bs_bs_banner

44 Drafts BC, Twomley KM, D’Agostino R, Lawrence J, Avis N, Ellis LR et al. Low to moderate dose anthracycline-based chemotherapy is associated with early noninvasive imaging evidence of subclinical cardiovascular disease. J Am Coll Cardiol Cardiovasc Imaging 2013; 6: 877–85. 45 Wojnowski L, Kulle B, Schirmer M, Schlüter G, Schmidt A, Rosenberger A et al. NAD(P)H oxidase and multidrug resistance genetic polymorphisms are associated with doxorubicin-associated cardiotoxicity. Circulation 2005; 112: 3754–62. 46 Sandri MT, Cardinale D, Zorzino L, Passerini R, Lentati P, Martinoni A et al. Minor increases in plasma troponin I predict decreased LVEF after high-dose chemotherapy. Clin Chem 2003; 49: 248–52.

47 Cardinale D, Sandri MT, Colombo A, Colombo N, Boeri M, Lamantia G et al. Prognostic value of troponin-I cardiac risk stratification of cancer patients undergoing high-dose chemotherapy. Circulation 2004; 109: 2749–54. 48 TAsmanian Study of Echocardiographic detection of Left ventricular dysfunction/TAS-ELF. Available from URL: http://www .australianclinicaltrials.gov.au/node/1716 49 Tebbi CK, London WB, Friedman D, Villaluna D, De Alarcon PA, Constine LS et al. Dezrazoxane-associated risk for acute myeloid leukaemia/myelodysplastic syndrome and other secondary malignancies in paediatric Hodgkin’s disease. J Clin Oncol 2007; 25: 493. 50 Bosch X, Rovira M, Sitges M, Domenech A, Oritz-Perez JT, de Caralt

TM et al. Enalapril and carvedilol for preventing chemotherapy-induced left ventricular systolic dysfunction in patients with malignant hemopathies. J Am Coll Cardiol 2013; 61: 2355–62. 51 Seicean S, Seicean A, Plana JC, Budd GT, Marwick TH. Effect of statin therapy on the risk for incident heart failure in patients with breast cancer receiving anthracycline chemotherapy: an observational clinical cohort study. J Am Coll Cardiol 2012; 60: 2384–90. 52 Johnson JB, Turek M, Law A, Stadnick E, Hopkins S, Graham N et al. Initial five years experience of the Ottawa hospital cardio-oncology clinic: patient characteristics and clinical outcomes. Can J Cardiol 2013; 29: S199.

C L I N I C A L P E R S P E CT I V E S

Current management of relapsing-remitting multiple sclerosis L. Sedal,1 I. B. Wilson1 and E. A. McDonald1,2 1

Neuroimmunology Clinic, Clinical Neurosciences, St Vincent’s Hospital Melbourne and 2MS Australia, Melbourne, Victoria, Australia

Key words multiple sclerosis, relapsing-remitting, progressive multifocal leukoencephalopathy, symptom management, disease-modifying treatment. Correspondence Leslie Sedal, Neurosciences Department, St Vincent’s Hospital Melbourne, 41 Victoria Parade, Fitzroy, Melbourne, Vic. 3065, Australia. Email: [email protected]

Abstract Multiple sclerosis was without effective disease-modifying therapy for many years. The introduction of the injectable therapies (interferon and glatiramer acetate) some 20 years ago was considered a major advance. Recent years have heralded a revolution in treatment options with the introduction of intravenous natalizumab and, even more recently, three oral agents. We are currently in a period of determining the best use of these therapies to ensure prevention of disease progression while maintaining patient safety. Despite these new treatments, there are still many patients living with disability as a result of multiple sclerosis and significant attention must be given to symptomatic management.

Received 27 February 2014; accepted 23 July 2014. doi:10.1111/imj.12558

950

© 2014 The Authors Internal Medicine Journal © 2014 Royal Australasian College of Physicians

Relapsing-remitting multiple sclerosis

Introduction After 20 years of injectable therapies, the landscape of relapsing-remitting multiple sclerosis (RRMS) treatment has been altered by the introduction of three oral therapies and refinements in our use of intravenous natalizumab. We have listed the current drugs available on the Pharmaceutical Benefits Scheme (PBS) in Australia for the treatment of RRMS (Table 1). Below, we discuss the disease-modifying treatments grouped according to route of administration. We then discuss the symptomatic management of the common symptoms of multiple sclerosis (MS).

now rare. Mitoxantrone was shown in controlled trials to be effective in severe RRMS and to some extent in secondary-progressive MS.3 The major disadvantage of mitoxantrone is the risk of cardiotoxicity and treatment-related leukaemia. The exact incidence of these complications is debated. While the latest meta-analysis showed a rate of 0.81% for treatment-related leukaemia, there is a large difference between different centres which remains unexplained. Regardless of the exact figures, these complications have been enough to limit its use.

Natalizumab

Older injectable drugs Currently, there is much excitement regarding the new oral agents. It is customary to make statements such as ‘the older drugs provided a 30% improvement in relapse rate’ and compare this with the higher percentages in newer drugs. However, the nature of the patients being treated in trials has changed dramatically over this time with generally lower relapse rates in the patients enrolled. This complicates comparisons and perhaps the differences may not be as great as they might at first appear. Reassuringly, and perhaps somewhat surprisingly, the 20-year follow up of the patients in the original Betaferon trial suggested a significant difference in life expectancy between those on the drug from the start and the placebo patients who started 5 years later.1 This relatively long period of experience is a major attraction of the injectable medications. In addition to confirming efficacy, it has resulted in a well-defined side-effect profile and a reassuring safety record. Such reassurance remains a key factor for some risk-averse patients. There have also been improvements in the formulation of the injectables. Rebif has a new formulation and a variety of injection devices; Betaferon has a new injection device; Avonex is to be followed by pegylated interferon, which would only have to be injected once a fortnight and as a subcutaneous drug; while Copaxone has a new formulation so that it can be injected three times a week instead of daily.2

Intravenous therapies Mitoxantrone The use of mitoxantrone, which prior to the introduction of natalizumab was the most efficacious agent, is

Funding: L. Sedal has, over the years, received travel grants from all of the major pharmaceutical companies involved in the field of multiple sclerosis. Conflict of interest: None. © 2014 The Authors Internal Medicine Journal © 2014 Royal Australasian College of Physicians

Of the current therapies in routine use, natalizumab is generally regarded as being the most efficacious for treating RRMS. It was approved in the United States in 2004 but was then temporarily withdrawn following the report of four cases of progressive multifocal leukoencephalopathy (PML). It was reintroduced on the basis that the relatively low incidence of PML could be balanced against its significant benefits. PML due to infection with JCV (John Cunningham virus, a polyoma virus) is an extremely serious complication with recent figures suggesting a mortality rate of 23% and incapacitating disability in a majority of the survivors. Much effort has gone into developing PML risk stratification for individual patients.4 A two-step antibody test has been developed, which determines exposure to and likely latent infection with JCV. The test is positive in 50–60% of the normal community, increasing with age. A negative antibody status confers essentially zero risk; however, as there have been cases of patients seroconverting while on treatment, a risk of 1 in 10 000 is usually quoted. Other risk factors for the development of PML include treatment duration of more than 2 years and prior treatment with immunosuppressant drugs. A patient with all these risk factors present has a risk of approximately 1 in 89 for developing PML. Antibody levels (referred to as the Antibody Index) are now available on special request. Preliminary, as yet unpublished, data have suggested that antibody levels also correlate with risk and may help further stratify an individual’s risk. There have also been advances in the radiological diagnosis of PML. It is now appreciated that the features of PML in this setting are different from those of PML that occur in the setting of human immunodeficiency virus infection.5 Our current practice is to perform a magnetic resonance imaging (MRI) scan every 4 months on JCVpositive patients on natalizumab in order to identify early signs of PML. JCV-negative patients are scanned every 6 to 12 months and JCV status is rechecked 6 monthly. 951

Sedal et al.

Table 1 Currently available disease-modifying medications for relapsing-remitting multiple sclerosis Serious side-effects

Injectable medications Interferon beta (Avonex, Rebif, Betaferon) Glatiramer acetate (Copaxone)

Hepatotoxicity Cytopenia

Oral medications‡ Teriflunomide (Aubagio) Hepatotoxicity Cytopenia Infections Fingolimod (Gilenya) Macular oedema Hepatotoxicity Lymphopenia Bradyarrhythmia Herpes virus infections (Zoster and herpes) Dimethyl fumarate BG12 Lymphopenia (Tecfidera) Proteinuria (PML?) Intravenous medications‡ Natalizumab (Tysabri) PML Hepatotoxicity

Common tolerability issues

Pregnancy category†

Dosing

Injection site reactions Flu-like reaction Depression Injection site reactions (including lipoatrophy) Post-injection reaction

D

Nausea Diarrhoea Hair thinning Headache Back pain

X

Daily

D

Daily

B1

Monitoring

Rebif: 3x/week SC FBC and LFT at baseline and 1, 3 Betaferon: 2nd daily SC and 6 months then yearly Avonex: Weekly, IM Daily, SC FBC and LFT at baseline and 1 month then yearly

FBC and LFT – monthly for 6 months then every 6–8 weeks indefinitely First dose cardiac monitoring (6 h) OCT and eye examination – baseline and at 3–6 months FBC and LFT at baseline, 1 month and then 4 monthly

Flushing B1 Gastrointestinal symptoms

Twice daily

FBC and urine protein – baseline, 1 month and then 6–12 monthly

Allergic/infusion reactions C Headache

Monthly

JCV testing (6 monthly if negative) MRI brain at baseline then 4–6 monthly if high JCV risk FBC and LFT at baseline, 3 months and then 6 monthly

†Australian Pregnancy Category. ‡Testing for other infections and immune status should be done at baseline for all these agents (including varicella zoster virus (VZV), herpes simplex virus and hepatitis serology, Tuberculosis exposure). Depending on the result, vaccination for VZV and hepatitis should then be considered prior to treatment. FBC, full blood count; IM, intramuscular; LFT, liver function tests; OCT, ocular coherence tomography; PML, progressive multifocal leukoencephalopathy; SC, subcutaneous.

Alemtuzumab Alemtuzumab was approved by the Australian Therapeutic Goods Administration in December 2013 but is yet to undergo PBS evaluation and is not yet in routine use. It is a humanised monoclonal antibody directed against CD52, a glycoprotein antigen found on lymphocytes and monocytes. It results in the rapid depletion of these cells with slow recovery, possibly taking years. In trials, it was given as a 5-day course followed by a further 3-day course 1 year later. It was studied in phase 3 trials in patients naïve to immunotherapy (CARE-MS I trial) and patients who had failed first-line treatment (CARE-MS II). Both studies showed significant reduction in annualised relapse rate and MRI measures compared with interferon beta-1a. There have been several safety concerns identified including increased infections and most concerningly a high rate of induced autoimmune disease. Autoimmune thyroid disease was seen in up to 20% of patients, immune thrombocytopenic purpure in 3% and case reports of glomerulonephritis – side-effects that will require strict monitoring for a prolonged period 952

after treatment. Alemtuzumab is thus likely to find a defined role as a second-line agent.

New oral agents Three new oral drugs have recently been added to the PBS. Fingolimod (brand name Gilenya) was added in 2012. Dimethyl fumarate (DMF, previously known as BG12, brand name Tefidera) and teriflunomide (brand name Aubagio) were added in December 2013. Each of the drugs has had two successful phase 3 trials of over 1000 patients; however, long-term data are not yet available. These drugs are all evolved from use in other fields of medicine. Fingolimod was introduced as a drug for immunosuppression of renal transplant patients (the MS dose is one tenth of the transplant dose). Teriflunomide is the active metabolite of leflunomide, which is used for the treatment of rheumatoid arthritis. DMF is one ingredient of a compound of fumarate esters, a mixture that has been used for over 20 years in Germany for the treatment of psoriasis. © 2014 The Authors Internal Medicine Journal © 2014 Royal Australasian College of Physicians

Relapsing-remitting multiple sclerosis

Fingolimod

Dimethyl fumarate (BG12)

The FREEDOMS (fingolimod vs placebo) and TRANSFORMS (fingolimod vs interferon beta-1a) trials have demonstrated the superior efficacy of fingolimod compared with placebo and interferon beta-1a treatment in RRMS. Logistically, fingolimod is the most difficult treatment to initiate; however, it is then usually well tolerated.6 The patient should be tested for varicella zoster virus and vaccinated if not immune. It is our practice also to screen for herpes simplex virus serology, tuberculosis exposure (with an interferon release assay) and hepatitis serology. An initial electrocardiogram is required to exclude rhythm disturbances and QT prolongation and then at least 6 h of supervised cardiac monitoring after the first capsule is required. An initial and 3-month visit to an ophthalmologist and ocular coherence tomography to exclude macular oedema is required as well as an initial skin check with annual reviews and review blood tests at 1, 3 and 6 months. High liver enzymes, shingles or herpes simplex infection may force discontinuation. It is normal for the lymphocyte count to fall significantly. If the count falls below 0.2 × 10−9/L on repeated occurrences, treatment is usually withheld. Some neurologists have advocated alternative day therapy in this situation; however, the efficacy of this approach is unproven. There have been some case reports of patients developing tumefactive demyelinating lesions during treatment with fingolimod – the association requires further delineation.

The DEFINE and CONFIRM trials demonstrated the efficacy of DMF relative to placebo. The CONFIRM trial also included a glatiramer acetate arm but was not powered to allow direct comparison; however, a greater reduction in relapse rate was observed with DMF. As well as having excellent trial results, this drug may also have neuroprotective properties.7 There is evidence that new gadolinium-enhancing lesions are less likely to convert to ‘black holes’ (a sign of neuronal damage) when compared with placebo. However, one concern is the report of four cases of PML in patients being treated with its dermatological predecessor of fumarate esters. The four patients had a common factor of low lymphocyte count and three were on concurrent immunosuppression. No cases of PML have been reported so far on DMF as formulated for MS. Although yearly blood testing is the widely recommended standard, it is our practice to perform 3 monthly white cell counts on our patients, even though severe lymphopenia is rare (4–5%). We are also cautious in its use in patients known to be antibody positive for the JCV until more is known. The two commonest side-effects are flushing, which is helped by the use of aspirin and gastrointestinal symptoms, which are treated symptomatically. Both of these symptoms are common in the first 4–6 weeks and then persist in ∼5% of patients after that.

Teriflunomide At first encounter, one would not have thought that a drug with complications of hair loss, potential foetal abnormalities and requiring monthly liver function tests for 6 months would be a great success in a disease of predominantly younger females. However, it certainly has a place for patients who are intolerant of the other medications and perhaps particularly in older patients where pregnancy is not an issue. The TOWER and TEMSO trials (teriflunomide vs placebo) have demonstrated its superior efficacy to placebo. The TENERE trial compared teriflunomide to interferon beta-1a with comparable results. Although direct comparison has not been made, it can be inferred that teriflunomide would not appear to be as efficacious as the other oral agents. The experience with leflunomide has helped provide a predictable side-effect profile. Although hepatic and haematological side-effects can be serious (hence the strict monitoring requirements), they are very rare. Hair loss and gastrointestinal disturbance will also often settle over time. © 2014 The Authors Internal Medicine Journal © 2014 Royal Australasian College of Physicians

Diagnostic criteria and access to treatment The diagnosis of MS relies on demonstrating dissemination of lesions in ‘time and space’. In the setting of a first clinical event, the latest revision of the McDonald criteria (2010)8 allows a diagnosis to be made with the very first MRI if it is performed with gadolinium. Lesions in different brain regions demonstrate dissemination in space and a mixture of age of the lesions demonstrates dissemination in time. An additional layer of complexity arises from PBS funding arrangements. In Australia, we have been very fortunate that the PBS has accepted all of the above mentioned drugs for support. However, eligibility is based on the older Schumacher criteria requiring two clinical attacks. Earlier treatment of patients positive by the McDonald criteria has demonstrated benefits.9 The provision by the drug companies of free medications to patients not meeting PBS criteria has somewhat made up for this discrepancy.

Evaluating the patient Table 2 outlines the important factors that must be taken into account when considering a patient for therapy. 953

Sedal et al.

Table 2 Questions posed when evaluating the patient Do they have MS and if so, of what type?

What is their individual prognosis?

If they have already been treated with immunomodulators, how successful has it been or are there other indications that therapy should be changed?

What is the patients’ attitude to risk and benefit in different therapies?

Are there other social factors that would influence the choice of the drug? Is there a past medical history that may be critical in choosing the drug?

What is their attitude to injections?

Given that therapy, once started, will be for many years it is important to be confident in the diagnosis of MS. Recognition of neuromyelitis optica is now an important consideration as it has a different treatment paradigm. The type of MS has important implications for prognosis and treatment It would obviously we ideal to be able to predict the aggressiveness of an individual’s disease when they are first seen in order to guide treatment decisions. Some adverse prognostic factors have been established by epidemiological research.10 It is difficult to apply such epidemiological factors to individuals but it provides some guide as to how aggressive therapy should be. Two major methods have been proposed for evaluating the effectiveness of therapy and at what threshold it should be changed.11 The Canadian system looks at the occurrence of clinical relapses, deterioration on physical examination and the development of new MRI lesions and establishes levels of concern for each of these characteristics. The second method comes from the Barcelona group who feel using the number of new lesions on MRI is a reliable guide to treatment failure. Some patients are mainly concerned that the treatment is as powerful as possible while some patients are more concerned about potential side effects or safety. Taking these concerns into account when counselling a patient for treatment is essential to promote adherence to therapy. Important social factors may include plans for a pregnancy, the presence of small children with disturbed sleep, occupation and travel plans. It is important to enquire about other medical history as it will guide which medications can be safely used. Factors to enquire about include renal or liver disease, known blood disorders, history of malignancy, history of shingles, recurrent herpes simplex infection, cardiovascular disease, diabetes or uveitis. A history of problems with menopausal flushing or irritable bowel syndrome might make a patient reluctant to start DMF. With new patients there is often a strong preference for tablets now that there is a choice. While the side effects of injections can be significant many patients tolerate them well for many years and we feel they should not be immediately excluded from discussion.

Choosing a drug is clearly more complex than in the past and the role of specialist MS nurses and other staff in helping with the necessary explanation, demonstration and organisation of necessary tests is invaluable.

Application to different MS groups Below, we consider the application of the above principles and information to some relevant groups of MS patients:

Clinical isolated syndrome (CIS) and McDonald-positive MS While benefits of treating this group of patients have been demonstrated, the treatments are not subsidised by the PBS for this indication. Treatment is determined by availability of compassionate access schemes provided by drug companies.9–11

Diagnosis of clinically definite MS These are patients who have had two clinical attacks and thus fulfil the PBS criteria. All the above drugs are potentially available at the discretion of the neurologist.

Patients already on injectable agents who are doing well If a patient has been on an injectable agent for some time and remains disease free, there would be no reason to change treatment on the grounds of efficacy. Treatment failure, as determined by clinical relapse or new lesions on MRI, should prompt consideration of a change of therapy, as should intolerable side-effects. The threshold of disease progression that should prompt a change is a matter of ongoing debate.

Aggressive MS Some patients will present with frequent relapses and rapid accumulation of disability. For this group, the drug of choice at the present time would be natalizumab if the patient were negative for antibodies to the JCV. Even if antibody positive, natalizumab might be considered after discussion of the risks. Failing this consideration may be given to alemtuzumab (when available), mitoxantrone or even haemopoietic stem cell transplantation. We feel fingolimod is the most appropriate oral agent to use in this setting.

Secondary-progressive MS If the patient is still having definite relapses, superimposed on the background of secondary progression,

954

© 2014 The Authors Internal Medicine Journal © 2014 Royal Australasian College of Physicians

Relapsing-remitting multiple sclerosis

evidence suggests they may still respond to treatment. In patients without relapses, there is no clearly effective treatment option. Mitoxantrone may be considered in some of these patients.3

Primary-progressive MS At the present time, there is no drug that is believed to alter the progression of primary-progressive MS though there are several trials underway.

Radiologically isolated syndrome This refers to the situation where white matter lesions, suggestive of demyelination, are seen incidentally on a MRI scan that is done for another indication and where the patient has never had symptoms referable to these lesions. It has become a common occurrence for neurologists to see anxious patients with a MRI report stating ‘white matter lesions non-specific in nature but demyelination cannot be excluded’. An assessment taking into account the clinical context, distribution of the lesions and evolution over time can often allow a diagnosis to be reached. In the majority of patients, the cause is benign and reassurance can be given. Serial MRI and clinical monitoring is appropriate for patients with lesions more in keeping with MS. An evolving technology that may provide assistance with these clinical difficulties is based on the well-known pathological fact that MS lesions usually have a central vein whereas most other causes of ‘white spots’ on MRI are related to arterioles. A clear distinction between the presence of arterioles or venules in the lesion can be made with a 7-Tesla MRI used for research.12 Protocols are emerging for 3-Tesla machines, which may allow this to be applied in routine clinical practice.13

Management of common MS symptoms Introduction While the diagnosis of MS and disease-modifying therapy has advanced rapidly in recent times, there still remains the challenge of improving symptom management to promote functional abilities, independence and quality of life. The economic cost of MS in Australia is estimated to be around $1.04 billion a year and people with MS are more likely to be unemployed than those with any other chronic disease.15 Ineffective management of MS symptoms in the workplace is the primary reason, rather than workplace-related factors.

Fatigue Fatigue is the ‘hidden disability’ affecting about 80% people with MS. Medications have been shown to be of little benefit in treating MS fatigue.16 A review of clinical trials of the anti-Parkinsonian drug amantadine (Symmetrel) shows small and inconsistent improvement in 20–40% of patients over the short term. The amphetamine-like drug modafinil (Modavigil) has been used but trial data are conflicting as to its efficacy and serious psychiatric side-effects can occur. Overall medications have proven disappointing in their effectiveness and a multidisciplinary approach remains paramount.

Heat intolerance An increase in temperature, whether it be ambient temperature, exercise induced or febrile illness, can cause a recurrence or worsening of MS symptoms. The avoidance of heat, use of air conditioners, cooling vests and cool fluids can help. People with MS with Australian Health Care Cards can obtain energy concessions for the use of air conditioners over the summer months.

Treatment of acute relapses It is first important to recognise the entity of pseudorelapse. This occurs when intercurrent infection causes an exacerbation of pre-existing symptoms, even those which may have appeared to have resolved completely in the past. This is presumably due to transient reduction in the effectiveness of conduction through previously demyelinated neurones and treatment should be directed at the infection. ‘True’ relapses should be assessed for severity, minor relapses may not require treatment and moderate severity may be treated with a trial of oral corticosteroids and severe or refractory relapses with intravenous corticosteroids.14 Plasma exchange may be considered in refractory cases. © 2014 The Authors Internal Medicine Journal © 2014 Royal Australasian College of Physicians

Mobility impairment Mobility issues occur in 69% of MS patients and are multifactorial in aetiology. Until recently, there has been no proven effective medical treatment. Slow release fampridine (Fampyra) has now been shown in multicentred, randomised, placebo-controlled phase 3 clinical trials that it can improve walking speed by 25%; however, the benefit was only seen in 35% of patients.17 Responders show a 20% or greater improvement in the ‘timed 25-foot walk test’ over 4 weeks. Dosage is 10 mg bd, 12 h apart. The commonest side-effects are urinary tract infections, dizziness and insomnia. It is contraindicated in those with a history of seizures or 955

Sedal et al.

renal impairment. It is not currently PBS subsidised, and although it can be obtained on a private script, it is prohibitively expensive for most patients. Further trials are underway to define further the practical usefulness beyond the simple measure of a walk test.

Spasticity Spasticity is a common problem in MS patients. It can be a two-edged sword as patients with considerable underlying weakness may benefit from the splinting effect that spasticity can provide. If treatment is indicated, baclofen (oral or intrathecal), benzodiazepines, botulinum toxin injections and physiotherapy can be used. A medicinal cannabis-based oral spray, Sativex, has been shown in clinical trials to reduce effectively moderate to severe spasticity in MS, as an adjunct to current treatments;18 however, it is not currently available in Australia.

Pain Pain as a symptom of MS is either neurogenic or secondary to musculoskeletal impairments due to altered gait or posture. If the pain is neuropathic in nature, it should be treated as per the guidelines for other types of neuropathic pain.

Tremor Intention tremor remains a difficult symptom to manage. Although there have been individual responses to a variety of drugs including gabapentin, clonazepam and isoniazid, there is no drug that is consistently effective. Recent trials of botulinum toxin have shown some benefit if the tremor is not too complex.19 Surgical treatment has never been as successful as in Parkinson

References 1 Goodin DS, Reder AT, Ebers GC, Cutter G, Kremenchutzky M, Oger J et al. Survival in MS: a randomized cohort study 21 years after the start of the pivotal IFNβ-1b trial. Neurology 2012; 78: 1315–22. 2 Khan O, Rieckmann P, Boyko A, Selmaj K, Zivadinov R. Three times weekly glatiramer acetate in relapsing-remitting multiple sclerosis. Ann Neurol 2013; 73: 705–13. 3 Hartung H-P, Gonsette R, König N, Kwiecinski H, Guseo A, Morrissey SP

956

disease; however, recently new targets have been identified for surgery and deep brain stimulation that suggest a better outcome.20

Bladder dysfunction Bladder symptoms are very common in MS affecting 80% of patients. It is first important to determine the cause – failure to store urine (detrusor dysfunction), failure to empty urine (sphincter dysfunction) or a combination of the two. Reversible exacerbating factors should be identified and treated. A ‘failure to store’ problem may warrant a trial of anticholinergics and a failure to empty may warrant intermittent self-catheterisation, or permanent catheter placement if more severe. Botulinum toxin injection may also be of assistance.

Sexual difficulties Sexual difficulties are common and require a broad biopsychosocial approach to assessment and management. The availability of several PDE5 inhibitors in recent years has added another treatment option for patients.

Conclusion The past few years have seen rapid advances in the treatment options available for patients with RRMS. The choices of therapy now offer much more flexibility for patients but have added a layer of complexity for neurologists initiating therapy and for all practitioners involved in monitoring ongoing therapy. The lack of advances in the treatment of progressive forms of MS has been disappointing and should be a major focus of ongoing work. Similarly, symptom management has made some tentative steps towards new therapies; however, there is still scope for major improvements in this field.

et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet 2002; 360: 2018–25. 4 Bloomgren G, Richman S, Hotermans C, Subramanyam M, Goelz S, Natarajan A et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med 2012; 366: 1870–80. 5 Wattjes MP, Richert ND, Killestein J, de Vos M, Sanchez E, Snaebjornsson P et al. The chameleon of neuroinflammation: magnetic resonance imaging characteristics of natalizumab-associated

progressive multifocal leukoencephalopathy. Mult Scler 2013; 19: 1826–40. 6 Pelletier D, Hafler DA. Fingolimod for multiple sclerosis. N Engl J Med 2012; 366: 339–47. 7 MacManus DG, Miller DH, Kappos L, Gold R, Havrdova E, Limmroth V et al. BG-12 reduces evolution of new enhancing lesions to T1-hypointense lesions in patients with multiple sclerosis. J Neurol 2011; 258: 449–56. 8 Selchen D, Bhan V, Blevins G, Devonshire V, Duquette P, Grand’Maison F et al. MS, MRI, and the

© 2014 The Authors Internal Medicine Journal © 2014 Royal Australasian College of Physicians

bs_bs_banner

9

10

11

12

13

2010 McDonald criteria: a Canadian expert commentary. Neurology 2012; 79(Suppl 2): S1–15. Miller DH, Chard DT, Ciccarelli O. Clinically isolated syndromes. Lancet Neurol 2012; 11: 157–69. Mowry EM. Natural history of multiple sclerosis: early prognostic factors. Neurol Clin 2011; 29: 279–92. Río J, Comabella M, Montalban X. Multiple sclerosis: current treatment algorithms. Curr Opin Neurol 2011; 24: 230–7. Tallantyre EC, Dixon JE, Donaldson I, Owens T, Morgan PS, Morris PG et al. Ultra-high-field imaging distinguishes MS lesions from asymptomatic white matter lesions. Neurology 2011; 76: 534–9. Sati P, George IC, Shea CD, Gaitán MI, Reich DS. FLAIR*: a combined MR

14

15

16

17

contrast technique for visualizing white matter lesions and parenchymal veins. Radiology 2012; 265: 926–32. Repovic P, Lublin FD. Treatment of multiple sclerosis exacerbations. Neurol Clin 2011; 29: 389–400. Simmons RD, Tribe KL, McDonald EA. Living with multiple sclerosis: longitudinal changes in employment and the importance of symptom management. J Neurol 2010; 257: 926–36. Kesselring J, Beer S. Symptomatic therapy and neurorehabilitation in multiple sclerosis. Lancet Neurol 2005; 4: 643–52. Goodman AD, Brown TR, Krupp LB, Schapiro RT, Schwid SR, Cohen R et al. Sustained-release oral fampridine in multiple sclerosis: a randomised,

double-blind, controlled trial. Lancet 2009; 373: 732–8. 18 Yadav V, Bever C, Bowen J, Bowling A, Weinstock-Guttman B, Cameron M et al. Summary of evidence-based guideline: complementary and alternative medicine in multiple sclerosis: report of the guideline development subcommittee of the American Academy of Neurology. Neurology 2014; 82: 1083–92. 19 Van Der Walt A, Sung S, Spelman T, Marriott M, Kolbe S, Mitchell P et al. A double-blind, randomized, controlled study of botulinum toxin type A in MS-related tremor. Neurology 2012; 79: 92–9. 20 Xie T, Bernard J, Warnke P. Post subthalamic area deep brain stimulation for tremors: a mini-review. Transl Neurodegener 2012; 1: 20.

ETHICS IN MEDICINE

An unequivocal good? Acknowledging the complexities of advance care planning K. Robins-Browne,1 V. Palmer1 and P. Komesaroff2 1

General Practice and Primary Health Care Academic Centre, The University of Melbourne and 2Faculty of Medicine, Nursing and Health Sciences,

Monash University, Melbourne, Victoria, Australia

Key words advance care planning, advance directive, ethics, ethical aspects. Correspondence Kate Robins-Browne, Department of General Practice, The University of Melbourne, 200 Berkeley Street, Carlton, Vic. 3053, Australia. Email: [email protected] Received 16 July 2014; accepted 30 July 2014. doi:10.1111/imj.12556

Abstract Over the past few decades advance care planning (ACP) has become the subject of debate, research and legislation in many countries. Encouraging people to express their preference for treatment in advance, ideally in written form, seems a natural way to identify what someone might have wanted when they can no longer participate in decision-making. The notion of ACP as an unequivocal good permeates much of the research and policy work in this area. For example, ACP is now actively encouraged in Australian federal and state government policies and the Victorian Government has recently published a practical ACP strategy for Victorian health services (2014–2018). However, advance care plan is ethically complex and the introduction of the Victorian health services strategy provides an opportunity to reflect on this complexity, particularly on the benefits and risks of ACP.

Introduction Over the past few decades, advance care planning (ACP) has become the subject of debate, research and legislation in many countries. Encouraging people to express their preference for treatment in advance, ideally in written © 2014 The Authors Internal Medicine Journal © 2014 Royal Australasian College of Physicians

form, seems a natural way to identify what someone might have wanted when they can no longer participate in decision-making. Effective communication is universally acknowledged as crucial and it is widely considered that ACP is an unequivocal good. However, ACP is in reality associated with significant ethical complexity, in part 957