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Should we rebrand multiple sclerosis a dementia?

Published:January 16, 2017DOI:https://doi.org/10.1016/j.msard.2017.01.008

      Keywords

      Multiple sclerosis (MS) is the commonest non-traumatic disabling condition to afflict young adults (

      Baneke, P., Browne, P., Thompson, A.J., Taylor, B., Battaglia, M., Pandit, L., Tremlett, H., Uitdehaag, B., Holloway, E., 2013. MSIF atlas of MS database update: multiple sclerosis resources in the world 2013, In: Mult. Scler. J. p. 652.

      ). Given sufficient time MS causes physically disability in the majority of people with MS (pwMS), but has a relatively modest impact on life expectancy reducing it by approximately 8 years (
      • Scalfari A.
      • Knappertz V.
      • Cutter G.
      • Goodin D.S.
      • Ashton R.
      • Ebers G.C.
      Mortality in patients with multiple sclerosis.
      ,
      • Smestad C.
      • Sandvik L.
      • Celius E.
      Excess mortality and cause of death in a cohort of Norwegian multiple sclerosis patients.
      ). As a result MS has a high socioeconomic impact (
      • Kobelt G.
      • Gisela K.
      Economic evidence in multiple sclerosis: a review.
      ). Evidence has emerged to support early treatment of MS to try and prevent irreversible damage from accruing that is linked to poor outcomes and long-term disability (

      Giovannoni, G., Butzkueven, H., Dhib-Jalbut, S., Hobart, J., Kobelt, G., Pepper, G., Sormani, M.-P., Thalheim, C., Traboulsee, A., Vollmer, T., n.d. Brain health: time matters in multiple sclerosis.

      ). Despite this many countries have restricted access to disease modifying therapies (DMTs), and several of the more effective DMTs have licenses that limit their use as second or even third line therapies (
      • Marziniak M.
      • Ghorab K.
      • Kozubski W.
      • Pfleger C.
      • Sousa L.
      • Vernon K.
      • Zaffaroni M.
      • Meuth S.G.
      Variations in multiple sclerosis practice within Europe – Is it time for a new treatment guideline?.
      ) (Ghorab

      Ghorab, K., Marziniak, M., Kozubski, W., Pfleger, C., Sousa, L., Vernon, K., Zaffaroni, M., Meuth, S., n.d. Variations in multiple sclerosis practice within Europe - is it time for a new treatment guideline? Mult. Scler. Relat. Disord.

      ). In response to this I launched a campaign, using social media, to redefine MS as a preventable dementia with the aim of getting the wider community, in particular the regulators, to re-evaluate their position on access to these more effective treatments. Neurologists are well aware that patients with MS may present with cognitive impairment as the dominant feature and most textbooks of neurology include MS in tables listing the causes of dementia. Therefore the concept of MS being a dementing illness is not novel.
      How do we define a dementia? The Diagnostic and Statistical Manual of Mental Disorders (DSM) defines dementia as a loss of mental ability severe enough to interfere with normal activities of daily living, lasting more than six months, not present since birth, and not associated with a loss or alteration of consciousness (
      • American Psychiatric Association
      Diagnostic and Statistical Manual of Mental Disorders: DSM-IV-TR.
      ). I would argue that a significant proportion of pwMS would fulfil these contemporary diagnostic criteria for having a dementia (
      • Reisberg B.
      Diagnostic criteria in dementia: a comparison of current criteria, research challenges, and implications for DSM-V.
      ); i.e. loss of cognition severe enough to interfere with normal activities of daily living, being present for more than six months, not present at birth, and finally in the vast majority of cases not being associated with a loss or alteration of consciousness. In the DSM activities of daily living are broken down into four domains, physical, mental, social and occupational. MS is well established as a physically disabling condition; in natural history studies the median time to reach the irreversible disability levels of EDSS 4, 6, and 7 is 8, 20, and 30 years, respectively (

      Confavreux, C., Christian, C., Alastair, C., 2006. The natural history of multiple sclerosis. In: McAlpine’s Multiple Sclerosis. pp. 183–272.

      ). The mental or cognitive domain is often overlooked with the majority of pwMS developing significant cognitive impairment with time (

      Langdon, D., Dawn, L., Clinical Neuropsychologist, Neuropsychology, A.R. in, Royal, H., London, U. of, 2010. Cognitive Impairment in Multiple Sclerosis - Recent Advances and Future Prospects. Eur. Neurol. Rev. 5, 69.

      ). Cognitive impairment is often present early in the course of the disease, deteriorates with time and is strongly associated with brain volume loss and T1 hypointense lesion volume on MRI (
      • Calabrese M.
      • Agosta F.
      • Rinaldi F.
      • Mattisi I.
      • Grossi P.
      • Favaretto A.
      • Atzori M.
      • Bernardi V.
      • Barachino L.
      • Rinaldi L.
      • Perini P.
      • Gallo P.
      • Filippi M.
      Cortical lesions and atrophy associated with cognitive impairment in relapsing-remitting multiple sclerosis.
      ,

      Langdon, D., Dawn, L., Clinical Neuropsychologist, Neuropsychology, A.R. in, Royal, H., London, U. of, 2010. Cognitive Impairment in Multiple Sclerosis - Recent Advances and Future Prospects. Eur. Neurol. Rev. 5, 69.

      ,
      • Penny S.A.
      • Summers M.M.
      • Swanton J.K.
      • Cipolotti L.
      • Miller D.H.
      • Ron M.A.
      Changing associations between cognitive impairment and imaging in multiple sclerosis as the disease progresses.
      ). In cross-sectional studies cognitive impairment is found in 30–57% of patients presenting with CIS (
      • Anhoque C.F.
      • Laurentino B.-N.
      • Domingues S.C.A.
      • Teixeira A.L.
      • Domingues R.B.
      Cognitive impairment is correlated with reduced quality of life in patients with clinically isolated syndrome.
      ,
      • Moghadam N.B.
      • Moayed M.E.
      • Sahraian M.A.
      • Ameli N.
      Cognitive impairment in patients with clinically isolated syndrome.
      ,
      • Panou T.
      • Theodora P.
      • Vasileios M.
      • Efrosyni P.
      • Simos P.G.
      • Andreas P.
      Early signs of memory impairment among multiple sclerosis patients with clinically isolated syndrome.
      ,
      • Štecková T.
      • Tereza Š.
      • Petr H.
      • Vladimíra S.
      • František O.
      • Jan M.
      • Petr K.
      Thalamic atrophy and cognitive impairment in clinically isolated syndrome and multiple sclerosis.
      ,
      • Zipoli V.
      • Goretti B.
      • Hakiki B.
      • Siracusa G.
      • Sorbi S.
      • Portaccio E.
      • Amato M.P.
      Cognitive impairment predicts conversion to multiple sclerosis in clinically isolated syndromes.
      )and in approximately 25% of patients with radiologically isolated syndromes (RIS)(
      • Amato M.P.
      • Hakiki B.
      • Goretti B.
      • Rossi F.
      • Stromillo M.L.
      • Giorgio A.
      • Roscio M.
      • Ghezzi A.
      • Guidi L.
      • Bartolozzi M.L.
      • Portaccio E.
      • De Stefano N.
      • Italian RIS/MS Study Group
      Association of MRI metrics and cognitive impairment in radiologically isolated syndromes.
      ), or asymptomatic MS. In an Argentinian study of subjects who developed CIS after leaving school it was found that their school performance in the last 3 years of school was poorer than age and sex matched controls implying that asymptomatic MS had affected their cognition years before clinical onset (
      • Sinay V.
      • Perez Akly M.
      • Zanga G.
      • Ciardi C.
      • Racosta J.M.
      School performance as a marker of cognitive decline prior to diagnosis of multiple sclerosis.
      ). Similarly, approximately 25% of subjects identified as having radiologically isolated syndromes (RIS), or asymptomatic MS, have significant cognitive impairment on formal testing (
      • Amato M.P.
      • Hakiki B.
      • Goretti B.
      • Rossi F.
      • Stromillo M.L.
      • Giorgio A.
      • Roscio M.
      • Ghezzi A.
      • Guidi L.
      • Bartolozzi M.L.
      • Portaccio E.
      • De Stefano N.
      • Italian RIS/MS Study Group
      Association of MRI metrics and cognitive impairment in radiologically isolated syndromes.
      ).
      The social impact of MS is rarely discussed. PwMS are more likely to be socially isolated (
      • Rimaz S.
      • Mohammad K.
      • Dastoorpoor M.
      • Jamshidi E.
      • Majdzadeh R.
      Investigation of relationship between social capital and quality of life in multiple sclerosis patients.
      ), split from their partners (
      • Pfleger C.
      • Flachs E.
      • Koch-Henriksen N.
      Social consequences of multiple sclerosis. Part 2. Divorce and separation: a historical prospective cohort study.
      ,
      • Stenager E.
      • Stenager E.N.
      • Knudsen L.
      • Jensen K.
      Multiple sclerosis: the impact on family and social life.
      ) and commit suicide (
      • Pompili M.
      • Forte A.
      • Palermo M.
      • Stefani H.
      • Lamis D.A.
      • Serafini G.
      • Amore M.
      • Girardi P.
      Suicide risk in multiple sclerosis: a systematic review of current literature.
      ). Compared to patients with other chronic diseases, such as cancer, patients with MS are twice as likely to be abandoned by their partners (
      • Glantz M.J.
      • Chamberlain M.C.
      • Liu Q.
      • Hsieh C.-C.
      • Edwards K.R.
      • Van Horn A.
      • Recht L.
      Gender disparity in the rate of partner abandonment in patients with serious medical illness.
      ). Anxiety and depression are common in pwMS (
      • Fiest K.M.
      • Walker J.R.
      • Bernstein C.N.
      • Graff L.A.
      • Zarychanski R.
      • Abou-Setta A.M.
      • Patten S.B.
      • Sareen J.
      • Bolton J.M.
      • Marriott J.J.
      • Fisk J.D.
      • Singer A.
      • Marrie R.A.
      • CIHR Team “Defining the burden and managing the effects of psychiatric comorbidity in chronic immunoinflammatory disease,”
      Systematic review and meta-analysis of interventions for depression and anxiety in persons with multiple sclerosis.
      ) and personality changes are well described (
      • Iacovides A.
      • Andreoulakis E.
      Bipolar disorder and resembling special psychopathological manifestations in multiple sclerosis: a review.
      ). These psychiatric manifestations of the disease may explain why MS has a greater impact on interpersonal relationships than other disabling diseases that don’t primarily involve the brain, for example rheumatoid arthritis and cancer. The final domain is occupation; approximately 50% of pwMS are unemployed 10 years after the onset of the disease at a stage of the disease with mild physical disability, i.e. approximately 3.0–3.5 on the Expanded Disability Status Scale (EDSS) (
      • Kobelt G.
      • Gisela K.
      Economic evidence in multiple sclerosis: a review.
      ). The early impact of MS on employment at low levels of physical disability is almost certainly due to ‘hidden symptoms’, in particular cognitive impairment, depression and anxiety (
      • Strober L.B.
      • Christodoulou C.
      • Benedict R.H.B.
      • Westervelt H.J.
      • Melville P.
      • Scherl W.F.
      • Weinstock-Guttman B.
      • Rizvi S.
      • Goodman A.D.
      • Krupp L.B.
      Unemployment in multiple sclerosis: the contribution of personality and disease.
      ).
      Brain volume loss, which is considered to be a biomarker, or integrator, of neuroaxonal loss in many neurodegenerative dementing diseases, occurs early in MS (
      • Amato M.P.
      • Hakiki B.
      • Goretti B.
      • Rossi F.
      • Stromillo M.L.
      • Giorgio A.
      • Roscio M.
      • Ghezzi A.
      • Guidi L.
      • Bartolozzi M.L.
      • Portaccio E.
      • De Stefano N.
      • Italian RIS/MS Study Group
      Association of MRI metrics and cognitive impairment in radiologically isolated syndromes.
      ,
      • Popescu V.
      • Agosta F.
      • Hulst H.E.
      • Sluimer I.C.
      • Knol D.L.
      • Sormani M.P.
      • Enzinger C.
      • Ropele S.
      • Alonso J.
      • Sastre-Garriga J.
      • Rovira A.
      • Montalban X.
      • Bodini B.
      • Ciccarelli O.
      • Khaleeli Z.
      • Chard D.T.
      • Matthews L.
      • Palace J.
      • Giorgio A.
      • De Stefano N.
      • Eisele P.
      • Gass A.
      • Polman C.H.
      • Uitdehaag B.M.J.
      • Messina M.J.
      • Comi G.
      • Filippi M.
      • Barkhof F.
      • Vrenken H.
      • MAGNIMS Study Group
      Brain atrophy and lesion load predict long term disability in multiple sclerosis.
      ). The rate of brain volume loss is relatively constant at all stages of the disease including CIS, relapse-remitting and both secondary and primary progressive MS (
      • De Stefano N.
      • Giorgio A.
      • Battaglini M.
      • Rovaris M.
      • Sormani M.P.
      • Barkhof F.
      • Korteweg T.
      • Enzinger C.
      • Fazekas F.
      • Calabrese M.
      • Dinacci D.
      • Tedeschi G.
      • Gass A.
      • Montalban X.
      • Rovira A.
      • Thompson A.
      • Comi G.
      • Miller D.H.
      • Filippi M.
      Assessing brain atrophy rates in a large population of untreated multiple sclerosis subtypes.
      ). Brain atrophy is also noted in subjects with RIS and probably explains the associated cognitive impairment that occurs in a proportion of subjects very early in the asymptomatic phase of the disease (
      • Amato M.P.
      • Hakiki B.
      • Goretti B.
      • Rossi F.
      • Stromillo M.L.
      • Giorgio A.
      • Roscio M.
      • Ghezzi A.
      • Guidi L.
      • Bartolozzi M.L.
      • Portaccio E.
      • De Stefano N.
      • Italian RIS/MS Study Group
      Association of MRI metrics and cognitive impairment in radiologically isolated syndromes.
      ,
      • De Stefano N.
      • Giorgio A.
      • Battaglini M.
      • Rovaris M.
      • Sormani M.P.
      • Barkhof F.
      • Korteweg T.
      • Enzinger C.
      • Fazekas F.
      • Calabrese M.
      • Dinacci D.
      • Tedeschi G.
      • Gass A.
      • Montalban X.
      • Rovira A.
      • Thompson A.
      • Comi G.
      • Miller D.H.
      • Filippi M.
      Assessing brain atrophy rates in a large population of untreated multiple sclerosis subtypes.
      ,
      • Zipoli V.
      • Goretti B.
      • Hakiki B.
      • Siracusa G.
      • Sorbi S.
      • Portaccio E.
      • Amato M.P.
      Cognitive impairment predicts conversion to multiple sclerosis in clinically isolated syndromes.
      ).
      As part of the “rebranding MS a dementia” campaign on our blog (www.ms-res.org) I did two short online surveys to explore whether or not pwMS are aware of MS being a potential dementia and being associated with progressive, and accelerated, brain atrophy. After the an online campaign using social media 67% of respondents agreed that MS is a dementing disease, with only 15% of respondents disagreeing and the remainder being unsure. Eighty percent of respondents had never had brain volume loss, or brain atrophy, discussed with them by their neurologist or other healthcare professionals. Eighty-five percent and 88% of respondents would want to know if they had brain atrophy and progressive brain atrophy, respectively. Importantly, 77% of subjects stated that this knowledge would affect their choice of DMT. Since running this campaign and speaking about it at numerous MS meetings I have been chastised that the message is too negative and potentially stigmatising for pwMS. In a subsequent survey 62% of respondents agreed that ‘rebranding MS a dementia’ would be stigmatizing, with 18% disagreeing with this and the remainder being undecided. However, in the same survey 98% of respondents said we should not ignore early cognitive impairment as an important issue in MS. 76% felt the early MS-related cognitive impairment justified the use of an early highly-effective treatment paradigm.
      In summary, MS is associated with early cognitive impairment and progressive brain volume loss that markedly reduces quality of life, daily functioning (
      • Glanz B.I.
      • Healy B.C.
      • Rintell D.J.
      • Jaffin S.K.
      • Rohit B.
      • Weiner H.L.
      The association between cognitive impairment and quality of life in patients with early multiple sclerosis.
      ) and employability (
      • Rao S.M.
      • Leo G.J.
      • Ellington L.
      • Nauertz T.
      • Bernardin L.
      • Unverzagt F.
      Cognitive dysfunction in multiple sclerosis. II. Impact on employment and social functioning.
      ) of pwMS. Despite the message that MS is a dementing illness being a negative one, unless pwMS and their families are made aware of this issue how can they weigh up the risks and benefits of DMTs; in particular the more effective DMTs, which generally come with more risks, but have been shown to greatest impact in reducing the rate of brain atrophy? I have tempered my message and now refer to MS as a ‘preventable cause of dementia’. I am not prepared to hide these facts from my patients. If pwMS are expected to make informed decisions about therapies with potentially life threatening adverse effects they need to know about the consequences of untreated, or undertreated, MS. In my opinion the days of the paternalistic healthcare professional are long gone; what we need are open and honest partnerships with our patients (
      • Giovannoni G.
      • Cook S.
      • Rammohan K.
      • Rieckmann P.
      • Sørensen P.S.
      • Vermersch P.
      • Hamlett A.
      • Viglietta V.
      • Greenberg S.
      • CLARITY study group
      Sustained disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with cladribine tablets in the CLARITY study: a post-hoc and subgroup analysis.
      ). This does not mean that one size fits all and where necessary a paternalistic approach to the management of specific patients with MS may be needed (
      • Rosenbaum L.
      • Lisa R.
      The paternalism preference — choosing unshared decision making.
      ); in my personal experience this is the minority of patients and requires a judgement call, which is why the practice of medicine remains an art rather than a science.

      Conflicts of interest

      GG has received compensation for participating on Advisory Boards in relation to clinical trial design, trial steering committees and data and safety monitoring committees from: Abbvie, Bayer-Schering Healthcare, Biogen-Idec, Eisai, Elan, Fiveprime, Genzyme, Genentech, GSK, GW Pharma, Ironwood, Merck, Merck-Serono, Novartis, Pfizer, Roche, Sanofi-Aventis, Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals.

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