuals at high risk for psychosis (5.7%), when compared to our findings in schizophrenic patients (21.1%).
We agree with Borgwardt et al. [2] that their use of a qualitative rather than a quantitative method may explain their finding of a lower estimated frequency of CSP. We would also argue that the acquisition of high-resolution, 1-mm contiguous MRI brain slices in our study may have led to a more accurate estimation of the prevalence of CSP, as well as allowing the quantitative assessment of their size. Borgwardt et al. [2] also stressed the value of searching for a wider range of structural brain anomalies in psychosis, instead of focusing on a single abnormality, such as the CSP. In regard to that, MRI images in our study [3] were also inspected visually for the presence of other gross anomalies in midline brain structures, by a consensus between two neuroradiologists blind to sex, diagnosis and clinical status of subjects. At this assessment, one of the patients with schizophrenia was found to have a lipoma adherent to the anterior face of the splenium of the corpus callosum; one other case
presented a parietal hemangioma, another patient presented total agenesis of the corpus callosum, while a fourth patient had a complete non-fusion of the entire length of the septum pellucidum – an anomaly termed ‘combined CSP and cavum vergae’. None of the observed abnormalities
implicated in a change in the diagnosis from DSM-IV schizophrenia to psychotic disorder due to an ‘organic’ medical condition. We did not find any other gross or pathological midline abnormalities in any of the
subjects studied. However, the following normal or minor brain variations were additionally found (data not presented before), only in the schizophrenia group: asymetrical ventricular system (n=4) and presence of
arachnoid cyst (n=1). Thus, taking all those findings together, it is possible to conclude that in our sample, there is also a significantly (p = 0.001) higher proportion of radiological findings in patients with
schizophrenia (9 of 38 or 23.7%) compared to healthy controls (none of 38). Although this was not the main objective of our study and the qualitative MRI assessment we have used was not standardized, our results are supportive of the findings reported by Borgwardt et al. [1] We suggest that future MRI studies, instead of focusing on either qualitative or quantitative assessments only, should systematically employ both approaches to evaluate the same sample. This may be of greater help for
our understanding of the role of developmental anomalies in the neuropathology of schizophrenia.
References
[1] S.J. Borgwardt, E.W. Radue, K. Götz, et al., Radiological findings in individuals at high risk of schizophrenia and patients with first episode psychosis. J Neurol Neurosurg Psychiatry 2006;77:229–33.
[2] Borgwardt SJ, Radue EW, Riecher-Rossler A. Cavum septum pellucidum in patients with first episode psychosis and individuals at high risk of psychosis. Eur Psychiatry 2006; 22:264.
[3] J.A. De Souza Crippa, A.W. Zuardi, G.F. Busatto, et al., Cavum septum pellucidum and adhesio interthalamica in schizophrenia: an MRI study. Eur Psychiatry 2006; 21: 291–9.
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.
We thank the author for his interest in our paper and agree with his
comments. In the case of relatively inexperienced clinicians we would
caution against over-confidence of PNES diagnosis, and we recommend
getting an expert opinion whenever possible. Whilst it has been shown that
expert epileptologists seldom all agree (1), perhaps for reasons including
"over-thinking" as suggested by Dr. Sethi, epilepsy group meetings ca...
We thank the author for his interest in our paper and agree with his
comments. In the case of relatively inexperienced clinicians we would
caution against over-confidence of PNES diagnosis, and we recommend
getting an expert opinion whenever possible. Whilst it has been shown that
expert epileptologists seldom all agree (1), perhaps for reasons including
"over-thinking" as suggested by Dr. Sethi, epilepsy group meetings can
help establish a consensus in the diagnoses of challenging seizure types
such some frontal lobe epilepsies.
(1) Benbadis SR, LaFrance WC, Jr., Papandonatos GD, et al. Interrater
reliability of EEG-video monitoring. Neurology. 2009;73(11):843-6. Epub
2009/09/16.
Dr. Sean O'Sullivan, Cork University Hospital Neurosciences
Department, University College Cork, Ireland
Autoimmune diseases are caused by aberrant response of immune system
directed against triggering epitopes.(1)Coincidental occurrence of
multiple autoimmune disorders in given patient suggests either common or
similar pathogenetic mechanisms.(1)The concept of molecular mimicry hold
that an agent may share epitopic determinants with nervous system tissues
and incites immune responses.
Chronic inflammatory demyelinating po...
Autoimmune diseases are caused by aberrant response of immune system
directed against triggering epitopes.(1)Coincidental occurrence of
multiple autoimmune disorders in given patient suggests either common or
similar pathogenetic mechanisms.(1)The concept of molecular mimicry hold
that an agent may share epitopic determinants with nervous system tissues
and incites immune responses.
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and
Multiple Sclerosis (MS) are acquired diseases evolving with progressions
and relapses.
Zéphir et al (2)recently reported five patients with relapsing
demyelinating disease affecting CNS and PNS and reviewed previously
described cases.
In Zephir et al (2)patients, demyelinating process started in CNS with
subsequent extension to peripheral nerves.
We experienced three patients affected by concurrent, both symptomatic,
peripheral and central demyelination. Chronology of their histories
demonstrated that bouts of symptoms initiated within PNS with extension
to CNS. Case 1 when aged 18 years, developed recurrent episodes of
unilateral complete facial palsy and distal paresthesias. On 1st
admission, deep jerks were unevokable. Brain magnetic resonance imaging
(MRI),visual evoked responses (VERs),nerve conduction were normal.Ten
years later, patient experienced hand tremor,distal extremity
numbness,imbalance.On examination, there were sustained nystagmus on
either lateral gaze, limb ataxia, positive Romberg sign, 3/5 MRC scale
distal weakness, loss of perception, areflexia. Routine laboratory tests
were normal, except for hypothyroidism due to earlier thyroiditis. CSF had
no oligoclonal IgG bands (OCIgG).Antibody assay for gangliosides, myelin
associated glycoprotein (MAG)was negative.PMP22 point
mutations,duplications,deletions and P0,connexin 32 mutations were
negative. Brain MRI was normal whereas there were multiple spinal cord
enhancing lesions fromC1 to Th7.
Electrophysiology showed demyelinating polyneuropathy with proximal and
distal motor conduction block (CB.(3)Sural potential had low amplitude(3
uV,normal >6.High doses of methylprednisolone(1gr i.v daily for 3 days)
had benefit. Four months later, patient presented with vertigo,dysarthria,
blurred vision. VERs were altered. On MRI, a bulbar enhancing lesion was
found. Methylprednisolone i.v was repeated.Immune globulin was afterwards
administered (1gr /kg/ body weight)every two to three months. During
following five years, serial electrophysiology confirmed demyelination as
indicated by slowed motor velocity (within 28 and 32 m/sec),delayed F
waves,dispersed motor responses throughout. Brain and spinal cord MRI
showed dissemination, fulfilling Barkhof's criteria for MS
diagnosis.(4)The disease had no further clinical recurrences.
Case 2 since early youth experienced tingling pain in hands and feets.
Fourteen years later, patient was admitted because of myalgias and limb
distal numbness. Neurological examination revealed 3/5 MRC proximal and
distal extremity weakness,areflexia. Electrophysiology demonstrated
sensorimotor demyelinating neuropathy with CB in both median and ulnar
nerves.Muscle biopsy had neurogenic features.Laboratory tests and brain
MRI were unremakable.At age of 35, patient was admitted because of blurred
vision, imbalance,acral paresthesias. On examination, there were
tremor,limb,trunk ataxia, areflexia, distal loss of strength (2/5
MRC),impaired sensation. CSF had increased protein (50 mg/dl, normal <
45) and OCIgG bands.VERs were normal.Brain MRI showed numerous
periventricular and subcortical T2 hyperintense lesions, fulfilling
Barkhof’s criteria for dissemination.(4)
Electrophysiology confirmed ongoing demyelination in peripheral nerves.(3)
No antiganglioside nor anti-MAG antibodies were detected. Oral prednisone
was given (50 mg every other day).One year later, patient developed renal
insufficiency due to hypertension. Cognitive decline and seizures
complicated the illness, which was marked by recurrent motor deficits in
lower limbs.
Our third case,with past history of hyperthyroidism, presented after two
years of lumbar pain,distal extremity numbness,waddling gait. On
examination, extremity strength was graded 3/5 proximally, 2/5 distally on
MRC scale. Moreover,there were stepping gait,areflexia,muscular
atrophy,distal impairment of all perception modalities. Electrophysiology
revealed sensorimotor demyelinating neuropathy, without CB. Sural biopsy
showed endoneural oedema, fiber loss, epineurial T cell infiltrates.VERs,
MRI and CSF were unremarkable.Immune globulin (0,4 gr /kg body weight for
four days ) was given and repeated with benefit.Type II diabetes was
discovered three years later. Patient motor deficits relapsed twice within
five years. On latest examination,there were nystagmus, scanned speech,
trunk ataxia. Brain MRI showed multiple T2 hyperintense, enhancing white
matter lesions suggestive of MS.(4) Serial electrophysiology confirmed
peripheral nerve demyelination.
Discussion: Our patients presented stepwise recurrent and chronically
progressive demyelinating process initiated within PNS with subsequent
extension to CNS.
PNS presenting symptoms predated by ten years in case 1,by two to three
years in case 2 and 3 CNS clinical and neuroradiological changes, which
progressed in parallel. Transiently their disease responded to steroids or
immunomodulating treatment. None had antecedent infections. Antibodies to
gangliosides and MAG were absent. No connexin 32, P0, PMP 22 mutations
were found. All patients had associated thyroid disfunction: case 2
developed diabetes. Exact significance of such association,if any, is not
clear,though it may suggest susceptibility to multiple immune mediated
diseases.
Case 2 developed renal failure related to hypertension years after
neurologic onset. CIDP of our patients was diagnosed on account of
required criteria.(3) Sural biopsy confirmed diagnosis of case 3. VERs
were abnormal only in case 2. Interestingly, CSF obtained after onset of
peripheral signs showed OCIgG only in second case.
MRI abnormalities in all fullfilled Barkhof’s criteria for
dissemination.(4)
Concurrent CIDP and CNS demyelination may progress either overtly or
clinically silent.(2)
Myelin P1 expressed in peripheral nerves is identical to central myelin
basic protein; moreover cross reactivity between cryptic antigenic targets
in CNS and PNS might be crucial.(1-2)
Zephyr et al (2) on account of clinical and laboratory data consider their
patients affected by new demyelinating entity distinct from classical MS
and CIDP:none of their cases had CB or abnormal temporal dispersion
although fulfilled criteria for CIDP.(3)
None of Zephyr et al patients (2) had CSF OCIgG bands, one had initial
pleiocytosis, three hyperproteinorrachia.
It is known that MS patients may lack oligoclonal bands.(5)
Among the 100 CIDP described by Bouchard et al (5) two out of five with
symptomatic CNS involvement had OCIgG bands , three MRI features of MS.
Overall neurologic features of reported cases (2,5) raise issue as to
whether they represent overlap version or distinct variant of CIDP and MS.
Regardless which mechanism may underlie their disease, patients with
concurrent CNS and PNS demyelination seem to share rather similar
immunopathogenesis suggesting a spectrum of dysimmune attacks against
myelin.(1, 2,5 )
References
1. Koller H,Schoeter M, Kieseier BC, Hartung HP . Cronic inflammatory
demyelinating polyneuropathy-update on pathogenesis , diagnostic criteria
and therapy. Curr Opin Neurol 2005;18: 273-8.
2. Zéphir H, Stojkovic T, Latour P et al Relapsing demyelinating disease
affecting both the central and peripheral nervous systems. J Neurol
Neurosurg Psychiatry 2008;79:1032-39.
3. Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task
Force. Research criteria for diagnosis of chronic inflammatory
demyelinating polyneuropathy. Neurology 1991 ;41: 617-18
4. Barkhof F, Filippi M, Miller DH.Comparaison of MRI imaging criteria at
first presentation to predict conversion to clinically definite multiple
sclerosis.Brain 1997;120:2059-69.
5. Bouchard C, Lacroix C, Plante’ V et al .Clinicopathologic findings and
prognosis of chronic inflammatory demyelinating polyneuropathy.Neurology
1999:52: 498-503.
This is a very interesting article. Dr. Young, et.al. report a rare sub-group of headache patients. Patients with unilateral motor symptom is commonly only seen in tertiary health center. The motor symptom will drive
the patients for visiting the health centers with full facilities. It is consistent with the facts that most headache patients want to know the origin of the headache. This article showe...
This is a very interesting article. Dr. Young, et.al. report a rare sub-group of headache patients. Patients with unilateral motor symptom is commonly only seen in tertiary health center. The motor symptom will drive
the patients for visiting the health centers with full facilities. It is consistent with the facts that most headache patients want to know the origin of the headache. This article showed that most patients experiences
significant impact of their headache. Allodynia can be very disturbing.
About 33% patients with MUMS lost their jobs because of the headache. The number is very significant. The patients with MUMS will also receive more procedure either diagnostic procedure and therapeutic procedure. In our
neurological daily practice, most patients ask "where does this headache come from?", "Is it any serious problems in my head?", or "is there any brain tumor?". Patients with motor symptoms surely have more anxiety and concern about their disease. This is possible, because about 40% patients has been told by the doctor that they have stroke. When the imaging is normal, almost 50% patients believed that their symptoms is migraine related. The MUMS must be recognized correctly, and treated well to minimize the disability. The good information for the patients will be also necessary to improve the compliance.
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.
Dear Sir,
We are pleased with the interest of Weerkamp in our work and are grateful
for his comments, giving us the chance to comment the results of our study
[1]. We would like to further thank him for having raised the issue of
several scales which have been developed to assess the non-motor symptoms
(NMS), but include such motor symptoms as morning dystonia and tremor on
awakening. However, this is not the case here. I...
Dear Sir,
We are pleased with the interest of Weerkamp in our work and are grateful
for his comments, giving us the chance to comment the results of our study
[1]. We would like to further thank him for having raised the issue of
several scales which have been developed to assess the non-motor symptoms
(NMS), but include such motor symptoms as morning dystonia and tremor on
awakening. However, this is not the case here. Indeed, the NMS-Quest does
not include such symptoms (nor they are discussed in our paper) and is
likely to reflect a "pure" non-motor involvement [2].
With regard of the possible confounding interaction between the motor
fluctuations and the NMS, it should be stressed that the NMS-Quest
assesses the presence of NMS which patients might have experienced in the
previous month. It is thereby very unlikely that the NMS-Quest may be
severely affected by the pharmacological state. Nevertheless, it has been
suggested that NMS may also fluctuate in more advanced stages of the
disease. However, our patients were all evaluated in the on-state when
assessed at follow-up and none of them had experienced motor fluctuations,
as we have stated in our work. On the other hand, the reliability of the
NMS-Quest in different pharmacological states has not been tested yet, and
it may be interesting to further compare it with different scales, such as
the Wearing-Off Questionnaires, which have been specifically developed for
the non-motor fluctuations [3].
With regard of the study's design and the aim to assess the NMS
progression, it should be noticed that, due to the efficacy of
pharmacological treatment, evaluation of the natural progression of both
motor and non-motor features of PD is nowadays impossible. Data on the
natural short-term worsening of motor symptoms have been indeed obtained
from patients in the placebo arms of controlled studies. To our knowledge,
no placebo-controlled study has been developed so far regarding the whole
NMS complex and its progression over the disease course and the
dopaminergic therapy introduction. The work which has been mentioned by
Weerkamp (the RECOVER study), neither included drug-naive PD patients at
enrollment nor provided long-term outcomes regarding the NMS. It only
showed the efficacy of 3-month lasting therapy with rotigotine on a few
NMS (i.e. sleep disturbances, which in our opinion may partially reflect
motor disturbances). This setting is far away from the clinical practice
and from our first aim, which was to evaluate the NMS burden in the first
4 years of the disease over the dopaminergic therapy introduction. A
control group of untreated patients would have given of course more
informations to discuss, but this kind of study's design is impossible at
present due to ethical issues. Assessment of the natural long-term
progression of NMS over the whole disease course is indeed possible only
by mean of comparisons of patients with and without L-Dopa and/or dopamine
agonists.
We finally want to thank Weerkamp for having brought to our attention the
recently published article focusing on NMS progression [4], which
unfortunately had not been published by the time of our submission.
Antonini and colleagues attempted to evaluated the NMS progression and its
relationship with quality of life in a large cohort PD patients. Although
they used a different scale for the assessment of NMS and included more
advanced (also fluctuating) patients with no informations regarding the
dopaminergic therapy (for details, see the PRIAMO study), their findings
are in line with our results and highlight the concept that NMS
progression pursues different patterns and that the relationship between
the dopaminergic therapy and the NMS improvement is not straightforward.
This is further supported by the results of other studies evaluating the
short-term effects of dopaminergic treatment on NMS in de novo PD patients
[5].
Assessing the non-motor progression is currently one of the most exciting
challenge of the research on PD: our results should serve as an incentive
for planning future studies targeting the non motor disturbances. Given
the absence of a reliable bio-marker which may be able to measure the
underlying pathological progression, further clinical studies are needed
to prospectively evaluate both NMS occurrence and severity and how they
are modified by specific therapies.
Roberto Erro, Paolo Barone.
Reference
[1] Erro R, Picillo M, Vitale C, et al. Non-motor symptoms in early
Parkinson's disease: a 2-year follow-up study on previously untreated
patients. J Neurol Neurosurg Psychiatry. 2013;84(1):14-7
[2] Martinez-Martin P, Schapira AH, Stocchi F, et al. Prevalence of
nonmotor symptoms in Parkinson's disease in an international Setting;
study using Nonmotor symptoms questionnaire in 545 patients. Mov Disord
2007;22:1623-9.
[3] Stacy M. The wearing-off phenomenon and the use of questionnaires to
facilitate its recognition in Parkinson's disease. J Neural Transm.
2010;117:837-46.
[4] Antonini A, Barone P, Marconi R, et al. The progression of non-motor
symptoms in Parkinson's disease and their contribution to motor disability
and quality of life. J Neurol. 2012;259:2621-31.
[5] Kim HJ, Park SY, Cho YJ, et al. Nonmotor symptoms in de novo Parkinson
disease before and after dopaminergic treatment. J Neurol Sci 2009;287:200
-4.
Dear Editor,
The role of inflammation in the etiopathogenesis of Alzheimer’s disease (AD) has been exhaustively analyzed by several authors, with a special focus on cytokines such as Tumor Necrosis Factor alpha (TNF-alpha), Interleukin-1 and Interleukink-6, demonstrated to be evidently connected with the neuroinflammatory processes; an augmented production of these cytokines have been revealed in AD subjects while a def...
We would like to share several observations that we made on Ammirati et al. recently published meta-analysis. The authors reviewed the available English-language literature from 1990 to the present, comparing microsurgery versus endoscopy for treatment of pituitary adenomas, and conducted a systematic review and meta-analysis of the data obtained. The authors concluded that the two treatment methods produced similar out...
Dear editor
It is interesting to note that, Figure 3 Shows that Mean Memory factor score for Neurofibrillary tangles(NFT) score-5 is 40.1,30.3 and 13.0 for plaques in CA1, plaques in subiculum and plaques in entorhinal cortex respectively which is less compared to the memory scores of higher NFT scores like 5 to 15 and >15. But this can be cautiously interpreted as memory scoring is not directly related t...
Dear Editor,
We would like to contribute on the article entitled “Radiological findings in individuals at high risk of schizophrenia and patients with first episode psychosis” by Borgwardt et al. [1] and on a letter by the same group [2], in which they comment on our own paper investigating this issue [3]. The authors highlight that they have found [1] a lower prevalence of cavum septum pellucidum (CSP) both in su...
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...
We thank the author for his interest in our paper and agree with his comments. In the case of relatively inexperienced clinicians we would caution against over-confidence of PNES diagnosis, and we recommend getting an expert opinion whenever possible. Whilst it has been shown that expert epileptologists seldom all agree (1), perhaps for reasons including "over-thinking" as suggested by Dr. Sethi, epilepsy group meetings ca...
Autoimmune diseases are caused by aberrant response of immune system directed against triggering epitopes.(1)Coincidental occurrence of multiple autoimmune disorders in given patient suggests either common or similar pathogenetic mechanisms.(1)The concept of molecular mimicry hold that an agent may share epitopic determinants with nervous system tissues and incites immune responses. Chronic inflammatory demyelinating po...
Dear Editor,
This is a very interesting article. Dr. Young, et.al. report a rare sub-group of headache patients. Patients with unilateral motor symptom is commonly only seen in tertiary health center. The motor symptom will drive the patients for visiting the health centers with full facilities. It is consistent with the facts that most headache patients want to know the origin of the headache. This article showe...
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...
Dear Sir, We are pleased with the interest of Weerkamp in our work and are grateful for his comments, giving us the chance to comment the results of our study [1]. We would like to further thank him for having raised the issue of several scales which have been developed to assess the non-motor symptoms (NMS), but include such motor symptoms as morning dystonia and tremor on awakening. However, this is not the case here. I...
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