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.

Conflict of Interest:

None declared

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.

Conflict of Interest:

None declared

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.

Conflict of Interest:

None declared

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.

Conflict of Interest:

None declared