Reflection and Reaction

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More than 160 years after the first systematic descriptionof multiple sclerosis (MS), our therapeutic tools forstopping disease progression are still limited, and there isnot even a cure, let alone a way of repairing damage to thenervous system. A major reason for limited treatmentoptions for MS is disease heterogeneity. MS can presentwith relapses and remissions or steady progression ofneurological disability, meaning the disease course isunpredictable in each patient. The pathological hallmarkin patients with acute and relapsing disease is theformation of focal inflammatory demyelinating lesions inwhite matter.1 Studies at the cellular and molecular levelsled to the classification of actively demyelinating MSplaques into distinct pathological patterns I-IV of MS.2

More than 80% of analysed lesions are pattern I withcellular cytotoxicity or pattern II with antibody andcomplement mediated demyelination. As yet there is nounequivocal surrogate marker that is indicative of orassociated with these lesion patterns.

Plasmapheresis made its way into neuroimmunologyin the 1980s, via myasthenia gravis to autoimmuneneuropathies, and finally into long-term MS treatment,mostly in combination with cytotoxic immuno-suppressive therapy.1 Although, plasmapheresis did notseem promising in modifying long-term relapsing orprogressive MS, Weinshenker and colleagues3 re-introduced plasmapheresis. In Weinshenker andcolleagues’ elegant, placebo-controlled, cross-overstudy, they offered plasmapheresis to those patientswith severe attacks of MS or inflammatory demyelinatingdisease who did not respond to (repeated) steroid pulsetherapy, thus indirectly selecting for patients in whomdisease pathology presumably was non-cellularinflammation—likely the same as pattern II, in whichdemyelination is caused by the deposition of antibodiesand activated complement.2 Weinshenker and colleagues

observed substantial amelioration with 45% of patientsreceiving seven treatment sessions of plasmapheresis.Importantly, plasmapheresis had to be given within6 weeks after onset of symptoms. On the basis of thiscontrolled study, the usefulness of plasmapheresis hasalso been extended to severe optic neuritis in patientswith MS or clinically isolated syndromes.4 In ourexperience, four or five plasmapheresis sessions, each at40 mL/kg bodyweight, were sufficient to yield similarresults. Limitations of this series4 arise from the open-study design, as a result of regulatory stipulations in theGerman medical system.

Keegan and colleagues5 studied histopathologicalpatterns in patients with fulminant attacks of MS andtreatment response to plasmapheresis. This consortiumof scientists, guided by the Mayo clinic, retrospectivelyanalysed 23 people who had had brain biopsy because offulminant inflammatory attacks in the presence oftumefactive lesions on MRI and for whom sufficient tissuewas available for molecular typing. Primary treatmentresponse was assessed independently from and withoutknowledge of the immunopathological classification.Four of the patients had to be excluded because otherdiagnoses were finally made or concomitant medicationwas taken. Finally, of the 19 remaining patients, threepatients had pattern I, ten patients had pattern II, and sixpatients had pattern III (distal oligodendrogliopathy). Theresults were clear and unequivocal; all patients of patternII responded to plasmapheresis with a median interval of3 days, whereas none of the other individuals improvedaccording to an established grading scale.3 During follow-up, two patients died and showed the same lesion patternon autopsy as in the biopsy.

This study is the first time that treatment success hasbeen associated with histopathological changes in MS.Although the treatment groups are small, the “black-

5 Azzimondi G, Bassein L, Fiorani L, et al. Variables associated with hospitalarrival time after stroke: effect of delay on the clinical efficiency of earlytreatment. Stroke 1997; 28: 537–42.

6 Nor AM, Davis J, Sen B, et al. The Recognition of Stroke in the EmergencyRoom (ROSIER) scale: development and validation of a stroke recognitioninstrument. Lancet Neurol 2005; 4: 727–34.

7 Kothari R, Pancioli A, Lui T, Brott T, Broderick J. Cincinnati PrehospitalStroke Scale: reproducibility and validity. Ann Emerg Med 1999;33: 373–78.

8 Harbison J, Massey A, Barnett L, Hodge D, Ford GA. Rapid ambulance

protocol for acute stroke. Lancet 1999; 353: 1935.9 Kidwell CS, Starkman S, Eckstein M, Weems K, Saver JL. Identifying stroke

in the field: prospective validation of the Los Angeles prehospital strokescreen (LAPSS). Stroke 2000; 31: 71–76.

10 Bray JE, Martin J, Cooper G, Barger B, Bernard S, Bladin C. Paramedicidentification of stroke: community validation of the MelbourneAmbulance Stroke Screen. Cerebrovasc Dis 2005; 20: 28–33.

11 Wojner-Alexandrov AW, Alexandrov AV, Rodriguez D, Persse D, Grotta JC.Houston paramedic and emergency stroke treatment and outcomes study(HoPSTO). Stroke 2005; 36: 1512–18.

Towards individualised multiple-sclerosis therapy

Reflection and Reaction

and-white effect” obtained here makes these findings soattractive to define algorithms of acute relapsemanagement; patients with severe, non-steroid-responsive symptoms should be offered plasmapheresis(four or five sessions) within 4 weeks. Unfortunately,the assignment in routine clinical settings is empiricaland lacks reliable surrogate markers in blood or on MRI.The rapid effects of plasmapheresis are best explainedby removal of pathogenic autoantibodies that initiallymediate block of reliable impulse propagation, but overperiods of 4 weeks or more incite structural damage inthe CNS. Furthermore, plasmapheresis does not havelong-term efficacy, as again proven in the Keegan paper.In the long term, this subgroup of plasmapheresis-responsive patients with MS might profit from B-celldirected approaches, such as mitoxantrone6 or anti-CD20 monoclonal antibodies,7,8 much more they wouldthan from interferon beta preparations.

Whether all subtypes of MS pathology are accountedfor in the I–IV classification is debatable.9 Buttherapeutic achievements based on this definitionmight provide the most convincing corroborativeevidence for validity of this concept, at least concerningthe existence of a distinct pattern II. There is a clear needfor more tailored individualised MS therapies.

Ralf Gold, Hans-Peter HartungInstitute for MS research, University of Goettingen andDepartment of Neurology, Heinrich-Heine-UniversityDüsseldorf, Germany r.gold@med.uni-goettingen.de

RG and H-PH received consultation fees, honoraria for presentations andboard activities, and travel compensations from Biogen Inc, Sanofi-Aventis,Schering, Serono, and TEVA. There is no conflict of interest relevant to ourcommentary.

1 Compston A, Ebers G, Lassmann H, McDonald J, Matthews PM, WekerleH. McAlpine’s multiple sclerosis, 3rd edn. London: Churchill Livingstone,1998.

2 Lassmann H, Bruck W, Lucchinetti C. Heterogeneity of multiple sclerosispathogenesis: implications for diagnosis and therapy. Trends Mol Med2001; 7: 115–21.

3 Weinshenker BG, O’Brien PC, Petterson TM, et al. A randomized trial ofplasma exchange in acute central nervous system inflammatorydemyelinating disease. Ann Neurol 1999; 46: 878–86.

4 Ruprecht K, Klinker E, Dintelmann T, Rieckmann P, Gold R. Plasmaexchange for severe optic neuritis: treatment of 10 patients. Neurology2004; 63: 1081–83.

5 Keegan M, Konig F, McClelland R, et al. Relation between humoralpathological changes in multiple sclerosis and response to therapeuticplasma exchange. Lancet 2005; 366: 579–82.

6 Chan A, Weilbach FX, Toyka KV, Gold R. Mitoxantrone induces cell deathin peripheral blood leucocytes of multiple sclerosis patients.Clin Exp Immunol 2005; 139: 152–58.

7 Cree BAC, Lamb S, Morgan K, Chen A, Waubant E, Genain C. An openlabel study of the effects of rituximab in neuromyelitis optica. Neurology2005; 64: 1270–72.

8 Stueve O, Cepok S, Elias B, Saleh A, Hartung HP, Hemmer B, Kieseier BC.Clinical stabilization and effective B cell depletion in cerebrospinal fluidand peripheral blood of a patient with fulminant relapsing-remittingmultiple sclerosis. Arch Neurol 2005; 62: 1–4.

9 Barnett MH, Prineas JW. Relapsing and remitting multiple sclerosis:pathology of the newly forming lesion. Ann Neurol 2004; 55: 458–68.

As the numbers of elderly people increase, there isgreater urgency to plan for appropriate health servicesand to identify modifiable risk factors for dementia.Estimates of the number of new dementia cases andascertainment of risk factors for dementia becomecritical and a recent study by Matthews and colleagues1

makes a contribution to these needs by addressing twomain questions. What is the frequency of new cases ofdementia in England and Wales? And, do the ratesacross the different sites vary with the site differences invascular risk factors? The research also highlights someof the methodological issues related to theidentification of dementia in epidemiological studies.

Matthews and colleagues report age, sex, and site-specific incidence rates of dementia in individuals age65 years and older living in five sites in England or Wales.The MRC-CFAS (Medical Research Council CognitiveFunction and Ageing Study) is one of the largest

population-based incidence studies of dementia; from acohort of 8826 (67·9% of the baseline cohort) people,370 incident cases developed during the 2 year follow-up. Incidence increased with age from 6·7 per 1000person-years in people age 65–69 years to 68·5 per 1000person-years in those age 85 years or older. An estimated180 000 (95% CI 105 000–325 000) new cases developeach year in England or Wales. These figures did not varysignificantly by site, and incidence in women tended tobe higher than in men older than age 80 years. Rateswere similar to those reported in an analysis of sevenEuropean studies.2 The paper raises severalmethodological issues important to the estimation ofreliable and unbiased incidence rates. The issue ofcounting all cases to estimate incidence, in particular, isaddressed in their discussion of their study design andanalytical sensitivity analyses. These data make clear thehigh numbers of individuals who will develop dementia,

Regional differences in rates of dementia: MRC-CFAS

694 http://neurology.thelancet.com Vol 4 November 2005