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Recent eLetters

Displaying 1-10 letters out of 516 published

  1. Paralympics and Conversion Disorder - "secondary gain" should not be a reason for exclusion

    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.

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  2. HIV and lower risk of multiple sclerosis: protective or subjugating effect?

    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.

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  3. The strange case of bilirubin in Parkinson's disease

    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.

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  4. Role of advanced MR techniques such as Diffusion Tensor Imaging in Leber's hereditary optic neuropathy and Multiple Sclerosis

    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.

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  5. Re:New Insights on AD: Comment on The identification of cognitive subtypes in Alzheimer's disease dementia using latent class analysis

    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.

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  6. Pathogenesis of anti-contactin-1 associated paranodopathy

    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.

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  7. A radiological curiosity of hyperammonaemia!

    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

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  8. New Insights on AD: Comment on The identification of cognitive subtypes in Alzheimer's disease dementia using latent class analysis

    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.

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  9. IgG subclass in combined central and peripheral demyelination associated with anti-neurofascin 155 antibodies

    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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  10. Sensory Ataxia and Anti-contactin-1 IgG4-Associated Paranodopathy

    With interest, we read an excellent paper written by a German group, in which four patients with chronic inflammatory demyelinating polyneuropathy (CIDP) carried IgG autoantibodies against contactin-1 (CNTN1) expressed at the paranodes in the peripheral nerves.[1] Human IgG antibodies consist of four subclasses (IgG1-4) with different structural and functional characteristics. IgG4 are generally believed to be non- inflammatory antibodies because they poorly bind to complement and Fc receptors Three of their patients had anti-CNTN1 IgG4 and sera from these three patients bound the paranodes in the mouse teased nerve fibers. On the other hand, the remaining patient with no anti-CNTN1 IgG4 antibodies in the serum did not bind the paranodes.

    In a large cohort of Japanese patients with CIDP (n = 533) and Guillain-Barre syndrome (GBS) (n = 200), our group identified anti-CNTN1 IgG antibodies in 16 sera from patients with CIDP and five with GBS.[2] IgG4 antibodies to CNTN1 were identified in 13 of 16 patients with CIDP, but none of those with GBS. IgG2 antibodies to CNTN1 were identified in three patients with CIDP and in five patients with GBS. We also blindly tested the sera on mouse teased fibers. Of interest, all the IgG4-positive CIDP sera strongly reacted against the paranodal domains but not for the IgG2-positive sera from patients with CIDP or GBS. These results are in line with those of the German group,[1] suggesting that only the IgG4 antibodies are pathogenic.

    We further tested whether these sera activate the complement pathway in vitro.[2] None of the sera with anti-CNTN1 IgG4 antibodies induced the deposition of activated C3 components on enzyme-linked immunosorbent assay plates. These results support that anti-CNTN1 IgG4 antibodies do not fix complement.

    The German group found out a typical clinical picture among the CIDP patients with anti-CNTN1 antibodies, namely acute onset of disease and severe motor symptoms, with three out of four patients manifesting action tremor.[1] However, in our cohort we found out that presence of anti-CNTN1 IgG4 antibodies was significantly associated with the clinical sign of sensory ataxia.[2] CNTN1 was widely expressed in large dorsal root ganglion neurons. Similarly, CIDP sera with anti-CNTN1 IgG4 antibodies stained large neurons in dorsal root ganglion sections and co-localized with CNTN1 staining in the soma and at the paranodes of sensory axons. These results support that the anti-CNTN1 autoantibodies induce the development of sensory ataxia. Nonetheless, the clinical feature of our patients contrasted with previous studies where none of the three German patients and only one of four Spanish patients with anti-CNTN1 IgG4 antibodies showed sensory ataxia.[1,3] The reason for this discrepancy is unclear, but this discrepancy should motivate international study groups to investigate the clinical feature of the anti-CNTN1 IgG4 antibodies among different countries, and their underlying mechanism.

    References 1. Doppler K, Appeltshauser L, Wilhelmi K, et al. Destruction of paranodal architecture in inflammatory neuropathy with anti-contactin-1 autoantibodies. J Neurol Neurosurg Psychiatry 2015 Feb 18. pii:jnnp-2014- 309916. doi: 10.1136/jnnp-2014-309916. 2. Miura Y, Devaux N, Fukami Y, et al. Contactin 1 IgG4 associated to chronic inflammatory demyelinating polyneuropathy with sensory ataxia. Brain 2015 Mar 25. pii: awv054. 3. Querol L, Nogales-Gadea G, Rojas-Garcia R, et al. Antibodies to contactin-1 in chronic inflammatory demyelinating polyneuropathy. Ann Neurol 2013;73:370-80.

    Conflict of Interest:

    None declared

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